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1
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Tampi RR, Joshi P, Jeste DV. Psychosis associated with dementia: evaluation and management. Schizophr Res 2025; 281:82-90. [PMID: 40319614 DOI: 10.1016/j.schres.2025.04.022] [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: 12/03/2024] [Revised: 04/08/2025] [Accepted: 04/15/2025] [Indexed: 05/07/2025]
Abstract
Dementia is one of the most common neurodegenerative disorders in the world, and 34-63 % of individuals with dementia have psychotic symptoms. Neurobiological correlates of dementia with psychosis include significantly increased densities of senile plaques and neurofibrillary tangles and higher D3 receptor density. Limitations of proposed diagnostic criteria include a lack of specificity for psychotic symptoms in individuals with dementia, a lack of consistent differentiation between symptoms, late recognition, and not accounting for comorbid depression or agitation that may be the primary symptom, which makes diagnosis challenging. This review aims to provide clinicians, researchers, and policymakers with a comprehensive evaluation of psychosis in dementia, covering its epidemiology, neurobiology, diagnosis, and treatment strategies. We review both psychosocial and pharmacological interventions for dementia-related psychosis. Psychosocial treatments such as meaningful communication between persons with dementia and their caregivers, simplifying the living environment, and optimizing tasks can help reduce the adverse impact of psychosis. Evidence from meta-analyses indicates modest efficacy for cholinesterase inhibitors, antidepressants, and antipsychotics for psychosis in dementia. The use of antipsychotic medications is limited by increased risks for serious adverse effects including cerebrovascular events and death. Emerging therapies such as xanomeline-trospium present promising avenues for treatment. By synthesizing current evidence and clinical guidelines, this review provides a framework for improving diagnosis and treatment of psychosis in dementia, helping clinicians and researchers refine patient care strategies while informing future research directions.
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Affiliation(s)
- Rajesh R Tampi
- Department of Psychiatry, Creighton University School of Medicine, 7710 Mercy Road, Suite 601, Omaha, NE 68124, USA; Department of Psychiatry, Yale School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511, USA.
| | - Pallavi Joshi
- Banner Alzheimer's Institute, 901 E Willetta St, Phoenix, AZ 85006, USA; Department of Psychiatry, University of Arizona College of Medicine-Phoenix, 475 N 5th, Phoenix, AZ 85004, USA
| | - Dilip V Jeste
- Global Research Network on Social Determinants of Mental Health and Exposomics, La Jolla, CA, USA
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2
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Antonsdottir IM, Creese B, Klei L, DeMichele‐Sweet MAA, Weamer EA, Garcia‐Gonzalez P, Marquie M, Boada M, Alarcón‐Martín E, Valero S, NIA‐LOAD Family Based Study Consortium, Alzheimer's Disease Genetics Consortium (ADGC), AddNeuroMed Consortium, Liu Y, Hooli B, Aarsland D, Selbaek G, Bergh S, Rongve A, Saltvedt I, Skjellegrind HK, Engdahl B, Andreassen OA, Borroni B, Mecocci P, Wedatilake Y, Mayeux R, Foroud T, Ruiz A, Lopez OL, Kamboh MI, Ballard C, Devlin B, Lyketsos C, Sweet RA. Genetic associations with psychosis and affective disturbance in Alzheimer's disease. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2024; 10:e12472. [PMID: 38784964 PMCID: PMC11114588 DOI: 10.1002/trc2.12472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 11/01/2023] [Accepted: 01/30/2024] [Indexed: 05/25/2024]
Abstract
INTRODUCTION Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. METHODS Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). RESULTS AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. DISCUSSION AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development. Highlights It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations.
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3
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Angelopoulou E, Koros C, Hatzimanolis A, Stefanis L, Scarmeas N, Papageorgiou SG. Exploring the Genetic Landscape of Mild Behavioral Impairment as an Early Marker of Cognitive Decline: An Updated Review Focusing on Alzheimer's Disease. Int J Mol Sci 2024; 25:2645. [PMID: 38473892 PMCID: PMC10931648 DOI: 10.3390/ijms25052645] [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: 01/08/2024] [Revised: 02/20/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
The clinical features and pathophysiology of neuropsychiatric symptoms (NPSs) in dementia have been extensively studied. However, the genetic architecture and underlying neurobiological mechanisms of NPSs at preclinical stages of cognitive decline and Alzheimer's disease (AD) remain largely unknown. Mild behavioral impairment (MBI) represents an at-risk state for incident cognitive impairment and is defined by the emergence of persistent NPSs among non-demented individuals in later life. These NPSs include affective dysregulation, decreased motivation, impulse dyscontrol, abnormal perception and thought content, and social inappropriateness. Accumulating evidence has recently begun to shed more light on the genetic background of MBI, focusing on its potential association with genetic factors related to AD. The Apolipoprotein E (APOE) genotype and the MS4A locus have been associated with affective dysregulation, ZCWPW1 with social inappropriateness and psychosis, BIN1 and EPHA1 with psychosis, and NME8 with apathy. The association between MBI and polygenic risk scores (PRSs) in terms of AD dementia has been also explored. Potential implicated mechanisms include neuroinflammation, synaptic dysfunction, epigenetic modifications, oxidative stress responses, proteosomal impairment, and abnormal immune responses. In this review, we summarize and critically discuss the available evidence on the genetic background of MBI with an emphasis on AD, aiming to gain insights into the potential underlying neurobiological mechanisms, which till now remain largely unexplored. In addition, we propose future areas of research in this emerging field, with the aim to better understand the molecular pathophysiology of MBI and its genetic links with cognitive decline.
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Affiliation(s)
- Efthalia Angelopoulou
- 1st Department of Neurology, Aiginition University Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.A.); (L.S.); (N.S.); (S.G.P.)
| | - Christos Koros
- 1st Department of Neurology, Aiginition University Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.A.); (L.S.); (N.S.); (S.G.P.)
| | - Alexandros Hatzimanolis
- 1st Department of Psychiatry, Aiginition University Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Leonidas Stefanis
- 1st Department of Neurology, Aiginition University Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.A.); (L.S.); (N.S.); (S.G.P.)
| | - Nikolaos Scarmeas
- 1st Department of Neurology, Aiginition University Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.A.); (L.S.); (N.S.); (S.G.P.)
- Department of Neurology, Columbia University, New York, NY 10032, USA
| | - Sokratis G. Papageorgiou
- 1st Department of Neurology, Aiginition University Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.A.); (L.S.); (N.S.); (S.G.P.)
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4
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Fan P, Kofler J, Ding Y, Marks M, Sweet RA, Wang L. Efficacy difference of antipsychotics in Alzheimer's disease and schizophrenia: explained with network efficiency and pathway analysis methods. Brief Bioinform 2022; 23:bbac394. [PMID: 36151774 PMCID: PMC9677501 DOI: 10.1093/bib/bbac394] [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: 05/10/2022] [Revised: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 12/14/2022] Open
Abstract
Approximately 50% of Alzheimer's disease (AD) patients will develop psychotic symptoms and these patients will experience severe rapid cognitive decline compared with those without psychosis (AD-P). Currently, no medication has been approved by the Food and Drug Administration for AD with psychosis (AD+P) specifically, although atypical antipsychotics are widely used in clinical practice. These drugs have demonstrated modest efficacy in managing psychosis in individuals with AD, with an increased frequency of adverse events, including excess mortality. We compared the differences between the genetic variations/genes associated with AD+P and schizophrenia from existing Genome-Wide Association Study and differentially expressed genes (DEGs). We also constructed disease-specific protein-protein interaction networks for AD+P and schizophrenia. Network efficiency was then calculated to characterize the topological structures of these two networks. The efficiency of antipsychotics in these two networks was calculated. A weight adjustment based on binding affinity to drug targets was later applied to refine our results, and 2013 and 2123 genes were identified as related to AD+P and schizophrenia, respectively, with only 115 genes shared. Antipsychotics showed a significantly lower efficiency in the AD+P network than in the schizophrenia network (P < 0.001) indicating that antipsychotics may have less impact in AD+P than in schizophrenia. AD+P may be caused by mechanisms distinct from those in schizophrenia which result in a decreased efficacy of antipsychotics in AD+P. In addition, the network analysis methods provided quantitative explanations of the lower efficacy of antipsychotics in AD+P.
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Affiliation(s)
- Peihao Fan
- School of Pharmacy, University of Pittsburgh
| | | | - Ying Ding
- Department of Biostatistics at the University of Pittsburgh
| | - Michael Marks
- Center for Neuroscience at the University of Pittsburgh and the Department of Neurobiology
| | - Robert A Sweet
- UPMC Endowed Professor of Psychiatric Neuroscience and Professor of Neurology at the University of Pittsburgh
| | - Lirong Wang
- department of pharmaceutical sciences, school of pharmacy at University of Pittsburgh, USA
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D'Antonio F, Di Vita A, Zazzaro G, Canevelli M, Trebbastoni A, Campanelli A, Ferracuti S, de Lena C, Guariglia C, Boccia M. Cortical complexity alterations in the medial temporal lobe are associated with Alzheimer's disease psychosis. NEUROPSYCHOLOGY, DEVELOPMENT, AND COGNITION. SECTION B, AGING, NEUROPSYCHOLOGY AND COGNITION 2022; 29:1022-1032. [PMID: 34294005 DOI: 10.1080/13825585.2021.1958139] [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: 03/09/2021] [Accepted: 07/14/2021] [Indexed: 06/13/2023]
Abstract
Psychosis is frequent in Alzheimer's disease (AD) and it is associated with a worse disease course. AD psychosis may represent a distinct AD phenotype, though its specific neurobiological underpinnings have yet to be identified. This study investigated neural underpinnings of AD psychosis using surface-based-morphometry.Data from 32 AD patients, 17 with psychosis (AD-P) and 15 without were analyzed. Average cortical complexity (fractal dimension, FD) was estimated for each theoretically motivated ROI and patient. First, we compared regional FD in AD-P and AD patients. Then we calculated the correlation coefficients between FD and the severity of misidentification and paranoid psychotic symptoms. AD-P showed decreased FD in ventral-visual-stream compared to AD, suggesting that perceptual processes might be pivotal in psychosis. A negative correlation was found between misidentification severity and FD in the entorhinal cortex suggesting that misidentification may be specifically associated with alterations in regions involved in high-level perceptual and contextualization processes.
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Affiliation(s)
- Fabrizia D'Antonio
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Antonella Di Vita
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
- Department of Psychology, Sapienza University of Rome, Rome, Italy
| | - Giulia Zazzaro
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Marco Canevelli
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | | | | | - Stefano Ferracuti
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Carlo de Lena
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Cecilia Guariglia
- Department of Psychology, Sapienza University of Rome, Rome, Italy
- Cognitive and Motor Rehabilitation and Neuroimaging Unit, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Maddalena Boccia
- Department of Psychology, Sapienza University of Rome, Rome, Italy
- Cognitive and Motor Rehabilitation and Neuroimaging Unit, IRCCS Fondazione Santa Lucia, Rome, Italy
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Hiu SKW, Bigirumurame T, Kunonga P, Bryant A, Pillai M. Neuropsychiatric Inventory domains cluster into neuropsychiatric syndromes in Alzheimer's disease: A systematic review and meta-analysis. Brain Behav 2022; 12:e2734. [PMID: 35939055 PMCID: PMC9480932 DOI: 10.1002/brb3.2734] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/01/2022] [Accepted: 07/17/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Studies of patients with Alzheimer's disease (AD) have observed that neuropsychiatric symptoms (NPS) tend to co-occur as neuropsychiatric syndromes and have generally shown mixed results regarding the number and composition of syndromes. We systematically reviewed how neuropsychiatric syndromes in AD have been defined and compared the different published definitions in a pooled sample of AD patients using meta-analytic structural equation modeling (MASEM). METHODS Studies examining the factor structure of the Neuropsychiatric Inventory (NPI) and published from 1994 to 2021 were included. We contacted the corresponding authors of eligible studies for correlation coefficients between NPI items. We pooled correlations under a random effects MASEM model and fitted and compared measurement models from published studies to identify a best-fitting model. RESULTS Twenty-five studies were included in the systematic review, and correlations were obtained from seven studies for MASEM. For the NPI-10 (seven studies, n = 5185), a five-factor structure was found to have a good fit to the data. For the NPI-12 (four studies, n = 2397), we were unable to identify a factor structure that displayed a good model fit. CONCLUSION This systematic review and meta-analysis contribute to the development of a theoretical model of neuropsychiatric syndromes in AD and reveals the barriers that accompany MASEM methodology.
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Affiliation(s)
- Shaun Kuan Wei Hiu
- Population Health Sciences Institute, Newcastle University, Newcastle University, UK
| | | | - Patience Kunonga
- Population Health Sciences Institute, Newcastle University, Newcastle University, UK
| | - Andrew Bryant
- Population Health Sciences Institute, Newcastle University, Newcastle University, UK
| | - Manjunadh Pillai
- Campus for Ageing and Vitality, Northumberland Tyne and Wear, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, UK
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Benmelouka AY, Ouerdane Y, Outani O, Alnasser YT, Alghamdi BS, Perveen A, Ashraf GM, Ebada MA. Alzheimer's Disease-Related Psychosis: An Overview of Clinical Manifestations, Pathogenesis, and Current Treatment. Curr Alzheimer Res 2022; 19:285-301. [PMID: 35440308 DOI: 10.2174/1567205019666220418151914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/25/2022] [Accepted: 03/06/2022] [Indexed: 11/22/2022]
Abstract
Behavioral and psychotic manifestations, including aggression, delusions, and hallucinations, are frequent comorbidities in patients with debilitating nervous illnesses such as Alzheimer's disease (AD), Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and Parkinson's disease. AD-related psychosis may be linked to a poor disease prognosis, highlighting that early detection and management are mandatory. The manifestations are variable and may be very heterogeneous, imposing a real diagnostic issue. Some assessment tools such as BEHAVE-AD, CERAD-BRSD, and the Psycho-Sensory Hallucinations Scale have been designed to facilitate the diagnosis. The mechanisms behind neurodegeneration-related psychosis are complex and are not fully understood, imposing a burden on researchers to find appropriate management modalities. Familial history and some genetic disturbances may have a determinant role in these delusions and hallucinations in cases with AD. The loss of neuronal cells, atrophy in some regions of the central nervous, and synaptic dysfunction may also contribute to these comorbidities. Furthermore, inflammatory disturbances triggered by pro-inflammatory agents such as interleukins and tumor necrosis factors are stratified among the potential risk factors of the onset of numerous psychotic symptoms in Alzheimer's patients. Little is known about the possible management tools; therefore, it is urgent to conduct well-designed trials to investigate pharmacological and non-pharmacological interventions that can improve the care process of these patients. This review summarizes the current findings regarding the AD-related psychosis symptoms, pathological features, assessment, and management.
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Affiliation(s)
| | | | - Oumaima Outani
- Faculty of Medicine and Pharmacy of Rabat, Mohammed 5 University
| | | | - Badrah S Alghamdi
- Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah.,Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah
| | - Asma Perveen
- Glocal University, Mirzapur Pole, Saharanpur, Uttar Pradesh
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah.,Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah
| | - Mahmoud Ahmed Ebada
- Faculty of Medicine, Zagazig University, Zagazig, Al-Sharkia.,Internal Medicine Resident, Ministry of Health and Population of Egypt, Cairo
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8
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DeChellis-Marks MR, Wei Y, Ding Y, Wolfe CM, Krivinko JM, MacDonald ML, Lopez OL, Sweet RA, Kofler J. Psychosis in Alzheimer's Disease Is Associated With Increased Excitatory Neuron Vulnerability and Post-transcriptional Mechanisms Altering Synaptic Protein Levels. Front Neurol 2022; 13:778419. [PMID: 35309563 PMCID: PMC8925864 DOI: 10.3389/fneur.2022.778419] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 02/04/2022] [Indexed: 12/01/2022] Open
Abstract
Alzheimer's disease with psychosis (AD+P) is a heritable phenotypic variant of the disease which is associated with more rapid cognitive deterioration compared to Alzheimer's disease without psychosis (AD-P). Cognitive decline in AD correlates with synapse loss, and our previous studies suggest that those with AD+P have a differentially affected synaptic proteome relative to those with AD-P. In this study, we utilized RNA-sequencing of dorsolateral prefrontal cortex (DLPFC) in a cohort of 80 AD cases to evaluate novel transcriptomic signatures that may confer risk of psychosis in AD. We found that AD+P was associated with a 9% reduction in excitatory neuron proportion compared to AD-P [Mean (SD) AD+P 0.295 (0.061); AD-P 0.324 (0.052), p = 0.026]. mRNA levels contributed only modestly to altered synaptic proteins in AD+P relative to AD-P. Instead, network analysis identified altered expression of gene modules from protein ubiquitination, unfolded protein response, eukaryotic initiation factor 2 (EIF2) signaling and endoplasmic reticulum stress pathways in AD+P. We previously found that neuropathologies account for ~18% of the variance in the occurrence of psychosis in AD. Further inclusion of cell type proportions and differentially expressed modules increased the percent of the variance in psychosis occurrence accounted for in our AD cohort to 67.5%.
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Affiliation(s)
| | - Yue Wei
- Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, United States
| | - Ying Ding
- Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, United States
| | - Cody M. Wolfe
- Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, Pittsburgh, PA, United States
| | - Joshua M. Krivinko
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Matthew L. MacDonald
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Oscar L. Lopez
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Robert A. Sweet
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Julia Kofler
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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9
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DeMichele-Sweet MAA, Klei L, Creese B, Harwood JC, Weamer EA, McClain L, Sims R, Hernandez I, Moreno-Grau S, Tárraga L, Boada M, Alarcón-Martín E, Valero S, Liu Y, Hooli B, Aarsland D, Selbaek G, Bergh S, Rongve A, Saltvedt I, Skjellegrind HK, Engdahl B, Stordal E, Andreassen OA, Djurovic S, Athanasiu L, Seripa D, Borroni B, Albani D, Forloni G, Mecocci P, Serretti A, De Ronchi D, Politis A, Williams J, Mayeux R, Foroud T, Ruiz A, Ballard C, Holmans P, Lopez OL, Kamboh MI, Devlin B, Sweet RA. Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease. Mol Psychiatry 2021; 26:5797-5811. [PMID: 34112972 PMCID: PMC8660923 DOI: 10.1038/s41380-021-01152-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 04/15/2021] [Accepted: 04/29/2021] [Indexed: 11/09/2022]
Abstract
Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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Affiliation(s)
| | - Lambertus Klei
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Byron Creese
- University of Exeter Medical School, College of Medicine and Health, Exeter, UK
- Norwegian, Exeter and King's College Consortium for Genetics of Neuropsychiatric Symptoms in Dementia, Exeter, UK
| | - Janet C Harwood
- Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK
| | - Elise A Weamer
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Lora McClain
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Rebecca Sims
- Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK
| | - Isabel Hernandez
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | - Sonia Moreno-Grau
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | - Lluís Tárraga
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | - Mercè Boada
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | - Emilio Alarcón-Martín
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Sergi Valero
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | - Yushi Liu
- Global Statistical Science, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Basavaraj Hooli
- Neurodegeneration Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Dag Aarsland
- Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London and Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway
| | - Geir Selbaek
- Norwegian National Advisory Unit in Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
- Department Geriatric Medicine, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Sverre Bergh
- Research Centre of Age-related Functional Decline and Disease, Innlandet Hospital Trust, Pb 68, Ottestad, Norway
| | - Arvid Rongve
- Department of Research and Innovation, Helse Fonna, Haugesund and Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway
| | - Ingvild Saltvedt
- Geriatric Department, St. Olav Hospital, University Hospital of Trondheim, Trondheim, Norway
- Department of Neuromedicine and Movement science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Håvard K Skjellegrind
- HUNT Research Centre, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Levanger, Norway
- Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
| | - Bo Engdahl
- Norwegian Institute of Public Health, Oslo, Norway
| | - Eystein Stordal
- Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ole A Andreassen
- NORMENT Centre, Institute of Clinical Medicine, University of Oslo, and Oslo University Hospital, Oslo, Norway
| | - Srdjan Djurovic
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
- NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Lavinia Athanasiu
- NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Davide Seripa
- Department of Hematology and Stem Cell Transplant, Vito Fazzi Hospital, Lecce, Italy
| | - Barbara Borroni
- Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Diego Albani
- Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Gianluigi Forloni
- Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Patrizia Mecocci
- Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alessandro Serretti
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Diana De Ronchi
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Antonis Politis
- 1st Department of Psychiatry, Eginition Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - Julie Williams
- Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK
- UK Dementia Research Institute @ Cardiff, School of Medicine, Cardiff University, Cardiff, UK
| | - Richard Mayeux
- Departments of Neurology, Psychiatry and Epidemiology, Columbia University, New York, NY, USA
| | - Tatiana Foroud
- Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Agustin Ruiz
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
| | | | - Peter Holmans
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
| | - Oscar L Lopez
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - M Ilyas Kamboh
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Bernie Devlin
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Robert A Sweet
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
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10
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Ballard C, Kales HC, Lyketsos C, Aarsland D, Creese B, Mills R, Williams H, Sweet RA. Psychosis in Alzheimer's Disease. Curr Neurol Neurosci Rep 2020; 20:57. [PMID: 33048274 PMCID: PMC7554014 DOI: 10.1007/s11910-020-01074-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW To review the incidence, treatment and genetics of psychosis in people with mild cognitive impairment (MCI) and Alzheimer's disease (AD). RECENT FINDINGS Psychosis in Alzheimer's disease (AD) has an incidence of ~ 10% per year. There is limited evidence regarding psychological interventions. Pharmacological management has focused on atypical antipsychotics, balancing modest benefits with evidence of long-term harms. The 5HT2A inverse agonist pimavanserin appears to confer benefit in PD psychosis with initial evidence of benefit in AD. Cholinesterase inhibitors give modest benefits in DLB psychosis. The utility of muscarinic agonists, lithium, glutamatergic and noradrenergic modulators needs further study. Recent work has confirmed the importance of psychosis in MCI as well as AD. The lack of evidence regarding psychological therapies is an urgent knowledge gap, but there is encouraging evidence for emerging pharmacological treatments. Genetics will provide an opportunity for precision medicine and new treatment targets.
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Affiliation(s)
- Clive Ballard
- The University of Exeter Medical School, College of Medicine and Health, The University of Exeter, St Luke's Campus, Magdalen Road, Exeter, EX1 2LU, UK.
| | | | | | - Dag Aarsland
- University Hospital Stavanger, Stavanger, Norway
- King's College London, London, UK
| | - Byron Creese
- The University of Exeter Medical School, College of Medicine and Health, The University of Exeter, St Luke's Campus, Magdalen Road, Exeter, EX1 2LU, UK
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11
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Srinivasan S, Tampi RR, Balaram K, Kapoor A. Pimavanserin for the treatment of psychosis in Alzheimer’s disease: A literature review. World J Psychiatry 2020; 10:162-174. [PMID: 32844093 PMCID: PMC7418577 DOI: 10.5498/wjp.v10.i7.162] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 05/25/2020] [Accepted: 06/10/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Alzheimer’s disease (AD) is among the most prevalent forms of dementia in the world and neuropathological studies suggest similar high prevalence of mixed (AD + vascular) dementias. Approximately 25%-50% of individuals with AD develop psychosis sometime during their illness. The presence of psychosis in AD worsens outcomes. Currently there are no United States Food and Drug Administration (FDA) approved medications for the treatment of psychosis in AD. Pimavanserin, a novel atypical antipsychotic medication, was approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson disease psychosis and is currently in clinical trials for the treatment of psychosis in AD.
AIM To evaluate the existing literature regarding the use of pimavanserin for treating psychosis among individuals with AD.
METHODS A literature review of clinical studies of pimavanserin treatment for psychosis in individuals with AD was performed using the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Trials were identified by systematically searching PubMed, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2019. The 5-point Jadad scoring system was used to assess the methodologic quality of the randomized placebo-controlled trials.
RESULTS A total of 499 citations were retrieved and pooled in EndNote and de-duplicated to 258 citations. This set was uploaded to Covidence for screening. Two separate screeners (Srinivasan S and Tampi RR) evaluated the titles, abstracts, and full text of eligible articles. Of the identified 258 abstracts, 98 articles underwent full text review and 2 publications from 1 randomized controlled trial (RCT) were included in the final analysis. The quality of evidence was assessed to be of good methodologic quality, scoring 4 out of 5 using the 5-point Jadad questionnaire with the Jadad Scoring calculation. This systematic review found only one RCT that evaluated the use of pimavanserin for the treatment of psychosis among individuals with AD. This phase 2 trial resulted in two publications, the second of which was a subgroup analysis from the original study. The evidence from these two publications showed that pimavanserin improves psychotic symptoms among individuals with AD when compared to placebo at week 6.
CONCLUSION Pimavanserin may be a pharmacologic consideration for the treatment for psychosis in AD. Additional RCTs are needed to assess the evidence of effectiveness before pimavanserin is considered a standard treatment.
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Affiliation(s)
- Shilpa Srinivasan
- Department of Neuropsychiatry and Behavioral Science, Palmetto Health USC Medical Group, University of South Carolina School of Medicine, Columbia, SC 29203, United States
| | - Rajesh R Tampi
- Department of Psychiatry and Behavioral Sciences, Cleveland Clinic Akron General, Akron, OH 44307, United States
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, United States
| | - Kripa Balaram
- MD, Department of Psychiatry, MetroHealth, Cleveland, OH 44109, United States
| | - Arushi Kapoor
- Penn Memory Center at the Penn Neuroscience Center, Perelman Center for Advanced Medicine, Philadelphia, PA 19104, United States
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12
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Seiler N, Nguyen T, Yung A, O'Donoghue B. Terminology and assessment tools of psychosis: A systematic narrative review. Psychiatry Clin Neurosci 2020; 74:226-246. [PMID: 31846133 DOI: 10.1111/pcn.12966] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 12/05/2019] [Indexed: 12/20/2022]
Abstract
AIM Phenomena within the psychosis continuum that varies in frequency/duration/intensity have been increasingly identified. Different terms describe these phenomena, however there is no standardization within the terminology. This review evaluated the definitions and assessment tools of seven terms - (i) 'psychotic experiences'; (ii) 'psychotic-like experiences'; (iii) 'psychotic-like symptoms'; (iv) 'attenuated psychotic symptoms'; (v) 'prodromal psychotic symptoms'; (vi) 'psychotic symptomatology'; and (vii) 'psychotic symptoms'. METHODS EMBASE, MEDLINE, and CINAHL were searched during February-March 2019. Inclusion criteria included 1989-2019, full text, human, and English. Papers with no explicit definition or assessment tool, duplicates, conference abstracts, systematic reviews, meta-analyses, or no access were excluded. RESULTS A total of 2238 papers were identified and of these, 627 were included. Definitions and assessment tools varied, but some trends were found. Psychotic experiences and psychotic-like experiences were transient and mild, found in the general population and those at-risk. Psychotic-like symptoms were subthreshold and among at-risk populations and non-psychotic mental disorders. Attenuated psychotic symptoms were subthreshold but associated with distress, risk, and help-seeking. Prodromal psychotic symptoms referred to the prodrome of psychotic disorders. Psychotic symptomatology included delusions and hallucinations within psychotic disorders. Psychotic symptoms was the broadest term, encompassing a range of populations but most commonly involving hallucinations, delusions, thought disorder, and disorganization. DISCUSSION A model for conceptualizing the required terms is proposed and future directions needed to advance this field of research are discussed.
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Affiliation(s)
- Natalie Seiler
- Orygen, the National Centre of Excellence in Youth Mental Health, Parkville, Melbourne, Australia.,Centre for Youth Mental Health, University of Melbourne, Parkville, Melbourne, Australia.,The University of Melbourne, Parkville, Melbourne, Australia.,Orygen Youth Health, Parkville, Melbourne, Australia
| | - Tony Nguyen
- Orygen, the National Centre of Excellence in Youth Mental Health, Parkville, Melbourne, Australia.,Centre for Youth Mental Health, University of Melbourne, Parkville, Melbourne, Australia.,The University of Melbourne, Parkville, Melbourne, Australia.,Orygen Youth Health, Parkville, Melbourne, Australia
| | - Alison Yung
- Orygen, the National Centre of Excellence in Youth Mental Health, Parkville, Melbourne, Australia.,Centre for Youth Mental Health, University of Melbourne, Parkville, Melbourne, Australia.,Orygen Youth Health, Parkville, Melbourne, Australia
| | - Brian O'Donoghue
- Orygen, the National Centre of Excellence in Youth Mental Health, Parkville, Melbourne, Australia.,Centre for Youth Mental Health, University of Melbourne, Parkville, Melbourne, Australia.,Orygen Youth Health, Parkville, Melbourne, Australia
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13
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Fischer CE, Ismail Z, Youakim JM, Creese B, Kumar S, Nuñez N, Ryan Darby R, Di Vita A, D’Antonio F, de Lena C, McGeown WJ, Ramit R, Rasmussen J, Bell J, Wang H, Bruneau MA, Panegyres PK, Lanctôt KL, Agüera-Ortiz L, Lyketsos C, Cummings J, Jeste DV, Sano M, Devanand D, Sweet RA, Ballard C. Revisiting Criteria for Psychosis in Alzheimer’s Disease and Related Dementias: Toward Better Phenotypic Classification and Biomarker Research. J Alzheimers Dis 2020; 73:1143-1156. [DOI: 10.3233/jad-190828] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Corinne E. Fischer
- Keenan Research Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada
- Department of Psychiatry, University of Toronto, Toronto, Canada
| | - Zahinoor Ismail
- Departments of Psychiatry, Clinical Neurosciences, and Community Health Sciences; Hotchkiss Brain Institute and O’Brien Institute for Public Health, University of Calgary, Calgary, Canada
| | | | - Byron Creese
- Medical School, College of Medicine and Health, University of Exeter, Exeter, UK
| | - Sanjeev Kumar
- Department of Psychiatry, University of Toronto, Toronto, Canada
- Centre for Addiction and Mental Health, Toronto, Canada
| | - Nicolas Nuñez
- Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA
| | - R. Ryan Darby
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Antonella Di Vita
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
- Department of Psychology, Sapienza University of Rome, Rome, Italy
| | - Fabrizia D’Antonio
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Carlo de Lena
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - William J. McGeown
- School of Psychological Sciences and Health, University of Strathclyde, Glasgow, UK
| | - Ravona Ramit
- Memory and Geriatric Psychiatry Clinic, Sheba Medical Center, Tel Hashomer, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | | | - Huali Wang
- Dementia Care and Research Center, Peking University Institute of Mental Health (Sixth Hospital), National Clinical Research Center for Mental Disorders, Beijing, China
| | - Marie-Andrée Bruneau
- Department of Psychiatry, University of Montreal, Centre de Recherche de l’Institut Universitaire de gériatrie de Montréal (CRIUGM), Montreal, Canada
| | - Peter K. Panegyres
- Director, Neurodegenerative Disorders Research Pty Ltd, West Perth, WA, Australia
| | - Krista L. Lanctôt
- Department of Psychiatry, University of Toronto, Toronto, Canada
- Hurvitz Brain Sciences Research, Sunnybrook Health Sciences Centre, Toronto, Canada
| | - Luis Agüera-Ortiz
- Department of Psychiatry Instituto de Investigación Sanitaria (imas12), Hospital Universitario 12 de Octubre, & Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain
| | - Constantine Lyketsos
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins Bayview, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Jeffrey Cummings
- UNLV Department of Brain Health and the Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA
| | - Dilip V. Jeste
- Departments of Psychiatry and Neurosciences, and Stein Institute for Research on Aging, University of California San Diego, San Diego, CA, USA
| | - Mary Sano
- Mt Sinai School of Medicine, Manhattan, NY, USA
| | - D.P. Devanand
- Department of Psychiatry, Columbia University, New York City, NY, USA
| | - Robert A. Sweet
- Departments of Psychiatry and Neurology, University of Pittsburgh, PA, USA
| | - Clive Ballard
- Medical School, College of Medicine and Health, University of Exeter, Exeter, UK
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14
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Krivinko JM, Koppel J, Savonenko A, Sweet RA. Animal Models of Psychosis in Alzheimer Disease. Am J Geriatr Psychiatry 2020; 28:1-19. [PMID: 31278012 PMCID: PMC6858948 DOI: 10.1016/j.jagp.2019.05.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/29/2019] [Accepted: 05/13/2019] [Indexed: 12/13/2022]
Abstract
Psychosis in Alzheimer Disease (AD) represents a distinct clinicopathologic variant associated with increased cognitive and functional morbidity and an accelerated disease course. To date, extant treatments offer modest benefits with significant risks. The development of new pharmacologic treatments for psychosis in AD would be facilitated by validated preclinical models with which to test candidate interventions. The current review provides a brief summary of the process of validating animal models of human disease together with a critical analysis of the challenges posed in attempting to apply those standards to AD-related behavioral models. An overview of phenotypic analogues of human cognitive and behavioral impairments, with an emphasis on those relevant to psychosis, in AD-related mouse models is provided, followed by an update on recent progress in efforts to translate findings in the pathophysiology of psychotic AD into novel models. Finally, some future directions are suggested to expand the catalogue of psychosis-relevant phenotypes that may provide a sturdier framework for model development and targets for preclinical treatment outcomes.
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Affiliation(s)
- Josh M. Krivinko
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Jeremy Koppel
- The Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
| | - Alena Savonenko
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD
| | - Robert A. Sweet
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA,Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA,Mental Illness Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA
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15
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D'Antonio F, Di Vita A, Zazzaro G, Brusà E, Trebbastoni A, Campanelli A, Ferracuti S, de Lena C, Guariglia C, Boccia M. Psychosis of Alzheimer's disease: Neuropsychological and neuroimaging longitudinal study. Int J Geriatr Psychiatry 2019; 34:1689-1697. [PMID: 31368183 DOI: 10.1002/gps.5183] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 07/28/2019] [Indexed: 11/11/2022]
Abstract
OBJECTIVES Psychosis of Alzheimer's disease (AD) may represent a distinct disease phenotype; however, neuropsychological profile and neural basis linked to this phenotype have not yet been clarified. In this study, we aimed at detecting whether impairment in specific cognitive domains predicts the onset of psychosis in AD patients and what grey matter alterations, their location, and the rate of atrophy are associated with psychosis of AD. METHODS Longitudinal neuropsychological data from AD patients with and without psychosis were analysed to determine whether the neuropsychological profile can predict the onset of psychosis. A voxel-based morphometry (VBM) on longitudinal T1-weighted images was used to explore differences in grey matter volume and in the rate of atrophy between groups. RESULTS Noncognitive domain predicted the psychosis onset. However, AD patients with psychosis exhibited greater atrophy in the right anterior-inferior temporal lobe, including the fusiform gyrus (cluster-p-family-wise error [pfwe] < 0.05; peak-p uncorrected [pUNC] < 0.001) as well as greater rate of atrophy in the right insula than nonpsychotic patients (cluster-pFWE = 0.075; peak-pUNC < 0.001). The anterior-inferior temporal lobe is part of the ventral visual stream, and the insula plays a key role in the salience network. CONCLUSIONS This finding suggests that damage in these areas underpins an impairment in the visual processing of the objects and an impairment in the attribution of salience to the misperceived stimuli, which in turn leads to the onset of psychosis. These findings tie in well with the neuropsychological model of psychosis, according to which the simultaneous presence of two factors, namely misperception and misattribution, underlies psychosis in dementia.
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Affiliation(s)
- Fabrizia D'Antonio
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.,PhD Program in Behavioral Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Antonella Di Vita
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.,Department of Psychology, Sapienza University of Rome, Rome, Italy
| | - Giulia Zazzaro
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Erica Brusà
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | | | | | - Stefano Ferracuti
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Carlo de Lena
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Cecilia Guariglia
- Department of Psychology, Sapienza University of Rome, Rome, Italy.,Cognitive and Motor Rehabilitation and Neuroimaging Unit, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Maddalena Boccia
- Cognitive and Motor Rehabilitation and Neuroimaging Unit, IRCCS Fondazione Santa Lucia, Rome, Italy
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16
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DeMichele-Sweet MAA, Weamer EA, Klei L, Vrana DT, Hollingshead DJ, Seltman HJ, Sims R, Foroud T, Hernandez I, Moreno-Grau S, Tárraga L, Boada M, Ruiz A, Williams J, Mayeux R, Lopez OL, Sibille EL, Kamboh MI, Devlin B, Sweet RA. Genetic risk for schizophrenia and psychosis in Alzheimer disease. Mol Psychiatry 2018; 23:963-972. [PMID: 28461698 PMCID: PMC5668212 DOI: 10.1038/mp.2017.81] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 02/23/2017] [Accepted: 02/24/2017] [Indexed: 12/29/2022]
Abstract
Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.
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Affiliation(s)
| | - Elise A. Weamer
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA
| | - Lambertus Klei
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
| | - Dylan T. Vrana
- Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA
| | - Deborah J. Hollingshead
- Genomics Research Core of the Health Sciences Core Research Facilities, University of Pittsburgh, Pittsburgh, PA
| | - Howard J. Seltman
- Department of Statistics, Carnegie Mellon University, Pittsburgh, PA
| | - Rebecca Sims
- Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK
| | - Tatiana Foroud
- Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Isabel Hernandez
- Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
| | - Sonia Moreno-Grau
- Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
| | - Lluís Tárraga
- Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
| | - Mercè Boada
- Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
| | - Agustin Ruiz
- Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
| | - Julie Williams
- Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK
| | - Richard Mayeux
- Departments of Neurology, Psychiatry and Epidemiology, Columbia University, New York, NY
| | - Oscar L. Lopez
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA
| | - Etienne L. Sibille
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Departments of Psychiatry and of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Campbell Family Mental Health Research Institute of CAMH, Toronto, ON, Canada
| | - M. Ilyas Kamboh
- Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA
| | - Bernie Devlin
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
| | - Robert A. Sweet
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA
- VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC) VA Pittsburgh Healthcare System, Pittsburgh, PA
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17
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Krivinko JM, Erickson SL, Abrahamson EE, Wills ZP, Ikonomovic MD, Penzes P, Sweet RA. Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice. Neurobiol Aging 2017; 54:59-70. [PMID: 28319837 PMCID: PMC5502748 DOI: 10.1016/j.neurobiolaging.2017.02.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 01/18/2017] [Accepted: 02/09/2017] [Indexed: 12/17/2022]
Abstract
Psychosis in Alzheimer's disease (AD+P) represents a distinct clinical and neurobiological AD phenotype and is associated with more rapid cognitive decline, higher rates of abnormal behaviors, and increased caregiver burden compared with AD without psychosis. On a molecular level, AD+P is associated with greater reductions in the protein kalirin, a guanine exchange factor which has also been linked to the psychotic disease, schizophrenia. In this study, we sought to determine the molecular and behavioral consequences of kalirin reduction in APPswe/PSEN1dE9 mice. We evaluated mice with and without kalirin reduction during tasks measuring psychosis-associated behaviors and spatial memory. We found that kalirin reduction in APPswe/PSEN1dE9 mice significantly attenuated psychosis-associated behavior at 12 months of age without changing spatial memory performance. The 12-month-old APPswe/PSEN1dE9 mice with reduced kalirin levels also had increased levels of the active, phosphorylated forms of p21 protein (Cdc42/Rac)-activated kinases (PAKs), which function in signaling pathways for maintenance of dendritic spine density, morphology, and function.
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Affiliation(s)
- Josh M Krivinko
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Susan L Erickson
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Eric E Abrahamson
- Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Zachary P Wills
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Milos D Ikonomovic
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Geriatric Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA
| | - Peter Penzes
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Robert A Sweet
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Mental Illness Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.
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18
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Røen I, Selbæk G, Kirkevold Ø, Engedal K, Testad I, Bergh S. Resourse Use and Disease Couse in dementia - Nursing Home (REDIC-NH), a longitudinal cohort study; design and patient characteristics at admission to Norwegian nursing homes. BMC Health Serv Res 2017; 17:365. [PMID: 28532443 PMCID: PMC5441072 DOI: 10.1186/s12913-017-2289-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 05/03/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Earlier studies of nursing home patients show a high prevalence of dementia, neuropsychiatric symptoms (NPS), pain, and dependency in activities of daily living. The REDIC-NH cohort was set up to study the disease course and the resources used in patients with dementia in Norway. The aim of this paper was to describe the methods and the data collection, and to present selected data about patients at admission to a nursing home. METHODS We included 696 patients at admission to a nursing home and followed them with biannual assessments until death. Baseline data were collected between March 2012 and November 2014. In October 2016, patients had either completed an 18-month follow-up (n = 349), passed 18 months without assessments (n = 22), or left the study (n = 324). Data on demographics, cognition, NPS, activities of daily living (ADL) functioning, physical health, medication, Quality of Life (QoL), resource use, and caregiver burden, in addition to DNA samples were collected. RESULTS Mean age of the participants at inclusion was 84.5 years (SD 7.5, range 50 - 105), 63.9% were women. According to data collected in the study, 83.8% had dementia, but only 55.9% of them had a diagnosis of dementia registered in their records. The most frequent dementia diagnosis was Alzheimer's disease, which was present in 71% of those with dementia. Patients with dementia more often experienced delusions, hallucinations, agitation, anxiety, disinhibition, irritability, and aberrant motor behaviour compared to patients without dementia. Depression and anxiety were the most common NPS symptoms. CONCLUSIONS Dementia and NPS were highly prevalent among persons admitted to nursing homes. Only 55.9% of the patients with dementia had a diagnosis of dementia registered in their records.
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Affiliation(s)
- Irene Røen
- Centre for Old Age Psychiatric Research, Innlandet Hospital Trust, Ottestad, Norway.
| | - Geir Selbæk
- Centre for Old Age Psychiatric Research, Innlandet Hospital Trust, Ottestad, Norway
- Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Øyvind Kirkevold
- Centre for Old Age Psychiatric Research, Innlandet Hospital Trust, Ottestad, Norway
- Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
- Norwegian University of Science and Technology (NTNU), Department of Health Science in Gjøvik, Gjøvik, Norway
| | - Knut Engedal
- Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
| | - Ingelin Testad
- Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway
| | - Sverre Bergh
- Centre for Old Age Psychiatric Research, Innlandet Hospital Trust, Ottestad, Norway
- Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
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Shah C, DeMichele-Sweet MAA, Sweet RA. Genetics of psychosis of Alzheimer disease. Am J Med Genet B Neuropsychiatr Genet 2017; 174:27-35. [PMID: 26756273 PMCID: PMC5154859 DOI: 10.1002/ajmg.b.32413] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023]
Abstract
Psychotic symptoms, comprised of delusions and hallucinations, occur in about half of individuals with Alzheimer disease (AD with psychosis, AD+P). These individuals have greater agitation, aggression, depression, functional impairment, and mortality than individuals without psychosis (AD-P). Although the exact etiopathogenesis of AD+P is unclear, the rapidly developing field of genomics continues to expand our understanding of this disease. Several independent studies have demonstrated familial aggregation and heritability of AD+P. Linkage studies have been suggestive of loci on several chromosomes associated with AD+P. Association studies examining apolipoprotein E gene, the best established genetic risk factor for late-onset AD, did not find any significant association of this gene with AD+P. Other candidate gene studies focusing on monoamine neurotransmitter systems have yielded equivocal results. A genome-wide association study and studies examining copy number variations recently have detected suggestive associations, but have been underpowered. Approaches to increase sizes of AD+P samples for genome wide association studies are discussed. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Chintan Shah
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Robert A. Sweet
- Department of Psychiatry and Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
- VISN 4 Mental Health Illness Research, Education and Clinical Center (MIRECC), VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
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Woodward MC. Pharmacological Treatment of Challenging Neuropsychiatric Symptoms of Dementia. JOURNAL OF PHARMACY PRACTICE AND RESEARCH 2015. [DOI: 10.1002/j.2055-2335.2005.tb00348.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Murray PS, Kirkwood CM, Gray MC, Fish KN, Ikonomovic MD, Hamilton RL, Kofler JK, Klunk WE, Lopez OL, Sweet RA. Hyperphosphorylated tau is elevated in Alzheimer's disease with psychosis. J Alzheimers Dis 2014; 39:759-73. [PMID: 24270207 DOI: 10.3233/jad-131166] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Psychosis occurs in 40-60% of Alzheimer's disease (AD) subjects, is heritable, and indicates a more rapidly progressive disease phenotype. Neuroimaging and postmortem evidence support an exaggerated prefrontal cortical synaptic deficit in AD with psychosis. Microtubule-associated protein tau is a key mediator of amyloid-β-induced synaptotoxicity in AD, and differential mechanisms of progressive intraneuronal phospho-tau accumulation and interneuronal spread of tau aggregates have recently been described. We hypothesized that psychosis in AD would be associated with greater intraneuronal concentration of phospho-tau and greater spread of tau aggregates in prefrontal cortex. We therefore evaluated prefrontal cortex phospho-tau in a cohort of 45 AD cases with and without psychosis. Intraneuronal phospho-tau concentration was higher in subjects with psychosis, while a measure of phospho-tau spread, volume fraction, was not. Across groups both measures were associated with lower scores on the Mini-Mental State Examination and Digit Span Backwards test. These novel findings indicate that tau phosphorylation may be accelerated in AD with psychosis, indicating a more dynamic, exaggerated pathology in AD with psychosis.
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Affiliation(s)
- Patrick S Murray
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA VISN 4 Mental Illness Research, Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA
| | - Caitlin M Kirkwood
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Megan C Gray
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Kenneth N Fish
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Milos D Ikonomovic
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Geriatric Research Educational and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA
| | - Ronald L Hamilton
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Julia K Kofler
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - William E Klunk
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Oscar L Lopez
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Robert A Sweet
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA VISN 4 Mental Illness Research, Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Koppel J, Acker C, Davies P, Lopez OL, Jimenez H, Azose M, Greenwald BS, Murray PS, Kirkwood CM, Kofler J, Sweet RA. Psychotic Alzheimer's disease is associated with gender-specific tau phosphorylation abnormalities. Neurobiol Aging 2014; 35:2021-8. [PMID: 24731519 PMCID: PMC4155748 DOI: 10.1016/j.neurobiolaging.2014.03.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 02/26/2014] [Accepted: 03/03/2014] [Indexed: 12/19/2022]
Abstract
Converging evidence suggests that psychotic Alzheimer's disease (AD + P) is associated with an acceleration of frontal degeneration, with tau pathology playing a primary role. Previous histopathologic and biomarker studies have specifically implicated tau pathology in this condition. To precisely quantify tau abnormalities in the frontal cortex in AD + P, we used a sensitive biochemical assay of total tau and 4 epitopes of phospho-tau relevant in AD pathology in a postmortem sample of AD + P and AD - P. Samples of superior frontal gyrus from 26 AD subjects without psychosis and 45 AD + P subjects with psychosis were analyzed. Results of enzyme-linked immunosorbent assay demonstrate that AD + P females, but not males, had significantly higher levels of phosphorylated tau in the frontal cortex. In males, but not females, AD + P was associated with the presence of α-synuclein pathology. These results support a gender dissociation of pathology in AD + P. The design of future studies aimed at the elucidation of cognitive and/or functional outcomes; regional brain metabolic deficits; or genetic correlates of AD + P should take gender into consideration.
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Affiliation(s)
- Jeremy Koppel
- The Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA; The Zucker Hillside Hospital, The North-Shore LIJ Health System, Glen Oaks, NY, USA.
| | - Chris Acker
- The Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA
| | - Peter Davies
- The Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA
| | - Oscar L Lopez
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Heidy Jimenez
- The Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA
| | | | - Blaine S Greenwald
- The Zucker Hillside Hospital, The North-Shore LIJ Health System, Glen Oaks, NY, USA
| | - Patrick S Murray
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Caitlin M Kirkwood
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Julia Kofler
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Robert A Sweet
- The Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, NY, USA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; VISN Q2 4 Mental Illness Research, Education and Clinical Center (MIRECC), VA Pittsburgh Healthcare System, Pittsburgh, PA, USA
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Koppel J, Sunday S, Goldberg TE, Davies P, Christen E, Greenwald BS. Psychosis in Alzheimer's disease is associated with frontal metabolic impairment and accelerated decline in working memory: findings from the Alzheimer's Disease Neuroimaging Initiative. Am J Geriatr Psychiatry 2014; 22:698-707. [PMID: 23672944 DOI: 10.1016/j.jagp.2012.10.028] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Revised: 09/20/2012] [Accepted: 10/26/2012] [Indexed: 10/26/2022]
Abstract
OBJECTIVE An ascendant body of evidence suggests that Alzheimer disease with psychosis (AD+P) is a distinct variant of illness with its own genetic diathesis and a unique clinical course. Impaired frontal lobe function has been previously implicated in AD+P. The current exploratory study, presented in two parts, evaluates both the regional brain metabolic and psychometric correlates of psychosis in a longitudinal sample of subjects with AD, made available by the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS In Part 1 of the study, 21 ADNI participants with AD who developed psychotic symptoms during the study but were not psychotic at baseline were matched with 21 participants with AD who never became psychotic during the study period, and mean brain [F(18)]fluorodeoxyglucose positron emission tomography (FDG-PET) Cerebral metabolic rate for glucose (CMRgl) by regions of interest (ROIs) were compared Additionally, 39 participants with active psychosis at the time of image acquisition were matched with 39 participants who were never psychotic during the study period, and mean brain FDG-PET CMRgl by sROI were compared. In Part 2 of the study, 354 ADNI participants with AD who were followed for 24 months with serial psychometric testing were identified, and cognitive performance and decline were evaluated for correlation with psychotic symptoms. RESULTS Part 1: There were no regional brain metabolic differences between those with AD destined to become psychotic and those who did not become psychotic. There was a significant reduction in mean orbitofrontal brain metabolism in those with active psychosis. Part 2: Over the course of study follow-up, psychosis was associated with accelerated decline in functional performance as measured by the Functional Assessment Questionnaire, the Mini-Mental State Examination, and Forward Digit Span. CONCLUSION In a sample drawn from the ADNI dataset, our exploratory FDG-PET findings and longitudinal cognitive outcomes support the hypofrontality model of AD+P. Focal frontal vulnerability may mediate the accelerated decline seen in AD+P.
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Affiliation(s)
- Jeremy Koppel
- Litwin Zucker Alzheimer's Research Center, Manhasset, NY.
| | - Suzanne Sunday
- Litwin Zucker Alzheimer's Research Center, Manhasset, NY
| | | | - Peter Davies
- Litwin Zucker Alzheimer's Research Center, Manhasset, NY
| | - Erica Christen
- Litwin Zucker Alzheimer's Research Center, Manhasset, NY
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Murray PS, Kumar S, Demichele-Sweet MAA, Sweet RA. Psychosis in Alzheimer's disease. Biol Psychiatry 2014; 75:542-52. [PMID: 24103379 PMCID: PMC4036443 DOI: 10.1016/j.biopsych.2013.08.020] [Citation(s) in RCA: 129] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 07/22/2013] [Accepted: 08/19/2013] [Indexed: 12/13/2022]
Abstract
Psychotic symptoms, delusions and hallucinations, occur in approximately 50% of individuals with Alzheimer's disease (AD) (AD with psychosis [AD + P]). Pharmacotherapies for AD + P have limited efficacy and can increase short-term mortality. These observations have motivated efforts to identify the underlying biology of AD + P. Psychosis in AD indicates a more severe phenotype, with more rapid cognitive decline beginning even before psychosis onset. Neuroimaging studies suggest that AD + P subjects demonstrate greater cortical synaptic impairments than AD subjects without psychosis, reflected in reduced gray matter volume, reduced regional blood flow, and reduced regional glucose metabolism. Neuroimaging and available postmortem evidence further indicate that the impairments in AD + P, relative to AD subjects without psychosis, are localized to neocortex rather than medial temporal lobe. Neuropathologic studies provide consistent evidence of accelerated accumulation of hyperphosphorylated microtubule associated protein tau in AD + P. Finally, studies of familial aggregation of AD + P have established that the risk for psychosis in AD is, in part, genetically mediated. Although no genes are established as associated with AD + P, the first genome-wide association study of AD + P has generated some promising leads. The study of the neurobiology of AD + P is rapidly accelerating and may be poised for translational discovery. This process can be enhanced by identifying points of convergence and divergence with the neurobiology of AD proper and of schizophrenia, by innovative extension of current approaches, and by development of relevant animal models.
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Affiliation(s)
- Patrick S Murray
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center, US Department of Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
| | - Sanjeev Kumar
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Robert A Sweet
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania; Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center, US Department of Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.
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Abstract
Psychosis occurs in approximately half of patients with Alzheimer disease (AD with psychosis, AD+P). AD+P patients have more rapid cognitive decline, greater behavioral symptoms, and higher mortality than do AD patients without psychosis. Studies in three independent cohorts have shown that psychosis in AD aggregates in families, with estimated heritability of 29.5 - 60.8%. These findings have motivated studies to investigate and uncover the genes responsible for the development of psychosis, with the ultimate goal of identifying potential biologic mechanisms that may serve as leads to specific therapies. Linkage analyses have implicated loci on chromosomes 2, 6, 7, 8, 15, and 21 with AD+P. Association studies of APOE do not support it as a risk gene for psychosis in AD. No other candidate genes, such as neurodegenerative and monoamine genes, show conclusive evidence of association with AD+P. However, a recent genome-side association study has produced some promising leads, including among them genes that have been associated with schizophrenia. This review summarizes the current knowledge of the genetic basis of AD+P.
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Affiliation(s)
| | - Robert A. Sweet
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA
- VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC), VA Pittsburgh Healthcare System, Pittsburgh, PA
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Koppel J, Greenwald BS. Optimal treatment of Alzheimer's disease psychosis: challenges and solutions. Neuropsychiatr Dis Treat 2014; 10:2253-62. [PMID: 25473289 PMCID: PMC4247130 DOI: 10.2147/ndt.s60837] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Psychotic symptoms emerging in the context of neurodegeneration as a consequence of Alzheimer's disease was recognized and documented by Alois Alzheimer himself in his description of the first reported case of the disease. Over a quarter of a century ago, in the context of attempting to develop prognostic markers of disease progression, psychosis was identified as an independent predictor of a more-rapid cognitive decline. This finding has been subsequently well replicated, rendering psychotic symptoms an important area of exploration in clinical history taking - above and beyond treatment necessity - as their presence has prognostic significance. Further, there is now a rapidly accreting body of research that suggests that psychosis in Alzheimer's disease (AD+P) is a heritable disease subtype that enjoys neuropathological specificity and localization. There is now hope that the elucidation of the neurobiology of the syndrome will pave the way to translational research eventuating in new treatments. To date, however, the primary treatments employed in alleviating the suffering caused by AD+P are the atypical antipsychotics. These agents are approved by the US Food and Drug Administration for the treatment of schizophrenia, but they have only marginal efficacy in treating AD+P and are associated with troubling levels of morbidity and mortality. For clinical approaches to AD+P to be optimized, this syndrome must be disentangled from other primary psychotic disorders, and recent scientific advances must be translated into disease-specific therapeutic interventions. Here we provide a review of atypical antipsychotic efficacy in AD+P, followed by an overview of critical neurobiological observations that point towards a frontal, tau-mediated model of disease, and we suggest a new preclinical animal model for future translational research.
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Affiliation(s)
- Jeremy Koppel
- The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA ; Zucker Hillside Hospital, Hofstra North Shore-Long Island Jewish School of Medicine, Glen Oaks, NY, USA
| | - Blaine S Greenwald
- Zucker Hillside Hospital, Hofstra North Shore-Long Island Jewish School of Medicine, Glen Oaks, NY, USA
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Apostolova LG, Di LJ, Duffy EL, Brook J, Elashoff D, Tseng CH, Fairbanks L, Cummings JL. Risk factors for behavioral abnormalities in mild cognitive impairment and mild Alzheimer's disease. Dement Geriatr Cogn Disord 2014; 37:315-26. [PMID: 24481207 PMCID: PMC4057985 DOI: 10.1159/000351009] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/26/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Behavioral symptoms are common in both mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS We analyzed the Neuropsychiatric Inventory Questionnaire data of 3,456 MCI and 2,641 mild AD National Alzheimer's Coordinating Center database participants. Using factor analysis and logistic regression we estimated the effects of age, sex, race, education, Mini-Mental State Examination, functional impairment, marital status and family history on the presence of behavioral symptoms. We also compared the observed prevalence of behavioral symptoms between amnestic and nonamnestic MCI. RESULTS Four factors were identified: affective behaviors (depression, apathy and anxiety); distress/tension behaviors (irritability and agitation); impulse control behaviors (disinhibition, elation and aberrant motor behavior), and psychotic behaviors (delusions and hallucinations). Male gender was significantly associated with all factors. Younger age was associated with a higher prevalence of distress/tension, impulse control and psychotic behaviors. Being married was protective against psychotic behaviors. Lower education was associated with the presence of distress/tension behaviors. Caucasians showed a higher prevalence of affective behaviors. Functional impairment was strongly associated with all behavioral abnormalities. Amnestic MCI patients had more elation and agitation relative to nonamnestic MCI patients. CONCLUSIONS Younger age, male gender and greater functional impairment were associated with higher overall presence of behavioral abnormalities in MCI and mild AD. Marital status, lower education and race had an effect on selected behaviors.
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Affiliation(s)
| | - Li Jie Di
- Department of Neurology, UCLA, Los Angeles, CA
| | - Erin L. Duffy
- Department of Medicine Statistics Core, UCLA, Los Angeles, CA
| | - Jenny Brook
- Department of Medicine Statistics Core, UCLA, Los Angeles, CA
| | - David Elashoff
- Department of Medicine Statistics Core, UCLA, Los Angeles, CA
| | - Chi-Hong Tseng
- Department of Medicine Statistics Core, UCLA, Los Angeles, CA
| | - Lynn Fairbanks
- Department of Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, CA
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Wang KS, Xu N, Wang L, Aragon L, Ciubuc R, Arana TB, Mao C, Petty L, Briones D, Su BB, Luo X, Camarillo C, Escamilla MA, Xu C. NRG3 gene is associated with the risk and age at onset of Alzheimer disease. J Neural Transm (Vienna) 2013; 121:183-92. [PMID: 24061483 DOI: 10.1007/s00702-013-1091-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Accepted: 09/03/2013] [Indexed: 10/26/2022]
Abstract
The Neuregulin 3 (NRG3) gene at 10q22-q24 has been implicated in multiple psychiatric traits such as cognitive impairment. We therefore hypothesized that NRG3 gene polymorphisms may play a role in Alzheimer disease (AD). This present study explored the association of NRG3 with the age at onset (AAO) of AD and the risk of developing AD. Secondary data analysis of 257 single-nucleotide polymorphisms (SNPs) in NRG3 gene was performed in 806 Alzheimer's disease patients and 782 controls using logistic regression and linear regression analyses. Eight SNPs were associated with the risk of AD (p < 0.05), while linear regression analysis showed 33 SNPs associated with the AAO of AD (p < 0.05). Two-SNP haplotype analyses based on UNPHASED revealed that the G-C haplotype from rs17685233 and rs17101017 was significantly associated with AD (p = 0.0031) and the A-G haplotype from rs504522 and rs474018 as well as the A-G haplotype from rs504522 and rs2483295 were more significantly associated with the AAO of AD (p = 6.72 × 10(-5)). Using an independent family-based sample, we found one SNP rs11192423 associated with AAO both in the case-control sample (p = 0.0155) and in the family sample (p = 0.0166). In addition, we observed nominally significant associations with AD and AAO for several flanking SNPs (p < 0.05). This is the first study demonstrating that genetic variants in the NRG3 gene play a role in AD. Our results also revealed that SNPs in the NRG3 genes were more strongly associated with AAO of AD.
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Affiliation(s)
- Ke-Sheng Wang
- Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, PO Box 70259, Lamb Hall, Johnson City, TN, 37614-1700, USA,
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Penzes P, Buonanno A, Passafaro M, Sala C, Sweet RA. Developmental vulnerability of synapses and circuits associated with neuropsychiatric disorders. J Neurochem 2013; 126:165-82. [PMID: 23574039 PMCID: PMC3700683 DOI: 10.1111/jnc.12261] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 04/08/2013] [Indexed: 12/20/2022]
Abstract
Psychiatric and neurodegenerative disorders, including intellectual disability, autism spectrum disorders (ASD), schizophrenia (SZ), and Alzheimer's disease, pose an immense burden to society. Symptoms of these disorders become manifest at different stages of life: early childhood, adolescence, and late adulthood, respectively. Progress has been made in recent years toward understanding the genetic substrates, cellular mechanisms, brain circuits, and endophenotypes of these disorders. Multiple lines of evidence implicate excitatory and inhibitory synaptic circuits in the cortex and hippocampus as key cellular substrates of pathogenesis in these disorders. Excitatory/inhibitory balance--modulated largely by dopamine--critically regulates cortical network function, neural network activity (i.e. gamma oscillations) and behaviors associated with psychiatric disorders. Understanding the molecular underpinnings of synaptic pathology and neuronal network activity may thus provide essential insight into the pathogenesis of these disorders and can reveal novel drug targets to treat them. Here, we discuss recent genetic, neuropathological, and molecular studies that implicate alterations in excitatory and inhibitory synaptic circuits in the pathogenesis of psychiatric disorders across the lifespan.
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Affiliation(s)
- Peter Penzes
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
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Pereira PA, Romano-Silva MA, Bicalho MAC, de Moraes EN, Malloy-Diniz L, Pimenta GJGS, Mello MP, Bozzi ICRS, de Marco LA, Nicolato R, Miranda DM. Catechol-O-methyltransferase genetic variant associated with the risk of Alzheimer's disease in a Brazilian population. Dement Geriatr Cogn Disord 2013; 34:90-5. [PMID: 22922787 DOI: 10.1159/000341578] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/20/2012] [Indexed: 11/19/2022] Open
Abstract
The aim of the present study was to examine the association between polymorphism in the catechol-O-methyltransferase(COMT) gene and Alzheimer's disease (AD) in a Brazilian population. The case-control method was used to study the association between AD and genetic variants of COMT. Six tag single-nucleotide polymorphisms(SNPs) in the COMT gene were genotyped by RT-PCR. Our findings showed that the 6 tag SNPs analyzed in this study were not associated with AD at the allele and genotype levels in comparison with the control group. No statistical difference was found between groups with and without behavioral and psychological symptoms of dementia (BPSD). Our results do not support the hypothesis that the polymorphisms of the COMT gene may be associated with susceptibility to AD with and without BPSD.
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Affiliation(s)
- Patricia Araújo Pereira
- INCT - de Medicina Molecular, Faculdade de Medicina,Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
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Hollingworth P, Sweet R, Sims R, Harold D, Russo G, Abraham R, Stretton A, Jones N, Gerrish A, Chapman J, Ivanov D, Moskvina V, Lovestone S, Priotsi P, Lupton M, Brayne C, Gill M, Lawlor B, Lynch A, Craig D, McGuinness B, Johnston J, Holmes C, Livingston G, Bass NJ, Gurling H, McQuillin A, GERAD Consortium, the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study Group, Holmans P, Jones L, Devlin B, Klei L, Barmada MM, Demirci FY, DeKosky ST, Lopez OL, Passmore P, Owen MJ, O’Donovan MC, Mayeux R, Kamboh MI, Williams J. Genome-wide association study of Alzheimer's disease with psychotic symptoms. Mol Psychiatry 2012; 17:1316-27. [PMID: 22005930 PMCID: PMC3272435 DOI: 10.1038/mp.2011.125] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Revised: 08/03/2011] [Accepted: 08/25/2011] [Indexed: 02/02/2023]
Abstract
Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.
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Affiliation(s)
- Paul Hollingworth
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Robert Sweet
- Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA
- Department of Neurology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA
- VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC), VA Pittsburgh Healthcare System, Pittsburgh, PA, 15206 USA
| | - Rebecca Sims
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Denise Harold
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Giancarlo Russo
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Richard Abraham
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Alexandra Stretton
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Nicola Jones
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Amy Gerrish
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Jade Chapman
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Dobril Ivanov
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Valentina Moskvina
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Simon Lovestone
- Department of Neuroscience, Institute of Psychiatry, Kings College, London, UK
| | - Petroula Priotsi
- Department of Neuroscience, Institute of Psychiatry, Kings College, London, UK
| | - Michelle Lupton
- Department of Neuroscience, Institute of Psychiatry, Kings College, London, UK
| | - Carol Brayne
- Institute of Public Health, University of Cambridge, Cambridge, UK
| | - Michael Gill
- Mercer’s Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland
| | - Brian Lawlor
- Mercer’s Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland
| | - Aoibhinn Lynch
- Mercer’s Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland
| | - David Craig
- Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University of Belfast, UK
| | - Bernadette McGuinness
- Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University of Belfast, UK
| | - Janet Johnston
- Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University of Belfast, UK
| | - Clive Holmes
- Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK
| | - Gill Livingston
- Department of Mental Health Sciences, University College London, UK
| | - Nicholas J. Bass
- Department of Mental Health Sciences, University College London, UK
| | - Hugh Gurling
- Department of Mental Health Sciences, University College London, UK
| | - Andrew McQuillin
- Department of Mental Health Sciences, University College London, UK
| | - GERAD Consortium
- Data used in the preparation of this article were obtained from the Genetic and Environmental Risk in Alzheimer’s disease GWAS (GERAD) genome-wide association study(2). As such, the investigators within the GERAD consortium contributed to the design and implementation of GERAD and/or provided data but did not participate in analysis or writing of this report. See supplementary content for members of the GERAD consortium
| | - the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study Group
- Data used in the preparation of this article were obtained from the National Institute on Aging Late-Onset Alzheimer’s disease Family Study Group (NIA-LOAD). As such, the investigators within the NIA-LOAD consortium contributed to the design and implementation of NIA-LOAD and/or provided data but did not participate in analysis or writing of this report. See supplementary content for members of the NIA-LOAD consortium
| | - Peter Holmans
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Lesley Jones
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Bernie Devlin
- Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA
| | - Lambertus Klei
- Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA
| | - M. Michael Barmada
- Taub Institute and the Department of Neurology , Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032, USA
| | - F. Yesim Demirci
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Steven T. DeKosky
- Department of Neurology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA
- University of Virginia School of Medicine, Charlottesville VA, 22908 USA
| | - Oscar L. Lopez
- Department of Neurology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA
| | - Peter Passmore
- Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University of Belfast, UK
| | - Michael J Owen
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Michael C O’Donovan
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Richard Mayeux
- Taub Institute and the Department of Neurology , Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032, USA
| | - M. Ilyas Kamboh
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Julie Williams
- Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
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Jellinger KA. Cerebral correlates of psychotic syndromes in neurodegenerative diseases. J Cell Mol Med 2012; 16:995-1012. [PMID: 21418522 PMCID: PMC4365880 DOI: 10.1111/j.1582-4934.2011.01311.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2011] [Accepted: 03/01/2011] [Indexed: 12/20/2022] Open
Abstract
Psychosis has been recognized as a common feature in neurodegenerative diseases and a core feature of dementia that worsens most clinical courses. It includes hallucinations, delusions including paranoia, aggressive behaviour, apathy and other psychotic phenomena that occur in a wide range of degenerative disorders including Alzheimer's disease, synucleinopathies (Parkinson's disease, dementia with Lewy bodies), Huntington's disease, frontotemporal degenerations, motoneuron and prion diseases. Many of these psychiatric manifestations may be early expressions of cognitive impairment, but often there is a dissociation between psychotic/behavioural symptoms and the rather linear decline in cognitive function, suggesting independent pathophysiological mechanisms. Strictly neuropathological explanations are likely to be insufficient to explain them, and a large group of heterogeneous factors (environmental, neurochemical changes, genetic factors, etc.) may influence their pathogenesis. Clinico-pathological evaluation of behavioural and psychotic symptoms (PS) in the setting of neurodegenerative and dementing disorders presents a significant challenge for modern neurosciences. Recognition and understanding of these manifestations may lead to the development of more effective preventive and therapeutic options that can serve to delay long-term progression of these devastating disorders and improve the patients' quality of life. A better understanding of the pathophysiology and distinctive pathological features underlying the development of PS in neurodegenerative diseases may provide important insights into psychotic processes in general.
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Association of serotonin and dopamine gene pathways with behavioral subphenotypes in dementia. Neurobiol Aging 2012; 33:791-803. [DOI: 10.1016/j.neurobiolaging.2010.06.011] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2010] [Revised: 06/10/2010] [Accepted: 06/16/2010] [Indexed: 11/22/2022]
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Murray PS, Kirkwood CM, Gray MC, Ikonomovic MD, Paljug WR, Abrahamson EE, Henteleff RA, Hamilton RL, Kofler JK, Klunk WE, Lopez OL, Penzes P, Sweet RA. β-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis. Neurobiol Aging 2012; 33:2807-16. [PMID: 22429885 DOI: 10.1016/j.neurobiolaging.2012.02.015] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Revised: 02/03/2012] [Accepted: 02/12/2012] [Indexed: 12/13/2022]
Abstract
Psychosis in Alzheimer disease differentiates a subgroup with more rapid decline, is heritable, and aggregates within families, suggesting a distinct neurobiology. Evidence indicates that greater impairments of cerebral cortical synapses, particularly in dorsolateral prefrontal cortex, may contribute to the pathogenesis of psychosis in Alzheimer disease (AD) phenotype. Soluble β-amyloid induces loss of dendritic spine synapses through impairment of long-term potentiation. In contrast, the Rho guanine nucleotide exchange factor (GEF) kalirin is an essential mediator of spine maintenance and growth in cerebral cortex. We therefore hypothesized that psychosis in AD would be associated with increased soluble β-amyloid and reduced expression of kalirin in the cortex. We tested this hypothesis in postmortem cortical gray matter extracts from 52 AD subjects with and without psychosis. In subjects with psychosis, the β-amyloid(1-42)/β-amyloid(1-40) ratio was increased, due primarily to reduced soluble β-amyloid(1-40), and kalirin-7, -9, and -12 were reduced. These findings suggest that increased cortical β-amyloid(1-42)/β-amyloid(1-40) ratio and decreased kalirin expression may both contribute to the pathogenesis of psychosis in AD.
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Affiliation(s)
- Patrick S Murray
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Proitsi P, Powell JF. Missense substitutions associated with behavioural disturbances in Alzheimer's disease (AD). Brain Res Bull 2012; 88:394-405. [PMID: 22414959 DOI: 10.1016/j.brainresbull.2012.02.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Revised: 02/03/2012] [Accepted: 02/24/2012] [Indexed: 11/18/2022]
Abstract
Behavioural and psychological symptoms in dementia, or BPSD, occur in the majority of Alzheimer's disease (AD) patients. They are associated with considerable patient morbidity and greater care-giver stress. There is some evidence suggesting that BPSD have a genetic component and a large number of studies have examined the association of candidate genes with these symptoms. This review provides a comprehensive summary of all the published studies investigating the association of candidate gene missense substitutions with BPSD. Missense substitutions could potentially alter protein function or render the protein non-functional, resulting in phenotypic consequences. More than 80 studies investigating the association of 8 missense substitutions in 7 genes with BPSD were identified. However, results of these studies are contradictory and do not provide firm support for these associations. Larger studies and more systematic approaches will delineate the association of missense substitutions with behavioural symptoms in AD.
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Affiliation(s)
- Petroula Proitsi
- King's College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, London SE5 8AF, UK.
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Panza F, Frisardi V, Seripa D, D'Onofrio G, Santamato A, Masullo C, Logroscino G, Solfrizzi V, Pilotto A. Apolipoprotein E genotypes and neuropsychiatric symptoms and syndromes in late-onset Alzheimer's disease. Ageing Res Rev 2012; 11:87-103. [PMID: 21763789 DOI: 10.1016/j.arr.2011.06.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2010] [Revised: 05/29/2011] [Accepted: 06/30/2011] [Indexed: 12/31/2022]
Abstract
Neuropsychiatric symptoms (NPS) in dementia, previously denominated as behavioural and psychological symptoms of dementia, are often more distressing, impairing, and costly than cognitive symptoms, representing a major health burden for older adults. These symptoms are common features of Alzheimer's disease (AD), and are one of the major risk factors for institutionalization. There is a high prevalence of neuropsychiatric disturbances in patients with AD, including depression, anxiety, apathy, psychosis, aggression, and agitation. At present, the role of the apolipoprotein E (APOE) genotypes in the development of NPS or neuropsychiatric syndromes/endophenotypes in AD patients is unclear. In this article, we summarized the findings of the studies of NPS and neuropsychiatric syndromes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between the APOE polymorphism and NPS in late-onset AD, other studies reported a significant association between the APOE ɛ4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. However, current cumulative evidence coming from the few existing longitudinal studies shows no association of APOE genotypes with NPS as a whole in AD. Some negative studies that focused on the distribution of APOE genotypes between AD patients with or without NPS further emphasized the importance of sub-grouping NPS in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, possible lack of statistical power to detect associations in the negative studies, and small sample sizes generating false positives that cannot be consistently replicated. Finally, many reviewed studies were cross-sectional, whereas it would be of paramount importance to evaluate the risk for incident NPS in relation to the APOE genotype in prospectively followed cohorts of AD patients. In fact, identifying predisposing genetic risk factors may allow us to understand the pathophysiological features of neuropsychiatric syndromes or symptoms in AD, so optimizing possible therapeutic options.
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Affiliation(s)
- Francesco Panza
- Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
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Hollingworth P, Harold D, Jones L, Owen MJ, Williams J. Alzheimer's disease genetics: current knowledge and future challenges. Int J Geriatr Psychiatry 2011; 26:793-802. [PMID: 20957767 DOI: 10.1002/gps.2628] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Accepted: 07/29/2010] [Indexed: 11/08/2022]
Abstract
Alzheimer's disease (AD) is highly heritable, but genetically complex. Recently, three large-scale genome-wide association studies have made substantial breakthroughs in disentangling the genetic architecture of the disease. These studies combined include data from over 43 000 independent individuals and provide compelling evidence that variants in four novel susceptibility genes (CLU, PICALM, CR1, BIN1) are associated with disease risk. These findings are tremendously exciting, not only in providing new avenues for exploration, but also highlighting the potential for further gene discovery when larger samples are analysed. Here we discuss progress to date in identifying risk genes for dementia, ways forward and how current findings are refining previous ideas and defining new putative primary disease mechanisms.
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Affiliation(s)
- Paul Hollingworth
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
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Narayanaswamy JC, Varghese M, Jain S, Sivakumar PT, Prakash O, Bharath S, Kandavel T. Is there a familial overlap between dementia and other psychiatric disorders? Int Psychogeriatr 2011; 23:749-55. [PMID: 21205363 DOI: 10.1017/s1041610210001572] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Cognitive and psychiatric features are important components of dementia. Early onset dementia (EOD) has been found to be associated with a greater genetic basis. If this is the case, EOD could have genetic association with psychiatric illnesses, given the presence of more behavioral disturbances in this condition. There is a definite need to explore the presence of psychiatric symptoms and disorders in families of patients with dementia. METHODS The authors compared 52 proband families of dementia and 45 control families in order to assess the familial co-aggregation of major psychiatric illnesses. The cumulative risk in first degree relatives in the two groups for major psychiatric illnesses was calculated using Kaplan Meier Survival analysis. Early onset and late onset dementia proband families were compared separately with control families for the same. RESULTS There was a significantly higher morbid risk for psychosis in dementia proband families (generalized Wilcoxon, Breslow -4.165, p = 0.041). Also, the morbid risk was higher in early onset dementia proband families (generalized Wilcoxon, Breslow -6.16, p = 0.013) while it was not so in late onset dementia proband families (generalized Wilcoxon, Breslow -2.99, p = 0.084). CONCLUSION There is a possible genetic overlap between dementia and psychosis. This appears to be more pronounced with early onset dementia than with late onset dementia.
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Affiliation(s)
- Janardhanan C Narayanaswamy
- Department of Psychiatry, Geriatric Clinic and Services, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
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Panza F, Seripa D, D'Onofrio G, Frisardi V, Solfrizzi V, Mecocci P, Pilotto A. Neuropsychiatric Symptoms, Endophenotypes, and Syndromes in Late-Onset Alzheimer's Disease: Focus on APOE Gene. Int J Alzheimers Dis 2011; 2011:721457. [PMID: 21559196 PMCID: PMC3090058 DOI: 10.4061/2011/721457] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2010] [Revised: 02/11/2011] [Accepted: 02/11/2011] [Indexed: 01/31/2023] Open
Abstract
Neuropsychiatric symptoms, previously denominated as behavioural and psychological symptoms of dementia, are common features of Alzheimer's disease (AD) and are one of the major risk factors for institutionalization. At present, the role of the apolipoprotein E (APOE) gene in the development of neuropsychiatric symptoms in AD patients is unclear. In this paper, we summarized the findings of the studies of neuropsychiatric symptoms and neuropsychiatric syndromes/endophenotypes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between APOE and neuropsychiatric symptoms in late-onset AD, other studies reported a significant association between the APOE ε4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. Furthermore, some negative studies that focused on the distribution of APOE genotypes between AD patients with or without neuropsychiatric symptoms further emphasized the importance of subgrouping neuropsychiatric symptoms in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, and possible lack of statistical power to detect associations in the negative studies.
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Affiliation(s)
- Francesco Panza
- Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, 71013 Foggia, Italy
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Demichele-Sweet MAA, Lopez OL, Sweet RA. Psychosis in Alzheimer's disease in the national Alzheimer's disease coordinating center uniform data set: clinical correlates and association with apolipoprotein e. Int J Alzheimers Dis 2011; 2011:926597. [PMID: 21461363 PMCID: PMC3065057 DOI: 10.4061/2011/926597] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Accepted: 01/03/2011] [Indexed: 11/20/2022] Open
Abstract
Approximately 50% of late-onset Alzheimer's disease (AD) patients develop psychosis (AD+P), a heritable phenotype associated with more rapid cognitive decline. Prior studies conflict regarding whether apolipoprotein E (APOE) ϵ4 alleles are associated with AD+P, possibly due to small sample sizes, inconsistent diagnostic criteria, and different methodologies to assess psychosis. We used the National Alzheimer's Coordinating Center Uniform Data Set to evaluate the largest uniformly characterized sample of AD+P subjects studied to date for the association of APOE ϵ4 genotype, along with other demographic and clinical variables. Greater cognitive impairment and depressive symptoms were associated with AD+P, while the Caucasian race was protective. Neither APOE ϵ4 carrier status nor allele number was associated with psychosis. The AD+P phenotype is not associated with the APOE ϵ4 genotype. AD+P may represent a useful phenotype for the discovery of non-APOE ϵ4 genetic variation contributing to the risk of AD.
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Nervi A, Reitz C, Tang MX, Santana V, Piriz A, Reyes D, Lantigua R, Medrano M, Jiménez-Velázquez IZ, Lee JH, Mayeux R. Familial aggregation of dementia with Lewy bodies. ACTA ACUST UNITED AC 2011; 68:90-3. [PMID: 21220678 DOI: 10.1001/archneurol.2010.319] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
BACKGROUND Familial aggregation of dementia with Lewy bodies (DLB) remains unclear. OBJECTIVES To determine the degree of family aggregation of DLB by comparing DLB risk between siblings of probands with clinically diagnosed DLB and siblings of probands with clinically diagnosed Alzheimer disease in a cohort of Caribbean Hispanic families and to explore the degree of aggregation of specific clinical manifestations (ie, cognitive fluctuations, visual hallucinations, and parkinsonism) in DLB. DESIGN Familial cohort study. SETTING Academic research. PATIENTS We separately compared risks of possible DLB, probable DLB, and clinical core features of DLB (cognitive fluctuations, visual hallucinations, and parkinsonism) between siblings of probands with clinically diagnosed DLB (n = 344) and siblings of probands with clinically diagnosed Alzheimer disease (n = 280) in 214 Caribbean Hispanic families with extended neurologic and neuropsychological assessment. MAIN OUTCOME MEASURES We applied general estimating equations to adjust for clustering within families. In these models, age and proband disease status were independent variables, and disease status of siblings was the measure of disease risk and the dependent variable. RESULTS Compared with siblings of probands having clinically diagnosed Alzheimer disease, siblings of probands having clinically diagnosed DLB had higher risks of probable DLB (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.04-5.04) and visual hallucinations (2.32; 1.16-4.64). They also had increased risks of possible DLB (OR, 1.51; 95% CI, 0.97-2.34) and cognitive fluctuations (1.55; 0.95-2.53). CONCLUSIONS Dementia with Lewy bodies and core features of DLB aggregate in families. Compared with siblings of probands having clinically diagnosed AD, siblings of probands having clinically diagnosed DLB are at increased risks of DLB and visual hallucinations. These findings are an important step in elucidating the genetic risk factors underlying DLB and in delineating DLB from other neurodegenerative diseases, such as Alzheimer disease.
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Affiliation(s)
- Angela Nervi
- Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
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Trajectory of cognitive decline as a predictor of psychosis in early Alzheimer disease in the cardiovascular health study. Am J Geriatr Psychiatry 2011; 19:160-8. [PMID: 20808116 PMCID: PMC3000865 DOI: 10.1097/jgp.0b013e3181e446c8] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To compare the trajectories of cognitive decline between groups with, and without, the later development of psychotic symptoms during Alzheimer disease (AD) or mild cognitive impairment (MCI). DESIGN : The authors examined cognitive function in a new analysis of an existing data set, the Cardiovascular Health Study, an epidemiologic, longitudinal follow-up study. Our analyses examined 9 years of follow-up data. SETTING Community. PARTICIPANTS The authors examined subjects who were without dementia at study entry, received a diagnosis of AD or MCI during follow-up, and had been rated on the Neuropsychiatric Inventory for the presence of psychosis; 362 participants for the modified Mini-Mental State Examination (3MS) analysis and 350 participants for the digit symbol substitution test (DSST) analysis had sufficient follow-up data and apolipoprotein-∊ (APOE) genotyping. MEASUREMENTS The 3MS and DSST were administered annually and analyzed using mixed-effects models including APOE4 status. RESULTS : Mean 3MS and DSST scores did not differ between AD with psychosis (AD + P) and without psychosis groups at baseline. The 3MS and DSST scores decreased more rapidly in subjects who ultimately developed psychosis. CONCLUSIONS Individuals who ultimately develop psychosis have more rapid cognitive deterioration during the earliest phases of AD than individuals with AD not developing psychosis. The genetic and other neurobiologic factors leading to the expression of AD + P may exert their effects by acceleration of the neurodegenerative process.
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DeMichele-Sweet MAA, Klei L, Devlin B, Ferrell RE, Weamer EA, Emanuel JE, Lopez OL, Sweet RA. No association of psychosis in Alzheimer disease with neurodegenerative pathway genes. Neurobiol Aging 2010; 32:555.e9-11. [PMID: 21093110 DOI: 10.1016/j.neurobiolaging.2010.10.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2010] [Revised: 09/24/2010] [Accepted: 10/03/2010] [Indexed: 01/21/2023]
Abstract
Psychotic symptoms occur in approximately 40% of subjects with Alzheimer disease (AD with psychosis; AD + P) and identify a subgroup with more rapid cognitive decline. We evaluated in 867 AD subjects the association of AD + P with genes which may modify the pathological process via effects on the accumulation of amyloid beta (Aβ) protein and/or hyperphosphorylated microtubule-associated protein tau (MAPT): amyloid precursor protein (APP), beta-site amyloid precursor protein cleaving enzyme (BACE1), sortilin-related receptor (SORL1), and MAPT. Each gene was thoroughly interrogated with tag single-nucleotide polymorphisms (SNPs), and gene-based tests were used to enhance power. We found no association of these genes with AD + P.
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DeMichele-Sweet MA, Sweet RA. Genetics of psychosis in Alzheimer's disease: a review. J Alzheimers Dis 2010; 19:761-80. [PMID: 20157235 DOI: 10.3233/jad-2010-1274] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
In and of itself, late-onset Alzheimer's disease (AD) can be a devastating illness. However, a sub-group of AD patients develop psychosis as the disease progresses. These patients have an added burden of greater cognitive impairment, higher rates of institutionalization, and higher mortality than AD patients without psychosis. While the etiopathogenesis such as psychosis in AD (AD+P) is not known, mounting evidence accrued over the past ten years indicates that AD+P represents a distinct phenotype with a genetic basis. Elucidating the genetic mechanism of AD+P is crucial if better pharmaceutical treatments are to be developed for these patients. The goal of this review is to summarize what is currently known regarding the genetic basis of psychosis in AD. Specific attention is given to familial aggregation and heritability, linkage to chromosomal loci, and associations of candidate genes of APOE and the monoamine neurotransmitter system.
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Sweet RA, Bennett DA, Graff-Radford NR, Mayeux R. Assessment and familial aggregation of psychosis in Alzheimer's disease from the National Institute on Aging Late Onset Alzheimer's Disease Family Study. Brain 2010; 133:1155-62. [PMID: 20147454 PMCID: PMC2912688 DOI: 10.1093/brain/awq001] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2009] [Revised: 11/23/2009] [Accepted: 12/16/2009] [Indexed: 01/28/2023] Open
Abstract
Determining the genetic architecture of late onset Alzheimer's disease remains an important research objective. One approach to the identification of novel genetic variants contributing to the disease is the classification of biologically meaningful subgroups within the larger late-onset Alzheimer's disease phenotype. The occurrence of psychotic symptoms in patients with late-onset Alzheimer's disease may identify one such group. We attempted to establish methods for the reliable assessment of psychotic symptoms in a large, geographically dispersed collection of families, multiply affected with late onset Alzheimer's disease, who were participants in the larger National Institute on Aging Late Onset Alzheimer's Disease Family Study; and to characterize the correlates and familial aggregation of psychosis within this cohort. We found that reliable assessments of psychotic symptoms during in-person or phone interviews were readily implemented. The presence of psychosis in late onset Alzheimer's disease was significantly associated with degree of cognitive impairment, and significantly, albeit modestly, correlated with the severity of other behavioural symptoms. Psychosis significantly aggregated within late onset Alzheimer's disease families suggesting that it may identify a genetically determined subgroup. Future studies should examine the linkage and association of psychosis with genetic variation within these families.
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Affiliation(s)
- Robert A Sweet
- Department of Psychiatry, University of Pittsburgh, Biomedical Science Tower, Rm W-1645, 3811 O'Hara Street, Pittsburgh, PA 15213-2593, USA.
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Pritchard AL, Ratcliffe L, Sorour E, Haque S, Holder R, Bentham P, Lendon CL. Investigation of dopamine receptors in susceptibility to behavioural and psychological symptoms in Alzheimer's disease. Int J Geriatr Psychiatry 2009; 24:1020-5. [PMID: 19235789 DOI: 10.1002/gps.2214] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Alzheimer's disease (AD) patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to the development of BPSD in AD has been supported. Polymorphisms within dopamine receptors DRD1, DRD2, DRD3 and DRD4 have previously been investigated in a few interesting studies that are reviewed here and extended using our patient cohort. METHODS Our large cohort of 395 probable AD patients had longitudinal information on the BPSD (Neuropsychiatric Inventory), which was used to dichotomise patients into whether they had ever suffered from a given symptom within the study period, or not. These measures were related to the DRD1 (A-48G), DRD2 (ser311cys; C-ins/del), DRD3 (ser9gly) and DRD4 (VNTR) genotype and allele frequencies. RESULTS Associations were revealed between DRD3 and elation, and between DRD4 with agitation/aggression and with depression; however, these findings do not remain significant after correction for multiple testing. No associations were found with the other genetic variants and these symptoms and no associations were observed between any of the polymorphic variants examined and delusions, hallucinations, psychosis and aberrant motor behaviour. CONCLUSION Our data, in combination with a review of the literature, reveal a potential role for the VNTR variant of DRD4 in the development of depression in AD patients. The findings presented here need to be replicated in large, well characterised longitudinal cohorts.
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Affiliation(s)
- Antonia L Pritchard
- Molecular Psychiatry Group, Population Studies and Human Genetics, G Floor CBCRC Building, Queensland Institute of Medical Research, Herston, Brisbane, 4006, Australia.
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Weamer EA, Emanuel JE, Varon D, Miyahara S, Wilkosz PA, Lopez OL, DeKosky ST, Sweet RA. The relationship of excess cognitive impairment in MCI and early Alzheimer's disease to the subsequent emergence of psychosis. Int Psychogeriatr 2009; 21:78-85. [PMID: 18814807 PMCID: PMC2678562 DOI: 10.1017/s1041610208007734] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Psychotic symptoms in Alzheimer disease (AD + P) identify a heritable phenotype associated with greater cognitive impairment. Knowing when the cognitive course of AD + P subjects diverges from that of subjects without psychosis would enhance understanding of how genetic variation results in AD + P and its associated cognitive burden. This study seeks to determine whether the degree of cognitive impairment and cognitive decline in early AD predicts subsequent AD + P onset. METHODS 361 subjects with possible or probable AD or mild cognitive impairment (MCI) without psychosis were evaluated every 6 months until psychosis onset. RESULTS Severity of cognitive dysfunction was a strong predictor of AD + P up to two years prior to psychosis onset. Cognition did not decline more rapidly prior to onset of AD + P. CONCLUSIONS Individuals who will develop AD + P already demonstrate excess cognitive impairment during the mild stages of disease. Genetic variation and brain pathophysiology may lead to a cognitive risk phenotype which is present prior to dementia onset.
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Affiliation(s)
- Elise A. Weamer
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA
| | - James E. Emanuel
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
| | - Daniel Varon
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
| | - Sachiko Miyahara
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA
| | | | - Oscar L. Lopez
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA
| | - Steven T. DeKosky
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA
| | - Robert A. Sweet
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA
- VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC), VA Pittsburgh Healthcare System, Pittsburgh, PA
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Wilkosz PA, Kodavali C, Weamer EA, Miyahara S, Lopez OL, Nimgaonkar VL, DeKosky ST, Sweet RA. Prediction of psychosis onset in Alzheimer disease: the role of depression symptom severity and the HTR2A T102C polymorphism. Am J Med Genet B Neuropsychiatr Genet 2007; 144B:1054-62. [PMID: 17525976 PMCID: PMC2818007 DOI: 10.1002/ajmg.b.30549] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Psychotic symptoms in Alzheimer disease (AD + P) identify a heritable phenotype associated with a more severe course. We recently found an association of AD + P with depression symptom severity. Reports have shown an association of a serotonin-2A receptor (HTR2A) gene T102C polymorphism with AD + P and with depression during AD. We examined the interaction of this common genetic polymorphism with depression and increased psychosis risk. Subjects with possible or probable AD or mild cognitive impairment (MCI) without psychosis at study entry were genotyped for the HTR2A T102C polymorphism and reassessed every 6 months until psychosis onset. Psychotic and depressive symptoms were rated using the CERAD behavioral rating scale (CBRS). Cox proportional hazard models with time-dependent covariates were used to examine associations with psychosis onset. A total of 324 Caucasian subjects completed at least one follow-up exam. Depressive symptom severity was a strong predictor of psychosis onset. Neither psychosis onset nor depression severity was associated with the HTR2A genotype. Genotype interacted with depression severity to moderate the risk of AD + P onset. This did not result from an interaction of HTR2A genotype with antidepressant use. Psychosis onset in AD is strongly associated with severity of depressive symptoms, an association that may be modified by HTR2A genotype.
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Affiliation(s)
| | | | - Elise A. Weamer
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
| | - Sachiko Miyahara
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA
| | - Oscar L. Lopez
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA
| | | | - Steven T. DeKosky
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA
| | - Robert A. Sweet
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA
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Pritchard AL, Pritchard CW, Bentham P, Lendon CL. Role of serotonin transporter polymorphisms in the behavioural and psychological symptoms in probable Alzheimer disease patients. Dement Geriatr Cogn Disord 2007; 24:201-6. [PMID: 17690552 DOI: 10.1159/000107081] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/27/2007] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Alzheimer disease (AD) patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in AD has been demonstrated. This is an investigation of whether the linked polymorphic region and variable number tandem repeat variants of the serotonin transporter (SERT) are associated with BPSD. METHODS The longitudinal measures of BPSD of our large cohort of 367 AD patients were assessed by the Neuropsychiatric Inventory. Measures with good evidence of serotonergic involvement (delusions, hallucinations, depression, anxiety, agitation/aggression and irritability) were related to genotype and allele frequencies of the linked polymorphic region and variable number tandem repeat variants. RESULTS Analysis revealed significant relationships between the linked polymorphic region variant long allele with irritability and the variable number tandem repeat 10-repeat allele with psychosis, but no associations were found with depression, anxiety or agitation/aggression. CONCLUSION Our data and review of previous studies suggest SERT could play a minor role in development of psychosis and aggressive/irritable tendencies; however, further investigations are required in large, well-characterized cohorts.
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Affiliation(s)
- Antonia L Pritchard
- Molecular Psychiatry Group, Queensland Institute of Medical Research, Herston, Brisbane, Australia.
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