|
1
|
Rangwala R, Bahia MM, Song J, Bega D, Martin-Harris B. Association between Perceived Dysphagia Symptoms and Swallowing Physiology in Parkinson's Disease. Mov Disord Clin Pract 2025. [PMID: 40396298 DOI: 10.1002/mdc3.70129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/23/2025] [Accepted: 05/01/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Swallowing disorders are prevalent in Parkinson's disease (PD). Swallowing assessment often relies on patient-reported outcome measures (PROMs). Although PROMs and physiologic swallowing measures correlate with disease severity, the relationship between PROMs and physiologic swallowing impairments is unclear. OBJECTIVES Our aim was to (1) delineate the relationship between perceived swallowing symptoms and physiologic swallowing impairments; and (2) determine the relationship between swallowing-related quality of life (QoL) and physiologic impairments. METHODS A total of 31 individuals with PD (mean age = 64.8, standard deviation = 9.4) and dysphagia were recruited. PROMs included the Sydney Swallow Questionnaire (SSQ) and Swallowing Quality of Life Survey (SWAL-QOL) to measure perceived swallowing-related symptoms and QoL, respectively. Participants underwent a Modified Barium Swallow Study (MBSS) to obtain physiologic swallowing measures, including the Modified Barium Swallow Impairment Profile (MBSImP) and Penetration-Aspiration Scale (PAS). Multiple linear regression analyses assessed the associations between PROMs and physiologic measures, controlling for disease duration. RESULTS Perceived swallowing difficulties indicated mild to moderate symptoms (SSQ: 20-871.5), and perceived swallowing-related QoL showed moderate to no impact (SWAL-QOL: 52.5%-100%). Swallowing components oral residue (97%) and delayed pharyngeal swallow (97%) were the most frequently impaired on the MBSImP. Furthermore, 45.2% of participants showed airway invasion (PAS ≥3) in at least one swallow trial. Regression analysis showed significant associations between MBSImP pharyngeal total score with SSQ (P < 0.001, R2 = 0.49) and SWAL-QOL (P = 0.014, R2 = 0.36). CONCLUSIONS These findings suggest that PROMs may not fully capture all aspects of physiological swallowing impairments. Relying solely on PROMs may overlook critical swallowing deficits not perceived by the patient, highlighting the need for objective swallowing assessments in PD.
Collapse
Affiliation(s)
- Rabab Rangwala
- Department of Communication Sciences and Disorders, School of Communication, Northwestern University, Evanston, Illinois, USA
| | - Mariana Mendes Bahia
- Department of Speech and Hearing Science, University of Illinois Urbana-Champaign, Champaign, Illinois, USA
- Think + Speak Lab, Shirley Ryan AbilityLab, Chicago, Illinois, USA
| | - Jing Song
- Department of Preventive Medicine (Biostatistics), Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Danny Bega
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Bonnie Martin-Harris
- Department of Communication Sciences and Disorders, School of Communication, Northwestern University, Evanston, Illinois, USA
- Otolaryngology - Head and Neck Surgery, Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| |
Collapse
|
|
2
|
Gui M, Lv L, Hu S, Qin L, Wang C. Sarcopenia in Parkinson's disease: from pathogenesis to interventions. Metabolism 2025; 169:156272. [PMID: 40258411 DOI: 10.1016/j.metabol.2025.156272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 04/04/2025] [Accepted: 04/17/2025] [Indexed: 04/23/2025]
Abstract
Parkinson's disease (PD) and sarcopenia are prevalent age-related conditions that often coexist in affected individuals. Sarcopenia is particularly common among PD patients, with severe cases affecting approximately one in five individuals with the disease. Furthermore, sarcopenia is closely linked to the accelerated progression of PD, diminished quality of life, greater susceptibility to falls and fractures, and increased mortality risk. Although the precise mechanisms remain unclear, numerous studies suggest that factors such as the accumulation of α-Synuclein in skeletal muscle, loss of motor neurons, inflammation, phosphate toxicity, hormonal dysregulation, vitamin D deficiency, intestinal flora imbalances, and dysfunction of the gut-muscle-brain axis contribute to sarcopenia in PD. Understanding these mechanisms provides valuable insights into the relationship between PD and sarcopenia and establishes a foundation for future research and therapeutic strategies. This review examines the mechanisms underlying sarcopenia in PD, methods for its screening and assessment, and potential avenues for future research, including strategies for risk reduction and treatment.
Collapse
Affiliation(s)
- Meilin Gui
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Lingling Lv
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Shenglan Hu
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Lixia Qin
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha 410011, China; Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, Second Xiangya Hospital, Central South University, Changsha 410011, China.
| | - Chunyu Wang
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha 410011, China; Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, Second Xiangya Hospital, Central South University, Changsha 410011, China; Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha 410011, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha 410011, China.
| |
Collapse
|
|
3
|
Forrest SL, Kovacs GG. Current concepts and molecular pathology of neurodegenerative diseases. Pathology 2025; 57:178-190. [PMID: 39672768 DOI: 10.1016/j.pathol.2024.10.006] [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: 10/15/2024] [Accepted: 10/27/2024] [Indexed: 12/15/2024]
Abstract
Neurodegenerative diseases are a pathologically, clinically and genetically diverse group of diseases characterised by selective dysfunction, loss of synaptic connectivity and neurodegeneration, and are associated with the deposition of misfolded proteins in neurons and/or glia. Molecular studies have highlighted the role of conformationally altered proteins in the pathogenesis of neurodegenerative diseases and have paved the way for developing disease-specific biomarkers that capture and differentiate the main type/s of protein abnormality responsible for neurodegenerative diseases, some of which are currently used in clinical practice. These proteins follow sequential patterns of anatomical involvement and disease spread in the brain and may also be detected in peripheral organs. Recent studies suggest that glia are likely to have an important role in pathological spread throughout the brain and even follow distinct progression patterns from neurons. In addition to morphological and molecular approaches to the classification of these disorders, a further new stratification level incorporates the structure of protein filaments detected by cryogenic electron microscopy. Rather than occurring in isolation, combined deposition of tau, amyloid-β, α-synuclein and TDP-43 are frequently observed in neurodegenerative diseases and in the ageing brain. These can be overlooked, and their clinicopathological relevance is difficult to interpret. This review provides an overview of disease pathogenesis and diagnostic implications, recent molecular and ultrastructural classification of neurodegenerative diseases, how to approach ageing-related and mixed pathologies, and the importance of the protein-based classification system for practising neuropathologists and clinicians. This review also informs general pathologists about the relevance of ongoing full body autopsy studies to understand the spectrum and pathogenesis of neurodegenerative diseases.
Collapse
Affiliation(s)
- Shelley L Forrest
- Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada; Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON, Canada; Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
| | - Gabor G Kovacs
- Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada; Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON, Canada; Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia; Edmond J. Safra Program in Parkinson's Disease, Rossy PSP Centre and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology and Department of Medicine, University of Toronto, Toronto, ON, Canada.
| |
Collapse
|
|
4
|
Wang M, Ma C, Liu A, Xiao H, Ren Y, Li Z, Wang Z, Xia Q, Dou P, Li B, Chen P. A bibliometric analysis of acupuncture for Parkinson's disease non-motor symptoms from 2003 to 2023. Complement Ther Med 2024; 87:103111. [PMID: 39542379 DOI: 10.1016/j.ctim.2024.103111] [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: 08/30/2024] [Revised: 11/01/2024] [Accepted: 11/11/2024] [Indexed: 11/17/2024] Open
Abstract
BACKGROUND Parkinson's disease non-motor symptoms (PD-NMS) significantly affect patients' quality of life. Acupuncture has emerged as a potential complementary therapy for PD-NMS. This study aims to investigate general research status, hotspots and trends of acupuncture as a treatment for PD-NMS. METHODS Literature on Web of Science Core Collection (WoSCC) from 2003 to 2023 was retrieved, and bibliometric analysis was conducted using VOSviewer and CiteSpace software. RESULTS 159 publications by 894 authors from 37 countries, 300 institutions, and 96 journals were retrieved and analyzed. The number of publications in this field is generally on the rise yearly. China was the leading contributor with 57 publications, and the United States followed with 36 publications and had the highest total citation count of 1562. Guangzhou University of Chinese Medicine ranked the highest with a total of 12 publications, while Harvard University had the highest average citation rate of 70 citations per publication. Evidence-Based Complementary and Alternative Medicine was the most prolific journal with 11 articles that had accumulated 122 citations. Park Hi-Joon was the leading contributor with seven articles and 314 citations. The keyword analysis highlighted emerging areas of interest like "deep brain stimulation" and "alpha-synuclein". CONCLUSION Different countries, institutions, and authors should enhance cooperations, and the underlying mechanisms of acupuncture for PD-NMS should be demonstrated. This study will be helpful for better understanding the current knowledge and gaps in the areas of acupuncture as a treatment of PD-NMS.
Collapse
Affiliation(s)
- Mina Wang
- Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing 100010, China; Beijing University of Chinese Medicine, Beijing 100029, China
| | - Chunying Ma
- Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing 100010, China
| | - Anming Liu
- Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing 100010, China; Beijing University of Chinese Medicine, Beijing 100029, China
| | - Hongli Xiao
- Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yashuo Ren
- Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zhuohao Li
- Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing 100010, China
| | - Zixi Wang
- Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing 100010, China
| | - Qiuyu Xia
- Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing 100010, China
| | - Pu Dou
- Beijing University of Chinese Medicine, Beijing 100029, China
| | - Bin Li
- Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing 100010, China.
| | - Peng Chen
- Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing 100010, China.
| |
Collapse
|
|
5
|
Mu L, Chen J, Li J, Nyirenda T, Hegland KW, Beach TG. Mechanisms of Swallowing, Speech and Voice Disorders in Parkinson's Disease: Literature Review with Our First Evidence for the Periperal Nervous System Involvement. Dysphagia 2024; 39:1001-1012. [PMID: 38498201 DOI: 10.1007/s00455-024-10693-3] [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: 08/21/2023] [Accepted: 02/29/2024] [Indexed: 03/20/2024]
Abstract
The majority of patients with Parkinson's disease (PD) develop swallowing, speech, and voice (SSV) disorders. Importantly, swallowing difficulty or dysphagia and related aspiration are life-threatening conditions for PD patients. Although PD treatments have significant therapeutic effects on limb motor function, their effects on SSV disorders are less impressive. A large gap in our knowledge is that the mechanisms of SSV disorders in PD are poorly understood. PD was long considered to be a central nervous system disorder caused by the death of dopaminergic neurons in the basal ganglia. Aggregates of phosphorylated α-synuclein (PAS) underlie PD pathology. SSV disorders were thought to be caused by the same dopaminergic problem as those causing impaired limb movement; however, there is little evidence to support this. The pharynx, larynx, and tongue play a critical role in performing upper airway (UA) motor tasks and their dysfunction results in disordered SSV. This review aims to provide an overview on the neuromuscular organization patterns, functions of the UA structures, clinical features of SSV disorders, and gaps in knowledge regarding the pathophysiology underlying SSV disorders in PD, and evidence supporting the hypothesis that SSV disorders in PD could be associated, at least in part, with PAS damage to the peripheral nervous system controlling the UA structures. Determining the presence and distribution of PAS lesions in the pharynx, larynx, and tongue will facilitate the identification of peripheral therapeutic targets and set a foundation for the development of new therapies to treat SSV disorders in PD.
Collapse
Affiliation(s)
- Liancai Mu
- Upper Airway Reserch Laboratory, Center for Discovery and Innovation, Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ, 07110, USA.
- Center for Discovery and Innovation, Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ, 07110, USA.
| | - Jingming Chen
- Upper Airway Reserch Laboratory, Center for Discovery and Innovation, Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ, 07110, USA
| | - Jing Li
- Upper Airway Reserch Laboratory, Center for Discovery and Innovation, Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ, 07110, USA
| | - Themba Nyirenda
- Upper Airway Reserch Laboratory, Center for Discovery and Innovation, Hackensack Meridian Health, 111 Ideation Way, Nutley, NJ, 07110, USA
| | - Karen Wheeler Hegland
- Upper Airway Dysfunction Laboratory, M.A. Program in Communication Sciences & Disorders, Department of Speech, Language and Hearing Sciences, College of Public Health and Health Professions, University of Florida, 1225 Center Dr., Gainesville, FL, 32611, USA
| | - Thomas G Beach
- Director of Neuroscience, Director of Brain and Body Donation Program, Banner Sun Health Research Institute, 10515 West Santa Fe Dr, Sun City, AZ, 85351, USA
| |
Collapse
|
|
6
|
Jordi L, Isacson O. Neuronal threshold functions: Determining symptom onset in neurological disorders. Prog Neurobiol 2024; 242:102673. [PMID: 39389338 PMCID: PMC11809673 DOI: 10.1016/j.pneurobio.2024.102673] [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: 05/22/2024] [Revised: 09/18/2024] [Accepted: 10/06/2024] [Indexed: 10/12/2024]
Abstract
Synaptic networks determine brain function. Highly complex interconnected brain synaptic networks provide output even under fluctuating or pathological conditions. Relevant to the treatment of brain disorders, understanding the limitations of such functional networks becomes paramount. Here we use the example of Parkinson's Disease (PD) as a system disorder, with PD symptomatology emerging only when the functional reserves of neurons, and their interconnected networks, are unable to facilitate effective compensatory mechanisms. We have denoted this the "threshold theory" to account for how PD symptoms develop in sequence. In this perspective, threshold functions are delineated in a quantitative, synaptic, and cellular network context. This provides a framework to discuss the development of specific symptoms. PD includes dysfunction and degeneration in many organ systems and both peripheral and central nervous system involvement. The threshold theory accounts for and explains the reasons why parallel gradually emerging pathologies in brain and peripheral systems generate specific symptoms only when functional thresholds are crossed, like tipping points. New and mounting evidence demonstrate that PD and related neurodegenerative diseases are multisystem disorders, which transcends the traditional brain-centric paradigm. We believe that representation of threshold functions will be helpful to develop new medicines and interventions that are specific for both pre- and post-symptomatic periods of neurodegenerative disorders.
Collapse
Affiliation(s)
- Luc Jordi
- Neuroregeneration Institute, McLean Hospital / Harvard Medical School, Belmont, MA 02478, USA.
| | - Ole Isacson
- Neuroregeneration Institute, McLean Hospital / Harvard Medical School, Belmont, MA 02478, USA; Department of Neurology and Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
7
|
Salsone M, Agosta F, Filippi M, Ferini-Strambi L. Sleep disorders and Parkinson's disease: is there a right direction? J Neurol 2024; 271:6439-6451. [PMID: 39133321 DOI: 10.1007/s00415-024-12609-5] [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: 04/17/2024] [Revised: 07/23/2024] [Accepted: 07/27/2024] [Indexed: 08/13/2024]
Abstract
In the last years, the hypothesis of a close relationship between sleep disorders (SDs) and Parkinson's disease (PD) has significantly strengthened. Whether this association is causal has been also highlighted by recent evidence demonstrating a neurobiological link between SDs and PD. Thus, the question is not whether these two chronic conditions are mutually connected, but rather how and when this relationship is expressed. Supporting this, not all SDs manifest with the same temporal sequence in PD patients. Indeed, SDs can precede or occur concomitantly with the onset of the clinical manifestation of PD. This review discusses the existing literature, putting under a magnifying glass the timing of occurrence of SDs in PD-neurodegeneration. Based on this, here, we propose two possible directions for studying the SDs-PD relationship: the first direction, from SDs to PD, considers SDs as potential biomarker/precursor of future PD-neurodegeneration; the second direction, from PD to SDs, considers SDs as concomitant symptoms in manifest PD, mainly related to primary PD-neuropathology and/or parkinsonian drugs. Furthermore, for each direction, we questioned SDs-PD relationship in terms of risk factors, neuronal circuits/mechanisms, and impact on the clinical phenotype and disease progression. Future research is needed to investigate whether targeting sleep may be the winning strategy to treat PD, in the context of a personalized precision medicine.
Collapse
Affiliation(s)
- Maria Salsone
- Vita-Salute San Raffaele University, Milan, Italy.
- IRCCS Istituto Policlinico San Donato, Milan, Italy.
| | - Federica Agosta
- Vita-Salute San Raffaele University, Milan, Italy
- Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Massimo Filippi
- Vita-Salute San Raffaele University, Milan, Italy
- Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Luigi Ferini-Strambi
- Vita-Salute San Raffaele University, Milan, Italy
- Division of Neuroscience, Sleep Disorders Center, San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
|
8
|
Duranti E, Villa C. From Brain to Muscle: The Role of Muscle Tissue in Neurodegenerative Disorders. BIOLOGY 2024; 13:719. [PMID: 39336146 PMCID: PMC11428675 DOI: 10.3390/biology13090719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/02/2024] [Accepted: 09/11/2024] [Indexed: 09/30/2024]
Abstract
Neurodegenerative diseases (NDs), like amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), primarily affect the central nervous system, leading to progressive neuronal loss and motor and cognitive dysfunction. However, recent studies have revealed that muscle tissue also plays a significant role in these diseases. ALS is characterized by severe muscle wasting as a result of motor neuron degeneration, as well as alterations in gene expression, protein aggregation, and oxidative stress. Muscle atrophy and mitochondrial dysfunction are also observed in AD, which may exacerbate cognitive decline due to systemic metabolic dysregulation. PD patients exhibit muscle fiber atrophy, altered muscle composition, and α-synuclein aggregation within muscle cells, contributing to motor symptoms and disease progression. Systemic inflammation and impaired protein degradation pathways are common among these disorders, highlighting muscle tissue as a key player in disease progression. Understanding these muscle-related changes offers potential therapeutic avenues, such as targeting mitochondrial function, reducing inflammation, and promoting muscle regeneration with exercise and pharmacological interventions. This review emphasizes the importance of considering an integrative approach to neurodegenerative disease research, considering both central and peripheral pathological mechanisms, in order to develop more effective treatments and improve patient outcomes.
Collapse
Affiliation(s)
| | - Chiara Villa
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy;
| |
Collapse
|
|
9
|
Sade O, Fischel D, Barak-Broner N, Halevi S, Gottfried I, Bar-On D, Sachs S, Mirelman A, Thaler A, Gour A, Kestenbaum M, Gana Weisz M, Anis S, Soto C, Roitman MS, Shahar S, Doppler K, Sauer M, Giladi N, Lev N, Alcalay RN, Hassin-Baer S, Ashery U. A novel super-resolution microscopy platform for cutaneous alpha-synuclein detection in Parkinson's disease. Front Mol Neurosci 2024; 17:1431549. [PMID: 39296283 PMCID: PMC11409901 DOI: 10.3389/fnmol.2024.1431549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 07/26/2024] [Indexed: 09/21/2024] Open
Abstract
Alpha-synuclein (aSyn) aggregates in the central nervous system are the main pathological hallmark of Parkinson's disease (PD). ASyn aggregates have also been detected in many peripheral tissues, including the skin, thus providing a novel and accessible target tissue for the detection of PD pathology. Still, a well-established validated quantitative biomarker for early diagnosis of PD that also allows for tracking of disease progression remains lacking. The main goal of this research was to characterize aSyn aggregates in skin biopsies as a comparative and quantitative measure for PD pathology. Using direct stochastic optical reconstruction microscopy (dSTORM) and computational tools, we imaged total and phosphorylated-aSyn at the single molecule level in sweat glands and nerve bundles of skin biopsies from healthy controls (HCs) and PD patients. We developed a user-friendly analysis platform that offers a comprehensive toolkit for researchers that combines analysis algorithms and applies a series of cluster analysis algorithms (i.e., DBSCAN and FOCAL) onto dSTORM images. Using this platform, we found a significant decrease in the ratio of the numbers of neuronal marker molecules to phosphorylated-aSyn molecules, suggesting the existence of damaged nerve cells in fibers highly enriched with phosphorylated-aSyn molecules. Furthermore, our analysis found a higher number of aSyn aggregates in PD subjects than in HC subjects, with differences in aggregate size, density, and number of molecules per aggregate. On average, aSyn aggregate radii ranged between 40 and 200 nm and presented an average density of 0.001-0.1 molecules/nm2. Our dSTORM analysis thus highlights the potential of our platform for identifying quantitative characteristics of aSyn distribution in skin biopsies not previously described for PD patients while offering valuable insight into PD pathology by elucidating patient aSyn aggregation status.
Collapse
Affiliation(s)
- Ofir Sade
- School of Neurobiology, Biochemistry, Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv, Israel
| | - Daphna Fischel
- School of Neurobiology, Biochemistry, Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Noa Barak-Broner
- School of Neurobiology, Biochemistry, Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv, Israel
| | - Shir Halevi
- School of Neurobiology, Biochemistry, Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Irit Gottfried
- School of Neurobiology, Biochemistry, Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv, Israel
| | - Dana Bar-On
- School of Neurobiology, Biochemistry, Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Stefan Sachs
- Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Anat Mirelman
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Movement Disorders Division, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Avner Thaler
- Movement Disorders Division, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Aviv Gour
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
- Department of Neurology, Meir Medical Center, Kfar Saba, Israel
| | - Meir Kestenbaum
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
- Department of Neurology, Meir Medical Center, Kfar Saba, Israel
| | - Mali Gana Weisz
- Movement Disorders Division, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Saar Anis
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
- Department of Neurology, Movement Disorders Institute, Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Claudio Soto
- Mitchell Center for Alzheimer's Disease and Related Brain Disorders, University of Texas Medical School, Houston, TX, United States
| | - Melanie Shanie Roitman
- Department of Neurology, Movement Disorders Institute, Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Shimon Shahar
- Department of Statistics, Exact Sciences Faculty, Tel Aviv University, Tel Aviv, Israel
| | - Kathrin Doppler
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
| | - Markus Sauer
- Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Nir Giladi
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Movement Disorders Division, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Nirit Lev
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
- Department of Neurology, Meir Medical Center, Kfar Saba, Israel
| | - Roy N Alcalay
- Movement Disorders Division, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Sharon Hassin-Baer
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
- Department of Neurology, Movement Disorders Institute, Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Uri Ashery
- School of Neurobiology, Biochemistry, Biophysics, Life Sciences Faculty, Tel Aviv University, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
10
|
de Araújo RCP, Godoy CMDA, Ferreira LMDBM, Godoy JF, Magalhães H. Relationship between oral status, swallowing function, and nutritional risk in older people with and without Parkinson's disease. Codas 2024; 36:e20230311. [PMID: 39109756 PMCID: PMC11340878 DOI: 10.1590/2317-1782/20242023311pt] [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: 12/03/2023] [Accepted: 02/02/2024] [Indexed: 08/25/2024] Open
Abstract
PURPOSE To compare oral status, swallowing function (through instrumental and SLH assessment), and nutritional risk between dysphagic individuals with and without Parkinson's disease. METHOD This is a cross-sectional retrospective study based on data collected from medical records. It included 54 dysphagic older adults, divided into two groups according to the diagnosis of Parkinson's disease. The study collected data on the speech-language-hearing assessment of postural control, tongue mobility and strength, maximum phonation time (MPT), and cough efficiency. Oral status was assessed using the number of teeth and the Eichner Index. The level of oral intake and pharyngeal signs of dysphagia were analyzed with four food consistencies, according to the International Dysphagia Diet Standardization Initiative classification, using fiberoptic endoscopic evaluation of swallowing, for comparison between groups. The severity of pharyngeal residues was analyzed and classified with the Yale Pharyngeal Residue Severity Rating Scale, and the nutritional risk was screened with the Malnutrition Screening Tool. RESULTS The group of older adults with Parkinson's disease was significantly different from the other group in that they had fewer teeth, unstable postural control, reduced tongue strength, reduced MPT, weak spontaneous coughing, pharyngeal signs, less oral intake, and nutritional risk. CONCLUSION Dysphagic older people with Parkinson's disease had different oral status, swallowing function, and nutritional risk from those without the diagnosis.
Collapse
Affiliation(s)
| | | | | | - Juliana Fernandes Godoy
- Departamento de Fonoaudiologia, Universidade Federal do Rio Grande do Norte – UFRN - Natal (RN), Brasil.
| | - Hipólito Magalhães
- Departamento de Fonoaudiologia, Universidade Federal do Rio Grande do Norte – UFRN - Natal (RN), Brasil.
| |
Collapse
|
|
11
|
Kerschner A, Hassan H, Kern M, Edeani F, Mei L, Sanvanson P, Shaker R, Yu E. Parkinson's disease is associated with low striated esophagus contractility potentially contributing to the development of dysphagia. Neurogastroenterol Motil 2024; 36:e14822. [PMID: 38798058 PMCID: PMC11246227 DOI: 10.1111/nmo.14822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 05/03/2024] [Accepted: 05/09/2024] [Indexed: 05/29/2024]
Abstract
BACKGROUND Parkinson's disease (PD) is the second most common neurodegenerative disorder, and more than 80% of PD patients will develop oropharyngeal dysphagia. Despite its striated histology, proximity to airway, and potential negative impact of its dysfunction on bolus transport and airway safety, the contractile function of the striated esophagus in PD patients has not been systematically studied. METHODS Using our repository of clinical manometry and the Milwaukee ManoBank, we analyzed high-resolution manometry (HRM) studies of 20 PD patients, mean age 69.1 (range 38-87 years); 30 non-PD patients with dysphagia, mean age 64.0 (44-86 years); and 32 healthy volunteers, mean age 65.3 (39-86 years). Patients with abnormal findings based on Chicago Classification 4.0 were identified. Repeat analysis was performed in 20% of the manometric tracings by a different investigator with inter-rater concordance between 0.91 and 0.99. KEY RESULTS The striated esophageal contractile integral in PD patients was significantly lower than that in non-PD dysphagic patients and healthy controls (p = 0.03 and <0.01, respectively). This significant difference persisted after excluding patients with concurrent Chicago Classification motility disorders (p = 0.02 and 0.01, respectively). In both analyses, the distal esophageal contractile integral did not show any significant difference between groups (p = 0.58 and 0.93, respectively). CONCLUSIONS & INFERENCES PD is associated with a significant decrease in striated esophagus contractility compared to non-PD and healthy controls. This finding may play a pathophysiologic role in development of dysphagia in this patient population.
Collapse
Affiliation(s)
- Alexander Kerschner
- Department of Internal Medicine, The Hub for Collaborative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Hamza Hassan
- Division of Gastroenterology and Hepatology, The Hub for Collaborative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Mark Kern
- Division of Gastroenterology and Hepatology, The Hub for Collaborative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Francis Edeani
- Division of Gastroenterology and Hepatology, The Hub for Collaborative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Ling Mei
- Division of Gastroenterology and Hepatology, The Hub for Collaborative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Patrick Sanvanson
- Division of Gastroenterology and Hepatology, The Hub for Collaborative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Reza Shaker
- Division of Gastroenterology and Hepatology, The Hub for Collaborative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Elliot Yu
- Division of Gastroenterology and Hepatology, The Hub for Collaborative Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| |
Collapse
|
|
12
|
Tang H, Zhang K, Zhang C, Zheng K, Gui L, Yan B. Bioinformatics-based identification of key candidate genes and signaling pathways in patients with Parkinson's disease and obstructive sleep apnea. Sleep Breath 2024; 28:1477-1489. [PMID: 38316731 DOI: 10.1007/s11325-024-03003-6] [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: 07/19/2023] [Revised: 01/12/2024] [Accepted: 01/15/2024] [Indexed: 02/07/2024]
Abstract
OBJECTIVES Existing evidence exhibits that obstructive sleep apnea (OSA) is a potential consequence of Parkinson's disease (PD) or a contributor to PD progression. This investigation aimed to detect potential critical genes and molecular mechanisms underlying interactions between PD and OSA through bioinformatics analyses. METHODS The Gene Expression Omnibus (GEO) database was employed to obtain the expression profiles GSE20163 and GSE135917. The identification of common genes connected to PD and OSA was performed utilizing weighted gene co-expression network analysis and the R 4.0.4 program. The Cytoscape program was utilized to generate a network of protein-protein interactions (PPI), and the CytoHubba plugin was utilized to detect hub genes. Subsequently, functional enrichment analyses of the hub genes were conducted. Markers with increased diagnostic values for PD and OSA were confirmed using the GEO datasets GSE8397 and GSE38792. RESULTS Typically, 57 genes that are common were identified in PD and OSA. Among these common genes, the top 10 hub genes in the PPI network were chosen. The verified datasets confirmed the presence of three important genes: CADPS, CHGA, and SCG3. Functional enrichment analysis revealed that these hub genes mostly participate in GABAergic synapses. CONCLUSION Our findings suggest that CADPS, CHGA, and SCG3 are key genes involved in molecular mechanisms underlying interactions between OSA and PD. Functional enrichment of hub genes indicated a link between GABAergic synapses and the shared pathogenesis of PD and OSA. These candidate genes and corresponding pathways offer novel insights regarding biological targets that underlie the transcriptional connection between OSA and PD.
Collapse
Affiliation(s)
- Huan Tang
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Kejia Zhang
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Chi Zhang
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Kai Zheng
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Luying Gui
- Department of Mathematics, Nanjing University of Science and Technology, Nanjing, China
| | - Bin Yan
- Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China.
| |
Collapse
|
|
13
|
Higuchi T, Chen X, Werner RA. Navigating new horizons: Prospects of NET-targeted radiopharmaceuticals in precision medicine. Theranostics 2024; 14:3178-3192. [PMID: 38855189 PMCID: PMC11155404 DOI: 10.7150/thno.96743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 04/23/2024] [Indexed: 06/11/2024] Open
Abstract
In the evolving landscape of precision medicine, NET-targeted radiopharmaceuticals are emerging as pivotal tools for the diagnosis and treatment of a range of conditions, from heart failure and neurodegenerative disorders to neuroendocrine cancers. This review evaluates the advancements offered by 18F-labeled PET tracers and 211At alpha-particle therapy, juxtaposed with current 123I-MIBG SPECT and 131I-MIBG therapies. The enhanced spatial resolution and capability for quantitative analysis render 18F-labeled PET tracers potential candidates for improved detection and management of diseases. Alpha-particle therapy with 211At may offer increased specificity and tumoricidal efficacy, pointing towards a shift in therapeutic protocols. While preliminary data is promising, these innovative approaches require thorough validation against current modalities. Ongoing clinical trials are pivotal to confirm the expected clinical benefits and to address safety concerns. This review underscores the need for rigorous research to verify the clinical utility of NET-targeted radiopharmaceuticals, which may redefine precision medicine paradigms and significantly impact patient care.
Collapse
Affiliation(s)
- Takahiro Higuchi
- Department of Nuclear Medicine and Comprehensive Heart Failure Center, University Hospital of Würzburg, Würzburg, Germany
- Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Xinyu Chen
- Nuclear Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Rudolf A Werner
- DZHK (German Centre for Cardiovascular Research), Partner Site Frankfurt Rhine-Main, Frankfurt, Germany
- Goethe University Frankfurt, Department of Nuclear Medicine, Clinic for Radiology and Nuclear Medicine, Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, Germany
- The Russell H Morgan Department of Radiology and Radiological Sciences, Division of Nuclear Medicine and Molecular Imaging, Johns Hopkins School of Medicine, Baltimore, MD, United States
| |
Collapse
|
|
14
|
Manes JL, Bullock L, Meier AM, Turner RS, Richardson RM, Guenther FH. A neurocomputational view of the effects of Parkinson's disease on speech production. Front Hum Neurosci 2024; 18:1383714. [PMID: 38812472 PMCID: PMC11133703 DOI: 10.3389/fnhum.2024.1383714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 04/23/2024] [Indexed: 05/31/2024] Open
Abstract
The purpose of this article is to review the scientific literature concerning speech in Parkinson's disease (PD) with reference to the DIVA/GODIVA neurocomputational modeling framework. Within this theoretical view, the basal ganglia (BG) contribute to several different aspects of speech motor learning and execution. First, the BG are posited to play a role in the initiation and scaling of speech movements. Within the DIVA/GODIVA framework, initiation and scaling are carried out by initiation map nodes in the supplementary motor area acting in concert with the BG. Reduced support of the initiation map from the BG in PD would result in reduced movement intensity as well as susceptibility to early termination of movement. A second proposed role concerns the learning of common speech sequences, such as phoneme sequences comprising words; this view receives support from the animal literature as well as studies identifying speech sequence learning deficits in PD. Third, the BG may play a role in the temporary buffering and sequencing of longer speech utterances such as phrases during conversational speech. Although the literature does not support a critical role for the BG in representing sequence order (since incorrectly ordered speech is not characteristic of PD), the BG are posited to contribute to the scaling of individual movements in the sequence, including increasing movement intensity for emphatic stress on key words. Therapeutic interventions for PD have inconsistent effects on speech. In contrast to dopaminergic treatments, which typically either leave speech unchanged or lead to minor improvements, deep brain stimulation (DBS) can degrade speech in some cases and improve it in others. However, cases of degradation may be due to unintended stimulation of efferent motor projections to the speech articulators. Findings of spared speech after bilateral pallidotomy appear to indicate that any role played by the BG in adult speech must be supplementary rather than mandatory, with the sequential order of well-learned sequences apparently represented elsewhere (e.g., in cortico-cortical projections).
Collapse
Affiliation(s)
- Jordan L. Manes
- Department of Speech, Language, and Hearing Sciences, Boston University, Boston, MA, United States
- Department of Communicative Disorders and Sciences, University at Buffalo, Buffalo, NY, United States
| | - Latané Bullock
- Program in Speech and Hearing Bioscience and Technology, Division of Medical Sciences, Harvard Medical School, Boston, MA, United States
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
| | - Andrew M. Meier
- Department of Speech, Language, and Hearing Sciences, Boston University, Boston, MA, United States
| | - Robert S. Turner
- Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, United States
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, United States
| | - R. Mark Richardson
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
| | - Frank H. Guenther
- Department of Speech, Language, and Hearing Sciences, Boston University, Boston, MA, United States
- Department of Biomedical Engineering, Boston University, Boston, MA, United States
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, United States
| |
Collapse
|
|
15
|
Doruk C, Curtis JA, Dakin AE, Troche MS. Cough and Swallowing Therapy and Their Effects on Vocal Fold Bowing and Laryngeal Lesions. Laryngoscope 2024; 134:1127-1132. [PMID: 37497803 DOI: 10.1002/lary.30922] [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: 03/28/2023] [Revised: 07/11/2023] [Accepted: 07/12/2023] [Indexed: 07/28/2023]
Abstract
OBJECTIVE Expiratory muscle strength training (EMST) and sensorimotor training of airway protection (smTAP) are two exercises intended to improve cough and swallowing in people with Parkinson's Disease (PwPD). The aims of this study were to (1) examine whether EMST or smTAP elicit changes to vocal fold bowing; and (2) describe the safety of EMST and smTAP as it relates to the development of vocal fold lesions. METHOD(S) This was a secondary analysis of data from PwPD who completed EMST or smTAP as part of a prospective randomized controlled trial. Vocal fold bowing (BI) and the presence of laryngeal lesions were blindly analyzed from flexible endoscopic evaluation of swallowing (FEES) using ImageJ software and operational definitions. Linear regression was used to examine the influence time (pre- vs. post-therapy) and therapy (EMST vs. smTAP) on vocal fold bowing. Descriptive statistics were used to describe the presence of laryngeal lesions. RESULT(S) Overall, 56 participants were included, 28 per group. The median BI scores pre- and post-therapy were 8.2% and 8.3% for the EMST group and 11.3% and 8.4% for the smTAP group, respectively. Statistical analyses revealed insufficient evidence to suggest an effect of time and treatment type on BI (p > 0.05) or on the presence of vocal fold lesions (p > 0.05). CONCLUSION Based on these and previous findings, it appears that changes in vocal fold bowing do not drive treatment effects following EMST and smTAP. Also, this study further supports the safety of smTAP and EMST despite the required forceful exhalation and repetitive coughing. LEVEL OF EVIDENCE 4 Laryngoscope, 134:1127-1132, 2024.
Collapse
Affiliation(s)
- Can Doruk
- Laboratory for the Study of Upper Airway Dysfunction, Department of Biobehavioral Sciences, Teachers College, Columbia University, New York, New York, USA
- Center for Voice and Swallowing, Department of Otolaryngology-Head & Neck Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - James A Curtis
- Aerodigestive Innovations Research lab (AIR), Department of Otolaryngology-Head & Neck Surgery, Weill Cornell Medical College, New York, New York, USA
| | - Avery E Dakin
- Laboratory for the Study of Upper Airway Dysfunction, Department of Biobehavioral Sciences, Teachers College, Columbia University, New York, New York, USA
| | - Michelle S Troche
- Laboratory for the Study of Upper Airway Dysfunction, Department of Biobehavioral Sciences, Teachers College, Columbia University, New York, New York, USA
| |
Collapse
|
|
16
|
Hirano M, Samukawa M, Isono C, Kusunoki S, Nagai Y. The effect of rasagiline on swallowing function in Parkinson's disease. Heliyon 2024; 10:e23407. [PMID: 38187336 PMCID: PMC10770448 DOI: 10.1016/j.heliyon.2023.e23407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 10/18/2023] [Accepted: 12/04/2023] [Indexed: 01/09/2024] Open
Abstract
Dysphagia, a potentially fatal symptom of Parkinson's disease, is characterized by frequent silent aspiration, a risk factor for aspiration pneumonia. The transdermal dopamine agonist rotigotine alleviates dysphagia in patients with Parkinson's disease and is more effective than oral levodopa, suggesting the importance of continuous dopaminergic stimulation during swallowing. Rasagiline is a monoamine oxidase B (MAOB) inhibitor that facilitates continuous dopaminergic stimulation. We hypothesized that MAOB inhibition by rasagiline would be effective in improving swallowing function in patients with early- and mid-to late-stage Parkinson's disease. To this end, we performed an analytical observational study to determine the effects of rasagiline (1 mg/day) on swallowing function using videofluoroscopic swallowing study. This open-label, evaluator-blinded study enrolled 32 patients with Parkinson's disease, among whom 19 were drug-naïve and 13 were receiving add-on therapy. Our results showed that rasagiline significantly improved all swallowing measures during the oral and pharyngeal phases, including oral transit time and pharyngeal transit time, in all enrolled patients. Similar results were found in drug-naïve and mid-to late-stage patients, with no intergroup differences. In conclusion, drugs capable of continuous dopaminergic stimulation may effectively improve swallowing function in patients with Parkinson's disease, with similar effects in early- and mid-to late-stage Parkinson's disease. This study has been the first to show that rasagiline significantly improves swallowing function in mid-to late-stage patients receiving add-on therapy.
Collapse
Affiliation(s)
- Makito Hirano
- Department of Neurology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan
| | - Makoto Samukawa
- Department of Neurology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan
| | - Chiharu Isono
- Department of Rehabilitation Medicine, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan
| | - Susumu Kusunoki
- Department of Neurology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan
| | - Yoshitaka Nagai
- Department of Neurology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan
| |
Collapse
|
|
17
|
Barnett DG, Lechner SA, Gammie SC, Kelm-Nelson CA. Thyroarytenoid Oxidative Metabolism and Synaptic Signaling Dysregulation in the Female Pink1-/- Rat. Laryngoscope 2023; 133:3412-3421. [PMID: 37293988 PMCID: PMC10709531 DOI: 10.1002/lary.30768] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/07/2023] [Accepted: 05/10/2023] [Indexed: 06/10/2023]
Abstract
OBJECTIVES AND HYPOTHESIS Vocal dysfunction, including hypophonia, in Parkinson disease (PD) manifests in the prodromal period and significantly impacts an individual's quality of life. Data from human studies suggest that pathology leading to vocal deficits may be structurally related to the larynx and its function. The Pink1-/- rat is a translational model used to study pathogenesis in the context of early-stage mitochondrial dysfunction. The primary objective of this work was to identify differentially expressed genes in the thyroarytenoid muscle and examine the dysregulated biological pathways in the female rat. METHODS RNA sequencing was used to determine thyroarytenoid (TA) muscle gene expression in adult female Pink1-/- rats compared with controls. A bioinformatic approach and the ENRICHR gene analysis tool were used to compare the sequencing dataset with biological pathways and processes, disease relationships, and drug-repurposing compounds. Weighted Gene Co-expression Network Analysis was used to construct biological network modules. The data were compared with a previously published dataset in male rats. RESULTS Significant upregulated pathways in female Pink1-/- rats included fatty acid oxidation and muscle contraction, synaptic transmission, and neuromuscular processes. Downregulated pathways included anterograde transsynaptic signaling, chemical synaptic transmission, and ion release. Several drug treatment options including cetuximab, fluoxetine, and resveratrol are hypothesized to reverse observed genetic dysregulation. CONCLUSIONS Data presented here are useful for identifying biological pathways that may underlie the mechanisms of peripheral dysfunction including neuromuscular synaptic transmission to the TA muscle. These experimental biomarkers have the potential to be targeted as sites for improving the treatment for hypophonia in early-stage PD. LEVEL OF EVIDENCE NA Laryngoscope, 133:3412-3421, 2023.
Collapse
Affiliation(s)
- David G.S. Barnett
- Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Wisconsin, Madison, Wisconsin
| | - Sarah A. Lechner
- Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Wisconsin, Madison, Wisconsin
| | - Stephen C. Gammie
- Department of Integrative Biology, University of Wisconsin, Madison, Wisconsin
| | - Cynthia A. Kelm-Nelson
- Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Wisconsin, Madison, Wisconsin
| |
Collapse
|
|
18
|
Konings B, Villatoro L, Van den Eynde J, Barahona G, Burns R, McKnight M, Hui K, Yenokyan G, Tack J, Pasricha PJ. Gastrointestinal syndromes preceding a diagnosis of Parkinson's disease: testing Braak's hypothesis using a nationwide database for comparison with Alzheimer's disease and cerebrovascular diseases. Gut 2023; 72:2103-2111. [PMID: 37620120 DOI: 10.1136/gutjnl-2023-329685] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 07/02/2023] [Indexed: 08/26/2023]
Abstract
OBJECTIVE Braak's hypothesis states that Parkinson's disease (PD) originates in the gastrointestinal (GI) tract, and similar associations have been established for Alzheimer's disease (AD) and cerebrovascular diseases (CVD). We aimed to determine the incidence of GI syndromes and interventions preceding PD compared with negative controls (NCs), AD and CVD. DESIGN We performed a combined case-control and cohort study using TriNetX, a US based nationwide medical record network. Firstly, we compared subjects with new onset idiopathic PD with matched NCs and patients with contemporary diagnoses of AD and CVD, to investigate preceding GI syndromes, appendectomy and vagotomy. Secondly, we compared cohorts with these exposures to matched NCs for the development of PD, AD and CVD within 5 years. RESULTS We identified 24 624 PD patients in the case-control analysis and matched 18 cohorts with each exposure to their NCs. Gastroparesis, dysphagia, irritable bowel syndrome (IBS) without diarrhoea and constipation showed specific associations with PD (vs NCs, AD and CVD) in both the case-control (odds ratios (ORs) vs NCs 4.64, 3.58, 3.53 and 3.32, respectively, all p<0.0001) and cohort analyses (relative risks (RRs) vs NCs 2.43, 2.27, 1.17 and 2.38, respectively, all p<0.05). While functional dyspepsia, IBS with diarrhoea, diarrhoea and faecal incontinence were not PD specific, IBS with constipation and intestinal pseudo-obstruction showed PD specificity in the case-control (OR 4.11) and cohort analysis (RR 1.84), respectively. Appendectomy decreased the risk of PD in the cohort analysis (RR 0.48). Neither inflammatory bowel disease nor vagotomy were associated with PD. CONCLUSION Dysphagia, gastroparesis, IBS without diarrhoea and constipation might specifically predict Parkinson's disease.
Collapse
Affiliation(s)
- Bo Konings
- Translational Research Centre for Gastrointestinal Disorders (TARGID), KU Leuven University Hospitals, Leuven, Belgium
| | - Luisa Villatoro
- Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Jef Van den Eynde
- Department of Cardiology, KU Leuven University Hospitals, Leuven, Belgium
| | | | - Robert Burns
- Department of Gastroenterology, Johns Hopkins Medicine, Baltimore, Maryland, USA
| | - Megan McKnight
- Department of Gastroenterology, Johns Hopkins Medicine, Baltimore, Maryland, USA
| | - Ken Hui
- Department of Gastroenterology, Johns Hopkins Medicine, Baltimore, Maryland, USA
| | - Gayane Yenokyan
- Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Jan Tack
- Translational Research Centre for Gastrointestinal Disorders (TARGID), KU Leuven University Hospitals, Leuven, Belgium
| | | |
Collapse
|
|
19
|
Mu L, Chen J, Sobotka S, Li J, Nyirenda T. Focal Application of Neurotrophic Factors Augments Outcomes of Nerve-Muscle-Endplate Grafting Technique for Limb Muscle Reinnervation. J Reconstr Microsurg 2023; 39:695-704. [PMID: 36948213 DOI: 10.1055/s-0043-1764487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
BACKGROUND We have developed a novel muscle reinnervation technique called "nerve-muscle-endplate grafting (NMEG) in the native motor zone (NMZ)." This study aimed to augment the outcomes of the NMEG-NMZ (NN) by focal application of exogenous neurotrophic factors (ENFs) for limb reinnervation. METHODS Adult rats were used to conduct NN plus ENF (NN/ENF) and autologous nerve grafting (ANG, technique control). The nerve innervating the left tibialis anterior (TA) muscle was resected and the denervated TA was immediately treated with NN/ENF or ANG. For NN procedure, an NMEG pedicle was taken from the lateral gastrocnemius muscle and transferred to the NMZ of the denervated TA. For ANG, the nerve gap was bridged with sural nerve. Three months after treatment, the extent of functional and neuromuscular recovery was assessed by measuring static toe spread, maximal muscle force, wet muscle weight, regenerated axons, and innervated motor endplates (MEPs). RESULTS NN/ENF resulted in 90% muscle force recovery of the treated TA, which is far superior to ANG (46%) and NN alone (79%) as reported elsewhere. Toe spread recovered up to 89 and 49% of the control for the NN/ENF and ANG groups, respectively. The average wet muscle weight was 87 and 52% of the control for muscles treated with NN/ENF and ANG, respectively. The mean number of the regenerated axons was 88% of the control for the muscles treated with NN/ENF, which was significantly larger than that for the ANG-repaired muscles (39%). The average percentage of the innervated MEPs in the NN/ENF-treated TA (89%) was higher compared with that in the ANG-repaired TA (48%). CONCLUSION ENF enhances nerve regeneration and MEP reinnervation that further augment outcomes of NN. The NN technique could be an alternative option to treat denervated or paralyzed limb muscles caused by traumatic nerve injuries or lesions.
Collapse
Affiliation(s)
- Liancai Mu
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
| | - Jingming Chen
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
| | - Stanislaw Sobotka
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
| | - Jing Li
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
| | - Themba Nyirenda
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
| |
Collapse
|
|
20
|
Yu Q, Hu X, Zheng T, Liu L, Kuang G, Liu H, Wang X, Li J, Huang J, Wang T, Lin Z, Xiong N. Obstructive sleep apnea in Parkinson's disease: A prevalent, clinically relevant and treatable feature. Parkinsonism Relat Disord 2023; 115:105790. [PMID: 37541789 DOI: 10.1016/j.parkreldis.2023.105790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 08/06/2023]
Abstract
Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by motor and non-motor symptoms, including obstructive sleep apnea (OSA), a common comorbid sleep disorder. The prevalence of OSA in PD is high, and its impact on quality of life, accident risk, and limited treatment options underscores the need for vigilant monitoring and effective interventions. OSA is observed in 20-70% of PD patients, whereas the general population exhibits a lower prevalence ranging from 2 to 14%. These discrepancies in prevalence may be attributed to differences in demographic characteristics, sample sizes with selection bias, and variations in scoring systems for apnea and hypopnea events used across different studies. This review highlights the potential pathogenesis of comorbid OSA in PD and provides an overview of ongoing clinical trials investigating interventions for this condition. Several mechanisms have been implicated in the development of OSA in PD, including intermittent hypoxemia, sleep fragmentation, alterations in the glymphatic system homeostasis, upper airway obstruction, and inflammation. Given the adverse effects of PD comorbid OSA, early intervention measures are crucial. It is imperative to conduct longitudinal studies and clinical trials to elucidate the pathogenesis and develop novel and effective interventions for OSA in PD patients. These efforts aim to delay the progression of PD, enhance patients' quality of life, and alleviate the burden on society and families.
Collapse
Affiliation(s)
- Qinwei Yu
- Department of Cardiology, Wuhan Red Cross Hospital, 392 Hongkong Road, Wuhan, Hubei China; Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xinyu Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Tao Zheng
- Department of Neurology, Wuhan Red Cross Hospital, 392 Hongkong Road, Wuhan, Hubei China
| | - Li Liu
- Department of Clinical Laboratory, People's Hospital of Maojian District, Shiyan City, Hubei China
| | - Guiying Kuang
- Department of Neurology, Wuhan Red Cross Hospital, 392 Hongkong Road, Wuhan, Hubei China
| | - Hanshu Liu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xinyi Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Jingwen Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Jinsha Huang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Tao Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Zhicheng Lin
- Laboratory of Psychiatric Neurogenomics, McLean Hospital; Harvard Medical School, Belmont, MA, 02478, USA
| | - Nian Xiong
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
| |
Collapse
|
|
21
|
Gandor F, Berger L, Gruber D, Warnecke T, Vogel A, Claus I. [Dysphagia in Parkinsonian Syndromes]. DER NERVENARZT 2023; 94:685-693. [PMID: 37115255 DOI: 10.1007/s00115-023-01475-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/08/2023] [Indexed: 04/29/2023]
Abstract
Dysphagia is a clinically relevant problem in Parkinson's disease as well as in atypical Parkinsonian syndromes, such as multiple system atrophy and diseases from the spectrum of 4‑repeat tauopathies, which affect most patients to a varying degree in the course of their disease. This results in relevant restrictions in daily life due to impaired intake of food, fluids, and medication with a subsequent reduction in quality of life. This article not only gives an overview of the pathophysiological causes of dysphagia in the various Parkinson syndromes, but also presents screening, diagnostic and treatment procedures that have been investigated for the different diseases.
Collapse
Affiliation(s)
- F Gandor
- Neurologisches Fachkrankenhaus für Bewegungsstörungen/Parkinson, Str. nach Fichtenwalde 16, 14547, Beelitz-Heilstätten, Deutschland.
- Klinik für Neurologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Deutschland.
| | - L Berger
- Neurologisches Fachkrankenhaus für Bewegungsstörungen/Parkinson, Str. nach Fichtenwalde 16, 14547, Beelitz-Heilstätten, Deutschland
- Klinik für Neurologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Deutschland
| | - D Gruber
- Neurologisches Fachkrankenhaus für Bewegungsstörungen/Parkinson, Str. nach Fichtenwalde 16, 14547, Beelitz-Heilstätten, Deutschland
- Klinik für Neurologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Deutschland
| | - T Warnecke
- Klinik für Neurologie und neurologische Frührehabilitation, Klinikum Osnabrück, Osnabrück, Deutschland
| | - A Vogel
- Neurologisches Fachkrankenhaus für Bewegungsstörungen/Parkinson, Str. nach Fichtenwalde 16, 14547, Beelitz-Heilstätten, Deutschland
| | - I Claus
- Klinik für Neurologie mit Institut für translationale Neurologie, Universitätsklinikum Münster, Münster, Deutschland
| |
Collapse
|
|
22
|
Khayyat YM, Abdul Wahab RA, Natto NK, Al Wafi AA, Al Zahrani AA. Impact of anxiety and depression on the swallowing process among patients with neurological disorders and head and neck neoplasia: systemic review. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2023; 59:75. [DOI: 10.1186/s41983-023-00674-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 05/23/2023] [Indexed: 09/25/2023] Open
Abstract
Abstract
Background
Dysphagia is associated with depression and anxiety due to the severity, impact of symptoms itself or secondary to the underlying cause. This is more recognizable to brain diseases that has consequences common to the neural supply of the swallowing act and the cognition and behavior. Limited data are available to explore, quantitate and monitor these neurological outcomes. Our aim of this research to review the literature pertinent to depressive disorders, anxiety, and/or the quality of life (QoL) and psychological well-being. Search of Medline and Google Scholar databases for relevant articles had revealed a total of 1568 citations; 30 articles met the inclusion and exclusion criteria.
Results
Data about the direct effect of dysphagia on psychiatric aspects are limited. Studies of the relationship between severity of dysphagia and depressive symptoms demonstrated that several evaluation tools are available for objective and subjective assessment. The severity and progression of dysphagia was significantly associated with increased depressive symptoms.
Conclusion
Dysphagia is associated with and positively correlated to depression and anxiety scores observed in Parkinson disease (PD), multiple sclerosis (MS) and stroke. Similar association is observed in patients with head and neck cancer, tongue cancer and oral cancer. A bidirectional positive correlation exists with a vicious circle that loops between dysphagia and psychological disease. Moreover, the severity of dysphagia shows correlation with depression and/or anxiety scores (Fig. 1, Graphical abstract).
Graphical Abstract
Collapse
|
|
23
|
Rudisch DM, Krasko MN, Burdick R, Broadfoot CK, Rogus-Pulia N, Ciucci MR. Dysphagia in Parkinson Disease: Part I - Pathophysiology and Diagnostic Practices. CURRENT PHYSICAL MEDICINE AND REHABILITATION REPORTS 2023; 11:176-187. [PMID: 37608845 PMCID: PMC10441627 DOI: 10.1007/s40141-023-00392-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2023] [Indexed: 03/30/2023]
Abstract
Purpose of Review Dysphagia affects the majority of individuals with Parkinson disease (PD) and is not typically diagnosed until later in disease progression. This review will cover the current understanding of PD pathophysiology, and provides an overview of dysphagia in PD including diagnostic practices, gaps in knowledge, and future directions. Recent Findings Many non-motor and other motor signs of PD appear in the prodrome prior to the manifestation of hall- mark signs and diagnosis. While dysphagia often presents already in the prodrome, it is not routinely addressed in standard neurology examinations. Summary Dysphagia in PD can result in compromised efficiency and safety of swallowing, which significantly contributes to malnutrition and dehydration, decrease quality of life, and increase mortality. The heterogeneous clinical presentation of PD complicates diagnostic procedures which often leads to delayed treatment. Research has advanced our knowledge of mechanisms underlying PD, but dysphagia is still largely understudied, especially in the prodromal stage.
Collapse
Affiliation(s)
- Denis Michael Rudisch
- Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Wisconsin-Madison, 1300 University Ave, Madison, WI 53706, USA
- Department of Communication Sciences and Disorders, University of Wisconsin-Madison, 1975 Willow Drive, Madison, WI 53706, USA
| | - Maryann N Krasko
- Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Wisconsin-Madison, 1300 University Ave, Madison, WI 53706, USA
- Department of Communication Sciences and Disorders, University of Wisconsin-Madison, 1975 Willow Drive, Madison, WI 53706, USA
| | - Ryan Burdick
- Department of Medicine, Division of Geriatrics and Gerontology, School of Medicine and Public Health, University of Wisconsin-Madison, 1685 Highland Avenue, Madison, WI 53705, USA
- Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705, USA
| | - Courtney K Broadfoot
- Department of Medicine, Division of Geriatrics and Gerontology, School of Medicine and Public Health, University of Wisconsin-Madison, 1685 Highland Avenue, Madison, WI 53705, USA
- Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705, USA
| | - Nicole Rogus-Pulia
- Department of Medicine, Division of Geriatrics and Gerontology, School of Medicine and Public Health, University of Wisconsin-Madison, 1685 Highland Avenue, Madison, WI 53705, USA
- Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705, USA
| | - Michelle R Ciucci
- Department of Surgery, Division of Otolaryngology-Head & Neck Surgery, University of Wisconsin-Madison, 1300 University Ave, Madison, WI 53706, USA
- Department of Communication Sciences and Disorders, University of Wisconsin-Madison, 1975 Willow Drive, Madison, WI 53706, USA
- Neuroscience Training Program, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI 53705, USA
| |
Collapse
|
|
24
|
Wu J, Wang Y, Wang X, Xie Y, Li W. A systematic review and meta-analysis of acupuncture in Parkinson's disease with dysphagia. Front Neurol 2023; 14:1099012. [PMID: 37305760 PMCID: PMC10251408 DOI: 10.3389/fneur.2023.1099012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 05/15/2023] [Indexed: 06/13/2023] Open
Abstract
Objective The systematic review and meta-analysis aimed to comprehensively evaluate acupuncture's efficacy and safety in treating dysphagia in Parkinson's disease (PD). Methods We searched PubMed, Cochrane Library, Embase, Web of Science, China Knowledge Infrastructure (CNKI), China Science Journal Database (VIP), Wan-fang Database, and the China Biomedical Literature Service System (CBM) for randomized controlled trials (RCTs) comparing the efficacy of acupuncture alone or in combination with control treatment in improving dysphagia by October 2022. The degree of dysphagia was the primary outcome indicator, with secondary outcomes including serum albumin (ALB) and hemoglobin (Hb) levels, the incidence of pneumonia, and adverse events. Two investigators independently extracted information according to the inclusion and exclusion criteria. Data synthesis was calculated by RevMan (V.5.4.1) software. Results This study included ten randomized controlled trials with 724 patients. Most RCTs have a high or uncertain risk of bias due to the lack of a blinded design. Meta-analysis showed that acupuncture combined with control treatment was superior to control treatment alone in improving Videofluoroscopic Swallowing Study (VFSS) scores (MD: 1.48; 95% CI: 1.16, 1.81; P < 0.00001) and reducing Standardized Swallowing Assessment (SSA) scores (MD: -3.08; 95% CI: -4.01, -2.15; P < 0.00001). Acupuncture combined with control therapy has a more significant benefit in improving the clinical efficiency of dysphagia in PD (RR: 1.40; 95%CI: 1.25, 1.58; P < 0.00001). Compared to the control group without acupuncture, acupuncture improved the nutritional status of patients and increased their serum ALB (MD: 3.38, 95%CI: 1.83, 4.92, P < 0.00001) and Hb levels (MD: 7.66; 95%CI: 5.57, 9.75; P < 0.00001). Three RCTs reported that the rate of pulmonary infections in the acupuncture group was lower than without acupuncture intervention (RR: 0.29, 95% CI: 0.14, 0.63; P = 0.001). Conclusion Acupuncture could be recommended as an adjunctive treatment for dysphagia in PD. However, due to the high risk of bias in the included studies, more high-quality evidence is needed to confirm the efficacy and safety of acupuncture for dysphagia in PD. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022370221.
Collapse
Affiliation(s)
- Jing Wu
- Basic Medical School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yi Wang
- Basic Medical School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xueyan Wang
- Clinical Medical School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yujia Xie
- Basic Medical School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Weihong Li
- Basic Medical School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
25
|
Yang Q, Wang Y, Zhao C, Pang S, Lu J, Chan P. α-Synuclein aggregation causes muscle atrophy through neuromuscular junction degeneration. J Cachexia Sarcopenia Muscle 2023; 14:226-242. [PMID: 36416282 PMCID: PMC9891985 DOI: 10.1002/jcsm.13123] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 09/15/2022] [Accepted: 10/12/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Sarcopenia is common in patients with Parkinson's disease (PD), showing mitochondrial oxidative stress in skeletal muscle. The aggregation of α-synuclein (α-Syn) to induce oxidative stress is a key pathogenic process of PD; nevertheless, we know little about its potential role in regulating peripheral nerves and the function of the muscles they innervate. METHODS To investigate the role of α-Syn aggregation on neuromuscular system, we used the Thy1 promoter to overexpress human α-Syn transgenic mice (mThy1-hSNCA). hα-Syn expression was evaluated by western blot, and its localization was determined by confocal microscopy. The impact of α-Syn aggregation on the structure and function of skeletal muscle mitochondria and neuromuscular junctions (NMJs), as well as muscle mass and function were characterized by flow cytometry, transmission electron microscopy, Seahorse XF24 metabolic assay, and AAV9 in vivo injection. We assessed the regenerative effect of mitochondrial-targeted superoxide dismutase (Mito-TEMPO) after skeletal muscle injury in mThy1-hSNCA mice. RESULTS Overexpressed hα-Syn protein localized in motor neuron axons and NMJs in muscle and formed aggregates. α-Syn aggregation increased the number of abnormal mitochondrial in the intramuscular axons and NMJs by over 60% (P < 0.01), which inhibited the release of acetylcholine (ACh) from presynaptic vesicles in NMJs (P < 0.05). The expression of genes associated with NMJ activity, neurotransmission and regulation of reactive oxygen species (ROS) metabolic process were significantly decreased in mThy1-hSNCA mice, resulting in ROS production elevated by ~220% (P < 0.05), thereby exacerbating oxidative stress. Such process altered mitochondrial spatial relationships to sarcomeric structures, decreased Z-line spacing by 36% (P < 0.05) and increased myofibre apoptosis by ~10% (P < 0.05). Overexpression of α-Syn altered the metabolic profile of muscle satellite cells (MuSCs), including basal respiratory capacity (~170% reduction) and glycolytic capacity (~150% reduction) (P < 0.05) and decreased cell migration and fusion during muscle regeneration (~60% and ~40%, respectively) (P < 0.05). We demonstrated that Mito-TEMPO treatment could restore the oxidative stress status (the complex I/V protein and enzyme activities increased ~200% and ~150%, respectively), which caused by α-Syn aggregation, and improve the ability of muscle regeneration after injury. In addition, the NMJ receptor fragmentation and ACh secretion were also improved. CONCLUSIONS These results reveal that the α-synuclein aggregation plays an important role in regulating acetylcholine release from neuromuscular junctions and induces intramuscular mitochondrial oxidative stress, which can provide new insights into the aetiology of muscle atrophy in patients with Parkinson's disease.
Collapse
Affiliation(s)
- Qiumei Yang
- Department of Neurology, Geriatrics and Neurobiology, National Clinical Research Center of Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Yanyan Wang
- Department of Neurology, Geriatrics and Neurobiology, National Clinical Research Center of Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Chunsong Zhao
- Department of Neurology, Geriatrics and Neurobiology, National Clinical Research Center of Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Shimin Pang
- Department of Neurology, Geriatrics and Neurobiology, National Clinical Research Center of Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jing Lu
- Department of Neurology, Geriatrics and Neurobiology, National Clinical Research Center of Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Piu Chan
- Department of Neurology, Geriatrics and Neurobiology, National Clinical Research Center of Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.,Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.,Clinical Center for Parkinson's Disease, Capital Medical University, Beijing Institute of Geriatrics, Beijing, China.,Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory for Parkinson's Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
| |
Collapse
|
|
26
|
Curtis JA, Borders JC, Dakin AE, Troche MS. The Role of Aspiration Amount on Airway Protective Responses in People with Neurogenic Dysphagia. Dysphagia 2022:10.1007/s00455-022-10546-x. [DOI: 10.1007/s00455-022-10546-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022]
|
|
27
|
Chau MJ, Quintero JE, Blalock E, Byrum S, Mackintosh SG, Samaan C, Gerhardt GA, van Horne CG. Transection injury differentially alters the proteome of the human sural nerve. PLoS One 2022; 17:e0260998. [PMID: 36417411 PMCID: PMC9683555 DOI: 10.1371/journal.pone.0260998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 09/09/2022] [Indexed: 11/25/2022] Open
Abstract
Regeneration after severe peripheral nerve injury is often poor. Knowledge of human nerve regeneration and the growth microenvironment is greatly lacking. We aimed to identify the regenerative proteins in human peripheral nerve by comparing the proteome before and after a transection injury. In a unique study design, we collected closely matched samples of naïve and injured sural nerve. Naïve and injured (two weeks after injury) samples were analyzed using mass spectrometry and immunoassays. We found significantly altered levels following the nerve injury. Mass spectrometry revealed that injury samples had 568 proteins significantly upregulated and 471 significantly downregulated compared to naïve samples (q-value ≤ 0.05 and Z ≥ |2| (log2)). We used Gene Ontology (GO) pathway overrepresentation analysis to highlight groups of proteins that were significantly upregulated or downregulated with injury-induced degeneration and regeneration. Significant protein changes in key pathways were identified including growth factor levels, Schwann cell de-differentiation, myelination downregulation, epithelial-mesenchymal transition (EMT), and axonal regeneration pathways. The proteomes of the uninjured nerve compared to the degenerating/regenerating nerve may reveal biomarkers to aid in the development of repair strategies such as infusing supplemental trophic factors and in monitoring neural tissue regeneration.
Collapse
Affiliation(s)
- Monica J. Chau
- Brain Restoration Center, College of Medicine, University of Kentucky, Lexington, KY, United States of America
- Department of Neurosurgery, College of Medicine, University of Kentucky, Lexington, KY, United States of America
| | - Jorge E. Quintero
- Brain Restoration Center, College of Medicine, University of Kentucky, Lexington, KY, United States of America
- Department of Neurosurgery, College of Medicine, University of Kentucky, Lexington, KY, United States of America
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY, United States of America
| | - Eric Blalock
- Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, United States of America
| | - Stephanie Byrum
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Samuel G. Mackintosh
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Christopher Samaan
- Brain Restoration Center, College of Medicine, University of Kentucky, Lexington, KY, United States of America
- Department of Neurosurgery, College of Medicine, University of Kentucky, Lexington, KY, United States of America
| | - Greg A. Gerhardt
- Brain Restoration Center, College of Medicine, University of Kentucky, Lexington, KY, United States of America
- Department of Neurosurgery, College of Medicine, University of Kentucky, Lexington, KY, United States of America
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY, United States of America
- Department of Neurology, College of Medicine, University of Kentucky, Lexington, KY, United States of America
| | - Craig G. van Horne
- Brain Restoration Center, College of Medicine, University of Kentucky, Lexington, KY, United States of America
- Department of Neurosurgery, College of Medicine, University of Kentucky, Lexington, KY, United States of America
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY, United States of America
- * E-mail:
| |
Collapse
|
|
28
|
Helwig M, Ulusoy A, Rollar A, O’Sullivan SA, Lee SSL, Aboutalebi H, Pinto-Costa R, Jevans B, Klinkenberg M, Di Monte DA. Neuronal hyperactivity-induced oxidant stress promotes in vivo α-synuclein brain spreading. SCIENCE ADVANCES 2022; 8:eabn0356. [PMID: 36044566 PMCID: PMC9432848 DOI: 10.1126/sciadv.abn0356] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 07/15/2022] [Indexed: 05/31/2023]
Abstract
Interneuronal transfer and brain spreading of pathogenic proteins are features of neurodegenerative diseases. Pathophysiological conditions and mechanisms affecting this spreading remain poorly understood. This study investigated the relationship between neuronal activity and interneuronal transfer of α-synuclein, a Parkinson-associated protein, and elucidated mechanisms underlying this relationship. In a mouse model of α-synuclein brain spreading, hyperactivity augmented and hypoactivity attenuated protein transfer. Important features of neuronal hyperactivity reported here were an exacerbation of oxidative and nitrative reactions, pronounced accumulation of nitrated α-synuclein, and increased protein aggregation. Data also pointed to mitochondria as key targets and likely sources of reactive oxygen and nitrogen species within hyperactive neurons. Rescue experiments designed to counteract the increased burden of reactive oxygen species reversed hyperactivity-induced α-synuclein nitration, aggregation, and interneuronal transfer, providing first evidence of a causal link between these pathological effects of neuronal stimulation and indicating a mechanistic role of oxidant stress in hyperactivity-induced α-synuclein spreading.
Collapse
Affiliation(s)
- Michael Helwig
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | - Ayse Ulusoy
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| | - Angela Rollar
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | | | - Shirley S. L. Lee
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | - Helia Aboutalebi
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | - Rita Pinto-Costa
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | - Benjamin Jevans
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | | | - Donato A. Di Monte
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| |
Collapse
|
|
29
|
Özçağlayan Ö, Altunan B, Kurtoğlu Özçağlayan Tİ, Ünal A. The Atrophy of the Vagus Nerve Correlated With Gastrointestinal Non-Motor Symptoms Scores, in Parkinson’s Disease: A Sonography Research Study. JOURNAL OF DIAGNOSTIC MEDICAL SONOGRAPHY 2022. [DOI: 10.1177/87564793221097008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Objective: To investigate the vagus nerve (VN) dimensional changes with Parkinson’s disease (PD), compared with healthy subjects. Additionally, it is important to investigate whether there is any relationships between these changes and patient’s motor and non-motor symptoms (NMS) of PD. Materials and Methods: A cohort of 43 patients with PD formed a group that was compared with 44 patients without PD, denoted as the healthy subject (HS) group. The diameter and areas of VN of study groups were measured using ultrasonography (US). The study groups were further divided into <65 and ≥65 subgroups, to evaluate the possible effect of age on the VN and evaluated relationships of VN dimensions, between subgroups. In the PD group, a correlational analysis was conducted between the diameter and area of the VN and the motor and NMS scores. Results: There was statistically significant difference in right ( P = .002) and left VN diameters ( P = .007) and in right ( P = .001) and left VN areas ( P = .007), between study groups. There was no significant difference in right and left VN diameters and the right and left VN areas, between subgroups. There was moderately negative correlation between gastrointestinal NMS scores and right VN area ( r = −0.499, P = .002), left VN area ( r = −0.499, P = .002), right VN diameter ( r = −0.378, P = .023), left VN diameter ( r = −0.385, P = .021), respectively. Conclusion: The US demonstrated that VN dimensions may possibly reduce in those patients affected by PD. In this cohort, it appears that an increase in gastrointestinal NMS scores may be explained by atrophy of the VN.
Collapse
Affiliation(s)
- Ömer Özçağlayan
- Department of Radiology, Istanbul Oncology Hospital, Istanbul, Turkey
| | - Bengü Altunan
- Department of Neurology, School of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
| | | | - Aysun Ünal
- Department of Neurology, School of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
| |
Collapse
|
|
30
|
Sasegbon A, Hammerbeck U, Michou E, Cheng I, Zhang M, James C, Hamdy S. A feasibility pilot study of the effects of neurostimulation on swallowing function in Parkinson’s Disease. AMRC OPEN RESEARCH 2022; 3:19. [PMID: 35726231 PMCID: PMC7612876 DOI: 10.12688/amrcopenres.13007.2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Introduction Dysphagia often occurs during Parkinson’s disease (PD) and can have severe consequences. Recently, neuromodulatory techniques have been used to treat neurogenic dysphagia. Here we aimed to compare the neurophysiological and swallowing effects of three different types of neurostimulation, 5 Hertz (Hz) repetitive transcranial magnetic stimulation (rTMS), 1 Hz rTMS and pharyngeal electrical stimulation (PES) in patients with PD. Method 12 PD patients with dysphagia were randomised to receive either 5 Hz rTMS, 1 Hz rTMS, or PES. In a cross-over design, patients were assigned to one intervention and received both real and sham stimulation. Patients received a baseline videofluoroscopic (VFS) assessment of their swallowing, enabling penetration aspiration scores (PAS) to be calculated for: thin fluids, paste, solids and cup drinking. Swallowing timing measurements were also performed on thin fluid swallows only. They then had baseline recordings of motor evoked potentials (MEPs) from both pharyngeal and (as a control) abductor pollicis brevis (APB) cortical areas using single-pulse TMS. Subsequently, the intervention was administered and post interventional TMS recordings were taken at 0 and 30 minutes followed by a repeat VFS within 60 minutes of intervention. Results All interventions were well tolerated. Due to lower than expected recruitment, statistical analysis of the data was not undertaken. However, with respect to PAS swallowing timings and MEP amplitudes, there was small but visible difference in the outcomes between active and sham. Conclusion PES, 5 Hz rTMS and 1 Hz rTMS are tolerable interventions in PD related dysphagia. Due to small patient numbers no definitive conclusions could be drawn from the data with respect to individual interventions improving swallowing function and comparative effectiveness between interventions. Larger future studies are needed to further explore the efficacy of these neuromodulatory treatments in Parkinson’s Disease associated dysphagia.
Collapse
Affiliation(s)
- Ayodele Sasegbon
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, Greater Manchester, Stott Lane, Salford M6 8HD, UK
| | - Ulrike Hammerbeck
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, Greater Manchester, Stott Lane, Salford M6 8HD, UK
| | - Emilia Michou
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, Greater Manchester, Stott Lane, Salford M6 8HD, UK
- Department of Speech and Language Therapy, University of Patras, Patras, Greece
| | - Ivy Cheng
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, Greater Manchester, Stott Lane, Salford M6 8HD, UK
| | - Mengqing Zhang
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, Greater Manchester, Stott Lane, Salford M6 8HD, UK
| | - Charlotte James
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, Greater Manchester, Stott Lane, Salford M6 8HD, UK
| | - Shaheen Hamdy
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, Greater Manchester, Stott Lane, Salford M6 8HD, UK
| |
Collapse
|
|
31
|
Warnecke T, Schäfer KH, Claus I, Del Tredici K, Jost WH. Gastrointestinal involvement in Parkinson's disease: pathophysiology, diagnosis, and management. NPJ Parkinsons Dis 2022; 8:31. [PMID: 35332158 PMCID: PMC8948218 DOI: 10.1038/s41531-022-00295-x] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
Growing evidence suggests an increasing significance for the extent of gastrointestinal tract (GIT) dysfunction in Parkinson's disease (PD). Most patients suffer from GIT symptoms, including dysphagia, sialorrhea, bloating, nausea, vomiting, gastroparesis, and constipation during the disease course. The underlying pathomechanisms of this α-synucleinopathy play an important role in disease development and progression, i.e., early accumulation of Lewy pathology in the enteric and central nervous systems is implicated in pharyngeal discoordination, esophageal and gastric motility/peristalsis impairment, chronic pain, altered intestinal permeability and autonomic dysfunction of the colon, with subsequent constipation. Severe complications, including malnutrition, dehydration, insufficient drug effects, aspiration pneumonia, intestinal obstruction, and megacolon, frequently result in hospitalization. Sophisticated diagnostic tools are now available that permit more detailed examination of specific GIT impairment patterns. Furthermore, novel treatment approaches have been evaluated, although high-level evidence trials are often missing. Finally, the burgeoning literature devoted to the GIT microbiome reveals its importance for neurologists. We review current knowledge about GIT pathoanatomy, pathophysiology, diagnosis, and treatment in PD and provide recommendations for management in daily practice.
Collapse
Affiliation(s)
- T Warnecke
- Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, 48149, Münster, Germany
| | - K-H Schäfer
- Research and Transfer Working Group Enteric Nervous System (AGENS), University of Applied Sciences Kaiserslautern, Campus Zweibrücken, 66482, Zweibrücken, Germany
| | - I Claus
- Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, 48149, Münster, Germany
| | - K Del Tredici
- Clinical Neuroanatomy, Department of Neurology, Center for Biomedical Research, University of Ulm, 89081, Ulm, Germany
| | - W H Jost
- Parkinson-Klinik Ortenau, 77709, Wolfach, Germany.
| |
Collapse
|
|
32
|
Kaczyńska K, Orłowska ME, Andrzejewski K. Respiratory Abnormalities in Parkinson's Disease: What Do We Know from Studies in Humans and Animal Models? Int J Mol Sci 2022; 23:ijms23073499. [PMID: 35408858 PMCID: PMC8998219 DOI: 10.3390/ijms23073499] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/18/2022] [Accepted: 03/22/2022] [Indexed: 12/12/2022] Open
Abstract
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease characterized by movement disorders due to the progressive loss of dopaminergic neurons in the ventrolateral region of the substantia nigra pars compacta (SNpc). Apart from the cardinal motor symptoms such as rigidity and bradykinesia, non-motor symptoms including those associated with respiratory dysfunction are of increasing interest. Not only can they impair the patients’ quality of life but they also can cause aspiration pneumonia, which is the leading cause of death among PD patients. This narrative review attempts to summarize the existing literature on respiratory impairments reported in human studies, as well as what is newly known from studies in animal models of the disease. Discussed are not only respiratory muscle dysfunction, apnea, and dyspnea, but also altered central respiratory control, responses to hypercapnia and hypoxia, and how they are affected by the pharmacological treatment of PD.
Collapse
|
|
33
|
Gandhi P, Steele CM. Effectiveness of Interventions for Dysphagia in Parkinson Disease: A Systematic Review. AMERICAN JOURNAL OF SPEECH-LANGUAGE PATHOLOGY 2022; 31:463-485. [PMID: 34890260 PMCID: PMC9159671 DOI: 10.1044/2021_ajslp-21-00145] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/18/2021] [Accepted: 09/10/2021] [Indexed: 05/31/2023]
Abstract
PURPOSE Dysphagia is a common sequela of Parkinson disease (PD) and is associated with malnutrition, aspiration pneumonia, and mortality. This review article synthesized evidence regarding the effectiveness of interventions for dysphagia in PD. METHOD Electronic searches were conducted in Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL, and speechBITE. Of the 2,015 articles identified, 26 met eligibility criteria: interventional or observational studies with at least five or more participants evaluating dysphagia interventions in adults with PD-related dysphagia, with outcomes measured using videofluoroscopic swallowing study (VFSS), fiberoptic endoscopic evaluation of swallowing (FEES), or electromyography (EMG). Risk of bias (RoB) was evaluated using the Evidence Project tool and predetermined criteria regarding the rigor of swallowing outcome measures. RESULTS Interventions were classified as follows: pharmacological (n = 11), neurostimulation (n = 8), and behavioral (n = 7). Primary outcome measures varied across studies, including swallowing timing, safety, and efficiency, and were measured using VFSS (n = 17), FEES (n = 6), and EMG (n = 4). Critical appraisal of study findings for RoB, methodological rigor, and transparency showed the majority of studies failed to adequately describe contrast media used, signal acquisition settings, and rater blinding to time point. Low certainty evidence generally suggested improved swallow timing with exercises with biofeedback and deep brain stimulation (DBS), improved safety with DBS and expiratory muscle strength training, and improved efficiency with the Lee Silverman Voice Treatment and levodopa. CONCLUSIONS Studies with lower RoB and greater experimental rigor showed potential benefit in improving swallowing efficiency but not safety. Further research investigating discrete changes in swallowing pathophysiology post-intervention is warranted to guide dysphagia management in PD. SUPPLEMENTAL MATERIAL https://doi.org/10.23641/asha.17132162.
Collapse
Affiliation(s)
- Pooja Gandhi
- Swallowing Rehabilitation Research Laboratory, Toronto Rehabilitation Institute—University Health Network, Ontario, Canada
- Rehabilitation Sciences Institute, Faculty of Medicine, University of Toronto, Ontario, Canada
| | - Catriona M. Steele
- Swallowing Rehabilitation Research Laboratory, Toronto Rehabilitation Institute—University Health Network, Ontario, Canada
- Rehabilitation Sciences Institute, Faculty of Medicine, University of Toronto, Ontario, Canada
| |
Collapse
|
|
34
|
Title: Identifying subtypes of treatment effects of subthalamic nucleus deep brain stimulation on motor symptoms in patients of late-stage Parkinson’s disease with cluster analysis. BRAIN HEMORRHAGES 2022. [DOI: 10.1016/j.hest.2022.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
|
|
35
|
Chechetkin AO, Moskalenko AN, Fedotova EY, Illarioshkin SN. Ultrasound imaging of vagus nerves in patients with Parkinson's disease. BULLETIN OF RUSSIAN STATE MEDICAL UNIVERSITY 2021. [DOI: 10.24075/brsmu.2021.054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Parkinson’s disease (PD) is a neurodegenerative multisystem disorder characterized by pathologic α-synuclein aggregation affecting, among other things, vagal fibers. The aim of this study was to investigate the cross-sectional area (CSA) of the vagus nerve (VN) in patients with PD using ultrasound imaging. The study was conducted in 32 patients with PD (15 men and 17 women; mean age 58 ± 10 years) and 32 healthy controls comparable with the main group in terms of sex and age. All study participants underwent ultrasound examination of the VN using a high-resolution transducer. Left VN CSA was significantly smaller in patients with PD than in the control group (1.78 ± 0.52 mm2 vs 2.11 ± 0.41 mm2; р = 0.007). A similar result was obtained for right VN CSA at the trend level. ROC analysis demonstrated that the threshold CSA value of < 2.10 mm2 for the left VN has low diagnostic sensivity (59%) for VN atrophy in patients with PD. Right VN CSA was significantly larger than left VN CSA in both groups (p < 0.001). The analysis of the PD group did not reveal any associations between VN CSA and age, duration and stage of the disease, motor (UPDRS III) and non-motor (NMSQ) scores. Patients with akinetic-rigid form of PD had smaller left VN CSA than patients with the mixed form of the disease (р < 0.05). A moderate inverse correlation was established between left VN CSA and the area of substantia nigra hyperechogenicity on both sides (р < 0.04); for the right VN a similar correlation was established at the trend level. High-resolution ultrasound of patients with PD demonstrated atrophy of the VN and the association of VN CSA with the clinical form of the disease and the ultrasound features of the substantia nigra.
Collapse
|
|
36
|
Evidente VGH, Evidente DH, Ortega SC, Levine TD, Freeman R, Gibbons C. X-Linked Dystonia-Parkinsonism ("Lubag") May Present with Peripheral Synucleinopathy. Mov Disord 2021; 37:130-136. [PMID: 34582053 DOI: 10.1002/mds.28801] [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: 07/28/2021] [Revised: 08/26/2021] [Accepted: 09/06/2021] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND X-linked dystonia parkinsonism (XDP) or "Lubag" is a genetic dystonia syndrome observed among Filipinos that can present with levodopa-responsive parkinsonism and abnormal dopamine transporter (DAT) imaging. OBJECTIVE The aim of this study is to describe the results of skin biopsies for phosphorylated α-synuclein (P-SYN) in XDP. METHOD This study used the retrospective chart review. RESULTS We report 6 patients who carried the XDP gene mutation with DAT imaging and skin biopsies to detect P-SYN. Five had segmental or multifocal dystonia and parkinsonism: 4 were levodopa-responsive and 1 non-levodopa-responsive. One patient was asymptomatic but had mild bradykinesia. Cutaneous P-SYN and abnormal DAT scans were noted in the 4 levodopa-responsive patients and 1 asymptomatic patient. CONCLUSION We report for the first time the presence of cutaneous P-SYN in XDP. Our findings suggest that XDP may be a hitherto-undescribed synucleinopathy or that some XDP patients may have concurrent Parkinson's disease.
Collapse
Affiliation(s)
| | | | - Susan C Ortega
- Movement Disorders Center of Arizona, Scottsdale, Arizona, USA
| | | | - Roy Freeman
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - ChristopherH Gibbons
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
37
|
Seo MH, Yeo S. Srpk3 Decrease Associated with Alpha-Synuclein Increase in Muscles of MPTP-Induced Parkinson's Disease Mice. Int J Mol Sci 2021; 22:9375. [PMID: 34502283 PMCID: PMC8430752 DOI: 10.3390/ijms22179375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/17/2021] [Accepted: 08/26/2021] [Indexed: 11/17/2022] Open
Abstract
Parkinson's disease (PD) is characterized by a loss of dopaminergic cells in the substantia nigra, and its histopathological features include the presence of fibrillar aggregates of α-synuclein (α-syn), which are called Lewy bodies and Lewy neurites. Lewy pathology has been identified not only in the brain but also in various tissues, including muscles. This study aimed to investigate the link between serine/arginine-rich protein specific kinase 3 (srpk3) and α-syn in muscles in PD. We conducted experiments on the quadriceps femoris of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and the C2C12 cell line after treatment with 1-methyl-4-phenylpyridinium (MPP+) and srpk3 short interfering RNA (siRNA). Compared to the control group, the MPTP group showed significantly reduced expression of srpk3, but increased expression of α-syn. In MPP+-treated C2C12 cells, srpk3 expression gradually decreased and α-syn expression increased with the increasing MPP+ concentration. Moreover, experiments in C2C12 cells using srpk3 siRNA showed increased expressions of α-syn and phosphorylated α-syn. Our results showed that srpk3 expression could be altered by MPTP intoxication in muscles, and this change may be related to changes in α-syn expression. Furthermore, this study could contribute to advancement of research on the mechanism by which srpk3 plays a role in PD.
Collapse
Affiliation(s)
- Min Hyung Seo
- Department of Meridian and Acupoint, College of Korean Medicine, Sang Ji University, Wonju 26339, Korea;
| | - Sujung Yeo
- Department of Meridian and Acupoint, College of Korean Medicine, Sang Ji University, Wonju 26339, Korea;
- Research Institute of Korean Medicine, Sang Ji University, Wonju 26339, Korea
| |
Collapse
|
|
38
|
Low serum uric acid levels are associated with the nonmotor symptoms and brain gray matter volume in Parkinson's disease. Neurol Sci 2021; 43:1747-1754. [PMID: 34405296 PMCID: PMC8860949 DOI: 10.1007/s10072-021-05558-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 07/30/2021] [Indexed: 12/21/2022]
Abstract
Background Uric acid (UA) plays a protective role in Parkinson’s disease (PD). To date, studies on the relationship between serum UA levels and nonmotor symptoms and brain gray matter volume in PD patients have been rare. Methods Automated enzymatic analysis was used to determine serum UA levels in 68 healthy controls and 88 PD patients, including those at the early (n = 56) and middle-late (n = 32) stages of the disease. Evaluation of motor symptoms and nonmotor symptoms in PD patients was assessed by the associated scales. Image acquisition was performed using a Siemens MAGNETOM Prisma 3 T MRI scanner. Results Serum UA levels in early stage PD patients were lower than those in healthy controls, and serum UA levels in the middle-late stage PD patients were lower than those in the early stage PD patients. Serum UA levels were significantly negatively correlated with the disease course, dysphagia, anxiety, depression, apathy, and cognitive dysfunction. ROC assessment confirmed that serum UA levels had good predictive accuracy for PD with dysphagia, anxiety, depression, apathy, and cognitive dysfunction. Furthermore, UA levels were significantly positively correlated with gray matter volume in whole brain. Conclusions This study shows that serum UA levels were correlated with the nonmotor symptoms of dysphagia, anxiety, depression, apathy, and cognitive dysfunction and the whole-brain gray matter volume. That is the first report examining the relationships between serum UA and clinical manifestations and imaging features in PD patients.
Collapse
|
|
39
|
The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson's Disease. Life (Basel) 2021; 11:life11080804. [PMID: 34440548 PMCID: PMC8401994 DOI: 10.3390/life11080804] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 12/14/2022] Open
Abstract
Parkinson’s disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, depression, pain and, in later stages, cognitive decline and dysautonomia. The main pathological features of PD are neuronal loss and consequent accumulation of Lewy bodies (LB) in the surviving neurons. Alpha-synuclein (α-syn) is the main component of LB, and α-syn aggregation and accumulation perpetuate neuronal degeneration. Mutations in the α-syn gene (SNCA) were the first genetic cause of PD to be identified. Generally, patients carrying SNCA mutations present early-onset parkinsonism with severe and early non-motor symptoms, including cognitive decline. Several SNCA polymorphisms were also identified, and some of them showed association with non-motor manifestations. The functional role of these polymorphisms is only partially understood. In this review we explore the contribution of SNCA and its product, α-syn, in predisposing to the non-motor manifestations of PD.
Collapse
|
|
40
|
Drobny A, Ngo PA, Neurath MF, Zunke F, López-Posadas R. Molecular Communication Between Neuronal Networks and Intestinal Epithelial Cells in Gut Inflammation and Parkinson's Disease. Front Med (Lausanne) 2021; 8:655123. [PMID: 34368179 PMCID: PMC8339315 DOI: 10.3389/fmed.2021.655123] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/14/2021] [Indexed: 12/18/2022] Open
Abstract
Intestinal symptoms, such as nausea, vomiting, and constipation, are common in Parkinson's disease patients. These clinical signs normally appear years before the diagnosis of the neurodegenerative disease, preceding the occurrence of motor manifestations. Moreover, it is postulated that Parkinson's disease might originate in the gut, due to a response against the intestinal microbiota leading to alterations in alpha-synuclein in the intestinal autonomic nervous system. Transmission of this protein to the central nervous system is mediated potentially via the vagus nerve. Thus, deposition of aggregated alpha-synuclein in the gastrointestinal tract has been suggested as a potential prodromal diagnostic marker for Parkinson's disease. Interestingly, hallmarks of chronic intestinal inflammation in inflammatory bowel disease, such as dysbiosis and increased intestinal permeability, are also observed in Parkinson's disease patients. Additionally, alpha-synuclein accumulations were detected in the gut of Crohn's disease patients. Despite a solid association between neurodegenerative diseases and gut inflammation, it is not clear whether intestinal alterations represent cause or consequence of neuroinflammation in the central nervous system. In this review, we summarize the bidirectional communication between the brain and the gut in the context of Parkinson's disease and intestinal dysfunction/inflammation as present in inflammatory bowel disease. Further, we focus on the contribution of intestinal epithelium, the communication between intestinal epithelial cells, microbiota, immune and neuronal cells, as well as mechanisms causing alterations of epithelial integrity.
Collapse
Affiliation(s)
- Alice Drobny
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Phuong A Ngo
- Medicine 1, University Hospital Erlangen, Erlangen, Germany
| | - Markus F Neurath
- Medicine 1, University Hospital Erlangen, Erlangen, Germany.,Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Friederike Zunke
- Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | | |
Collapse
|
|
41
|
Beach TG, Adler CH, Sue LI, Shill HA, Driver-Dunckley E, Mehta SH, Intorcia AJ, Glass MJ, Walker JE, Arce R, Nelson CM, Serrano GE. Vagus Nerve and Stomach Synucleinopathy in Parkinson's Disease, Incidental Lewy Body Disease, and Normal Elderly Subjects: Evidence Against the "Body-First" Hypothesis. JOURNAL OF PARKINSONS DISEASE 2021; 11:1833-1843. [PMID: 34151862 PMCID: PMC10082635 DOI: 10.3233/jpd-212733] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson's disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla. OBJECTIVE We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD. METHODS Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were taken from the gastric body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology. RESULTS Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive. CONCLUSION As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease.
Collapse
Affiliation(s)
| | - Charles H Adler
- Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Lucia I Sue
- Banner Sun Health Research Institute, Sun City, AZ, USA
| | | | | | - Shyamal H Mehta
- Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | | | | | | | - Richard Arce
- Banner Sun Health Research Institute, Sun City, AZ, USA
| | | | | |
Collapse
|
|
42
|
Lerner A. The intestinal luminal sources of α-synuclein: a gastroenterologist perspective. Nutr Rev 2021; 80:282-293. [PMID: 33942062 DOI: 10.1093/nutrit/nuab024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease is characterized by nonmotor/motor dysfunction, midbrain dopaminergic neuronal death, and α-synuclein (aSN) deposits. The current hypothesis is that aSN accumulates in the enteric nervous system to reach the brain. However, invertebrate, vertebrate, and nutritional sources of aSN reach the luminal compartment. Submitted to local amyloidogenic forces, the oligomerized proteins' cargo can be sensed and sampled by a specialized mucosal cell to be transmitted to the adjacent enteric nervous system, starting their upward journey to the brain. The present narrative review extends the current mucosal origin of Parkinson's disease, presenting the possibility that the disease starts in the intestinal lumen. If substantiated, eliminating the nutritional sources of aSN (eg, applying a vegetarian diet) might revolutionize the currently used dopaminergic pharmacologic therapy.
Collapse
Affiliation(s)
- Aaron Lerner
- A. Lerner is with the Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| |
Collapse
|
|
43
|
The emerging role of the sympathetic nervous system in skeletal muscle motor innervation and sarcopenia. Ageing Res Rev 2021; 67:101305. [PMID: 33610815 DOI: 10.1016/j.arr.2021.101305] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/06/2021] [Accepted: 02/15/2021] [Indexed: 12/30/2022]
Abstract
Examining neural etiologic factors'role in the decline of neuromuscular function with aging is essential to our understanding of the mechanisms underlying sarcopenia, the age-dependent decline in muscle mass, force and power. Innervation of the skeletal muscle by both motor and sympathetic axons has been established, igniting interest in determining how the sympathetic nervous system (SNS) affect skeletal muscle composition and function throughout the lifetime. Selective expression of the heart and neural crest derivative 2 gene in peripheral SNs increases muscle mass and force regulating skeletal muscle sympathetic and motor innervation; improving acetylcholine receptor stability and NMJ transmission; preventing inflammation and myofibrillar protein degradation; increasing autophagy; and probably enhancing protein synthesis. Elucidating the role of central SNs will help to define the coordinated response of the visceral and neuromuscular system to physiological and pathological challenges across ages. This review discusses the following questions: (1) Does the SNS regulate skeletal muscle motor innervation? (2) Does the SNS regulate presynaptic and postsynaptic neuromuscular junction (NMJ) structure and function? (3) Does sympathetic neuron (SN) regulation of NMJ transmission decline with aging? (4) Does maintenance of SNs attenuate aging sarcopenia? and (5) Do central SN group relays influence sympathetic and motor muscle innervation?
Collapse
|
|
44
|
Ma C, Zhang W, Cao M. Role of the Peripheral Nervous System in PD Pathology, Diagnosis, and Treatment. Front Neurosci 2021; 15:598457. [PMID: 33994915 PMCID: PMC8119739 DOI: 10.3389/fnins.2021.598457] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 03/30/2021] [Indexed: 12/13/2022] Open
Abstract
Studies on Parkinson disease (PD) have mostly focused on the central nervous system—specifically, on the loss of mesencephalic dopaminergic neurons and associated motor dysfunction. However, the peripheral nervous system (PNS) is gaining prominence in PD research, with increasing clinical attention being paid to non-motor symptoms. Researchers found abnormal deposition of α-synuclein and neuroinflammation in the PNS. Attempts have been made to use these pathological changes during the clinical diagnosis of PD. Animal studies demonstrated that combined transplantation of autologous peripheral nerves and cells with tyrosine hydroxylase activity can reduce dopaminergic neuronal damage, and similar effects were observed in some clinical trials. In this review, we will systematically explain PNS performance in PD pathology and its clinical diagnostic research, describe PNS experimental results [especially Schwann cell (SC) transplantation in the treatment of PD animal models] and the results of clinical trials, and discuss future directions. The mechanism by which SCs produce such a therapeutic effect and the safety of transplantation therapy are briefly described.
Collapse
Affiliation(s)
- Chengxiao Ma
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Wen Zhang
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China.,Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Maohong Cao
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China
| |
Collapse
|
|
45
|
High-resolution ultrasound changes of the vagus nerve in idiopathic Parkinson's disease (IPD): a possible additional index of disease. Neurol Sci 2021; 42:5205-5211. [PMID: 33821361 PMCID: PMC8642255 DOI: 10.1007/s10072-021-05183-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/13/2021] [Indexed: 12/13/2022]
Abstract
Background and rationale Histopathological studies revealed degeneration of the dorsal motor nucleus of the vagus nerve (VN) early in the course of idiopathic Parkinson’s disease (IPD). Degeneration of VN axons should be detectable by high-resolution ultrasound (HRUS) as a thinning of the nerve trunk. In order to establish if the VN exhibits sonographic signs of atrophy in IPD, we examined patients with IPD compared with age-matched controls. Material and methods We measured the caliber (cross-sectional area, CSA) and perimeter of the VN in 20 outpatients with IPD (8 females and 12 males; mean age 73.0 + 8.6 years) and in age-matched controls using HRUS. Evaluation was performed by blinded raters using an Esaote MyLab Gamma device in conventional B-Mode with an 8–19 MHz probe. Results In both sides, the VN CSA was significantly smaller in IPD outpatients than in controls (right 2.37 + 0.91, left 1.87 + 1.35 mm2 versus 6.0 + 1.33, 5.6 + 1.26 mm2; p <0.001), as well as the perimeter (right 5.06 + 0.85, left 4.78 + 1.74 mm versus 8.87 + 0.86, 8.58 + 0.97 mm; p <0.001). There were no significant correlations between VN CSA and age, the Hoehn and Yahr scale, L-dopa therapy, and disease duration. Conclusion Our findings provide evidence of atrophy of the VNs in IPD patients by HRUS. Moreover, HRUS of the VN represent a non-invasive easy imaging modality of screening in IPD patients independent of disease stage and duration and an interesting possible additional index of disease.
Collapse
|
|
46
|
Koziorowski D, Figura M, Milanowski ŁM, Szlufik S, Alster P, Madetko N, Friedman A. Mechanisms of Neurodegeneration in Various Forms of Parkinsonism-Similarities and Differences. Cells 2021; 10:656. [PMID: 33809527 PMCID: PMC7999195 DOI: 10.3390/cells10030656] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 02/06/2023] Open
Abstract
Parkinson's disease (PD), dementia with Lewy body (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA) belong to a group of neurodegenerative diseases called parkinsonian syndromes. They share several clinical, neuropathological and genetic features. Neurodegenerative diseases are characterized by the progressive dysfunction of specific populations of neurons, determining clinical presentation. Neuronal loss is associated with extra- and intracellular accumulation of misfolded proteins. The parkinsonian diseases affect distinct areas of the brain. PD and MSA belong to a group of synucleinopathies that are characterized by the presence of fibrillary aggregates of α-synuclein protein in the cytoplasm of selected populations of neurons and glial cells. PSP is a tauopathy associated with the pathological aggregation of the microtubule associated tau protein. Although PD is common in the world's aging population and has been extensively studied, the exact mechanisms of the neurodegeneration are still not fully understood. Growing evidence indicates that parkinsonian disorders to some extent share a genetic background, with two key components identified so far: the microtubule associated tau protein gene (MAPT) and the α-synuclein gene (SNCA). The main pathways of parkinsonian neurodegeneration described in the literature are the protein and mitochondrial pathways. The factors that lead to neurodegeneration are primarily environmental toxins, inflammatory factors, oxidative stress and traumatic brain injury.
Collapse
Affiliation(s)
- Dariusz Koziorowski
- Department of Neurology, Faculty of Heath Science, Medical University of Warsaw, 03-285 Warsaw, Poland; (M.F.); (Ł.M.M.); (S.S.); (P.A.); (N.M.); (A.F.)
| | - Monika Figura
- Department of Neurology, Faculty of Heath Science, Medical University of Warsaw, 03-285 Warsaw, Poland; (M.F.); (Ł.M.M.); (S.S.); (P.A.); (N.M.); (A.F.)
| | - Łukasz M. Milanowski
- Department of Neurology, Faculty of Heath Science, Medical University of Warsaw, 03-285 Warsaw, Poland; (M.F.); (Ł.M.M.); (S.S.); (P.A.); (N.M.); (A.F.)
- Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
- Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Stanisław Szlufik
- Department of Neurology, Faculty of Heath Science, Medical University of Warsaw, 03-285 Warsaw, Poland; (M.F.); (Ł.M.M.); (S.S.); (P.A.); (N.M.); (A.F.)
| | - Piotr Alster
- Department of Neurology, Faculty of Heath Science, Medical University of Warsaw, 03-285 Warsaw, Poland; (M.F.); (Ł.M.M.); (S.S.); (P.A.); (N.M.); (A.F.)
| | - Natalia Madetko
- Department of Neurology, Faculty of Heath Science, Medical University of Warsaw, 03-285 Warsaw, Poland; (M.F.); (Ł.M.M.); (S.S.); (P.A.); (N.M.); (A.F.)
| | - Andrzej Friedman
- Department of Neurology, Faculty of Heath Science, Medical University of Warsaw, 03-285 Warsaw, Poland; (M.F.); (Ł.M.M.); (S.S.); (P.A.); (N.M.); (A.F.)
| |
Collapse
|
|
47
|
Cheng J, Liao Y, Dong Y, Hu H, Yang N, Kong X, Li S, Li X, Guo J, Qin L, Yu J, Ma C, Li J, Li M, Tang B, Yuan Z. Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice. Autophagy 2020; 16:2193-2205. [PMID: 32003282 PMCID: PMC7751565 DOI: 10.1080/15548627.2020.1719723] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 10/17/2019] [Accepted: 01/17/2020] [Indexed: 02/07/2023] Open
Abstract
Microglial activation-induced neuroinflammation is closely associated with the development of Parkinson disease (PD). Macroautophagy/autophagy regulates many biological processes, but the role of autophagy in microglial activation during PD development remains largely unclear. In this study, we showed that deletion of microglial Atg5 caused PD-like symptoms in mice, characterized by impairment in motor coordination and cognitive learning, loss of tyrosine hydroxylase (TH) neurons, enhancement of neuroinflammation and reduction in dopamine levels in the striatum. Mechanistically, we found that inhibition of autophagy led to NLRP3 (NLR family pyrin domain containing 3) inflammasome activation via PDE10A (phosphodiesterase 10A)-cyclic adenosine monophosphate (cAMP) signaling in microglia, and the sequential upregulation of downstream IL1B/IL-1β in turn increased the expression of MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]), a pro-inflammatory cytokine. Inhibition of NLRP3 inflammasome activation by administration of MCC950, a specific inhibitor for NLRP3, decreased MIF expression and neuroinflammatory levels, and rescued the loss of TH neurons in the substantial nigra (SN). Interestingly, we found that serum MIF levels in PD patients were significantly elevated. Taken together, our results reveal an important role of autophagy in microglial activation-driven PD-like symptoms, thus providing potential targets for the clinical treatment of PD. Abbreviations: ATG: autophagy related; cAMP: cyclic adenosine monophosphate; cKO: conditional knockout; NOS2/INOS: nitric oxide synthase 2, inducible; IL1B: interleukin 1 beta; ITGAM/CD-11b: integrin alpha M/cluster of differentiation molecule 11B; MAP1LC3: microtubule-associated protein 1 light chain 3; MIF: macrophage migration inhibitory factor (glycosylation-inhibiting factor); NLRP3: NLR family pyrin domain containing 3; PBS: phosphate-buffered saline; PD: parkinson disease; PDE10A: phosphodiesterase 10A; SN: substantial nigra; TH: tyrosine hydroxylase; TNF: tumor necrosis factor; WT: wild type.
Collapse
Affiliation(s)
- Jinbo Cheng
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
- Center on Translational Neuroscience, College of Life & Environmental Science, Minzu University of China, Beijing, China
| | - Yajin Liao
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
- Center on Translational Neuroscience, College of Life & Environmental Science, Minzu University of China, Beijing, China
| | - Yuan Dong
- Department of Biochemistry, Medical College, Qingdao University, Qingdao, Shandong, China
| | - Han Hu
- Institute of Apicultural Research, Chinese Academy of Agricultural Science, Beijing, China
| | - Nannan Yang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiangxi Kong
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Shuoshuo Li
- The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xiaoheng Li
- Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
| | - Jifeng Guo
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorder, Central South University, Changsha, Hunan, China
| | - Lixia Qin
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jiezhong Yu
- The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Research Center of Neurobiology, Shanxi University of Chinese Medicine, Taiyuan, China
| | - Cungen Ma
- The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Research Center of Neurobiology, Shanxi University of Chinese Medicine, Taiyuan, China
| | - Jianke Li
- Institute of Apicultural Research, Chinese Academy of Agricultural Science, Beijing, China
| | - Mingtao Li
- Department of Pharmacology and the Proteomics Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Beisha Tang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorder, Central South University, Changsha, Hunan, China
| | - Zengqiang Yuan
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
- Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing, China
| |
Collapse
|
|
48
|
Gastrointestinal dysfunction in the synucleinopathies. Clin Auton Res 2020; 31:77-99. [PMID: 33247399 DOI: 10.1007/s10286-020-00745-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/04/2020] [Indexed: 12/15/2022]
Abstract
Interest in gastrointestinal dysfunction in Parkinson's disease has blossomed over the past 30 years and has generated a wealth of investigation into this non-motor aspect of the disorder, research that has encompassed its pathophysiology, its clinical features, and its impact on quality of life. The question of gastrointestinal dysfunction in the other synucleinopathies has not received nearly as much attention, but information and knowledge are growing. In this review, the current knowledge, controversies, and gaps in our understanding of the pathophysiology of gastrointestinal dysfunction in Parkinson's disease and the other synucleinopathies will be addressed, and extended focus will be directed toward the clinical problems involving saliva management, swallowing, gastric emptying, small intestinal function, and bowel function that are so problematic in these disorders.
Collapse
|
|
49
|
Fricova D, Harsanyiova J, Kralova Trancikova A. Alpha-Synuclein in the Gastrointestinal Tract as a Potential Biomarker for Early Detection of Parkinson's Disease. Int J Mol Sci 2020; 21:E8666. [PMID: 33212934 PMCID: PMC7698349 DOI: 10.3390/ijms21228666] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/15/2020] [Accepted: 11/16/2020] [Indexed: 12/19/2022] Open
Abstract
The primary pathogenesis associated with Parkinson's disease (PD) occurs in peripheral tissues several years before the onset of typical motor symptoms. Early and reliable diagnosis of PD could provide new treatment options for PD patients and improve their quality of life. At present, however, diagnosis relies mainly on clinical symptoms, and definitive diagnosis is still based on postmortem pathological confirmation of dopaminergic neuronal degeneration. In addition, the similarity of the clinical, cognitive, and neuropathological features of PD with other neurodegenerative diseases calls for new biomarkers, suitable for differential diagnosis. Alpha-synuclein (α-Syn) is a potential PD biomarker, due to its close connection with the pathogenesis of the disease. Here we summarize the currently available information on the possible use of α-Syn as a biomarker of early stages of PD in gastrointestinal (GI) tissues, highlight its potential to distinguish PD and other neurodegenerative diseases, and suggest alternative methods (primarily developed for other tissue analysis) that could improve α-Syn detection procedures or diagnostic methods in general.
Collapse
Affiliation(s)
- Dominika Fricova
- Institute of Neuroimmunology, Slovak Academy of Sciences, 814 38 Bratislava, Slovakia;
| | - Jana Harsanyiova
- Department of Pathophysiology, Jessenius Faculty of Medicine in Martin, Comenius University, 814 99 Bratislava, Slovakia;
| | - Alzbeta Kralova Trancikova
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University, 814 99 Bratislava, Slovakia
| |
Collapse
|
|
50
|
Glass TJ, Kelm-Nelson CA, Szot JC, Lake JM, Connor NP, Ciucci MR. Functional characterization of extrinsic tongue muscles in the Pink1-/- rat model of Parkinson disease. PLoS One 2020; 15:e0240366. [PMID: 33064741 PMCID: PMC7567376 DOI: 10.1371/journal.pone.0240366] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 09/24/2020] [Indexed: 12/27/2022] Open
Abstract
Parkinson disease (PD) is associated with speech and swallowing difficulties likely due to pathology in widespread brain and nervous system regions. In post-mortem studies of PD, pathology has been reported in pharyngeal and laryngeal nerves and muscles. However, it is unknown whether PD is associated with neuromuscular changes in the tongue. Prior work in a rat model of PD (Pink1-/-) showed oromotor and swallowing deficits in the premanifest stage which suggested sensorimotor impairments of these functions. The present study tested the hypothesis that Pink1-/- rats show altered tongue function coinciding with neuromuscular differences within tongue muscles compared to wildtype (WT). Male Pink1-/- and WT rats underwent behavioral tongue function assays at 4 and 6 months of age (n = 7–8 rats per group), which are time points early in the disease. At 6 months, genioglossus (GG) and styloglossus (SG) muscles were analyzed for myosin heavy chain isoforms (MyHC), α-synuclein levels, myofiber size, centrally nucleated myofibers, and neuromuscular junction (NMJ) innervation. Pink1-/- showed greater tongue press force variability, and greater tongue press forces and rates as compared to WT. Additionally, Pink1-/- showed relative increases of MyHC 2a in SG, but typical MyHC profiles in GG. Western blots revealed Pink1-/- had more α-synuclein protein than WT in GG, but not in SG. There were no differences between Pink1-/- and WT in myofiber size, centrally-nucleated myofibers, or NMJ innervation. α-synuclein protein was observed in nerves, NMJ, and vessels in both genotypes. Findings at these early disease stages suggest small changes or no changes in several peripheral biological measures, and intact motor innervation of tongue muscles. Future work should evaluate these measures at later disease stages to determine when robust pathological peripheral change contributes to functional change, and what CNS deficits cause behavioral changes. Understanding how PD affects central and peripheral mechanisms will help determine therapy targets for speech and swallowing disorders.
Collapse
Affiliation(s)
- Tiffany J. Glass
- Department of Surgery, University of Wisconsin, Madison, Wisconsin, United States of America
- * E-mail:
| | - Cynthia A. Kelm-Nelson
- Department of Surgery, University of Wisconsin, Madison, Wisconsin, United States of America
| | - John C. Szot
- Department of Surgery, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Jacob M. Lake
- Department of Surgery, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Nadine P. Connor
- Department of Surgery, University of Wisconsin, Madison, Wisconsin, United States of America
- Department of Communication Sciences and Disorders, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Michelle R. Ciucci
- Department of Surgery, University of Wisconsin, Madison, Wisconsin, United States of America
- Department of Communication Sciences and Disorders, University of Wisconsin, Madison, Wisconsin, United States of America
| |
Collapse
|