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Shir D, Lee N, McCarter SJ, Ramanan VK, Botha H, Knopman DS, Petersen RC, Boeve BF, Day GS, Graff-Radford NR, Jones DT, Murray ME, Nguyen AT, Reichard RR, Dickson DW, Tajfirouz D, Machulda MM, Whitwell JL, Josephs KA, Graff-Radford J. Longitudinal Evolution of Posterior Cortical Atrophy: Diagnostic Delays, Overlapping Phenotypes, and Clinical Outcomes. Neurology 2025; 104:e213559. [PMID: 40198862 PMCID: PMC11984831 DOI: 10.1212/wnl.0000000000213559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 02/18/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND AND OBJECTIVES Although several large studies have evaluated individuals with posterior cortical atrophy (PCA) cross-sectionally, its longitudinal progression remains poorly characterized. The objectives of this study were to determine the longitudinal trajectory of PCA, encompassing the temporal aspects of diagnosis, the spectrum of clinical manifestations, and patient outcomes. METHODS This retrospective study included participants evaluated and diagnosed with PCA at the Mayo Clinic, between 1995 and 2023. Clinical data (demographics, neurologic evaluations, and cognitive tests at initial presentation and late stage) were extracted from medical records. Initial clinical diagnoses during previous medical evaluations, including ophthalmologic assessments after onset of neurologic symptoms, were documented. Participants were retrospectively classified as PCA-pure if they solely met PCA criteria or as PCA-plus if they exhibited complex phenotypes also meeting criteria for other neurodegenerative syndromes. CSF analyses and neuropathology findings were documented. RESULTS The cohort of 558 participants (65% female) had a mean age at symptom onset of 61 ± 8 years, with 68% meeting early-onset criteria (younger than 65 years). The mean duration from symptom onset to diagnosis was 3.6 ± 2.5 years. Ophthalmologic/optometric evaluations (49%) and completion of ophthalmologic procedures (16%) were common before PCA diagnosis. Psychiatric diagnoses were made in 23% of participants before PCA diagnosis, particularly among younger women. Common initial symptoms included misplacement of items, difficulties with reading and driving, and concerns pertaining to basic visual processing. Notable signs were constructional apraxia, dyscalculia, simultanagnosia, and space perception deficits. CSF biomarkers were consistent with Alzheimer disease in 139 of 158 individuals (88%). Superimposed features of non-PCA clinical syndromes were observed in a quarter of the participants at presentation, with frequency of PCA-plus cases increasing longitudinally. Longitudinal analysis of Short Test of Mental Status scores predicted an initial rapid decline in cognitive function, with the rate of decline gradually slowing over 0-10 years (time coefficient [SE] = -4.20 [0.29], p < 0.001). DISCUSSION This study highlights the protracted time from symptom onset and frequent misdiagnoses/misattribution of symptoms in PCA. Ophthalmologic evaluations often preceded neurologic assessments. Psychiatric diagnoses were more frequent among younger women. These observations highlight the need to improve diagnostic processes and earlier recognition of PCA, which may enhance the effectiveness of emerging disease-modifying therapies.
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Affiliation(s)
- Dror Shir
- Department of Neurology, Mayo Clinic, Rochester, MN
- Cognitive Neurology Unit, Neurological Institute, Tel Aviv Medical Center, Israel
| | - Noah Lee
- Mayo Clinic Alix School of Medicine, Rochester, MN
| | | | | | - Hugo Botha
- Department of Neurology, Mayo Clinic, Rochester, MN
| | | | | | | | | | | | | | - Melissa E Murray
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL
| | - Aivi T Nguyen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - R Ross Reichard
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Dennis W Dickson
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL
| | - Deena Tajfirouz
- Department of Neurology, Mayo Clinic, Rochester, MN
- Department of Ophthalmology, Mayo Clinic, Rochester, MN
| | - Mary M Machulda
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN; and
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Kaur S, Darden CJ, Adegbola GM, Warrington JP. History of hypertensive disorders of pregnancy and risk of Alzheimer's disease and vascular dementia. Front Neuroendocrinol 2025; 78:101198. [PMID: 40368008 DOI: 10.1016/j.yfrne.2025.101198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 05/08/2025] [Accepted: 05/11/2025] [Indexed: 05/16/2025]
Abstract
The incidence of dementia, and specifically, Alzheimer's disease, is higher in women than men, even in middle age, making it possible to rule out lifespan differences between men and women as a contributing factor. Thus, it is plausible that pregnancy experience, which is unique to women, may play a contributing role. In this review, we discuss the different hypertensive disorders of pregnancy (HDP), Alzheimer's and vascular dementia, clinical, epidemiological, and preclinical studies that link a history of HDP with dementia. We also present potential mechanisms linking HDP, Alzheimer's, and vascular dementia. Several key symptoms that are shared among the disorders are presented as potential underlying mechanisms that link the adverse pregnancy disorder with the long-term postpartum neurological changes. Further, we present limitations of the existing literature, gaps, and opportunities for further research.
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Affiliation(s)
- Simranjit Kaur
- School of Medicine, Department of Neurology, Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, United States
| | - Chauncey J Darden
- School of Medicine, Department of Neurology, Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, United States
| | - Goodness M Adegbola
- School of Medicine, Department of Neurology, Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, United States
| | - Junie P Warrington
- School of Medicine, Department of Neurology, Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, United States.
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Peng W, Yuan Y, Lei J, Zhao Y, Li Y, Qu Q, Wang J. Long-Term High-Fat Diet Impairs AQP4-Mediated Glymphatic Clearance of Amyloid Beta. Mol Neurobiol 2025; 62:1079-1093. [PMID: 38958889 DOI: 10.1007/s12035-024-04320-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 06/19/2024] [Indexed: 07/04/2024]
Abstract
As a risk factor for Alzheimer's disease (AD), studies have demonstrated that long-term high-fat diet (HFD) could accelerate the deposition of amyloid beta (Aβ) in the brain. The glymphatic system plays a critical role in Aβ clearance from the brain. However, studies investigating the effects of long-term HFD on glymphatic function have reported paradoxical outcomes, and whether glymphatic dysfunction is involved in the disturbance of Aβ clearance in long-term HFD-fed mice has not been determined. In the present study, we injected fluorescently labeled Aβ into the hippocampus and found that Aβ clearance was decreased in HFD-fed mice. We found that long-term HFD-fed mice had decreased glymphatic function by injecting fluorescent tracers into the cisterna magna and corpus striatum. In long-term HFD-fed mice, aquaporin-4 (AQP4) polarization in the cortex was disrupted, and glymphatic clearance activity was positively correlated with the AQP4 polarization index. In HFD-fed mice, the disturbance of Aβ clearance from the hippocampus was exacerbated by TGN-020, a specific inhibitor of AQP4, whereas TGN-073, an enhancer of AQP4, ameliorated it. These findings suggest that long-term HFD disrupts Aβ clearance by inhibiting AQP4-mediated glymphatic function. The underlying mechanism may involve the disruption of AQP4 polarization.
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Affiliation(s)
- Wei Peng
- Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Rd, Xi'an, 710061, China
| | - Ye Yuan
- Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Rd, Xi'an, 710061, China
| | - Jingna Lei
- Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Rd, Xi'an, 710061, China
| | - Yi Zhao
- Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Rd, Xi'an, 710061, China
| | - Yan Li
- Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qiumin Qu
- Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Rd, Xi'an, 710061, China.
- Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Jin Wang
- Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Rd, Xi'an, 710061, China.
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Ingram RU, Ocal D, Halai A, Pobric G, Cash DM, Crutch S, Yong KX, Lambon Ralph MA. Graded Multidimensional Clinical and Radiologic Variation in Patients With Alzheimer Disease and Posterior Cortical Atrophy. Neurology 2024; 103:e209679. [PMID: 39042846 PMCID: PMC11314952 DOI: 10.1212/wnl.0000000000209679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 05/17/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Alzheimer disease (AD) spans heterogeneous typical and atypical phenotypes. Posterior cortical atrophy (PCA) is a striking example, characterized by prominent impairment in visual and other posterior functions in contrast to typical, amnestic AD. The primary study objective was to establish how the similarities and differences of cognition and brain volumes within AD and PCA (and by extension other AD variants) can be conceptualized as systematic variations across a transdiagnostic, graded multidimensional space. METHODS This was a cross-sectional, single-center, observational, cohort study performed at the National Hospital for Neurology & Neurosurgery, London, United Kingdom. Data were collected from a cohort of patients with PCA and AD, matched for age, disease duration, and Mini-Mental State Examination (MMSE) scores. There were 2 sets of outcome measures: (1) scores on a neuropsychological battery containing 22 tests spanning visuoperceptual and visuospatial processing, episodic memory, language, executive functions, calculation, and visuospatial processing and (2) measures extracted from high-resolution T1-weighted volumetric MRI scans. Principal component analysis was used to extract the transdiagnostic dimensions of phenotypical variation from the detailed neuropsychological data. Voxel-based morphometry was used to examine associations between the PCA-derived clinical phenotypes and the structural measures. RESULTS We enrolled 93 participants with PCA (mean: age = 59.9 years, MMSE = 21.2; 59/93 female) and 58 AD participants (mean: age = 57.1 years, MMSE = 19.7; 22/58 female). The principal component analysis for PCA (sample adequacy confirmed: Kaiser-Meyer-Olkin = 0.865) extracted 3 dimensions accounting for 61.0% of variance in patients' performance, reflecting general cognitive impairment, visuoperceptual deficits, and visuospatial impairments. Plotting AD cases into the PCA-derived multidimensional space, and vice versa, revealed graded, overlapping variations between cases along these dimensions, with no evidence for categorical-like patient clustering. Similarly, the relationship between brain volumes and scores on the extracted dimensions was overlapping for PCA and AD cases. DISCUSSION These results provide evidence supporting a reconceptualization of clinical and radiologic variation in these heterogenous AD phenotypes as being along shared phenotypic continua spanning PCA and AD, arising from systematic graded variations within a transdiagnostic, multidimensional neurocognitive geometry.
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Affiliation(s)
- Ruth U Ingram
- From the Division of Psychology and Mental Health (R.U.I., G.P.), University of Manchester; Dementia Research Centre (D.O., D.M.C., S.C., K.X.Y.), UCL Institute of Neurology, London; and MRC Cognition and Brain Sciences Unit (A.H., M.A.L.R.), University of Cambridge, United Kingdom
| | - Dilek Ocal
- From the Division of Psychology and Mental Health (R.U.I., G.P.), University of Manchester; Dementia Research Centre (D.O., D.M.C., S.C., K.X.Y.), UCL Institute of Neurology, London; and MRC Cognition and Brain Sciences Unit (A.H., M.A.L.R.), University of Cambridge, United Kingdom
| | - Ajay Halai
- From the Division of Psychology and Mental Health (R.U.I., G.P.), University of Manchester; Dementia Research Centre (D.O., D.M.C., S.C., K.X.Y.), UCL Institute of Neurology, London; and MRC Cognition and Brain Sciences Unit (A.H., M.A.L.R.), University of Cambridge, United Kingdom
| | - Gorana Pobric
- From the Division of Psychology and Mental Health (R.U.I., G.P.), University of Manchester; Dementia Research Centre (D.O., D.M.C., S.C., K.X.Y.), UCL Institute of Neurology, London; and MRC Cognition and Brain Sciences Unit (A.H., M.A.L.R.), University of Cambridge, United Kingdom
| | - David M Cash
- From the Division of Psychology and Mental Health (R.U.I., G.P.), University of Manchester; Dementia Research Centre (D.O., D.M.C., S.C., K.X.Y.), UCL Institute of Neurology, London; and MRC Cognition and Brain Sciences Unit (A.H., M.A.L.R.), University of Cambridge, United Kingdom
| | - Sebastian Crutch
- From the Division of Psychology and Mental Health (R.U.I., G.P.), University of Manchester; Dementia Research Centre (D.O., D.M.C., S.C., K.X.Y.), UCL Institute of Neurology, London; and MRC Cognition and Brain Sciences Unit (A.H., M.A.L.R.), University of Cambridge, United Kingdom
| | - Keir X Yong
- From the Division of Psychology and Mental Health (R.U.I., G.P.), University of Manchester; Dementia Research Centre (D.O., D.M.C., S.C., K.X.Y.), UCL Institute of Neurology, London; and MRC Cognition and Brain Sciences Unit (A.H., M.A.L.R.), University of Cambridge, United Kingdom
| | - Matthew A Lambon Ralph
- From the Division of Psychology and Mental Health (R.U.I., G.P.), University of Manchester; Dementia Research Centre (D.O., D.M.C., S.C., K.X.Y.), UCL Institute of Neurology, London; and MRC Cognition and Brain Sciences Unit (A.H., M.A.L.R.), University of Cambridge, United Kingdom
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Singh NA, Graff-Radford J, Machulda MM, Carlos AF, Schwarz CG, Senjem ML, Jack CR, Lowe VJ, Josephs KA, Whitwell JL. Atypical Alzheimer's disease: new insights into an overlapping spectrum between the language and visual variants. J Neurol 2024; 271:3571-3585. [PMID: 38551740 PMCID: PMC11273322 DOI: 10.1007/s00415-024-12297-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 02/28/2024] [Accepted: 03/01/2024] [Indexed: 05/30/2024]
Abstract
Overlap between language and visual variants of atypical Alzheimer's disease (AD) has been reported. However, the extent, frequency of overlap, and its neuroanatomical underpinnings remain unclear. Eighty-two biomarker-confirmed AD patients who presented with either predominant language (n = 34) or visuospatial/perceptual (n = 48) deficits underwent detailed clinical examinations, MRI, and [18F]flortaucipir-PET. Subgroups were defined based on language/visual testing and patterns of volume loss and tau uptake were assessed. 28% of the language group had visual dysfunction (marked in 8%), and 47% of the visual group had language impairment (marked in 26%). Progressive involvement of the parieto-occipital and frontal lobes was noted with greater visual impairment in the language group, and greater left parieto-temporal and frontal involvement with worsening language impairment in the visual group. Only 25% of our cohort showed a pure language or visual presentation, highlighting the high frequency of syndromic overlap in atypical AD and the diagnostic challenge of categorical phenotyping.
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Affiliation(s)
| | | | - Mary M Machulda
- Department of Psychiatry & Psychology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA
| | - Arenn F Carlos
- Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA
| | | | - Matthew L Senjem
- Department of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA
| | - Clifford R Jack
- Department of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA
| | - Val J Lowe
- Department of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA
| | - Keith A Josephs
- Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA
| | - Jennifer L Whitwell
- Department of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
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Singh NA, Sintini I. Editorial: New insights into atypical Alzheimer's disease: from clinical phenotype to biomarkers. Front Neurosci 2024; 18:1414443. [PMID: 38745936 PMCID: PMC11091363 DOI: 10.3389/fnins.2024.1414443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 04/16/2024] [Indexed: 05/16/2024] Open
Affiliation(s)
| | - Irene Sintini
- Department of Radiology, Mayo Clinic, Rochester, MN, United States
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Ahmed S, Caswell J, Butler CR, Bose A. Secondary language impairment in posterior cortical atrophy: insights from sentence repetition. Front Neurosci 2024; 18:1359186. [PMID: 38576871 PMCID: PMC10993779 DOI: 10.3389/fnins.2024.1359186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 01/23/2024] [Indexed: 04/06/2024] Open
Abstract
Introduction Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive impairment in visuospatial and perceptual function linked to atrophy of the occipito-parietal cortex. Besides the salient visual impairment, several studies have documented subtle changes in language may also be present. Sentence repetition is a highly constrained linguistic task involving multiple linguistic and cognitive processes and have been shown to be impaired in other AD spectrum disorders, with little consensus on its relevance in PCA. This aim of this study was to further delineate the linguistic and cognitive features of impaired language in PCA using a sentence repetition task. Method Seven PCA patients and 16 healthy controls verbally repeated 16 sentences from the Boston Diagnostic Aphasia Examination. Responses were transcribed orthographically and coded for accuracy (percentage accuracy; percentage Correct Information Units; Levenshtein Distance) and for temporal characteristics (preparation duration (ms); utterance duration (ms); silent pause duration (ms); speech duration (ms); dysfluency duration (ms)). The potential modulating effects of attentional control and working memory capacity were explored. Results PCA patients showed lower overall accuracy with retained semantic content of the sentences, and lower phonological accuracy. Temporal measures revealed longer preparation and utterance duration for PCA patients compared to controls, alongside longer speech duration but comparable dysfluency duration. PCA patients also showed comparable silent pause duration to controls. Attentional control, measured using the Hayling sentence completion task, predicted accuracy of sentence repetition. Discussion The findings suggest that sentence repetition is impaired in PCA and is characterized by phonological, response planning and execution difficulties, underpinned in part by attentional control mechanisms. The emerging profile of language impairment in PCA suggests vulnerability of similar cognitive systems to other Alzheimer's syndromes, with subtle differences in clinical presentation.
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Affiliation(s)
- Samrah Ahmed
- School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom
| | - Josie Caswell
- School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom
| | - Christopher R. Butler
- Faculty of Medicine, Department of Brain Sciences, Imperial College London, London, United Kingdom
| | - Arpita Bose
- School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom
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St-Georges MA, Wang L, Chapleau M, Migliaccio R, Carrier T, Montembeault M. Social cognition and behavioral changes in patients with posterior cortical atrophy. J Neurol 2024; 271:1439-1450. [PMID: 38032370 DOI: 10.1007/s00415-023-12089-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023]
Abstract
Posterior cortical atrophy (PCA) is a rare neurodegenerative condition characterized by progressive visual and visuospatial dysfunction. The consensus criteria state that patients should present "relatively spared behavior and personality" in early stages. However, limited research has focused on these symptoms in PCA. This study compared 157 patients with PCA in early stages of the disease with 352 healthy controls (HC), 202 typical AD (tAD), and 177 logopenic variant primary progressive aphasia (lvPPA) patients from the National Alzheimer's Coordinating Center (NACC) dataset. They were compared using clinician ratings of behavioral symptoms, informant- and clinician-filled questionnaires and patient-facing tests of behavior and social cognition. Results showed that PCA individuals exhibited many behavioral symptoms, the more frequently reported being anxiety, depression, apathy, and irritability. During cognitive testing, clinicians observed disorganized and reactive behaviors, but no insensitive behaviors. Informant reports indicated that PCA patients exhibited higher levels of inhibition and anxiety in response to stimuli associated with non-reward, novelty, and punishment. Social norms knowledge and empathy were overall preserved, although slight decreases in perspective-taking and socioemotional sensitivity were observed on informant-rated questionnaires. Except for more elevated neuropsychiatric symptoms in tAD, the three AD variants had similar profiles. Our findings provide insights into the social cognition and behavioral profiles of PCA, highlighting patterns of preservations and mild impairments, even in the early stages of the disease. These results contribute to a more complete understanding of non-visual symptoms in PCA and have implications for diagnostic and intervention strategies.
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Affiliation(s)
| | - Linshan Wang
- Department of Psychology, McGill University, Montréal, QC, H3A 1G1, Canada
| | - Marianne Chapleau
- Memory & Aging Center, University of California in San Francisco, San Francisco, CA, 94158, USA
| | - Raffaella Migliaccio
- FrontLab, INSERM U1127, Institut du cerveau, Hôpital Pitié-Salpêtrière, Paris, France
- Centre de Référence des Démences Rares ou Précoces, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
- Department of Neurology, Institute of Memory and Alzheimer's Disease, Centre of Excellence of Neurodegenerative Disease, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Thomas Carrier
- Douglas Research Centre, Montréal, QC, H4H 1R3, Canada
- Département de Psychologie, Université du Québec à Montréal, Montréal, QC, H2X 3P2, Canada
| | - Maxime Montembeault
- Douglas Research Centre, Montréal, QC, H4H 1R3, Canada.
- Department of Psychiatry, McGill University, Montréal, QC, H3A 1A1, Canada.
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Rezaii N, Hochberg D, Quimby M, Wong B, McGinnis S, Dickerson BC, Putcha D. Language uncovers visuospatial dysfunction in posterior cortical atrophy: a natural language processing approach. Front Neurosci 2024; 18:1342909. [PMID: 38379764 PMCID: PMC10876777 DOI: 10.3389/fnins.2024.1342909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 01/18/2024] [Indexed: 02/22/2024] Open
Abstract
Introduction Posterior Cortical Atrophy (PCA) is a syndrome characterized by a progressive decline in higher-order visuospatial processing, leading to symptoms such as space perception deficit, simultanagnosia, and object perception impairment. While PCA is primarily known for its impact on visuospatial abilities, recent studies have documented language abnormalities in PCA patients. This study aims to delineate the nature and origin of language impairments in PCA, hypothesizing that language deficits reflect the visuospatial processing impairments of the disease. Methods We compared the language samples of 25 patients with PCA with age-matched cognitively normal (CN) individuals across two distinct tasks: a visually-dependent picture description and a visually-independent job description task. We extracted word frequency, word utterance latency, and spatial relational words for this comparison. We then conducted an in-depth analysis of the language used in the picture description task to identify specific linguistic indicators that reflect the visuospatial processing deficits of PCA. Results Patients with PCA showed significant language deficits in the visually-dependent task, characterized by higher word frequency, prolonged utterance latency, and fewer spatial relational words, but not in the visually-independent task. An in-depth analysis of the picture description task further showed that PCA patients struggled to identify certain visual elements as well as the overall theme of the picture. A predictive model based on these language features distinguished PCA patients from CN individuals with high classification accuracy. Discussion The findings indicate that language is a sensitive behavioral construct to detect visuospatial processing abnormalities of PCA. These insights offer theoretical and clinical avenues for understanding and managing PCA, underscoring language as a crucial marker for the visuospatial deficits of this atypical variant of Alzheimer's disease.
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Affiliation(s)
- Neguine Rezaii
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Daisy Hochberg
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Megan Quimby
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Bonnie Wong
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Scott McGinnis
- Center for Brain Mind Medicine, Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
| | - Bradford C. Dickerson
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States
- Alzheimer’s Disease Research Center, Massachusetts General Hospital, Charlestown, MA, United States
| | - Deepti Putcha
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
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Handa H, Sugiyama A, Kaname T, Shigemoto Y, Sato N, Hirano S, Nakagawa Y, Uzawa A, Aotsuka A, Kuwabara S. Frontal deficits and atrophy in a patient with familial encephalopathy with neuroserpin inclusion bodies detected by single-case voxel-based morphometry: a case report. BMC Neurol 2024; 24:9. [PMID: 38166833 PMCID: PMC10759324 DOI: 10.1186/s12883-023-03511-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare genetic disorder characterized by progressive cognitive decline and myoclonic epilepsy, caused by pathogenic variants of SERPINI1. We reported a case of genetically confirmed FENIB with de novo H338R mutation in the SERPINI1, in which frontal deficits including inattention and disinhibition, and relevant atrophy in the vmPFC on brain MRI were observed in the early stage of the disease. CASE PRESENTATION A 23-year-old Japanese man presented with progressive inattention and disinhibition over 4 years followed by myoclonic epilepsy. The whole-genome sequencing and filtering analysis showed de novo heterozygous H338R mutation in the SERPINI1, confirming the diagnosis of FENIB. Single-case voxel-based morphometry using brain magnetic resonance imaging obtained at the initial visit revealed focal gray matter volume loss in the ventromedial prefrontal cortices, which is presumed to be associated with inattention and disinhibition. CONCLUSION Frontal deficits including inattention and disinhibition can be the presenting symptoms of patients with FENIB. Single-case voxel-based morphometry may be useful for detecting regional atrophy of the frontal lobe in FENIB. Detecting these abnormalities in the early stage of disease may be key findings for differentiating FENIB from other causes of progressive myoclonic epilepsy.
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Affiliation(s)
- Hideo Handa
- Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan
- Department of Neurology, Chiba Aoba Municipal Hospital, Chiba, Japan
| | - Atsuhiko Sugiyama
- Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan.
| | - Tadashi Kaname
- Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Yoko Shigemoto
- Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Noriko Sato
- Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Shigeki Hirano
- Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan
| | - Yuki Nakagawa
- Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan
- Department of Neurology, Chiba Aoba Municipal Hospital, Chiba, Japan
| | - Akiyuki Uzawa
- Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan
| | - Akiyo Aotsuka
- Department of Neurology, Chiba Aoba Municipal Hospital, Chiba, Japan
| | - Satoshi Kuwabara
- Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan
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11
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Rezaii N, Hochberg D, Quimby M, Wong B, McGinnis S, Dickerson BC, Putcha D. Language Uncovers Visuospatial Dysfunction in Posterior Cortical Atrophy: A Natural Language Processing Approach. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.11.21.23298864. [PMID: 38045263 PMCID: PMC10690359 DOI: 10.1101/2023.11.21.23298864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Introduction Posterior Cortical Atrophy (PCA) is a syndrome characterized by a progressive decline in higher-order visuospatial processing, leading to symptoms such as space perception deficit, simultanagnosia, and object perception impairment. While PCA is primarily known for its impact on visuospatial abilities, recent studies have documented language abnormalities in PCA patients. This study aims to delineate the nature and origin of language impairments in PCA, hypothesizing that language deficits reflect the visuospatial processing impairments of the disease. Methods We compared the language samples of 25 patients with PCA with age-matched cognitively normal (CN) individuals across two distinct tasks: a visually-dependent picture description and a visually-independent job description task. We extracted word frequency, word utterance latency, and spatial relational words for this comparison. We then conducted an in-depth analysis of the language used in the picture description task to identify specific linguistic indicators that reflect the visuospatial processing deficits of PCA. Results Patients with PCA showed significant language deficits in the visually-dependent task, characterized by higher word frequency, prolonged utterance latency, and fewer spatial relational words, but not in the visually-independent task. An in-depth analysis of the picture description task further showed that PCA patients struggled to identify certain visual elements as well as the overall theme of the picture. A predictive model based on these language features distinguished PCA patients from CN individuals with high classification accuracy. Discussion The findings indicate that language is a sensitive behavioral construct to detect visuospatial processing abnormalities of PCA. These insights offer theoretical and clinical avenues for understanding and managing PCA, underscoring language as a crucial marker for the visuospatial deficits of this atypical variant of Alzheimer's disease.
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Affiliation(s)
- Neguine Rezaii
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Daisy Hochberg
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Megan Quimby
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Bonnie Wong
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
| | - Scott McGinnis
- Center for Brain Mind Medicine, Department of Neurology, Brigham & Women’s Hospital, Boston, MA 02115
| | - Bradford C Dickerson
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129
- Alzheimer’s Disease Research Center, Massachusetts General Hospital, Charlestown, MA 02129
| | - Deepti Putcha
- Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
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12
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Sintini I, Graff-Radford J, Schwarz CG, Machulda MM, Singh NA, Carlos AF, Senjem ML, Jack CR, Lowe VJ, Josephs KA, Whitwell JL. Longitudinal rates of atrophy and tau accumulation differ between the visual and language variants of atypical Alzheimer's disease. Alzheimers Dement 2023; 19:4396-4406. [PMID: 37485642 PMCID: PMC10592409 DOI: 10.1002/alz.13396] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/19/2023] [Accepted: 06/19/2023] [Indexed: 07/25/2023]
Abstract
INTRODUCTION Atypical variants of Alzheimer's disease (AD) include the visual variant, known as posterior cortical atrophy (PCA), and the language variant, known as logopenic progressive aphasia (LPA). Clinically, rates of disease progression differ between them. METHODS We evaluated 34 PCA and 29 LPA participants. Structural magnetic resonance imaging and 18 F-flortaucipir positron emission tomography were performed at baseline and at 1-year follow-up. Rates of change in tau uptake and grey matter volumes were compared between PCA and LPA with linear mixed-effects models and voxel-based analyses. RESULTS PCA had faster rates of occipital atrophy. LPA had faster rates of left temporal atrophy and faster rates of tau accumulation in the parietal, right temporal, and occipital lobes. Age was negatively associated with rates of atrophy and tau accumulation. DISCUSSION Longitudinal patterns of neuroimaging abnormalities differed between PCA and LPA, although with divergent results for tau accumulation and atrophy. HIGHLIGHTS The language variant of Alzheimer's disease accumulates tau faster than the visual variant. Each variant shows faster rates of atrophy than the other in its signature regions. Age negatively influences rates of atrophy and tau accumulation in both variants.
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Affiliation(s)
- Irene Sintini
- Department of Radiology, Mayo Clinic, Rochester, MN, USA, 55905
| | | | | | - Mary M. Machulda
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester MN, USA, 55905
| | | | - Arenn F. Carlos
- Department of Neurology, Mayo Clinic, Rochester, MN, USA, 55905
| | - Matthew L. Senjem
- Department of Radiology, Mayo Clinic, Rochester, MN, USA, 55905
- Department of Information Technology, Mayo Clinic, Rochester, MN, USA, 55905
| | | | - Val J. Lowe
- Department of Radiology, Mayo Clinic, Rochester, MN, USA, 55905
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13
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Mandelli ML, Lorca-Puls DL, Lukic S, Montembeault M, Gajardo-Vidal A, Licata A, Scheffler A, Battistella G, Grasso SM, Bogley R, Ratnasiri BM, La Joie R, Mundada NS, Europa E, Rabinovici G, Miller BL, De Leon J, Henry ML, Miller Z, Gorno-Tempini ML. Network anatomy in logopenic variant of primary progressive aphasia. Hum Brain Mapp 2023; 44:4390-4406. [PMID: 37306089 PMCID: PMC10318204 DOI: 10.1002/hbm.26388] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/21/2023] [Accepted: 05/17/2023] [Indexed: 06/13/2023] Open
Abstract
The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis.
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Affiliation(s)
- Maria Luisa Mandelli
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
| | - Diego L Lorca-Puls
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
- Sección de Neurología, Departamento de Especialidades, Facultad de Medicina, Universidad de Concepción, Concepción, Chile
| | - Sladjana Lukic
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
- Department of Communication Sciences and Disorders, Adelphi University, Garden City, New York, USA
| | - Maxime Montembeault
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
- Department of Psychiatry, Douglas Mental Health University Institute, McGill University, Montréal, Canada
| | - Andrea Gajardo-Vidal
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
- Faculty of Health Sciences, Universidad del Desarrollo, Concepción, Chile
| | - Abigail Licata
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
| | - Aaron Scheffler
- Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA
| | - Giovanni Battistella
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
- Department of Otolaryngology, Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA
| | - Stephanie M Grasso
- Department of Speech, Language, and Hearing Sciences, University of Texas, Austin, Texas, USA
| | - Rian Bogley
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
| | - Buddhika M Ratnasiri
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
| | - Renaud La Joie
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
| | - Nidhi S Mundada
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
| | - Eduardo Europa
- Department of Communicative Disorders and Sciences, San Jose State University, San Jose, California, USA
| | - Gil Rabinovici
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
| | - Bruce L Miller
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
| | - Jessica De Leon
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
| | - Maya L Henry
- Department of Speech, Language, and Hearing Sciences, University of Texas, Austin, Texas, USA
| | - Zachary Miller
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
| | - Maria Luisa Gorno-Tempini
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
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14
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Omori T, Funayama M, Anamizu S, Ishikawa M, Niida R, Tabuchi H. A Selective Hand Posture Apraxia in an Individual With Posterior Cortical Atrophy and Probable Corticobasal Syndrome. Cogn Behav Neurol 2023; 36:118-127. [PMID: 36961317 DOI: 10.1097/wnn.0000000000000339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 11/09/2022] [Indexed: 03/25/2023]
Abstract
A selective impairment for making hand postures that are required to use specific tools has rarely been reported in individuals with acquired brain injury, and such an impairment has not been documented at all in individuals with degenerative disorders. We describe an individual with posterior cortical atrophy and probable corticobasal syndrome who was unable to use tools because of an inability to make the proper hand posture required for each tool. This individual was, however, able to use the tools properly once her hand postures were corrected, and her ability to manipulate the tools (ie, timing, arm posture, and amplitude) was intact. Also, she had no difficulty with a test of her manipulation knowledge. Areas of hypoperfusion observed by single-photon emission computerized tomography included the anterior intraparietal sulcus in the left parietal lobe, which is an area that has been proposed to control hand postures. This selective impairment might be explained by the reasoning-based hypothesis for apraxia, which attributes hand posture errors in the absence of manipulation errors to dysfunction in one of the three independent pathways that subserve tool use, rather than the manipulation-based hypothesis for apraxia, which attributes hand posture errors to impaired manipulation knowledge. This is the first case with a degenerative disorder that revealed a selective impairment for making hand postures for tool use, which might be explained mainly by apraxia of hand postures along with visuospatial dysfunction (simultanagnosia) and/or sensory disturbance.
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Affiliation(s)
- Tomohiro Omori
- Department of Rehabilitation, International University of Health and Welfare, Narita Hospital, Narita-City, Japan
| | - Michitaka Funayama
- Department of Neuropsychiatry, Ashikaga Red Cross Hospital, Ashikaga-City, Japan
| | - Sachiko Anamizu
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Mei Ishikawa
- Department of Rehabilitation, Kawagoe Rehabilitation Hospital, Kawagoe-City, Japan
| | - Richi Niida
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Hajime Tabuchi
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
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15
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Mandelli ML, Lorca-Puls DL, Lukic S, Montembeault M, Gajardo-Vidal A, Licata A, Scheffler A, Battistella G, Grasso SM, Bogley R, Ratnasiri BM, La Joie R, Mundada NS, Europa E, Rabinovici G, Miller BL, De Leon J, Henry ML, Miller Z, Gorno-Tempini ML. Network anatomy in logopenic variant of primary progressive aphasia. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.05.15.23289065. [PMID: 37292690 PMCID: PMC10246009 DOI: 10.1101/2023.05.15.23289065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills, resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through pre-determined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically-fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporo-parietal junction regions, predominantly follows at least two partially non-overlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis.
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16
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Singh NA, Tosakulwong N, Graff-Radford J, Machulda MM, Pham NTT, Sintini I, Weigand SD, Schwarz CG, Senjem ML, Carrasquillo MM, Ertekin-Taner N, Jack CR, Lowe VJ, Josephs KA, Whitwell JL. APOE ε4 influences medial temporal atrophy and tau deposition in atypical Alzheimer's disease. Alzheimers Dement 2023; 19:784-796. [PMID: 35691047 PMCID: PMC9742387 DOI: 10.1002/alz.12711] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 05/02/2022] [Accepted: 05/04/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Apolipoprotein E (APOE) ε4 is an important genetic risk factor for typical Alzheimer's disease (AD), influencing brain volume and tau burden. Little is known about its influence in atypical presentations of AD. METHODS An atypical AD cohort of 140 patients diagnosed with either posterior cortical atrophy or logopenic progressive aphasia underwent magnetic resonance imaging and positron emission tomography. Linear mixed effects models were fit to assess the influence of APOE ε4 on cross-sectional and longitudinal regional metrics. RESULTS At baseline, APOE ε4 carriers had smaller hippocampal and amygdala volumes and greater tau standardized uptake volume ratio in the hippocampus and entorhinal cortex compared to non-carriers while longitudinally, APOE ε4 non-carriers showed faster rates of atrophy and tau accumulation in the entorhinal cortex, with faster tau accumulation in the hippocampus. DISCUSSION APOE ε4 influences patterns of neurodegeneration and tau deposition and was associated with more medial temporal involvement, although there is evidence that non-carriers may be catching up over time.
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Affiliation(s)
| | | | | | - Mary M. Machulda
- Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA
| | | | - Irene Sintini
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Stephen D. Weigand
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | | | | | | | | | | | - Val J. Lowe
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
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17
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Characterization of the logopenic variant of Primary Progressive Aphasia: A systematic review and meta-analysis. Ageing Res Rev 2022; 82:101760. [PMID: 36244629 DOI: 10.1016/j.arr.2022.101760] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 10/11/2022] [Indexed: 01/31/2023]
Abstract
The linguistic and anatomical variability of the logopenic variant of Primary Progressive Aphasia (lv-PPA) as defined by current diagnostic criteria has been the topic of an intense debate. The present review and meta-analysis aims at characterizing the profile of lv-PPA, by a comprehensive analysis of the available literature on the neuropsychological, neuroimaging, electrophysiological, pathological, and genetic features of lv-PPA. We conducted a systematic bibliographic search, leading to the inclusion of 207 papers. Of them, 12 were used for the Anatomical Likelihood Estimation meta-analysis on grey matter revealed by magnetic resonance imaging data. The results suggest that the current guidelines outline a relatively consistent syndrome, characterized by a core set of linguistic and, to a lesser extent, non-linguistic deficits, mirroring the involvement of left temporal and parietal regions typically affected by Alzheimer Disease pathology. Variations of the lv-PPA profile are discussed in terms of heterogeneity of the neuropsychological instruments and the diagnostic criteria adopted.
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18
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Butts AM, Machulda MM, Martin P, Przybelski SA, Duffy JR, Graff-Radford J, Knopman DS, Petersen RC, Jack CR, Lowe VJ, Josephs KA, Whitwell JL. Temporal Cortical Thickness and Cognitive Associations among Typical and Atypical Phenotypes of Alzheimer's Disease. J Alzheimers Dis Rep 2022; 6:479-491. [PMID: 36186727 PMCID: PMC9484150 DOI: 10.3233/adr-220010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 06/29/2022] [Indexed: 11/15/2022] Open
Abstract
Background The hippocampus and temporal lobe are atrophic in typical amnestic Alzheimer's disease (tAD) and are used as imaging biomarkers in treatment trials. However, a better understanding of how temporal structures differ across atypical AD phenotypes and relate to cognition is needed. Objective Our goal was to compare temporal lobe regions between tAD and two atypical AD phenotypes (logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA)), and assess cognitive associations. Methods We age and gender-matched 77 tAD participants to 50 LPA and 27 PCA participants, all of which were amyloid-positive. We used linear mixed-effects models to compare FreeSurfer-derived hippocampal volumes and cortical thickness of entorhinal, inferior and middle temporal, and fusiform gyri, and to assess relationships between imaging and memory, naming, and visuospatial function across and within AD phenotype. Results Hippocampal volume and entorhinal thickness were smaller bilaterally in tAD than LPA and PCA. PCA showed greater right inferior temporal and bilateral fusiform thinning and LPA showed greater left middle and inferior temporal and left fusiform thinning. Atypical AD phenotypes differed with greater right hemisphere thinning in PCA and greater left hemisphere thinning in LPA. Verbal and visual memory related most strongly to hippocampal volume; naming related to left temporal thickness; and visuospatial related to bilateral fusiform thickness. Fewer associations remained when examined within AD group. Conclusion Atypical AD phenotypes are associated with greater thinning of lateral temporal structures, with relative sparing of medial temporal lobe, compared to tAD. These findings may have implications for future clinical trials in AD.
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Affiliation(s)
- Alissa M. Butts
- Department of Neurology, Division of Neuropsychology, Medical College of Wisconsin, Milwaukee, WI, USA,External Research Collaborator, Mayo Clinic, Rochester, MN, USA
| | - Mary M. Machulda
- Department of Psychiatry and Psychology, Division of Neuropsychology, Mayo Clinic, Rochester, MN, USA
| | - Peter Martin
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | | | | | | | | | | | | | - Val J. Lowe
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | | | - Jennifer L. Whitwell
- Department of Radiology, Mayo Clinic, Rochester, MN, USA,Correspondence to: Jennifer L. Whitwell, PhD, Professor of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA. E-mail:
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19
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Ramanan S, Irish M, Patterson K, Rowe JB, Gorno-Tempini ML, Lambon Ralph MA. Understanding the multidimensional cognitive deficits of logopenic variant primary progressive aphasia. Brain 2022; 145:2955-2966. [PMID: 35857482 PMCID: PMC9473356 DOI: 10.1093/brain/awac208] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 05/06/2022] [Accepted: 05/27/2022] [Indexed: 02/02/2023] Open
Abstract
The logopenic variant of primary progressive aphasia is characterized by early deficits in language production and phonological short-term memory, attributed to left-lateralized temporoparietal, inferior parietal and posterior temporal neurodegeneration. Despite patients primarily complaining of language difficulties, emerging evidence points to performance deficits in non-linguistic domains. Temporoparietal cortex, and functional brain networks anchored to this region, are implicated as putative neural substrates of non-linguistic cognitive deficits in logopenic variant primary progressive aphasia, suggesting that degeneration of a shared set of brain regions may result in co-occurring linguistic and non-linguistic dysfunction early in the disease course. Here, we provide a Review aimed at broadening the understanding of logopenic variant primary progressive aphasia beyond the lens of an exclusive language disorder. By considering behavioural and neuroimaging research on non-linguistic dysfunction in logopenic variant primary progressive aphasia, we propose that a significant portion of multidimensional cognitive features can be explained by degeneration of temporal/inferior parietal cortices and connected regions. Drawing on insights from normative cognitive neuroscience, we propose that these regions underpin a combination of domain-general and domain-selective cognitive processes, whose disruption results in multifaceted cognitive deficits including aphasia. This account explains the common emergence of linguistic and non-linguistic cognitive difficulties in logopenic variant primary progressive aphasia, and predicts phenotypic diversification associated with progression of pathology in posterior neocortex.
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Affiliation(s)
- Siddharth Ramanan
- Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK
| | - Muireann Irish
- The University of Sydney, Brain and Mind Centre and School of Psychology, Sydney, Australia
| | - Karalyn Patterson
- Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK
| | - James B Rowe
- Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK
- Department of Clinical Neurosciences, Cambridge University Centre for Frontotemporal Dementia, Cambridge, UK
- Cambridge University Hospitals NHS Trust, Cambridge, UK
| | | | - Matthew A Lambon Ralph
- Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK
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20
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Therriault J, Pascoal TA, Savard M, Mathotaarachchi S, Benedet AL, Chamoun M, Tissot C, Lussier FZ, Rahmouni N, Stevenson J, Qureshi MNI, Kang MS, Thomas É, Vitali P, Soucy JP, Massarweh G, Saha-Chaudhuri P, Gauthier S, Rosa-Neto P. Intrinsic connectivity of the human brain provides scaffold for tau aggregation in clinical variants of Alzheimer's disease. Sci Transl Med 2022; 14:eabc8693. [PMID: 36001678 DOI: 10.1126/scitranslmed.abc8693] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) phenotypes might result from differences in selective vulnerability. Evidence from preclinical models suggests that tau pathology has cell-to-cell propagation properties. Therefore, here, we tested the cell-to-cell propagation framework in the amnestic, visuospatial, language, and behavioral/dysexecutive phenotypes of AD. We report that each AD phenotype is associated with a distinct network-specific pattern of tau aggregation, where tau aggregation is concentrated in brain network hubs. In all AD phenotypes, regional tau load could be predicted by connectivity patterns of the human brain. Furthermore, regions with greater connectivity displayed similar rates of longitudinal tau accumulation in an independent cohort. Connectivity-based tau deposition was not restricted to a specific vulnerable network but was rather a general property of brain organization, linking selective vulnerability and transneuronal spreading models of neurodegeneration. Together, this study indicates that intrinsic brain connectivity provides a framework for tau aggregation across diverse phenotypic manifestations of AD.
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Affiliation(s)
- Joseph Therriault
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
| | - Tharick A Pascoal
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
| | - Mélissa Savard
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada
| | - Sulantha Mathotaarachchi
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada
| | - Andréa L Benedet
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
| | - Mira Chamoun
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada
| | - Cécile Tissot
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
| | - Firoza Z Lussier
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
| | - Nesrine Rahmouni
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
| | - Jenna Stevenson
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
| | - Muhammad Naveed Iqbal Qureshi
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
| | - Min Su Kang
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
| | - Émilie Thomas
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada
| | - Paolo Vitali
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada
| | - Jean-Paul Soucy
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada
| | - Gassan Massarweh
- Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada.,Department of Radiochemistry, McGill University, Montreal, Quebec H3A 2B4, Canada
| | | | - Serge Gauthier
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Department of Psychiatry, McGill University, Montreal, Quebec H3A 1G1, Canada
| | - Pedro Rosa-Neto
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 0G4, Canada.,Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada.,Department of Psychiatry, McGill University, Montreal, Quebec H3A 1G1, Canada
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21
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Buckley RF, O'Donnell A, McGrath ER, Jacobs HI, Lois C, Satizabal CL, Ghosh S, Rubinstein ZB, Murabito JM, Sperling RA, Johnson KA, Seshadri S, Beiser AS. Menopause Status Moderates Sex Differences in Tau Burden: A Framingham PET Study. Ann Neurol 2022; 92:11-22. [PMID: 35471588 PMCID: PMC9233144 DOI: 10.1002/ana.26382] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 04/20/2022] [Accepted: 04/22/2022] [Indexed: 11/29/2022]
Abstract
OBJECTIVE Women have a higher lifetime risk of Alzheimer's disease (AD) than men. Among cognitively normal (CN) older adults, women exhibit elevated tau positron emission tomography (PET) signal compared with men. We explored whether menopause exacerbates sex differences in tau deposition in middle-aged adults. METHODS 328 CN participants from the Framingham Study (mean age = 57 years (±10 years), 161 women, of whom, 104 were post-menopausal) underwent tau and β-amyloid (Aβ)-PET neuroimaging. We examined global Aβ-PET, and tau-PET signal in 5 regions identified a priori as demonstrating significant sex differences in older adults (in temporal, inferior parietal, middle frontal, and lateral occipital regions). We examined sex and menopause status-related differences in each region-of-interest, using linear regressions, as well as interactions with Aβ and APOEε4 genotype. RESULTS Women exhibited higher tau-PET signal (p < 0.002), and global Aβ-PET (p = 0.010), than men in inferior parietal, rostral middle frontal, and lateral occipital regions. Compared with age-matched men, post-menopausal women showed significantly higher tau-PET signal in parieto-occipital regions (p < 0.0001). By contrast, no differences in tau-PET signal existed between pre-menopausal women and men. Aβ-PET was not associated with menopausal status or age. Neither Aβ-PET nor APOEε4 status moderated sex or menopause associations with tau-PET. INTERPRETATION Clear divergence in tauopathy between the sexes are apparent approximately 20 years earlier than previously reported. Menopause status moderated sex differences in Aβ and tau-PET burden, with tau first appearing post-menopause. Sex and menopause differences consistently appeared in middle frontal and parieto-occipital regions but were not moderated by Aβ burden or APOEε4, suggesting that menopause-related tau vulnerability may be independent of AD-related pathways. ANN NEUROL 2022;92:11-22.
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Affiliation(s)
- Rachel F. Buckley
- Department of NeurologyMassachusetts General Hospital and Harvard Medical SchoolBostonMAUSA
- Center for Alzheimer Research and Treatment, Department of NeurologyBrigham and Women's HospitalBostonMAUSA
- Melbourne School of Psychological Science and Florey InstitutesUniversity of MelbourneParkvilleVICAustralia
| | - Adrienne O'Donnell
- Department of BiostatisticsBoston University School of Public HealthBostonMAUSA
- Framingham Heart StudyFraminghamMAUSA
| | - Emer R. McGrath
- Framingham Heart StudyFraminghamMAUSA
- HRB Clinical Research FacilityNational University of Ireland GalwayGalwayIreland
| | - Heidi I.L. Jacobs
- Gordon Center for Medical Imaging, Department of RadiologyMassachusetts General Hospital/Harvard Medical SchoolBostonMAUSA
- Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Alzheimer Centre LimburgMaastricht UniversityMaastrichtThe Netherlands
| | - Cristina Lois
- Gordon Center for Medical Imaging, Department of RadiologyMassachusetts General Hospital/Harvard Medical SchoolBostonMAUSA
| | - Claudia L. Satizabal
- Framingham Heart StudyFraminghamMAUSA
- Glen Biggs Institute for Alzheimer's & Neurodegenerative DiseasesUniversity of Texas Health San AntonioSan AntonioTXUSA
- Department of NeurologyBoston University School of MedicineBostonMAUSA
| | | | - Zoe B. Rubinstein
- Gordon Center for Medical Imaging, Department of RadiologyMassachusetts General Hospital/Harvard Medical SchoolBostonMAUSA
| | | | - Reisa A. Sperling
- Department of NeurologyMassachusetts General Hospital and Harvard Medical SchoolBostonMAUSA
- Center for Alzheimer Research and Treatment, Department of NeurologyBrigham and Women's HospitalBostonMAUSA
| | - Keith A. Johnson
- Center for Alzheimer Research and Treatment, Department of NeurologyBrigham and Women's HospitalBostonMAUSA
- Gordon Center for Medical Imaging, Department of RadiologyMassachusetts General Hospital/Harvard Medical SchoolBostonMAUSA
| | - Sudha Seshadri
- Framingham Heart StudyFraminghamMAUSA
- Glen Biggs Institute for Alzheimer's & Neurodegenerative DiseasesUniversity of Texas Health San AntonioSan AntonioTXUSA
- Department of NeurologyBoston University School of MedicineBostonMAUSA
| | - Alexandra S. Beiser
- Department of BiostatisticsBoston University School of Public HealthBostonMAUSA
- Framingham Heart StudyFraminghamMAUSA
- Department of NeurologyBoston University School of MedicineBostonMAUSA
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22
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Lukic S, Licata AE, Weis E, Bogley R, Ratnasiri B, Welch AE, Hinkley LBN, Miller Z, Garcia AM, Houde JF, Nagarajan SS, Gorno-Tempini ML, Borghesani V. Auditory Verb Generation Performance Patterns Dissociate Variants of Primary Progressive Aphasia. Front Psychol 2022; 13:887591. [PMID: 35814055 PMCID: PMC9267767 DOI: 10.3389/fpsyg.2022.887591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Primary progressive aphasia (PPA) is a clinical syndrome in which patients progressively lose speech and language abilities. Three variants are recognized: logopenic (lvPPA), associated with phonology and/or short-term verbal memory deficits accompanied by left temporo-parietal atrophy; semantic (svPPA), associated with semantic deficits and anterior temporal lobe (ATL) atrophy; non-fluent (nfvPPA) associated with grammar and/or speech-motor deficits and inferior frontal gyrus (IFG) atrophy. Here, we set out to investigate whether the three variants of PPA can be dissociated based on error patterns in a single language task. We recruited 21 lvPPA, 28 svPPA, and 24 nfvPPA patients, together with 31 healthy controls, and analyzed their performance on an auditory noun-to-verb generation task, which requires auditory analysis of the input, access to and selection of relevant lexical and semantic knowledge, as well as preparation and execution of speech. Task accuracy differed across the three variants and controls, with lvPPA and nfvPPA having the lowest and highest accuracy, respectively. Critically, machine learning analysis of the different error types yielded above-chance classification of patients into their corresponding group. An analysis of the error types revealed clear variant-specific effects: lvPPA patients produced the highest percentage of "not-a-verb" responses and the highest number of semantically related nouns (production of baseball instead of throw to noun ball); in contrast, svPPA patients produced the highest percentage of "unrelated verb" responses and the highest number of light verbs (production of take instead of throw to noun ball). Taken together, our findings indicate that error patterns in an auditory verb generation task are associated with the breakdown of different neurocognitive mechanisms across PPA variants. Specifically, they corroborate the link between temporo-parietal regions with lexical processing, as well as ATL with semantic processes. These findings illustrate how the analysis of pattern of responses can help PPA phenotyping and heighten diagnostic sensitivity, while providing insights on the neural correlates of different components of language.
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Affiliation(s)
- Sladjana Lukic
- Department of Communication Sciences and Disorders, Ruth S. Ammon College of Education and Health Sciences, Adelphi University, Garden City, NY, United States
- Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
| | - Abigail E. Licata
- Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
- Department of Neurology, Dyslexia Center, University of California, San Francisco, San Francisco, CA, United States
| | - Elizabeth Weis
- Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
| | - Rian Bogley
- Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
- Department of Neurology, Dyslexia Center, University of California, San Francisco, San Francisco, CA, United States
| | - Buddhika Ratnasiri
- Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
| | - Ariane E. Welch
- Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
| | - Leighton B. N. Hinkley
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
| | - Z. Miller
- Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
- Department of Neurology, Dyslexia Center, University of California, San Francisco, San Francisco, CA, United States
| | - Adolfo M. Garcia
- Cognitive Neuroscience Center, Universidad de San Andrés, Buenos Aires, Argentina
- Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, United States
- National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
- Departamento de Lingüística y Literatura, Facultad de Humanidades, Universidad de Santiago de Chile, Santiago, Chile
| | - John F. Houde
- Department of Otolaryngology – Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, United States
| | - Srikantan S. Nagarajan
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
| | - Maria Luisa Gorno-Tempini
- Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
- Department of Neurology, Dyslexia Center, University of California, San Francisco, San Francisco, CA, United States
| | - Valentina Borghesani
- Department of Psychology, Université de Montréal, Montréal, QC, Canada
- Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal, Montréal, QC, Canada
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23
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González R, Rojas M, Rosselli M, Ardila A. Linguistic profiles of variants of primary progressive aphasia. JOURNAL OF COMMUNICATION DISORDERS 2022; 97:106202. [PMID: 35255297 DOI: 10.1016/j.jcomdis.2022.106202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 02/17/2022] [Accepted: 02/23/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Several subtypes of primary progressive aphasia (PPA) have been proposed. Most reports use small samples, and few have included Spanish-speaking participants. AIM To analyze the language profile and nonlinguistic deficits in a large sample of PPA Spanish monolingual participants. METHOD 177 individuals were diagnosed with PPA in a sample consisting of 69 men and 108 women (Mage = 66.40 years, SD = 9.30). The participants were assessed using the Spanish versions of the Western Aphasia Battery Revised (SWAB-R) and the Boston Diagnostic Aphasia Examination (SBDAE). Non-verbal reasoning was evaluated with the Raven's Colored Progressive Matrices. RESULTS 41.8% of the sample met the criteria for the logopenic variant (lvPPA), while 28.2% met the criteria for semantic (svPPA), 15.3% for lexical (lxvPPA), and 14.7% for nonfluent/agrammatic (nfvPPA) variants. Language difficulties were similar in all variants except for lxvPPA. Scores on Spontaneous Language, Auditory Comprehension, Repetition, and Naming were significantly higher for the lxvPPA group. Raven's Colored Progressive Matrices scores were significantly lower in lvPPA. Years of education correlated with all test scores, while age was negatively associated with naming. When the PPA variants were classified according to the traditional aphasia classification, discrepancies were evident. Furthermore, the most frequent type of aphasia was Amnesic, while the least frequent was Wernicke's aphasia. CONCLUSION The SWAB-R is useful in describing the clinical characteristics of aphasia for each variant of PPA, but quantitative scores from this battery are not capable of distinguishing between variants of PPA, with the exception of lxvPPA.
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Affiliation(s)
- Rafael González
- Departamento de Neurología y Neurocirugía, Hospital Clínico de la Universidad de Chile, Santiago, Chile
| | - Macarena Rojas
- Departamento de Neurología y Neurocirugía, Hospital Clínico de la Universidad de Chile, Santiago, Chile
| | - Mónica Rosselli
- Department of Psychology, Charles E. Schmidt College of Science, Florida Atlantic University, Davie, Florida, USA.
| | - Alfredo Ardila
- Institute of Linguistics and Intercultural Communication, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Psychology Doctoral Program, Albizu University, Miami, Florida, USA
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24
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Brodeur C, Belley É, Deschênes LM, Enriquez-Rosas A, Hubert M, Guimond A, Bilodeau J, Soucy JP, Macoir J. Primary and Secondary Progressive Aphasia in Posterior Cortical Atrophy. Life (Basel) 2022; 12:life12050662. [PMID: 35629330 PMCID: PMC9142989 DOI: 10.3390/life12050662] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/20/2022] [Accepted: 04/25/2022] [Indexed: 12/26/2022] Open
Abstract
Background: Posterior cortical atrophy (PCA) is a clinico-radiological syndrome characterized by a progressive decline in visuospatial/visuoperceptual processing. PCA is accompanied by the impairment of other cognitive functions, including language abilities. Methods: The present study focused on three patients presenting with language complaints and a clinical profile that was compatible with PCA. In addition to neurological and neuroimaging examinations, they were assessed with comprehensive batteries of neuropsychological and neurolinguistic tests. Results: The general medical profile of the three patients is consistent with PCA, although they presented with confounding factors, making diagnosis less clear. The cognitive profile of the three patients was marked by Balint and Gerstmann’s syndromes as well as impairments affecting executive functions, short-term and working memory, visuospatial and visuoperceptual abilities, and sensorimotor execution abilities. Their language ability was characterized by word-finding difficulties and impairments of sentence comprehension, sentence repetition, verbal fluency, narrative speech, reading, and writing. Conclusions: This study confirmed that PCA is marked by visuospatial and visuoperceptual deficits and reported evidence of primary and secondary language impairments in the three patients. The similarities of some of their language impairments with those found in the logopenic variant of primary progressive aphasia is discussed from neurolinguistic and neuroanatomical points of view.
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Affiliation(s)
- Catherine Brodeur
- Institut Universitaire de Gériatrie de Montréal, Montreal, QC H3W 1W5, Canada; (C.B.); (A.E.-R.); (M.H.); (A.G.); (J.B.)
- Université de Montréal, Montreal, QC H3T 1J4, Canada;
- Centre de Recherche de l’IUGM, Montreal, QC H3W 1W6, Canada
| | - Émilie Belley
- Département de Réadaptation, Faculté de Médecine, Université Laval, Quebec, QC G1V 0A6, Canada; (É.B.); (L.-M.D.)
| | - Lisa-Marie Deschênes
- Département de Réadaptation, Faculté de Médecine, Université Laval, Quebec, QC G1V 0A6, Canada; (É.B.); (L.-M.D.)
| | - Adriana Enriquez-Rosas
- Institut Universitaire de Gériatrie de Montréal, Montreal, QC H3W 1W5, Canada; (C.B.); (A.E.-R.); (M.H.); (A.G.); (J.B.)
| | - Michelyne Hubert
- Institut Universitaire de Gériatrie de Montréal, Montreal, QC H3W 1W5, Canada; (C.B.); (A.E.-R.); (M.H.); (A.G.); (J.B.)
| | - Anik Guimond
- Institut Universitaire de Gériatrie de Montréal, Montreal, QC H3W 1W5, Canada; (C.B.); (A.E.-R.); (M.H.); (A.G.); (J.B.)
| | - Josée Bilodeau
- Institut Universitaire de Gériatrie de Montréal, Montreal, QC H3W 1W5, Canada; (C.B.); (A.E.-R.); (M.H.); (A.G.); (J.B.)
| | - Jean-Paul Soucy
- Université de Montréal, Montreal, QC H3T 1J4, Canada;
- McConnell Brain Imaging Centre, McGill University, Montreal, QC H3A 2B4, Canada
- Concordia University, Montreal, QC H4B 1R6, Canada
| | - Joël Macoir
- Département de Réadaptation, Faculté de Médecine, Université Laval, Quebec, QC G1V 0A6, Canada; (É.B.); (L.-M.D.)
- Centre de Recherche CERVO (CERVO Brain Research Centre), Quebec, QC G1J 2G3, Canada
- Correspondence: ; Tel.: +1-418-656-2131 (ext. 412190)
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25
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Daly T, Mastroleo I, Migliaccio R. Avoiding Over-Reliance on Multi-Domain Interventions for Dementia Prevention. J Alzheimers Dis 2022; 90:989-992. [PMID: 35275544 DOI: 10.3233/jad-215647] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Given the unknown therapeutic value of targeting Alzheimer's disease pathology and the discovery of robust risk factors for dementia, non-pharmacological risk reduction (RR) is increasingly offered as an alternative to targeting Alzheimer's disease pathology. While RR will surely be a useful tool to make public health gains, we propose solutions to three possible issues with over-reliance on multi-domain interventions to achieve RR: limited individual impact, an exclusive focus on later life, and overlooking social determinants of dementia. We argue in favor of a broader debate within the research community and greater society about how different therapeutic avenues should be explored.
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Affiliation(s)
- Timothy Daly
- Sorbonne Université, Science Norms Democracy, UMR 8011, Paris, France.,Programa de Bioética, Facultad Latinoamericana de Ciencias Sociales (FLACSO), Argentina
| | - Ignacio Mastroleo
- Programa de Bioética, Facultad Latinoamericana de Ciencias Sociales (FLACSO), Argentina.,National Scientific and Technical Research Council (CONICET), Argentina
| | - Raffaella Migliaccio
- Sorbonne Université, Institut du Cerveau, Paris Brain Institute, ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France.,FrontLab, ICM, Paris, France.,AP-HP, Hôpital de la Pitié Salpêtrière, Institute of Memory and Alzheimer's Disease (IM2A), Centre of Excellence of Neurodegenerative Disease (CoEN), National Reference Centre for Rare and Early Dementias, Department of Neurology, Paris, France
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26
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Putcha D, Eckbo R, Katsumi Y, Dickerson BC, Touroutoglou A, Collins JA. Tau and the fractionated default mode network in atypical Alzheimer's disease. Brain Commun 2022; 4:fcac055. [PMID: 35356035 PMCID: PMC8963312 DOI: 10.1093/braincomms/fcac055] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/26/2022] [Accepted: 03/07/2022] [Indexed: 11/12/2022] Open
Abstract
Alzheimer's disease-related atrophy in the posterior cingulate cortex, a key node of the default mode network, is present in the early stages of disease progression across clinical phenotypic variants of the disease. In the typical amnestic variant, posterior cingulate cortex neuropathology has been linked with disrupted connectivity of the posterior default mode network, but it remains unclear if this relationship is observed across atypical variants of Alzheimer's disease. In the present study, we first sought to determine if tau pathology is consistently present in the posterior cingulate cortex and other posterior nodes of the default mode network across the atypical Alzheimer's disease syndromic spectrum. Second, we examined functional connectivity disruptions within the default mode network and sought to determine if tau pathology is related to functional disconnection within this network. We studied a sample of 25 amyloid-positive atypical Alzheimer's disease participants examined with high-resolution MRI, tau (18F-AV-1451) PET, and resting-state functional MRI. In these patients, high levels of tau pathology in the posteromedial cortex and hypoconnectivity between temporal and parietal nodes of the default mode network were observed relative to healthy older controls. Furthermore, higher tau signal and reduced grey matter density in the posterior cingulate cortex and angular gyrus were associated with reduced parietal functional connectivity across individual patients, related to poorer cognitive scores. Our findings converge with what has been reported in amnestic Alzheimer's disease, and together these observations offer a unifying mechanistic feature that relates posterior cingulate cortex tau deposition to aberrant default mode network connectivity across heterogeneous clinical phenotypes of Alzheimer's disease.
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Affiliation(s)
- Deepti Putcha
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ryan Eckbo
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Yuta Katsumi
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Bradford C. Dickerson
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Alzheimer’s Disease Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Alexandra Touroutoglou
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jessica A. Collins
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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27
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Migliaccio R, Cacciamani F. The temporal lobe in typical and atypical Alzheimer disease. HANDBOOK OF CLINICAL NEUROLOGY 2022; 187:449-466. [PMID: 35964987 DOI: 10.1016/b978-0-12-823493-8.00004-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Alzheimer disease (AD) is defined neuropathologically by abnormal extra-cellular β-amyloid plaques combined with intraneuronal tau aggregation. Patients sharing the same neuropathological features but presenting different clinical manifestations and evolutions have led to the notion of AD spectrum. This spectrum encompasses typical and atypical forms of AD. For all of them, specific parts of the temporal lobes, as well as their structural and functional connections with other brain regions, are affected. In typical amnestic late-onset Alzheimer's disease (>65 years old; LOAD), tau pathology gradually spreads to the brain from the medial temporal lobe (MTL). MTL is an inhomogeneous structure consisting of several subregions densely connected to each other and to other cortical and subcortical brain regions. These regions play a crucial role in the storage of information in episodic memory. In less common early-onset AD (<65 years old; EOAD), a large proportion of patients presents atypical clinical manifestations, in which memory impairment is not inaugural and predominant. Instead, these patients have predominant and/or isolated deficits in language, visuospatial, motor, or executive/behavioral functions. In atypical variants, brain damage is mainly centered on the posterior regions, with relative sparing of the MTL. However, the temporal lobe also appears to be variably and specifically damaged in some subtypes of EOAD. For example, the left superior temporal gyrus is the core of brain damage in the language variant, as well as the ventral regions of the temporal lobe play an important role in the clinic of the visual variant.
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Affiliation(s)
- Raffaella Migliaccio
- Paris Brain Institute, INSERM U1127, Hôpital de la Pitié-Salpêtrière, Paris, France; Department of Neurology, Institut de la mémoire et de la maladie d'Alzheimer, Hôpital de la Pitié-Salpêtrière, Paris, France.
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North C, Desai R, Saunders R, Suárez-González A, Bamiou D, Costafreda SG, de Haan G, Halls G, Heutink J, O'Nions E, Utoomprurkporn N, John A, Stott J. Neuropsychological deficits in Posterior Cortical Atrophy and typical Alzheimer's disease: A meta-analytic review. Cortex 2021; 143:223-236. [PMID: 34464853 DOI: 10.1016/j.cortex.2021.07.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 05/13/2021] [Accepted: 07/30/2021] [Indexed: 11/27/2022]
Abstract
AIMS To identify cognitive tests that best differentiate between Posterior Cortical Atrophy (PCA) and typical Alzheimer's Disease (tAD), as well as PCA and healthy control (HC) participants. METHOD Medline, PsycInfo and Web of Science were systematically searched using terms related to PCA, tAD, and cognitive testing. Seventeen studies were identified, including 441 PCA, 391 tAD, and 284 HC participants. Standardised effect sizes of mean scores were calculated to measure performance differences on cognitive tests for PCA versus tAD and PCA versus HC groups. Meta-analyses used a random effects model. RESULTS The most discriminating cognitive tests for PCA and tAD presentations were measures of visuospatial function and verbal memory. Large, significant effect sizes were produced for all measures of visuospatial function, most notably for Rey-Osterrieth Copy (Hedges' g = -2.79), VOSP Fragmented letters (Hedges' g = -1.73), VOSP Dot Counting (Hedges' g = -1.74), and VOSP Cube Analysis (Hedges' g = -1.98). For measures of verbal memory, the RAVLT delay and Digit Span Backwards produced significant medium effects (Hedges' g = .62 and -.56, respectively). CONCLUSION Establishing a common framework for testing individuals with PCA has important implications for diagnosis and treatment, and forms a practical objective for future research. Findings from this meta-analysis suggest that measures of visuospatial function and verbal memory would form an important part of this framework.
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Affiliation(s)
- Courtney North
- ADAPT Lab, Research Department of Clinical, Educational and Health Psychology, University College London, London, UK
| | - Roopal Desai
- ADAPT Lab, Research Department of Clinical, Educational and Health Psychology, University College London, London, UK.
| | - Rob Saunders
- Centre for Outcomes Research and Effectiveness, University College London, UK
| | | | - Doris Bamiou
- UCL Ear Institute, University College London, UK
| | - Sergi G Costafreda
- ADAPT Lab, Research Department of Clinical, Educational and Health Psychology, University College London, London, UK
| | - Gera de Haan
- University of Groningen, Groningen, the Netherlands; Royal Dutch Visio, Centre of Expertise for Blind and Partially Sighted People, Huizen, the Netherlands
| | - Georgia Halls
- ADAPT Lab, Research Department of Clinical, Educational and Health Psychology, University College London, London, UK
| | - Joost Heutink
- University of Groningen, Groningen, the Netherlands; Royal Dutch Visio, Centre of Expertise for Blind and Partially Sighted People, Huizen, the Netherlands
| | - Elizabeth O'Nions
- ADAPT Lab, Research Department of Clinical, Educational and Health Psychology, University College London, London, UK
| | - Nattawan Utoomprurkporn
- UCL Ear Institute, University College London, UK; Faculty of Medicine, Chulalongkorn University, Thailand
| | - Amber John
- ADAPT Lab, Research Department of Clinical, Educational and Health Psychology, University College London, London, UK
| | - Joshua Stott
- ADAPT Lab, Research Department of Clinical, Educational and Health Psychology, University College London, London, UK
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Clinical and radiological profile of posterior cortical atrophy and comparison with a group of typical Alzheimer disease and amnestic mild cognitive impairment. Acta Neurol Belg 2021; 121:1009-1018. [PMID: 33230741 DOI: 10.1007/s13760-020-01547-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/08/2020] [Indexed: 12/21/2022]
Abstract
Posterior cortical atrophy (PCA) is a rare dementia affecting higher visual processing and other posterior cortical functions with atrophy and hypometabolism in occipito-parieto-temporal areas, more on right side. The objective of the study was to explore the clinical, neuropsychological, and radiological features of PCA patients and to compare them with typical multi-domain amnestic Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) patients. Four out of 9 patients of PCA fulfilling the criteria of Tang-Wai et al. (2004), 10 patients each of AD and aMCI fulfilling NIA-AA criteria were chosen. Patients were assessed clinically by experienced neurologists. Neuropsychological assessment was performed with standardized validated tests. Each patient underwent an MRI. FDG-PET was done for all PCA and six AD patients. PCA patients were younger, cognitively more impaired with rapid progression showing predominant visuospatial deficits consistent with the damage to the upstream of visual processing. AD patients presented predominantly with amnestic symptoms, with visuospatial dysfunction in some and aMCI had mild memory loss. Marked atrophy and hypometabolism in occipital, parietal and temporal areas in PCA, atrophy and hypometabolism in medial temporal areas in AD and minimal non-localized atrophy in MRI in aMCI were seen. Two PCA patients showed hypometabolism extending to the medial temporal and one to the frontal cortex. The clinical and imaging features of PCA are consistent with the damage predominantly to the upstream of visual processing. The difference between PCA and typical AD suggests involvement of AD pathology at different sites within a common disease-relevant network of brain regions.
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Shea YF, Pan Y, Mak HKF, Bao Y, Lee SC, Chiu PKC, Chan HWF. A systematic review of atypical Alzheimer's disease including behavioural and psychological symptoms. Psychogeriatrics 2021; 21:396-406. [PMID: 33594793 DOI: 10.1111/psyg.12665] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/06/2021] [Accepted: 01/25/2021] [Indexed: 12/20/2022]
Abstract
Alzheimer's disease (AD) is the commonest cause of dementia, characterized by the clinical presentation of progressive anterograde episodic memory impairment. However, atypical presentation of patients is increasingly recognized. These atypical AD include logopenic aphasia, behavioural variant AD, posterior cortical atrophy, and corticobasal syndrome. These atypical AD are more common in patients with young onset AD before the age of 65 years old. Since medical needs (including the behavioural and psychological symptoms of dementia) of atypical AD patients could be different from typical AD patients, it is important for clinicians to be aware of these atypical forms of AD. In addition, disease modifying treatment may be available in the future. This review aims at providing an update on various important subtypes of atypical AD including behavioural and psychological symptoms.
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Affiliation(s)
- Yat-Fung Shea
- Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Pok Fu Lam, Hong Kong
| | - Yining Pan
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Henry Ka-Fung Mak
- Department of Diagnostic Radiology, LKS Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Yiwen Bao
- Department of Diagnostic Radiology, LKS Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Shui-Ching Lee
- Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Pok Fu Lam, Hong Kong
| | - Patrick Ka-Chun Chiu
- Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Pok Fu Lam, Hong Kong
| | - Hon-Wai Felix Chan
- Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Pok Fu Lam, Hong Kong
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31
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Sáiz-Vázquez O, Gracia-García P, Ubillos-Landa S, Puente-Martínez A, Casado-Yusta S, Olaya B, Santabárbara J. Depression as a Risk Factor for Alzheimer's Disease: A Systematic Review of Longitudinal Meta-Analyses. J Clin Med 2021; 10:jcm10091809. [PMID: 33919227 PMCID: PMC8122638 DOI: 10.3390/jcm10091809] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 01/08/2023] Open
Abstract
Alzheimer’s disease (AD) is the most frequent cause of dementia, linked to morbidity and mortality among elderly patients. Recently, several clinical studies suggested that depression is a potential risk factor for cognitive decline and AD. A review of meta-analyses was performed, calculating pooled odds ratios to estimate the risk of AD in people with a prior diagnosis (or clinically significant symptoms) of depression. A total of six meta-analyses which represented 28 individual studies were analyzed. A significant association between depression and AD was found (OR = 1.54, 95% CI [1.02–2.31]; p = 0.038). The results showed that heterogeneity across studies was substantial. We found a significant positive effect size for clinical measures of depression, but not for symptomatic rating scales, in the association of depression with risk of AD. The type of rating scale used to assess depression and the cut-off criteria selected also moderated the relationship between depression and AD risk. We found that studies that used clinically significant criteria for diagnosis of depression had more consistent and significant results than studies that used symptomatic scales.
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Affiliation(s)
- Olalla Sáiz-Vázquez
- Department of Occupational Therapy, Faculty of Health Science, University of Burgos, C/Paseo de los Comendadores, Hospital Militar, 1, 09001 Burgos, Spain;
| | | | - Silvia Ubillos-Landa
- Department of Social Psychology, Faculty of Health Science, University of Burgos, C/Villadiego, 1, 09001 Burgos, Spain
- Correspondence: ; Tel.: +34-947-258-074
| | - Alicia Puente-Martínez
- Department of Social Psychology, Faculty of Health Science, University of Burgos, C/Paseo de los Comendadores, Hospital Militar, 1, 09001 Burgos, Spain;
| | - Silvia Casado-Yusta
- Department of Applied Economy, Faculty of Economics and Business Sciences, University of Burgos, Pza. De la Infanta Dª Elena, 09001 Burgos, Spain;
| | - Beatriz Olaya
- Research, Innovation and Teaching Unit, Parc Sanitari Sant Joan de Déu, Universitat de Barcelona, Carrer Doctor Pujadas 42, 08830 Sant Boi de Llobregat, Spain;
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Ministry of Science and Innovation, Av. Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029 Madrid, Spain;
| | - Javier Santabárbara
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Ministry of Science and Innovation, Av. Monforte de Lemos 3-5, Pabellón 11, Planta 0, 28029 Madrid, Spain;
- Department of Microbiology, Pediatrics, Radiology and Public Health, University of Zaragoza, C/Domingo Miral s/n, 50009 Zaragoza, Spain
- Aragonese Institute of Health Sciences (IIS Aragón), 50009 Zaragoza, Spain
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Keator LM, Yourganov G, Faria AV, Hillis AE, Tippett DC. Application of the dual stream model to neurodegenerative disease: Evidence from a multivariate classification tool in primary progressive aphasia. APHASIOLOGY 2021; 36:618-647. [PMID: 35493273 PMCID: PMC9053317 DOI: 10.1080/02687038.2021.1897079] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 02/19/2021] [Indexed: 05/20/2023]
Abstract
Background A clinical diagnosis of primary progressive aphasia relies on behavioral characteristics and patterns of atrophy to determine a variant: logopenic; nonfluent/agrammatic; or semantic. The dual stream model (Hickok & Poeppel, 2000; 2004; 2007; 2015) is a contemporary paradigm that has been applied widely to understand brain-behavior relationships; however, applications to neurodegenerative diseases like primary progressive aphasia are limited. Aims The primary aim of this study is to determine if the dual stream model can be applied to a neurodegenerative disease, such as primary progressive aphasia, using both behavioral and neuroimaging data. Methods & Procedures We analyzed behavioral and neuroimaging data to apply a multivariate classification tool (support vector machines) to determine if the dual stream model extends to primary progressive aphasia. Sixty-four individuals with primary progressive aphasia were enrolled (26 logopenic variant, 20 nonfluent/agrammatic variant, and 18 semantic variant) and administered four behavioral tasks to assess three linguistic domains (naming, repetition, and semantic knowledge). We used regions of interest from the dual stream model and calculated the cortical volume for gray matter regions and white matter structural volumes and fractional anisotropy. We applied a multivariate classification tool (support vector machines) to distinguish variants based on behavioral performance and patterns of atrophy. Outcomes & Results Behavioral performance discriminates logopenic from semantic variant and nonfluent/agrammatic from semantic variant. Cortical volume distinguishes all three variants. White matter structural volumes and fractional anisotropy primarily distinguish nonfluent/agrammatic from semantic variant. Regions of interest that contribute to each classification in cortical and white matter analyses demonstrate alignment of logopenic and nonfluent/agrammatic variants to the dorsal stream, while the semantic variant aligns with the ventral stream. Conclusions A novel implementation of an automated multivariate classification suggests that the dual stream model can be extended to primary progressive aphasia. Variants are distinguished by behavioral and neuroanatomical patterns and align to the dorsal and ventral streams of the dual stream model.
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Affiliation(s)
- Lynsey M. Keator
- Department of Neurology, Johns Hopkins University School of Medicine, Phipps 446, 600 N. Wolfe Street, Baltimore, MD 21287
| | - Grigori Yourganov
- Department of Psychology, McCausland Center for Brain Imaging, 6 Medical Park Road, University of South Carolina, Columbia, South Carolina 29201
| | - Andreia V. Faria
- The Russell H. Morgan Department of Radiology and Radiological Science, 1800 Orleans Street, Johns Hopkins University, Baltimore, MD 21287
| | - Argye E. Hillis
- Department of Neurology, Johns Hopkins University School of Medicine, Phipps 446, 600 N. Wolfe Street, Baltimore, MD 21287
- Department of Physical Medicine and Rehabilitation, 600 N. Wolfe Street, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Department of Cognitive Science, Krieger School of Arts and Sciences, 3400 N. Charles Street, Johns Hopkins University, Baltimore, MD 21218
| | - Donna C. Tippett
- Department of Neurology, Johns Hopkins University School of Medicine, Phipps 446, 600 N. Wolfe Street, Baltimore, MD 21287
- Department of Physical Medicine and Rehabilitation, 600 N. Wolfe Street, Johns Hopkins University School of Medicine, Baltimore, MD 21287
- Department of Otolaryngology—Head and Neck Surgery, 601 N. Caroline Street, 6 floor, Johns Hopkins University School of Medicine, Baltimore, MD 21287
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33
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Ingram RU, Halai AD, Pobric G, Sajjadi S, Patterson K, Lambon Ralph MA. Graded, multidimensional intra- and intergroup variations in primary progressive aphasia and post-stroke aphasia. Brain 2021; 143:3121-3135. [PMID: 32940648 PMCID: PMC7586084 DOI: 10.1093/brain/awaa245] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 05/30/2020] [Accepted: 06/17/2020] [Indexed: 12/14/2022] Open
Abstract
Language impairments caused by stroke (post-stroke aphasia, PSA) and neurodegeneration (primary progressive aphasia, PPA) have overlapping symptomatology, nomenclature and are classically divided into categorical subtypes. Surprisingly, PPA and PSA have rarely been directly compared in detail. Rather, previous studies have compared certain subtypes (e.g. semantic variants) or have focused on a specific cognitive/linguistic task (e.g. reading). This study assessed a large range of linguistic and cognitive tasks across the full spectra of PSA and PPA. We applied varimax-rotated principal component analysis to explore the underlying structure of the variance in the assessment scores. Similar phonological, semantic and fluency-related components were found for PSA and PPA. A combined principal component analysis across the two aetiologies revealed graded intra- and intergroup variations on all four extracted components. Classification analysis was used to test, formally, whether there were any categorical boundaries for any subtypes of PPA or PSA. Semantic dementia formed a true diagnostic category (i.e. within group homogeneity and distinct between-group differences), whereas there was considerable overlap and graded variations within and between other subtypes of PPA and PSA. These results suggest that (i) a multidimensional rather than categorical classification system may be a better conceptualization of aphasia from both causes; and (ii) despite the very different types of pathology, these broad classes of aphasia have considerable features in common.
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Affiliation(s)
- Ruth U Ingram
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, UK
| | - Ajay D Halai
- MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK
| | - Gorana Pobric
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, UK
| | - Seyed Sajjadi
- Department of Neurology, University of California, Irvine, Irvine, USA
| | - Karalyn Patterson
- MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.,Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
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Sanches C, Stengel C, Godard J, Mertz J, Teichmann M, Migliaccio R, Valero-Cabré A. Past, Present, and Future of Non-invasive Brain Stimulation Approaches to Treat Cognitive Impairment in Neurodegenerative Diseases: Time for a Comprehensive Critical Review. Front Aging Neurosci 2021; 12:578339. [PMID: 33551785 PMCID: PMC7854576 DOI: 10.3389/fnagi.2020.578339] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022] Open
Abstract
Low birth rates and increasing life expectancy experienced by developed societies have placed an unprecedented pressure on governments and the health system to deal effectively with the human, social and financial burden associated to aging-related diseases. At present, ∼24 million people worldwide suffer from cognitive neurodegenerative diseases, a prevalence that doubles every five years. Pharmacological therapies and cognitive training/rehabilitation have generated temporary hope and, occasionally, proof of mild relief. Nonetheless, these approaches are yet to demonstrate a meaningful therapeutic impact and changes in prognosis. We here review evidence gathered for nearly a decade on non-invasive brain stimulation (NIBS), a less known therapeutic strategy aiming to limit cognitive decline associated with neurodegenerative conditions. Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation, two of the most popular NIBS technologies, use electrical fields generated non-invasively in the brain to long-lastingly enhance the excitability/activity of key brain regions contributing to relevant cognitive processes. The current comprehensive critical review presents proof-of-concept evidence and meaningful cognitive outcomes of NIBS in eight of the most prevalent neurodegenerative pathologies affecting cognition: Alzheimer's Disease, Parkinson's Disease, Dementia with Lewy Bodies, Primary Progressive Aphasias (PPA), behavioral variant of Frontotemporal Dementia, Corticobasal Syndrome, Progressive Supranuclear Palsy, and Posterior Cortical Atrophy. We analyzed a total of 70 internationally published studies: 33 focusing on Alzheimer's disease, 19 on PPA and 18 on the remaining neurodegenerative pathologies. The therapeutic benefit and clinical significance of NIBS remains inconclusive, in particular given the lack of a sufficient number of double-blind placebo-controlled randomized clinical trials using multiday stimulation regimes, the heterogeneity of the protocols, and adequate behavioral and neuroimaging response biomarkers, able to show lasting effects and an impact on prognosis. The field remains promising but, to make further progress, research efforts need to take in account the latest evidence of the anatomical and neurophysiological features underlying cognitive deficits in these patient populations. Moreover, as the development of in vivo biomarkers are ongoing, allowing for an early diagnosis of these neuro-cognitive conditions, one could consider a scenario in which NIBS treatment will be personalized and made part of a cognitive rehabilitation program, or useful as a potential adjunct to drug therapies since the earliest stages of suh diseases. Research should also integrate novel knowledge on the mechanisms and constraints guiding the impact of electrical and magnetic fields on cerebral tissues and brain activity, and incorporate the principles of information-based neurostimulation.
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Affiliation(s)
- Clara Sanches
- Cerebral Dynamics, Plasticity and Rehabilitation Group, FRONTLAB Team, CNRS UMR 7225, INSERM U 1127, Institut du Cerveau, Sorbonne Universités, Paris, France
| | - Chloé Stengel
- Cerebral Dynamics, Plasticity and Rehabilitation Group, FRONTLAB Team, CNRS UMR 7225, INSERM U 1127, Institut du Cerveau, Sorbonne Universités, Paris, France
| | - Juliette Godard
- Cerebral Dynamics, Plasticity and Rehabilitation Group, FRONTLAB Team, CNRS UMR 7225, INSERM U 1127, Institut du Cerveau, Sorbonne Universités, Paris, France
| | - Justine Mertz
- Cerebral Dynamics, Plasticity and Rehabilitation Group, FRONTLAB Team, CNRS UMR 7225, INSERM U 1127, Institut du Cerveau, Sorbonne Universités, Paris, France
| | - Marc Teichmann
- Cerebral Dynamics, Plasticity and Rehabilitation Group, FRONTLAB Team, CNRS UMR 7225, INSERM U 1127, Institut du Cerveau, Sorbonne Universités, Paris, France
- National Reference Center for Rare or Early Onset Dementias, Department of Neurology, Institute of Memory and Alzheimer’s Disease, Pitié-Salpêtrière Hospital, Assistance Publique -Hôpitaux de Paris, Paris, France
| | - Raffaella Migliaccio
- Cerebral Dynamics, Plasticity and Rehabilitation Group, FRONTLAB Team, CNRS UMR 7225, INSERM U 1127, Institut du Cerveau, Sorbonne Universités, Paris, France
- National Reference Center for Rare or Early Onset Dementias, Department of Neurology, Institute of Memory and Alzheimer’s Disease, Pitié-Salpêtrière Hospital, Assistance Publique -Hôpitaux de Paris, Paris, France
| | - Antoni Valero-Cabré
- Cerebral Dynamics, Plasticity and Rehabilitation Group, FRONTLAB Team, CNRS UMR 7225, INSERM U 1127, Institut du Cerveau, Sorbonne Universités, Paris, France
- Laboratory for Cerebral Dynamics Plasticity & Rehabilitation, Boston University School of Medicine, Boston, MA, United States
- Cognitive Neuroscience and Information Technology Research Program, Open University of Catalonia, Barcelona, Spain
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35
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Catricalà E, Polito C, Presotto L, Esposito V, Sala A, Conca F, Gasparri C, Berti V, Filippi M, Pupi A, Sorbi S, Iannaccone S, Magnani G, Cappa SF, Perani D. Neural correlates of naming errors across different neurodegenerative diseases: An FDG-PET study. Neurology 2020; 95:e2816-e2830. [PMID: 33004608 DOI: 10.1212/wnl.0000000000010967] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 07/23/2020] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE To investigate the types of errors produced in a picture naming task by patients with neurodegenerative dementia due to different etiologies and their neural correlates. METHODS The same standardized picture naming test was administered to a consecutive sample of patients (n = 148) who had been studied with [18F] FDG-PET. The errors were analyzed in 3 categories (visual, semantic, and phonologic). The PET data were analyzed using an optimized single-subject procedure, and the statistical parametric mapping multiple regression design was used to explore the correlation between each type of error and brain hypometabolism in the whole group. Metabolic connectivity analyses were run at the group level on 7 left hemisphere cortical areas corresponding to an a priori defined naming network. RESULTS Semantic errors were predominant in most patients, independent of clinical diagnosis. In the whole group analysis, visual errors correlated with hypometabolism in the right inferior occipital lobe and in the left middle occipital lobe. Semantic errors correlated with hypometabolism in the left fusiform gyrus, the inferior and middle temporal gyri, and the temporal pole. Phonologic errors were associated with hypometabolism in the left superior and middle temporal gyri. Both positive (occipital-posterior fusiform) and negative (anterior fusiform gyrus and the superior anterior temporal lobe) connectivity changes were associated with semantic errors. CONCLUSIONS Naming errors reflect the dysfunction of separate stages of the naming process and are specific markers for different patterns of brain involvement. These correlations are not limited to primary progressive aphasia but extend to other neurodegenerative dementias.
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Affiliation(s)
- Eleonora Catricalà
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Cristina Polito
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Luca Presotto
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Valentina Esposito
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Arianna Sala
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Francesca Conca
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Celeste Gasparri
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Valentina Berti
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Massimo Filippi
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Alberto Pupi
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Sandro Sorbi
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Sandro Iannaccone
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Giuseppe Magnani
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
| | - Stefano F Cappa
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy.
| | - Daniela Perani
- From the Faculty of Psychology (E.C., F.C., C.G., S.F.C.), Institute for Advanced Studies, IUSS, Pavia; Nuclear Medicine Unit (C.P., V.B., A.P.), Department of Experimental and Clinical Biomedical Sciences, and NEUROFARBA, Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence; Nuclear Medicine Unit (L.P., A.S., D.P.), IRCCS San Raffaele Hospital, Milan; Faculty of Psychology (V.E., A.S., D.P.), Vita-Salute San Raffaele University, Milan; Department of Neurology and INSPE (M.F., G.M.), San Raffaele Scientific Institute, Milan; Clinical Neuroscience Department (S.I.), San Raffaele Turro Hospital, Milan; IRCCS Fondazione Don Carlo Gnocchi (S.S.), Florence, and IRCCS Fondazione Istituto Neurologico Casimiro Mondino (S.F.C.), Pavia, Italy
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Fumagalli GG, Basilico P, Arighi A, Mercurio M, Scarioni M, Carandini T, Colombi A, Pietroboni AM, Sacchi L, Conte G, Scola E, Triulzi F, Scarpini E, Galimberti D. Parieto-occipital sulcus widening differentiates posterior cortical atrophy from typical Alzheimer disease. Neuroimage Clin 2020; 28:102453. [PMID: 33045537 PMCID: PMC7559336 DOI: 10.1016/j.nicl.2020.102453] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/17/2020] [Accepted: 09/24/2020] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Posterior Cortical Atrophy (PCA) is an atypical presentation of Alzheimer disease (AD) characterized by atrophy of posterior brain regions. This pattern of atrophy is usually evaluated with Koedam visual rating scale, a score developed to enable visual assessment of parietal atrophy on magnetic resonance imaging (MRI). However, Koedam scale is complex to assess and its utility in the differential diagnosis between PCA and typical AD has not been demonstrated yet. The aim of this study is therefore to spot a simple and reliable MRI element able to differentiate between PCA and typical AD using visual rating scales. METHODS 15 patients who presented with progressive complex visual disorders and predominant occipitoparietal hypometabolism on PET-FDG were selected from our centre and compared with 30 typical AD patients and 15 healthy subjects. We used previously validated visual rating scales including Koedam scale, which we divided into three major components: posterior cingulate, precuneus and parieto-occipital. Subsequently we validated the results using the automated software Brainvisa Morphologist and Voxel Based Morphometry (VBM). RESULTS Patients with PCA, compared to typical AD, showed higher widening of the parieto-occipital sulcus, assessed both with visual rating scales and Brainvisa. In the corresponding areas, the VBM analysis showed an inverse correlation between the results obtained from the visual evaluation scales with the volume of the grey matter and a direct correlation between the same results with the cerebrospinal fluid volume. CONCLUSIONS A visually based rating scale for parieto-occipital sulcus can distinguish Posterior Cortical Atrophy from typical Alzheimer disease.
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Affiliation(s)
- Giorgio G Fumagalli
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50121 Firenze, Italy.
| | | | - Andrea Arighi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy
| | - Matteo Mercurio
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy
| | - Marta Scarioni
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy; Department of Neurology, Amsterdam University Medical Centers, Location VUmc, Alzheimer Center, Amsterdam, the Netherlands
| | - Tiziana Carandini
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy
| | - Annalisa Colombi
- Department of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, Milan, Italy
| | - Anna M Pietroboni
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy
| | - Luca Sacchi
- Department of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, Milan, Italy
| | - Giorgio Conte
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy
| | - Elisa Scola
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy
| | - Fabio Triulzi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy; Department of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, Milan, Italy
| | - Elio Scarpini
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, Dino Ferrari Center, CRC Molecular Basis of Neuro-Psycho-Geriatrics Diseases, University of Milan, Milan, Italy
| | - Daniela Galimberti
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via F. Sforza, 35, 20122 Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, Dino Ferrari Center, CRC Molecular Basis of Neuro-Psycho-Geriatrics Diseases, University of Milan, Milan, Italy
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de Best PB, Abulafia R, McKyton A, Levin N. Convergence Along the Visual Hierarchy Is Altered in Posterior Cortical Atrophy. Invest Ophthalmol Vis Sci 2020; 61:8. [PMID: 32897377 PMCID: PMC7488212 DOI: 10.1167/iovs.61.11.8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 08/17/2020] [Indexed: 12/14/2022] Open
Abstract
Purpose Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome manifesting with visuospatial processing impairment. We recently suggested that abnormal population receptive field properties are associated with the symptoms of PCA patients. Specifically, simultanagnosia, the inability to perceive multiple items simultaneously, can be explained by smaller peripheral population receptive fields, and foveal crowding, in which nearby distractors interfere with object perception, may result from larger foveal population receptive fields. These effects occurred predominantly in V1, even though atrophy mainly involves high-order areas. In this study, we used connective field modeling to better understand these inter-area interactions. Methods We used functional magnetic resonance imaging to scan six PCA patients and eight controls while they viewed drifting bar stimuli. Resting-state data were also collected. Connective field modeling was applied for both conditions: once when the source was V1 and the targets were extrastriate areas and once for the opposite direction. The difference between the two was defined as convergence magnitude. Results With stimulus, the convergence magnitude of the controls increased along the visual pathway, suggesting that spatial integration from V1 becomes larger up the visual hierarchy. No such slope was found in the PCA patients. The difference between the groups originated mainly from the dorsal pathway. Without stimulus, the convergence magnitude was negative, slightly more so for the PCA patients, with no slope, suggesting constant divergence along the visual hierarchy. Conclusions Atrophy in one part of the visual system can affect other areas within the network through complex intervisual area interactions, resulting in modulation of population receptive field properties and an ensemble of visuocognitive function impairments.
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Affiliation(s)
- Pieter B. de Best
- fMRI Unit, Neurology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ruth Abulafia
- fMRI Unit, Neurology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ayelet McKyton
- fMRI Unit, Neurology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Netta Levin
- fMRI Unit, Neurology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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Cortical diffusivity investigation in posterior cortical atrophy and typical Alzheimer's disease. J Neurol 2020; 268:227-239. [PMID: 32770413 PMCID: PMC7815619 DOI: 10.1007/s00415-020-10109-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 06/26/2020] [Accepted: 07/22/2020] [Indexed: 11/24/2022]
Abstract
Objectives To investigate the global cortical and regional quantitative features of cortical neural architecture in the brains of patients with posterior cortical atrophy (PCA) and typical Alzheimer’s disease (tAD) compared with elderly healthy controls (HC). Methods A novel diffusion MRI method, that has been shown to correlate with minicolumnar organization changes in the cerebral cortex, was used as a surrogate of neuropathological changes in dementia. A cohort of 15 PCA patients, 23 tAD and 22 healthy elderly controls (HC) were enrolled to investigate the changes in cortical diffusivity among groups. For each subject, 3 T MRI T1-weighted images and diffusion tensor imaging (DTI) scans were analysed to extract novel cortical DTI derived measures (AngleR, PerpPD and ParlPD). Receiver operating characteristics (ROC) curve analysis and the area under the curve (AUC) were used to assess the group discrimination capability of the method. Results The results showed that the global cortical DTI derived measures were able to detect differences, in both PCA and tAD patients compared to healthy controls. The AngleR was the best measure to discriminate HC from tAD (AUC = 0.922), while PerpPD was the best measure to discriminate HC from PCA (AUC = 0.961). Finally, the best global measure to differentiate the two patient groups was ParlPD (AUC = 0.771). The comparison between PCA and tAD patients revealed a different pattern of damage within the AD spectrum and the regional comparisons identified significant differences in key regions including parietal and temporal lobe cortical areas. The best AUCs were shown by PerpPD right lingual cortex (AUC = 0.856), PerpPD right superior parietal cortex (AUC = 0.842) and ParlPD right lateral occipital cortex (AUC = 0.826). Conclusions Diagnostic group differences were found, suggesting that the new cortical DTI analysis method may be useful to investigate cortical changes in dementia, providing better characterization of neurodegeneration, and potentially aiding differential diagnosis and prognostic accuracy. Electronic supplementary material The online version of this article (10.1007/s00415-020-10109-w) contains supplementary material, which is available to authorized users.
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Kas A, Migliaccio R, Tavitian B. A future for PET imaging in Alzheimer's disease. Eur J Nucl Med Mol Imaging 2020; 47:231-234. [PMID: 31858177 DOI: 10.1007/s00259-019-04640-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Aurélie Kas
- Nuclear Medicine Department Pitié-Salpêtrière Hospital, APHP Sorbonne-Université, Paris, France.,Laboratoire d'Imagerie Biomédicale, Sorbonne Université, Paris, France
| | - Raffaella Migliaccio
- Neurology Departement, Pitié-Salpêtrière Hospital, Institut de la mémoire et de la maladie d'Alzheimer, IM2A, Reference Centre for Rare Dementias and Early Onset Alzheimer's Disease, Paris, France.,Institut du cerveau et de la moelle épinière, Frontlab ICM, INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, Pitié-Salpêtrière Hospital, Paris, France
| | - Bertrand Tavitian
- Université de Paris, PARCC, INSERM, In vivo Imaging Research, 75015, Paris, France. .,Radiology Department, APHP Centre, Hôpital Européen Georges Pompidou, 75015, Paris, France.
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Olds JJ, Hills WL, Warner J, Falardeau J, Alasantro LH, Moster ML, Egan RA, Cornblath WT, Lee AG, Frishberg BM, Turbin RE, Katz DM, Charley JA, Pelak VS. Posterior Cortical Atrophy: Characteristics From a Clinical Data Registry. Front Neurol 2020; 11:358. [PMID: 32581988 PMCID: PMC7297208 DOI: 10.3389/fneur.2020.00358] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 04/14/2020] [Indexed: 12/02/2022] Open
Abstract
Background: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that presents with higher-order visual dysfunction with relative sparing of memory and other cognitive domains, and it is most commonly associated with Alzheimer's disease pathology. There is a lack of data regarding the presentation of PCA to non-cognitive specialists. Therefore, we collected clinical data from neuro-ophthalmologists regarding the presentation of PCA to their practices and compared data to published cohorts and a published survey of cognitive specialists. Methods: Members of the North American Neuro-Ophthalmology Society Listserv (NANOSnet) were invited to complete an online, retrospective, chart-review data-entry survey regarding their patients with PCA, and REDCap was used for data collection. Results: Data for 38 patients were entered by 12 neuro-ophthalmologists. Patient mean age at presentation was 67.8 years, and 74% of patients were women. Difficulty reading was reported at presentation by 91% of patients, and poor performance on color vision, stereopsis, and visual field testing (performed reliably by 36/38 patients) were common findings. Most patients who were treated were treated with donepezil and/or memantine. Conclusions: Compared to published data from cognitive specialists, patients presenting to neuro-ophthalmology with PCA were more likely to be older and female and have a reading complaint. Reliable visual field testing was the norm with homonymous defects in the majority of patients. The neuro-ophthalmologist plays an important role in diagnosing PCA in older adults with unexplained visual signs and symptoms, and future studies of PCA should involve multiple specialists in order to advance our understanding of PCA and develop effective treatments.
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Affiliation(s)
- Jennifer J Olds
- Department of Ophthalmology, Keesler Air Force Base, Biloxi, MS, United States
| | - William L Hills
- Department of Neurology & Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, United States
| | - Judith Warner
- Department of Ophthalmology & Neurology, John A. Moran Eye Center, University of Utah, Salt Lake City, UT, United States
| | - Julie Falardeau
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, United States
| | - Lori Haase Alasantro
- Department of Neuroscience, The Neurology Center of Southern California, University of California San Diego School of Medicine, Carlsbad, CA, United States
| | - Mark L Moster
- Department of Neurology and Ophthalmology, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, PA, United States
| | - Robert A Egan
- Eye & Vascular Neurology, LLC, Carlton, OR, United States
| | - Wayne T Cornblath
- Department of Ophthalmology, Visual Sciences & Neurology, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, United States
| | - Andrew G Lee
- Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, TX, United States
| | - Benjamin M Frishberg
- Department of Neuroscience, The Neurology Center of Southern California, University of California San Diego School of Medicine, Carlsbad, CA, United States
| | - Roger E Turbin
- Division of Neuro-ophthalmology and Orbital Surgery, Rutgers New Jersey Medical School, Institute of Ophthalmology and Visual Sciences, Newark, NJ, United States
| | - David M Katz
- Bethesda Neurology, LLC, Department of Ophthalmology & Neurology, Howard University Hospital, Georgetown University Hospital, Washington, DC, United States
| | - John A Charley
- Retired Private Practice Ophthalmologist, Pittsburgh, PA, United States
| | - Victoria S Pelak
- Department of Neurology & Ophthalmology, UCHealth Sue Anschutz-Rodgers Eye Center and the Neurosciences Center, University of Colorado School of Medicine, Aurora, CO, United States
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Word retrieval across the biomarker-confirmed Alzheimer's disease syndromic spectrum. Neuropsychologia 2020; 140:107391. [PMID: 32057937 DOI: 10.1016/j.neuropsychologia.2020.107391] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 01/30/2020] [Accepted: 02/09/2020] [Indexed: 11/20/2022]
Abstract
Alzheimer's disease (AD) is now conceptualized as a biological entity defined by amyloid and tau deposition and neurodegeneration, with heterogeneous clinical presentations. With the aid of in vivo biomarkers, clinicians are better poised to examine clinical syndromic variability arising from a common pathology. Word retrieval deficits, measured using verbal fluency and confrontation naming tests, are hallmark features of the early clinical stages of the amnestic presentations of AD, specifically in category fluency and naming with relatively spared letter fluency. As yet, there is no consensus regarding performance on these tests in atypical clinical phenotypes of AD, including posterior cortical atrophy (PCA) and logopenic primary progressive aphasia (lvPPA), in individuals who are amyloid-positive (Aβ+) but present with different clinical profiles and patterns of neurodegeneration compared to amnestic AD. The goal of the current study is to determine how Aβ+ individuals across the syndromic spectrum of AD perform on three different word retrieval tasks. A secondary goal is to determine the neuroanatomical substrates underlying word retrieval performance in these Aβ+ individuals. Thirty-two Aβ+ participants with the amnestic presentation, 16 with Aβ+ PCA, 22 with Aβ+ lvPPA, and 99 amyloid-negative (Aβ-) control participants were evaluated with verbal fluency and visual confrontation naming tests as well as high-resolution MRI. The Aβ+ patient groups were rated at very mild or mild levels of severity (CDR 0.5 or 1) and had comparable levels of global cognitive impairment (average MMSE = 23.7 ± 3.9). Behaviorally, we found that the word retrieval profile of PCA patients is comparable to that of amnestic patients, characterized by intact letter fluency but impaired category fluency and visual confrontation naming, while lvPPA patients demonstrated impairment across all tests of word retrieval. Across all AD variants, we observed that letter fluency was associated with cortical thickness in prefrontal, central precuneus, lateral parietal and temporal cortex, while category fluency and naming were associated with cortical thickness in left middle frontal gyrus, posterior middle temporal gyrus, and lateral parietal cortex. Visual confrontation naming was uniquely associated with atrophy in inferior temporal and visual association cortex. We conclude that a better understanding of the word retrieval profiles and underlying neurodegeneration across the AD syndromic spectrum will help improve interpretation of neuropsychological profiles with regard to the localization of neurodegeneration, particularly in the atypical AD variants.
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Abstract
PURPOSE OF REVIEW Early-onset Alzheimer disease (AD) is defined as having an age of onset younger than 65 years. While early-onset AD is often overshadowed by the more common late-onset AD, recognition of the differences between early- and late-onset AD is important for clinicians. RECENT FINDINGS Early-onset AD comprises about 5% to 6% of cases of AD and includes a substantial percentage of phenotypic variants that differ from the usual amnestic presentation of typical AD. Characteristics of early-onset AD in comparison to late-onset AD include a larger genetic predisposition (familial mutations and summed polygenic risk), more aggressive course, more frequent delay in diagnosis, higher prevalence of traumatic brain injury, less memory impairment and greater involvement of other cognitive domains on presentation, and greater psychosocial difficulties. Neuroimaging features of early-onset AD in comparison to late-onset AD include greater frequency of hippocampal sparing and posterior neocortical atrophy, increased tau burden, and greater connectomic changes affecting frontoparietal networks rather than the default mode network. SUMMARY Early-onset AD differs substantially from late-onset AD, with different phenotypic presentations, greater genetic predisposition, and differences in neuropathologic burden and topography. Early-onset AD more often presents with nonamnestic phenotypic variants that spare the hippocampi and with greater tau burden in posterior neocortices. The early-onset AD phenotypic variants involve different neural networks than typical AD. The management of early-onset AD is similar to that of late-onset AD but with special emphasis on targeting specific cognitive areas and more age-appropriate psychosocial support and education.
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Abstract
PURPOSE OF REVIEW This article presents an overview of the clinical syndrome of posterior cortical atrophy (PCA), including its pathologic underpinnings, clinical presentation, investigation findings, diagnostic criteria, and management. RECENT FINDINGS PCA is usually an atypical form of Alzheimer disease with relatively young age at onset. New diagnostic criteria allow patients to be diagnosed on a syndromic basis as having a primary visual (pure) form or more complex (plus) form of PCA and, when possible, on a disease-specific basis using biomarkers or underlying pathology. Imaging techniques have demonstrated that some pathologic processes are concordant (atrophy, hypometabolism, tau deposition) with clinical symptoms and some are discordant (widespread amyloid deposition). International efforts are under way to establish the genetic underpinnings of this typically sporadic form of Alzheimer disease. In the absence of specific disease-modifying therapies, a number of practical suggestions can be offered to patients and their families to facilitate reading and activities of daily living, promote independence, and improve quality of life SUMMARY: While rare, PCA is an important diagnostic entity for neurologists, ophthalmologists, and optometrists to recognize to allow for early accurate diagnosis and appropriate patient management. PCA provides an important opportunity to investigate the causes of selective vulnerability in Alzheimer disease.
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Gabere M, Pham NTT, Graff-Radford J, Machulda MM, Duffy JR, Josephs KA, Whitwell JL, Alzheimer’s Disease Neuroimaging Initiative. Automated Hippocampal Subfield Volumetric Analyses in Atypical Alzheimer's Disease. J Alzheimers Dis 2020; 78:927-937. [PMID: 33074228 PMCID: PMC7732352 DOI: 10.3233/jad-200625] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are two of the most common variants of atypical Alzheimer's disease (AD). Both PCA and LPA are associated with relative sparing of hippocampus compared to neocortex, although hippocampal atrophy is observed. It is unclear whether regional patterns of hippocampal subfield involvement differ between PCA and LPA, and whether they differ from typical AD. OBJECTIVE To assess volume of specific subfields of the hippocampus in PCA, LPA, and typical AD. METHODS Fifty-nine patients with PCA and 77 patients with LPA were recruited and underwent T1-weighted MRI and Pittsburgh Compound B (PiB) PET at Mayo Clinic. Thirty-six probable AD patients and 100 controls were identified from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal subfield volumes were calculated using Freesurfer, and volumes were compared between PCA, LPA, AD, and controls using Kruskal-Wallis and Dunn tests. RESULTS The LPA and PCA groups both showed the most striking abnormalities in CA4, presubiculum, molecular layer of the hippocampus, molecular and granule cell layers of the dentate gyrus, and the hippocampal-amygdala transition area, although atrophy was left-sided in LPA. PCA showed smaller volume of right presubiculum compared to LPA, with trends for smaller volumes of right parasubiculum and fimbria. LPA showed a trend for smaller volumes of left CA1 compared to PCA. The AD group showed smaller volumes of the right subiculum, CA1, and presubiculum compared to LPA. CONCLUSION Patterns of hippocampal subfield atrophy differ across the different syndromic variants of AD.
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Affiliation(s)
- Musa Gabere
- Department of Neurology, Mayo Clinic Rochester MN USA
| | | | | | - Mary M. Machulda
- Department of Psychiatry and Psychology, Mayo Clinic Rochester MN USA
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Ziegler GC, Haarmann A, Daniels C, Herr A. The Difficult Diagnosis of Posterior Cortical Atrophy in a 62-Year-Old Woman. J Geriatr Psychiatry Neurol 2020; 33:59-64. [PMID: 31203704 PMCID: PMC6900588 DOI: 10.1177/0891988719856696] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Posterior cortical atrophy (PCA) describes a rare heterogenous neurodegenerative syndrome with early visuospatial and visuoperceptual deficits due to atrophy of parieto-occipital brain regions. Here, we describe the case of a 62-year-old woman showing severe cognitive impairments as well as hemianopsia and all core symptoms of Bálint's syndrome. Years ago, the patient had complained about a "tunnel view" and concentration problems. The diagnostic results point to a case of PCA with underlying Alzheimer pathology. The disease course until diagnosis lasted for 7 years, reflecting the diagnostic difficulties with this still largely unknown syndrome. The unfamiliar symptom presentation including fluctuations in cognitive performance, affective symptoms, cerebrospinal fluid (CSF) biomarkers, which were at first inconspicuous, and a former suspected diagnosis of dissociative pseudodementia, altogether brought considerable uncertainty to the involved health-care professionals. We conclude that cases of "atypical dementia" presenting with visual symptoms, even if appearing unspecific at first, are suspect of PCA. This case report provides an ostensive overview of PCA, including imaging data, CSF-findings, original drawings and handwriting samples from the patient.
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Affiliation(s)
- Georg C. Ziegler
- Neurogerontopsychiatric Day Care Unit, Department of Psychiatry,
Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg,
Würzburg, Germany,Georg C. Ziegler, Department of Psychiatry,
Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of
Würzburg, Margarete-Höppel-Platz 1, 97080 Würzburg, Germany.
| | - Axel Haarmann
- Department of Neurology, University Hospital of Würzburg, Würzburg,
Germany
| | - Christine Daniels
- Department of Neurology, University Hospital of Würzburg, Würzburg,
Germany
| | - Alexandra Herr
- Neurogerontopsychiatric Day Care Unit, Department of Psychiatry,
Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg,
Würzburg, Germany
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Migliaccio R, Agosta F, Basaia S, Cividini C, Habert MO, Kas A, Montembeault M, Filippi M. Functional brain connectome in posterior cortical atrophy. Neuroimage Clin 2019; 25:102100. [PMID: 31865020 PMCID: PMC6931188 DOI: 10.1016/j.nicl.2019.102100] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 10/17/2019] [Accepted: 11/18/2019] [Indexed: 01/29/2023]
Abstract
This study investigated the functional brain connectome architecture in patients with Posterior Cortical Atrophy (PCA). Eighteen PCA patients and 29 age- and sex- matched healthy controls were consecutively recruited in a specialized referral center. Participants underwent neurologic examination, cerebrospinal fluid (CSF) examination for Alzheimer's disease (AD) biomarkers, cognitive assessment, and brain MRI. For a smaller subset of participants, FDG-PET examination was available. We assessed topological brain network properties and regional functional connectivity as well as intra- and inter-hemispheric connectivity, using graph analysis and connectomics. Supplementary analyses were performed to explore the association between the CSF AD profile and the connectome status, and taking into account hypometabolic, atrophic, and spared regions (nodes). PCA patients showed diffuse functional connectome alterations at both global and regional level, as well as a connectivity breakdown between the posterior brain nodes. They had a widespread loss of both intra- and inter-hemispheric connections, exceeding the structural damage, and including the frontal connections. In PCA, connectome alterations were identified in all the brain nodes irrespectively of their structural and metabolic classification and were associated with a connectivity breakdown between damaged and spared areas. Taken together, these findings suggest the potentially high sensitivity of graph-analysis and connectomic in capturing the progression and maybe early signs of neurodegeneration in PCA patients.
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Affiliation(s)
- Raffaella Migliaccio
- FrontLab, INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, and Université Pierre et Marie Curie-Paris 6, UMR S1127, Institut du Cerveau et de la Moelle épinière (ICM), Pitié-Salpêtrière hospital, Paris, France; Institut de la mémoire et de la maladie d'Alzheimer, IM2A, Reference Centre for Rare dementias and Early Onset Alzheimer's disease, Neurology Departement, Pitié-Salpêtrière hospital, Paris, France.
| | - Federica Agosta
- Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Silvia Basaia
- Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Camilla Cividini
- Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Marie-Odile Habert
- Department of Nuclear Medicine, Pitié-Salpêtrière hospital, Paris, France; LIB, Inserm U1146, Université Pierre et Marie Curie, Paris 6, Paris, France
| | - Aurélie Kas
- Department of Nuclear Medicine, Pitié-Salpêtrière hospital, Paris, France; LIB, Inserm U1146, Université Pierre et Marie Curie, Paris 6, Paris, France
| | - Maxime Montembeault
- Memory & Aging Center, Deparment of Neurology, University of California in San Francisco, San Francisco, United-States
| | - Massimo Filippi
- Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
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Miller ZA, Rosenberg L, Santos-Santos MA, Stephens M, Allen IE, Hubbard HI, Cantwell A, Mandelli ML, Grinberg LT, Seeley WW, Miller BL, Rabinovici GD, Gorno-Tempini ML. Prevalence of Mathematical and Visuospatial Learning Disabilities in Patients With Posterior Cortical Atrophy. JAMA Neurol 2019; 75:728-737. [PMID: 29630699 DOI: 10.1001/jamaneurol.2018.0395] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Importance Increased prevalence of language-based learning disabilities (LDs) has been previously reported in patients with primary progressive aphasia (PPA). This study hypothesized that patients with focal neurodegenerative syndromes outside the language network, such as posterior cortical atrophy (PCA), would have a higher rate of nonlanguage LDs, congruent with their mainly visuospatial presentation. Objective To investigate the prevalence and type of LD (language and/or mathematical and visuospatial) in a large cohort of patients with PCA compared with patients with logopenic variant PPA (lvPPA) and amnestic Alzheimer disease (AD). Design, Setting, and Participants This case-control study reviewed 279 medical records from a university-based clinic and research center for patients with neurodegenerative diseases for LD history, including patients with PCA (n = 95), patients with lvPPA (n = 84), and a matched cohort with amnestic AD (n = 100). No records were excluded. The study compared cognitive and neuroimaging features of patients with PCA with and without LDs. A review of the records of patients presenting from March 1, 1999, to August 31, 2014, revealed 95 PCA cases and 84 lvPPA cases. Then 100 patients with amnestic AD from this same period were chosen for comparison, matching against the groups for age, sex, and disease severity. Data analysis was performed from September 8, 2013, to November 6, 2017. Main Outcomes and Measures Prevalence of total LD history and prevalence of language and mathematical or visuospatial LD history across all cohorts. Results A total of 179 atypical AD cases (95 with PCA and 84 with lvPPA) and 100 disease control cases (amnestic AD) were included in the study. The groups were not statistically different for mean (SD) age at first visit (PCA, 61.9 [7.0] years; lvPPA, 65.1 [8.7] years; amnestic AD, 64.0 [12.6] years; P = .08), mean (SD) age at first symptom (PCA, 57.5 [7.0] years; lvPPA, 61.1 [9.0] years; amnestic AD, 59.6 [13.7] years; P = .06), or sex (PCA, 66.3% female; lvPPA, 56.0% female; amnestic AD, 57.0% female; P = .30) but differed on non-right-hand preference (PCA, 18.3%; lvPPA, 20.2%; amnestic AD, 7.7%; P = .04), race/ethnicity (PCA, 88.3% white; lvPPA, 99.0% white; amnestic AD, 80.0% white; P < .001), and mean (SD) educational level (PCA, 15.7 [3.2] years; lvPPA, 16.2 [3.3] years; amnestic AD, 14.8 [3.5] years; P = .02). A total of 18 of the 95 patients with PCA (18.9%) reported a history of LD, which is greater than the 3 of 100 patients (3.0%) in the amnestic AD cohort (P < .001) and the 10.0% expected rate in the general population (P = .007). In the PCA cohort, 13 of 95 patients (13.7%) had a nonlanguage mathematical and/or visuospatial LD; this rate was greater than that in the amnestic AD (1 of 100 [1.0%]; P < .001) and lvPPA (2 of 84 [2.4%]; P = .006) cohorts and greater than the 6.0% expected general population rate of mathematical LD (P = .003). Compared with the patients with PCA without LDs, the group with LDs had greater preservation of global cognition and a more right-lateralized pattern of atrophy. Conclusions and Relevance Nonlanguage mathematical and visuospatial LDs were associated with focal, visuospatial predominant neurodegenerative clinical syndromes. This finding supports the hypothesis that neurodevelopmental differences in specific brain networks are associated with phenotypic manifestation of later-life neurodegenerative disease.
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Affiliation(s)
- Zachary A Miller
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco
| | - Lynne Rosenberg
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco
| | - Miguel A Santos-Santos
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco
| | - Melanie Stephens
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco
| | - Isabel E Allen
- Department of Biostatistics, University of California, San Francisco
| | - H Isabel Hubbard
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco
| | - Averill Cantwell
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco
| | - Maria Luisa Mandelli
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco
| | - Lea T Grinberg
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco.,Department of Pathology, University of California, San Francisco
| | - William W Seeley
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco.,Department of Pathology, University of California, San Francisco
| | - Bruce L Miller
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco
| | - Gil D Rabinovici
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco
| | - Maria Luisa Gorno-Tempini
- Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco
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48
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Bera G, Migliaccio R, Michelin T, Lamari F, Ferrieux S, Nogues M, Bertin H, Habert MO, Dubois B, Teichmann M, Kas A. Parietal Involvement in the Semantic Variant of Primary Progressive Aphasia with Alzheimer's Disease Cerebrospinal Fluid Profile. J Alzheimers Dis 2019; 66:271-280. [PMID: 30282352 DOI: 10.3233/jad-180087] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Semantic variant of primary progressive aphasia (svPPA) is typically associated with non-Alzheimer's disease (AD) pathology. However, some anatomopathological studies have found AD lesions in those patients. We compared brain perfusion SPECT of 18 svPPA patients with cerebrospinal fluid (CSF) biomarkers indicative of non-AD pathology (svPPA-nonAD) and three svPPA patients with CSF biomarkers indicative of underlying AD (svPPA-AD). All svPPA patients had severe left temporopolar hypoperfusion. SvPPA-nonAD had additional anterior cingulate and mediofrontal hypoperfusion, whereas svPPA-AD had greater left parietal and posterior cingulate involvement. Parietal damage in svPPA constitutes a biomarker for underlying Alzheimer pathology thus refining the classification of this PPA variant.
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Affiliation(s)
- Géraldine Bera
- Service de Médecine Nucléaire, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, AP-HP, Paris CEDEX 13, France.,INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, and Université Pierre et Marie Curie-Paris 6, UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), FrontLab, Paris CEDEX 13, France
| | - Raffaella Migliaccio
- INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, and Université Pierre et Marie Curie-Paris 6, UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), FrontLab, Paris CEDEX 13, France.,Département de Neurologie, Institut de la mémoire et de la maladie d'Alzheimer, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, AP-HP, Paris CEDEX 13, France
| | - Thibaut Michelin
- Service de Médecine Nucléaire, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, AP-HP, Paris CEDEX 13, France
| | - Foudil Lamari
- Laboratoire de Biochimie, AP-HP, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, Paris CEDEX 13, France
| | - Sophie Ferrieux
- Département de Neurologie, Institut de la mémoire et de la maladie d'Alzheimer, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, AP-HP, Paris CEDEX 13, France
| | - Marie Nogues
- Département de Neurologie, Institut de la mémoire et de la maladie d'Alzheimer, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, AP-HP, Paris CEDEX 13, France
| | | | - Marie Odile Habert
- Service de Médecine Nucléaire, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, AP-HP, Paris CEDEX 13, France.,CATI, http://www.cati-neuroimaging.com.,Laboratoire d'Imagerie Biomédicale, INSERM U1146, Sorbonne Universités et Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Bruno Dubois
- INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, and Université Pierre et Marie Curie-Paris 6, UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), FrontLab, Paris CEDEX 13, France.,Département de Neurologie, Institut de la mémoire et de la maladie d'Alzheimer, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, AP-HP, Paris CEDEX 13, France
| | - Marc Teichmann
- INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, and Université Pierre et Marie Curie-Paris 6, UMR S 1127, Institut du Cerveau et de la Moelle épinière (ICM), FrontLab, Paris CEDEX 13, France.,Département de Neurologie, Institut de la mémoire et de la maladie d'Alzheimer, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, AP-HP, Paris CEDEX 13, France
| | - Aurélie Kas
- Service de Médecine Nucléaire, Groupe Hospitalier Pitié Salpêtrière-Charles Foix, AP-HP, Paris CEDEX 13, France.,CATI, http://www.cati-neuroimaging.com.,Laboratoire d'Imagerie Biomédicale, INSERM U1146, Sorbonne Universités et Université Pierre et Marie Curie-Paris 6, Paris, France
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49
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Putcha D, Brickhouse M, Touroutoglou A, Collins JA, Quimby M, Wong B, Eldaief M, Schultz A, El Fakhri G, Johnson K, Dickerson BC, McGinnis SM. Visual cognition in non-amnestic Alzheimer's disease: Relations to tau, amyloid, and cortical atrophy. Neuroimage Clin 2019; 23:101889. [PMID: 31200149 PMCID: PMC6562373 DOI: 10.1016/j.nicl.2019.101889] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/28/2019] [Accepted: 06/01/2019] [Indexed: 12/15/2022]
Abstract
Heterogeneity within the Alzheimer's disease (AD) syndromic spectrum is typically classified in a domain-specific manner (e.g., language vs. visual cognitive function). The central aim of this study was to investigate whether impairment in visual cognitive tasks thought to be subserved by posterior cortical dysfunction in non-amnestic AD presentations is associated with tau, amyloid, or neurodegeneration in those regions using 18F-AV-1451 and 11C-PiB positron emission tomography (PET) and magnetic resonance imaging (MRI). Sixteen amyloid-positive patients who met criteria for either Posterior Cortical Atrophy (PCA; n = 10) or logopenic variant Primary Progressive Aphasia (lvPPA; n = 6) were studied. All participants underwent a structured clinical assessment, neuropsychological battery, structural MRI, amyloid PET, and tau PET. The neuropsychological battery included two visual cognitive tests: VOSP Number Location and Benton Facial Recognition. Surface-based whole-cortical general linear models were used to first explore the similarities and differences between these biomarkers in the two patient groups, and then to assess their regional associations with visual cognitive test performance. The results show that these two variants of AD have both dissociable and overlapping areas of tau and atrophy, but amyloid is distributed with a stereotyped localization in both variants. Performance on both visual cognitive tests were associated with tau and atrophy in the right lateral and medial occipital association cortex, superior parietal cortex, and posterior ventral occipitotemporal cortex. No cortical associations were observed with amyloid PET. We further demonstrate that cortical atrophy has a partially mediating effect on the association between tau pathology and visual cognitive task performance. Our findings show that non-amnestic variants of AD have partially dissociable spatial patterns of tau and atrophy that localize as expected based on symptoms, but similar patterns of amyloid. Further, we demonstrate that impairments of visual cognitive dysfunction are strongly associated with tau in visual cortical regions and mediated in part by atrophy.
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Affiliation(s)
- Deepti Putcha
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
| | - Michael Brickhouse
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Alexandra Touroutoglou
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jessica A Collins
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Megan Quimby
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Bonnie Wong
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Mark Eldaief
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Aaron Schultz
- Alzheimer's Disease Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Georges El Fakhri
- Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Keith Johnson
- Alzheimer's Disease Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Bradford C Dickerson
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Alzheimer's Disease Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Scott M McGinnis
- Frontotemporal Disorders Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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50
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Ossenkoppele R, Iaccarino L, Schonhaut DR, Brown JA, La Joie R, O'Neil JP, Janabi M, Baker SL, Kramer JH, Gorno-Tempini ML, Miller BL, Rosen HJ, Seeley WW, Jagust WJ, Rabinovici GD. Tau covariance patterns in Alzheimer's disease patients match intrinsic connectivity networks in the healthy brain. Neuroimage Clin 2019; 23:101848. [PMID: 31077982 PMCID: PMC6510968 DOI: 10.1016/j.nicl.2019.101848] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 04/02/2019] [Accepted: 05/01/2019] [Indexed: 01/06/2023]
Abstract
According to the network model of neurodegeneration, the spread of pathogenic proteins occurs selectively along connected brain regions. We tested in vivo whether the distribution of filamentous tau (measured with [18F]flortaucipir-PET), fibrillar amyloid-β ([11C]PIB-PET) and glucose hypometabolism ([18F]FDG-PET) follows the intrinsic functional organization of the healthy brain. We included 63 patients with Alzheimer's disease (AD; 30 male, 63 ± 8 years) who underwent [18F]flortaucipir, [11C]PIB and [18F]FDG PET, and 1000 young adults (427 male, 21 ± 3 years) who underwent task-free fMRI. We selected six predefined disease epicenters as seeds for whole-brain voxelwise covariance analyses to compare correlated patterns of tracer uptake across AD patients against fMRI intrinsic connectivity patterns in young adults. We found a striking convergence between [18F]flortaucipir covariance patterns and intrinsic connectivity maps (range Spearman rho's: 0.32-0.78, p < .001), which corresponded with expected functional networks (range goodness-of-fit: 3.8-8.2). The topography of amyloid-β covariance patterns was more diffuse and less network-specific, while glucose hypometabolic patterns were more spatially restricted than tau but overlapped with functional networks. These findings suggest that the spatial patterns of tau and glucose hypometabolism observed in AD resemble the functional organization of the healthy brain, supporting the notion that tau pathology spreads through circumscribed brain networks and drives neurodegeneration.
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Affiliation(s)
- Rik Ossenkoppele
- Memory and Aging Center, University of California San Francisco, San Francisco, CA 94143, USA; Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA; Department of Neurology & Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam 1081 HZ, the Netherlands.
| | - Leonardo Iaccarino
- Memory and Aging Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Daniel R Schonhaut
- Memory and Aging Center, University of California San Francisco, San Francisco, CA 94143, USA; Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
| | - Jesse A Brown
- Memory and Aging Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Renaud La Joie
- Memory and Aging Center, University of California San Francisco, San Francisco, CA 94143, USA; Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
| | - James P O'Neil
- Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Mustafa Janabi
- Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Suzanne L Baker
- Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Joel H Kramer
- Memory and Aging Center, University of California San Francisco, San Francisco, CA 94143, USA
| | | | - Bruce L Miller
- Memory and Aging Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Howard J Rosen
- Memory and Aging Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - William W Seeley
- Memory and Aging Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA
| | - William J Jagust
- Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Gil D Rabinovici
- Memory and Aging Center, University of California San Francisco, San Francisco, CA 94143, USA; Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA
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