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Medicine â€ș Neurology

Parkinson's Disease Mechanisms and Treatments

Works Count: 97497

Description

This cluster of papers explores the pathophysiology, clinical features, diagnosis, genetic risk factors, and management of Parkinson's disease. It delves into the role of a-synuclein, neurodegeneration, dopaminergic neurons, oxidative stress, and mitochondrial dysfunction in the development and progression of the disease. Additionally, it discusses the non-motor symptoms and Lewy body pathology associated with Parkinson's disease.

Keywords

Parkinson's Disease; a-Synuclein; Neurodegeneration; Dopaminergic Neurons; Genetic Risk Factors; Oxidative Stress; Diagnostic Criteria; Lewy Body Pathology; Mitochondrial Dysfunction; Non-motor Symptoms

Chronic systemic pesticide exposure reproduces features of Parkinson's disease

2000-12-01
Ranjita Betarbet , Todd Sherer , Gillian M. MacKenzie +3 more
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α-Synuclein in Lewy bodies

1997-08-28
Maria Grazia Spillantini , Marie L. Schmidt , Virginia M.‐Y. Lee +3 more
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Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030

2006-11-03
E. Ray Dorsey , Radu Constantinescu , James P. Thompson +7 more
Based on published prevalence studies, we used two different methodologies to project the number of individuals with Parkinson disease (PD) in Western Europe’s 5 most and the world’s 10 most 
 Based on published prevalence studies, we used two different methodologies to project the number of individuals with Parkinson disease (PD) in Western Europe’s 5 most and the world’s 10 most populous nations. The number of individuals with PD over age 50 in these countries was between 4.1 and 4.6 million in 2005 and will double to between 8.7 and 9.3 million by 2030.

Recent developments in Parkinson's disease

1986-01-01
Stanley Fahn , RL Elton , C. D. Marsden +2 more

Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice

2012-11-15
Kelvin C. Luk , Victoria Kehm , Jenna C. Carroll +4 more
Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between 
 Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson's disease.
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The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia

2003-12-30
J.J. Zarranz , Javier Alegre‐Abarrategui , Juan Carlos Gómez‐Esteban +7 more
Abstract Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family 
 Abstract Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to α‐synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the α‐synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary α‐synucleinopathies, dementia with Lewy bodies is related to mutation of α‐synuclein.

A Drosophila model of Parkinson's disease

2000-03-01
Mel Β. Feany , Welcome Bender

Brain dopamine and the syndromes of Parkinson and Huntington Clinical, morphological and neurochemical correlations

1973-12-01
H. Bernheimer , W Birkmayer , Oleh Hornykiewicz +2 more

The FAB

2000-12-12
Bruno Dubois , Andrea Slachevsky , Irene Litvan +1 more
<h3>Objective</h3> Sarcopaenia and physical function impairment may have a greater effect on survival than other clinical characteristics, including multimorbidity. In this study, we evaluated the impact of sarcopaenia on all-cause 
 <h3>Objective</h3> Sarcopaenia and physical function impairment may have a greater effect on survival than other clinical characteristics, including multimorbidity. In this study, we evaluated the impact of sarcopaenia on all-cause mortality and the interaction among muscle loss, physical function impairment and multimorbidity on mortality risk over 10 years in older community-dwellers. <h3>Design</h3> Prospective cohort study. <h3>Setting</h3> Population-based study. <h3>Participants</h3> All persons aged 80+ years living in the community in the Sirente geographic area (L9Aquila, Italy) (n=364). Participants were categorised in the sarcopaenic or non-sarcopaenic group based on the European Working Group on Sarcopenia in Older People criteria. <h3>Primary and secondary outcome measures</h3> (1) All-cause mortality over 10 years according to the presence of sarcopaenia and (2) impact of physical function impairment, assessed using the Short Physical Performance Battery (SPPB), and multimorbidity on 10-year mortality risk in persons with sarcopaenia. <h3>Results</h3> Sarcopaenia was identified in 103 participants (29.1%). A total of 253 deaths were recorded over 10 years: 90 among sarcopaenic participants (87.4%) and 162 among non-sarcopaenic persons (65.1%; p&lt;0.001). Participants with sarcopaenia had a higher risk of death than those without sarcopaenia (HR=2.15; 95% CI 1.02 to 4.54). When examining the effect of sarcopaenia and physical function impairment on mortality, participants with low physical performance levels showed greater mortality. Conversely, the mortality risk was unaffected by multimorbidity. <h3>Conclusions</h3> Our findings show that physical function impairment, but not multimorbidity, is predictive of mortality in older community-dwellers with sarcopaenia. Hence, in sarcopaenic older persons, interventions against functional decline may be more effective at preventing or postponing negative health outcomes than those targeting multimorbidity.

Non-motor symptoms of Parkinson's disease: diagnosis and management

2006-02-20
К. Ray Chaudhuri , Daniel G. Healy , Anthony H.V. Schapira

D <sub>1</sub> and D <sub>2</sub> Dopamine Receptor-regulated Gene Expression of Striatonigral and Striatopallidal Neurons

1990-12-07
Charles R. Gerfen , Thomas M. Engber , Lawrence C. Mahan +4 more
The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from 
 The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from the loss of striatal dopamine in patients with Parkinson's disease. Rats with lesions of the nigrostriatal dopamine pathway caused by 6-hydroxydopamine (6-OHDA) serve as a model for Parkinson's disease and show alterations in gene expression in the two major output systems of the striatum to the globus pallidus and substantia nigra. Striatopallidal neurons show a 6-OHDA-induced elevation in their specific expression of messenger RNAs (mRNAs) encoding the D 2 dopamine receptor and enkephalin, which is reversed by subsequent continuous treatment with the D 2 agonist quinpirole. Conversely, striatonigral neurons show a 6-OHDA-induced reduction in their specific expression of mRNAs encoding the D 1 dopamine receptor and substance P, which is reversed by subsequent daily injections of the D 1 agonist SKF-38393. This treatment also increases dynorphin mRNA in striatonigral neurons. Thus, the differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D 1 and D 2 dopamine receptor subtypes, respectively.

Stages in the development of Parkinson’s disease-related pathology

2004-08-23
Heiko Braak , Estifanos Ghebremedhin , Udo RĂŒb +2 more

Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.

1992-03-01
Andrew Hughes , S. E. Daniel , Linda Kilford +1 more
Few detailed clinico-pathological correlations of Parkinson9s disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson9s disease are 
 Few detailed clinico-pathological correlations of Parkinson9s disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson9s disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer9s disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson9s disease as a single distinct morbid entity.
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Diagnostic Criteria for Parkinson Disease

1999-01-01
Douglas J. Gelb , Eugene Oliver , Sid Gilman
The clinical diagnosis of Parkinson disease (PD) is based on the identification of some combination of the cardinal motor signs of bradykinesia, rigidity, tremor, and postural instability, but few attempts 
 The clinical diagnosis of Parkinson disease (PD) is based on the identification of some combination of the cardinal motor signs of bradykinesia, rigidity, tremor, and postural instability, but few attempts have been made to develop explicit diagnostic criteria. We propose a clinical diagnostic classification based on a comprehensive review of the literature regarding the sensitivity and specificity of the characteristic clinical features of PD. Three levels of diagnostic confidence are differentiated: Definite, Probable, and Possible. The diagnoses of Possible and Probable PD are based on clinical criteria alone. Neuropathologic confirmation is required for the diagnosis of Definite PD in patients with the clinical diagnosis of Possible or Probable PD. Criteria for histopathologic confirmation of PD are also presented.

Unified Parkinson's Disease Rating Scale

2012-02-07
Stanley Fahn

The Sydney multicenter study of Parkinson's disease: The inevitability of dementia at 20 years

2008-02-28
M. A. Hely , Wayne G.J. Reid , Michael Adena +2 more
After 20 years follow-up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (74%) have died. The mortality rate fell in the first 3 years of treatment, then 
 After 20 years follow-up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (74%) have died. The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1. Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non-levodopa responsive features of the disease. Dementia is present in 83% of 20-year survivors. Dementia correlates with increasing age and probably reflects an interplay of multiple pathologies. Seventeen people with dementia had postmortems. Eight had diffuse Lewy bodies as the only cause of dementia, while others had mixed neuropathology. Only one person lives independently and 48% are in nursing homes. Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%. The challenge is to understand the cellular mechanisms underlying the diverse features of advanced PD that go far beyond a lack of dopamine.
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Oxidative stress in Parkinson's disease

2003-01-01
Peter Jenner
Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinson's disease (PD). However, oxidative stress is intimately linked to other components of the degenerative process, such as 
 Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinson's disease (PD). However, oxidative stress is intimately linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation. It is therefore difficult to determine whether oxidative stress leads to, or is a consequence of, these events. Oxidative damage to lipids, proteins, and DNA occurs in PD, and toxic products of oxidative damage, such as 4-hydroxynonenal (HNE), can react with proteins to impair cell viability. There is convincing evidence for the involvement of nitric oxide that reacts with superoxide to produce peroxynitrite and ultimately hydroxyl radical production. Recently, altered ubiquitination and degradation of proteins have been implicated as key to dopaminergic cell death in PD. Oxidative stress can impair these processes directly, and products of oxidative damage, such as HNE, can damage the 26S proteasome. Furthermore, impairment of proteasomal function leads to free radical generation and oxidative stress. Oxidative stress occurs in idiopathic PD and products of oxidative damage interfere with cellular function, but these form only part of a cascade, and it is not possible to separate them from other events involved in dopaminergic cell death. Ann Neurol 2003;53 (suppl 3):S26–S38

α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies

1998-05-26
Maria Grazia Spillantini , R. Anthony Crowther , Ross Jakes +2 more
Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson’s disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show 
 Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson’s disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown composition. We show here that Lewy bodies and Lewy neurites from Parkinson’s disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of α-synuclein, showing the presence of full-length or close to full-length α-synuclein. The number of α-synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for α-synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer’s disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-α-synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended α-synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that α-synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.
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Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology

2004-11-01
Alexander Zimprich , Saskia Biskup , Petra Leitner +7 more
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Staging of brain pathology related to sporadic Parkinson’s disease

2002-12-28
Heiko Braak , Kelly Del Tredici , Udo RĂŒb +3 more

Systematic review of levodopa dose equivalency reporting in Parkinson's disease

2010-11-10
Claire L Tomlinson , Rebecca Stowe , Smitaa Patel +3 more
Abstract Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce 
 Abstract Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications. © 2010 Movement Disorder Society

AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease

1998-02-01
Rejko KrĂŒger , W. Kuhn , Thomas MĂŒller +7 more

AGEING AND PARKINSON'S DISEASE: SUBSTANTIA NIGRA REGIONAL SELECTIVITY

1991-01-01
Julian Fearnley , Andrew J. Lees
The micro-architecture of the substantia nigra was studied in control cases of varying age and patients with parkinsonism. A single 7Ό section stained with haematoxylin and eosin was examined at 
 The micro-architecture of the substantia nigra was studied in control cases of varying age and patients with parkinsonism. A single 7Ό section stained with haematoxylin and eosin was examined at a specific level within the caudal nigra using strict criteria. The pars compacta was divided into a ventral and a dorsaltier, and each tier was further subdivided into 3 regions. In 36 control cases there was a linear fallout of pigmented neurons with advancing age in the pars compacta of the caudal substantia nigra at a rate of 4.7% per decade. Regionally, the lateral ventral tier was relatively spared (2.1% loss per decade) compared with the medial ventral tier (5.4%) and the dorsal tier (6.9%). In 20 Parkinson's disease (PD) cases of varying disease duration there was an exponential loss of pigmented neurons with a 45% loss in the first decade. Regionally, the pattern was opposite to ageing. Loss was greatest in the lateral ventral tier (average loss 91%) followed by the medial ventral tier (71%) and the dorsal tier (56%). The presymptomatic phase of PD from the onset of neuronal loss was estimated to be about 5 yrs. This phase is represented by incidental Lewy body cases: individuals who die without clinical signs of PD or dementia, but who are found to have Lewy bodies at post-mortem. In 7 cases cell loss was confined to the lateral ventral tier (average loss 52%) congruent with the lateral ventral selectivity of symptomatic PD. It was calculated that at the onset of symptoms there was a 68% cell loss in the lateral ventral tier and a 48% loss in the caudal nigra as a whole. The regional selectivity of PD is relatively specific. In 15 cases of striatonigral degeneration the distribution of cell loss was similar, but the loss in the dorsal tier was greater than PD by 21%. In 14 cases of Steele-Richardson- Olszewski syndrome (SRO) there was no predilection for the lateral ventral tier, but a tendency to involve the medial nigra and spare the lateral. These findings suggest that agerelated of pigmented nigral cells is not an important factor in the pathogenesis of PD.

Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease

2004-11-01
Coro Paisàn‐Ruìz , Shushant Jain , E. Whitney Evans +7 more
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Diagnosis and management of dementia with Lewy bodies

2005-12-27
Ian G. McKeith , Dennis W. Dickson , James Lowe +7 more
The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods 
 The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∌50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Mutations in the <i>DJ-1</i> Gene Associated with Autosomal Recessive Early-Onset Parkinsonism

2003-01-10
Vincenzo Bonifati , Patrizia Rizzu , Marijke J. van Baren +7 more
The DJ-1 gene encodes a ubiquitous, highly conserved protein. Here, we show that DJ-1 mutations are associated with PARK7, a monogenic form of human parkinsonism. The function of the DJ-1 
 The DJ-1 gene encodes a ubiquitous, highly conserved protein. Here, we show that DJ-1 mutations are associated with PARK7, a monogenic form of human parkinsonism. The function of the DJ-1 protein remains unknown, but evidence suggests its involvement in the oxidative stress response. Our findings indicate that loss of DJ-1 function leads to neurodegeneration. Elucidating the physiological role of DJ-1 protein may promote understanding of the mechanisms of brain neuronal maintenance and pathogenesis of Parkinson's disease.

MDS clinical diagnostic criteria for Parkinson's disease

2015-10-01
Ronald B. Postuma , Daniela Berg , Matthew Stern +7 more
This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may 
 This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances. © 2015 International Parkinson and Movement Disorder Society
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α-Synuclein Locus Triplication Causes Parkinson's Disease

2003-10-31
Andrew Singleton , Matthew J. Farrer , Janel Johnson +7 more
Impaired Autophagic-Lysosomal Fusion in Parkinson's Patient Midbrain Neurons Occurs through Loss of ykt6 and Is Rescued by Farnesyltransferase Inhibition, Impaired Autophagic-Lysosomal Fusion in Parkinson's Patient Midbrain Neurons Occurs through Loss of ykt6 and Is Rescued by Farnesyltransferase Inhibition,
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<i>Movement</i> Disorder Society Task Force report on the Hoehn and Yahr staging scale: Status and recommendations The <i>Movement</i> Disorder Society Task Force on rating scales for Parkinson's disease

2004-06-16
Christopher G. Goetz , Werner Poewe , Olivier Rascol +7 more
The Movement Disorder Society Task Force for Rating Scales for Parkinson's disease (PD) prepared a critique of the Hoehn and Yahr scale (HY). Strengths of the HY scale include its 
 The Movement Disorder Society Task Force for Rating Scales for Parkinson's disease (PD) prepared a critique of the Hoehn and Yahr scale (HY). Strengths of the HY scale include its wide utilization and acceptance. Progressively higher stages correlate with neuroimaging studies of dopaminergic loss, and high correlations exist between the HY scale and some standardized scales of motor impairment, disability, and quality of life. Weaknesses include the scale's mixing of impairment and disability and its non-linearity. Because the HY scale is weighted heavily toward postural instability as the primary index of disease severity, it does not capture completely impairments or disability from other motor features of PD and gives no information on nonmotor problems. Direct clinimetric testing of the HY scale has been very limited, but the scale fulfills at least some criteria for reliability and validity, especially for the midranges of the scale (Stages 2-4). Although a "modified HY scale" that includes 0.5 increments has been adopted widely, no clinimetric data are available on this adaptation. The Task Force recommends that: (1) the HY scale be used in its original form for demographic presentation of patient groups; (2) when the HY scale is used for group description, medians and ranges should be reported and analysis of changes should use nonparametric methods; (3) in research settings, the HY scale is useful primarily for defining inclusion/exclusion criteria; (4) to retain simplicity, clinicians should "rate what you see" and therefore incorporate comorbidities when assigning a HY stage; and (5) because of the wide usage of the modified HY scale with 0.5 increments, this adaptation warrants clinimetric testing. Without such testing, however, the original five-point scales should be maintained.

Epidemiology of Parkinson's disease

2006-05-20
Lonneke ML de Lau , Monique M.B. Breteler

Hereditary Early-Onset Parkinson's Disease Caused by Mutations in <i>PINK1</i>

2004-04-20
Enza Maria Valente , Patrick M. Abou‐Sleiman , Viviana Caputo +7 more
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to 
 Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.
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Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)

1996-07-01
Irene Litvan , Y. Agid , Donald B. Calne +7 more
To improve the specificity and sensitivity of the clinical diagnosis of progressive supranuclear palsy (PSP, Steele-Richardson-Olszewski syndrome), the National Institute of Neurological Disorders and Stroke (NINDS) and the Society for 
 To improve the specificity and sensitivity of the clinical diagnosis of progressive supranuclear palsy (PSP, Steele-Richardson-Olszewski syndrome), the National Institute of Neurological Disorders and Stroke (NINDS) and the Society for PSP, Inc. (SPSP) sponsored an international workshop to develop an accurate and universally accepted set of criteria for this disorder. The NINDS-SPSP criteria, which were formulated from an extensive review of the literature, comparison with other previously published sets of criteria, and the consensus of experts, were validated on a clinical data set from autopsy-confirmed cases of PSP. The criteria specify three degrees of diagnostic certainty: possible PSP, probable PSP, and definite PSP. Possible PSP requires the presence of a gradually progressive disorder with onset at age 40 or later, either vertical supranuclear gaze palsy or both slowing of vertical saccades and prominent postural instability with falls in the first year of onset, as well as no evidence of other diseases that could explain these features. Probable PSP requires vertical supranuclear gaze palsy, prominent postural instability, and falls in the first year of onset, as well as the other features of possible PSP. Definite PSP requires a history of probable or possible PSP and histopathologic evidence of typical PSP. Criteria that support the diagnosis of PSP, and that exclude diseases often confused with PSP, are presented. The criteria for probable PSP are highly specific, making them suitable for therapeutic, analytic epidemiologic, and biologic studies, but not very sensitive. The criteria for possible PSP are substantially sensitive, making them suitable for descriptive epidemiologic studies, but less specific. An appendix provides guidelines for diagnosing and monitoring clinical disability in PSP. <b>NEUROLOGY 1996;47: </b> 1-9

Movement Disorder Society‐sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS): Scale presentation and clinimetric testing results

2008-11-15
Christopher G. Goetz , Barbara C. Tilley , Stephanie R. Shaftman +7 more
We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using 
 We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79–0.93 across parts) and correlated with the original UPDRS (ρ = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD. © 2008 Movement Disorder Society
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Parkinson's disease: clinical features and diagnosis

2008-03-14
Joseph Jankovic
Parkinson's disease (PD) is a progressive neurological disorder characterised by a large number of motor and non-motor features that can impact on function to a variable degree. This review describes 
 Parkinson's disease (PD) is a progressive neurological disorder characterised by a large number of motor and non-motor features that can impact on function to a variable degree. This review describes the clinical characteristics of PD with emphasis on those features that differentiate the disease from other parkinsonian disorders.A MedLine search was performed to identify studies that assess the clinical characteristics of PD. Search terms included "Parkinson's disease", "diagnosis" and "signs and symptoms".Because there is no definitive test for the diagnosis of PD, the disease must be diagnosed based on clinical criteria. Rest tremor, bradykinesia, rigidity and loss of postural reflexes are generally considered the cardinal signs of PD. The presence and specific presentation of these features are used to differentiate PD from related parkinsonian disorders. Other clinical features include secondary motor symptoms (eg, hypomimia, dysarthria, dysphagia, sialorrhoea, micrographia, shuffling gait, festination, freezing, dystonia, glabellar reflexes), non-motor symptoms (eg, autonomic dysfunction, cognitive/neurobehavioral abnormalities, sleep disorders and sensory abnormalities such as anosmia, paresthesias and pain). Absence of rest tremor, early occurrence of gait difficulty, postural instability, dementia, hallucinations, and the presence of dysautonomia, ophthalmoparesis, ataxia and other atypical features, coupled with poor or no response to levodopa, suggest diagnoses other than PD.A thorough understanding of the broad spectrum of clinical manifestations of PD is essential to the proper diagnosis of the disease. Genetic mutations or variants, neuroimaging abnormalities and other tests are potential biomarkers that may improve diagnosis and allow the identification of persons at risk.
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Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease

1997-06-27
Mihael H. Polymeropoulos , Christian Lavedan , Elisabeth Leroy +7 more
Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was 
 Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.
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Second consensus statement on the diagnosis of multiple system atrophy

2008-08-25
S. Gilman , Gregor K. Wenning , Phillip A. Low +7 more
<b>Background: </b> A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have 
 <b>Background: </b> A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here. <b>Methods: </b> Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology. <b>Results: </b> The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS α-synuclein–positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality. <b>Conclusions: </b> These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.
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Diagnostic criteria for mild cognitive impairment in Parkinson's disease: <i>Movement</i> Disorder Society Task Force guidelines

2012-01-24
Irene Litvan , Jennifer G. Goldman , Alexander I. Tröster +7 more
Abstract Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a 
 Abstract Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long‐term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage. © 2012 Movement Disorder Society
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Clinical diagnostic criteria for dementia associated with Parkinson's disease

2007-05-31
Murat Emre , Dag Aarsland , Richard G. Brown +7 more
Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated 
 Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.

A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

1983-07-01
Richard S. Burns , Chuang C. Chiueh , Sanford P. Markey +3 more
A syndrome similar to idiopathic parkinsonism developed after intravenous self-administration of an illicit drug preparation in which N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) might have been responsible for the toxicity. In the present study 
 A syndrome similar to idiopathic parkinsonism developed after intravenous self-administration of an illicit drug preparation in which N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) might have been responsible for the toxicity. In the present study we show that intravenous administration of NMPTP to the rhesus monkey produces a disorder like parkinsonism (akinesia, rigidity, postural tremor, flexed posture, eyelid closure, drooling) that is reversed by the administration of L-dopa. NMPTP treatment decreases the release of dopamine and dopamine accumulates in swollen, distorted axons in the nigrostriatal pathway just above the substantia nigra, followed by severe nerve cell loss in the pars compacta of the substantia nigra and a marked reduction in the dopamine content of the striatum. The pathological and biochemical changes produced by NMPTP are similar to the well-established changes in patients with parkinsonism. Thus, the NMPTP-treated monkey provides a model that can be used to examine mechanisms and explore therapies of parkinsonism.
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Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease

2016-12-01
Timothy R. Sampson , Justine W. Debelius , Taren Thron +7 more
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Epidemiology of Parkinson’s disease

2017-02-01
Ole‐Bjþrn Tysnes , Anette Storstein

Diagnosis and management of dementia with Lewy bodies

2017-06-08
Ian G. McKeith , Bradley F. Boeve , Dennis W. Dickson +7 more
The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for 
 The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.
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Global, regional, and national burden of Parkinson's disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

2018-10-01
E. Ray Dorsey , Alexis Elbaz , Emma Nichols +7 more
Neurological disorders are now the leading source of disability globally, and ageing is increasing the burden of neurodegenerative disorders, including Parkinson's disease. We aimed to determine the global burden of 
 Neurological disorders are now the leading source of disability globally, and ageing is increasing the burden of neurodegenerative disorders, including Parkinson's disease. We aimed to determine the global burden of Parkinson's disease between 1990 and 2016 to identify trends and to enable appropriate public health, medical, and scientific responses.Through a systematic analysis of epidemiological studies, we estimated global, regional, and country-specific prevalence and years of life lived with disability for Parkinson's disease from 1990 to 2016. We estimated the proportion of mild, moderate, and severe Parkinson's disease on the basis of studies that used the Hoehn and Yahr scale and assigned disability weights to each level. We jointly modelled prevalence and excess mortality risk in a natural history model to derive estimates of deaths due to Parkinson's disease. Death counts were multiplied by values from the Global Burden of Disease study's standard life expectancy to compute years of life lost. Disability-adjusted life-years (DALYs) were computed as the sum of years lived with disability and years of life lost. We also analysed results based on the Socio-demographic Index, a compound measure of income per capita, education, and fertility.In 2016, 6·1 million (95% uncertainty interval [UI] 5·0-7·3) individuals had Parkinson's disease globally, compared with 2·5 million (2·0-3·0) in 1990. This increase was not solely due to increasing numbers of older people, because age-standardised prevalence rates increased by 21·7% (95% UI 18·1-25·3) over the same period (compared with an increase of 74·3%, 95% UI 69·2-79·6, for crude prevalence rates). Parkinson's disease caused 3·2 million (95% UI 2·6-4·0) DALYs and 211 296 deaths (95% UI 167 771-265 160) in 2016. The male-to-female ratios of age-standardised prevalence rates were similar in 2016 (1·40, 95% UI 1·36-1·43) and 1990 (1·37, 1·34-1·40). From 1990 to 2016, age-standardised prevalence, DALY rates, and death rates increased for all global burden of disease regions except for southern Latin America, eastern Europe, and Oceania. In addition, age-standardised DALY rates generally increased across the Socio-demographic Index.Over the past generation, the global burden of Parkinson's disease has more than doubled as a result of increasing numbers of older people, with potential contributions from longer disease duration and environmental factors. Demographic and potentially other factors are poised to increase the future burden of Parkinson's disease substantially.Bill & Melinda Gates Foundation.
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Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

2019-11-06
Mike A. Nalls , Cornelis Blauwendraat , Costanza L. Vallerga +7 more
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Diagnosis and Treatment of Parkinson Disease

2020-02-11
Melissa J. Armstrong , Michael S. Okun
<h3>Importance</h3> Parkinson disease is the most common form of parkinsonism, a group of neurological disorders with Parkinson disease–like movement problems such as rigidity, slowness, and tremor. More than 6 million 
 <h3>Importance</h3> Parkinson disease is the most common form of parkinsonism, a group of neurological disorders with Parkinson disease–like movement problems such as rigidity, slowness, and tremor. More than 6 million individuals worldwide have Parkinson disease. <h3>Observations</h3> Diagnosis of Parkinson disease is based on history and examination. History can include prodromal features (eg, rapid eye movement sleep behavior disorder, hyposmia, constipation), characteristic movement difficulty (eg, tremor, stiffness, slowness), and psychological or cognitive problems (eg, cognitive decline, depression, anxiety). Examination typically demonstrates bradykinesia with tremor, rigidity, or both. Dopamine transporter single-photon emission computed tomography can improve the accuracy of diagnosis when the presence of parkinsonism is uncertain. Parkinson disease has multiple disease variants with different prognoses. Individuals with a diffuse malignant subtype (9%-16% of individuals with Parkinson disease) have prominent early motor and nonmotor symptoms, poor response to medication, and faster disease progression. Individuals with mild motor-predominant Parkinson disease (49%-53% of individuals with Parkinson disease) have mild symptoms, a good response to dopaminergic medications (eg, carbidopa-levodopa, dopamine agonists), and slower disease progression. Other individuals have an intermediate subtype. For all patients with Parkinson disease, treatment is symptomatic, focused on improvement in motor (eg, tremor, rigidity, bradykinesia) and nonmotor (eg, constipation, cognition, mood, sleep) signs and symptoms. No disease-modifying pharmacologic treatments are available. Dopamine-based therapies typically help initial motor symptoms. Nonmotor symptoms require nondopaminergic approaches (eg, selective serotonin reuptake inhibitors for psychiatric symptoms, cholinesterase inhibitors for cognition). Rehabilitative therapy and exercise complement pharmacologic treatments. Individuals experiencing complications, such as worsening symptoms and functional impairment when a medication dose wears off ("off periods"), medication-resistant tremor, and dyskinesias, benefit from advanced treatments such as therapy with levodopa-carbidopa enteral suspension or deep brain stimulation. Palliative care is part of Parkinson disease management. <h3>Conclusions and Relevance</h3> Parkinson disease is a heterogeneous disease with rapidly and slowly progressive forms. Treatment involves pharmacologic approaches (typically with levodopa preparations prescribed with or without other medications) and nonpharmacologic approaches (such as exercise and physical, occupational, and speech therapies). Approaches such as deep brain stimulation and treatment with levodopa-carbidopa enteral suspension can help individuals with medication-resistant tremor, worsening symptoms when the medication wears off, and dyskinesias.

Parkinson's disease

2021-04-11
Bastiaan R. Bloem , Michael S. Okun , Christine Klein
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Parkinson disease

2017-03-22
Werner Poewe , Klaus Seppi , Caroline M. Tanner +5 more

Parkinson's disease

2015-04-19
Lorraine V. Kalia , Anthony E. Lang

Parkinson's Disease

2003-09-01
William T. Dauer , Serge Przedborski
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Global kinetic model of lipid-induced <i>α</i> -synuclein aggregation and its inhibition by small molecules

2025-06-25
Alisdair Stevenson , Roxine Staats , Alexander J. Dear +7 more | Proceedings of the National Academy of Sciences
The aggregation of α -synuclein into amyloid fibrils is a hallmark of Parkinson’s disease. This process has been shown to directly involve interactions between proteins and lipid surfaces when the 
 The aggregation of α -synuclein into amyloid fibrils is a hallmark of Parkinson’s disease. This process has been shown to directly involve interactions between proteins and lipid surfaces when the latter are present. Despite this importance, the molecular mechanisms of lipid-induced amyloid aggregation have remained largely elusive. Here, we present a global kinetic model to describe lipid-induced amyloid aggregation of α -synuclein. Using this framework, we find that α -synuclein fibrils form via a two-step primary nucleation mechanism and that lipid molecules are directly involved in both the nucleation and fibril elongation steps, giving rise to lipid–protein coaggregates. To illustrate the applicability of this kinetic approach to drug discovery, we identify the mechanism of action of squalamine, a known inhibitor of lipid-induced α -synuclein aggregation, revealing that this small molecule reduces the rate of lipid-dependent primary nucleation. Our work will likely guide the rational design of α -synuclein aggregation inhibitors.

Autonomic cardiovascular dysregulation and other non-motor manifestations of Parkinson’s disease

2025-06-24
A A Pilipovich , Vorob'eva Ov , S. A. Makarov | Neurology neuropsychiatry Psychosomatics
Most patients with Parkinson’s disease (PD) experience autonomic cardiovascular dysfunction (insufficiency), which, together with other nonmotor manifestations, negatively affects quality of life and disease progression. Objective: to assess the relationship 
 Most patients with Parkinson’s disease (PD) experience autonomic cardiovascular dysfunction (insufficiency), which, together with other nonmotor manifestations, negatively affects quality of life and disease progression. Objective: to assess the relationship between autonomic cardiovascular dysfunction and other non-motor symptoms of PD. Material and methods. A total of 252 patients with PD Hoehn and Yahr stages I–III were examined. The evaluation included: a questionnaire aimed at identifying symptoms of orthostatic intolerance (OI), orthostatic test, evaluation using the Unified Parkinson’s Disease Rating Scale (UPDRS I–IV), the Schwab and England Activities of Daily Living Scale (Sch&amp;En), the Mini-Mental State Examination (MMSE), the Non-Motor Symptoms Questionnaire (NMSQ), the Beck Depression Inventory, the Spielberger State-Trait Anxiety Inventory, the Glasgow Dyspepsia Severity Score (GDSS), the Gastrointestinal Symptom Rating Scale (GSRS), the Bristol Stool Form Scale (BSFS), and the International Prostate Symptom Score (IPSS). A subset of patients (n=31) underwent heart rate variability (HRV) assessment. Results. Among patients with OI symptoms (35.3% of all participants) we found the worst non-motor outcomes UPDRS I (p&lt;0.0001), cognitive and affective disturbances, sleep disorders, worse NMSQ scores (p=0.038), MMSE scores (p=0.007), IPSS scores (p=0.006), GDSS scores (p&lt;0.0001), GSRS scores (p=0.004), and greater tendency toward constipation according BSFS (p=0.001; Mann–Whitney U test for independent samples). Significant negative correlations in HRV indices (TP, LF, HF, SDNN, RMSSD) were associated with the same non-motor components of UPDRS, depression and anxiety scales, GSRS, and IPSS. Conclusion. The data indicate that one-third of stages I–III PD patients exhibit clinical signs of autonomic dysregulation affecting the cardiovascular system, gastrointestinal tract, and bladder. These are closely associated with other non-motor symptoms of PD, forming a unified neurodegenerative process involving both central and peripheral components of the nervous system. We propose that OI symptoms may serve as clinical markers of emerging widespread autonomic failure.

Correction to: Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration <i>in vivo</i>

2025-06-24
| Brain

Self‐reported autonomic dysfunction could be a predictive marker for sarcopenia in Parkinson's disease

2025-06-24
Motohiro Okumura , Yohei Mukai , Reiko Saika +1 more | Geriatrics and gerontology international/Geriatrics & gerontology international
Aim Autonomic dysfunction and motor symptoms are prevalent in Parkinson's disease (PD). Motor symptoms influence sarcopenia; however, the association between sarcopenia and non‐motor symptoms, particularly autonomic dysfunction, remains unclear. This 
 Aim Autonomic dysfunction and motor symptoms are prevalent in Parkinson's disease (PD). Motor symptoms influence sarcopenia; however, the association between sarcopenia and non‐motor symptoms, particularly autonomic dysfunction, remains unclear. This study determined the effect of autonomic dysfunction on sarcopenia in patients with PD. Methods Consecutive patients with PD (Hoehn and Yahr stages 1–3) without apparent dementia were screened. The Scales for Outcomes in Parkinson's Disease‐Autonomic Questionnaire (SCOPA‐AUT) was utilized to evaluate the severity of autonomic dysfunction. Sarcopenia was assessed using the 2019 Asian Diagnostic Criteria. This study examined whether the SCOPA‐AUT and its domains were associated with sarcopenia and used receiver operating characteristic analysis to evaluate their predictive performance. Results Of the 124 patients (76 [61%] men; median age, 68 years) included, sarcopenia was identified in 31 (25%). Poisson regression analysis with a robust variance estimator showed that a higher SCOPA‐AUT score is associated with sarcopenia (prevalence ratio 1.078, 95% CI 1.034–1.122, p &lt; 0.001). Regarding SCOPA‐AUT domains, higher scores for gastrointestinal functioning, urinary functioning and pupillomotor functioning were significantly associated with sarcopenia. Receiver operating characteristic analysis showed that the optimal cut‐off value for SCOPA‐AUT was 16 (area under the curve 0.730, 95% CI 0.615–0.844). For each SCOPA‐AUT domain, a cut‐off of 8 for gastrointestinal functioning (area under the curve 0.744, 95% CI 0.630–0.858) predicted sarcopenia more reliably than urinary and pupillomotor functioning. Conclusions Higher SCOPA‐AUT scores, particularly in the gastrointestinal function domain, might be an optimal predictive marker for sarcopenia in patients with PD. Geriatr Gerontol Int 2025; ‱‱: ‱‱–‱‱ .

Cortical volumetry and longitudinal cognitive changes in Parkinson’s disease: insights from the COPPADIS cohort

2025-06-24
Tania Álvarez-Avellón , Carmen Solares , Juan César Álvarez Carriles +5 more | Brain Imaging and Behavior
Abstract Cognitive decline is a major non-motor symptom in Parkinson’s disease (PD), often linked to brain atrophy. This study examines the relationship between cortical atrophy and age groups in predicting 
 Abstract Cognitive decline is a major non-motor symptom in Parkinson’s disease (PD), often linked to brain atrophy. This study examines the relationship between cortical atrophy and age groups in predicting cognitive decline in PD over five years. 188 PD patients from the COPPADIS cohort were stratified by age: young (30–55 years, N = 47), middle-aged (56–65 years, N = 59), and older adults (66–75 years, N = 82). Baseline cortical volume was assessed using T1-weighted MRI, and cognitive decline was evaluated using the annual rate of change of the Parkinson’s Disease-Cognitive Rating Scale (PD-CRS). Parametric or non-parametric tests were applied to evaluate group differences. Main analyses consist of several multiple regression analyses to examine associations between baseline brain atrophy and cognitive decline by age group. Older adults exhibited significantly greater cognitive decline in comparison to the younger age groups in the three compose scores of the PDCRS -Fronto-subcortical (H(2) = 41.08, p &lt; 0.001), Posterior Cortical (H(2) = 22.03, p &lt; 0.001), and Total(H(2) = 41.13, p &lt; 0.001). Higher educational level has a significant positive effect on older adults, specifically for working memory performance, delayed verbal memory and the fronto-subcortical composed score. Multiple regression models underscored the predictive value of the bilateral hippocampus, bilateral medial orbitofrontal cortex, right precuneus, and right isthmus cingulate gyrus, together with being an older adult or having a higher education. MRI measures, age, and education predict cognitive decline in PD. Longitudinal assessments are essential for refining atrophy-cognition correlations and optimizing patient stratification.

Sarcopenia, malnutrition, and fatigue in de Novo Parkinson’s disease– support for early rehabilitation

2025-06-24
Beata Lindholm , Ylva Dernbrant , Albert Westergren +1 more | Neurological Sciences
Abstract Objective Sarcopenia (loss of muscle strength/mass) reduces physical performance (walking, strength, mobility) and is common in Parkinson’s disease (PD), but data on newly diagnosed, untreated patients (“de novo”) are 
 Abstract Objective Sarcopenia (loss of muscle strength/mass) reduces physical performance (walking, strength, mobility) and is common in Parkinson’s disease (PD), but data on newly diagnosed, untreated patients (“de novo”) are scarce. Fatigue is frequent in PD and linked to physical decline and malnutrition, key sarcopenia risk factors. We aimed to describe sarcopenia prevalence, malnutrition risk, and fatigue in de novo PD and explore differences based on fatigue presence. Methods Participants ( n = 49) underwent physical tests [chair stand test (CST), hand grip strength, gait speed, Timed Up and Go test (TUG)] to assess sarcopenia. Malnutrition risk and fatigue were assessed using the Nutrition Form version 2 (MEONF-II) and the 16-item Parkinson’s Disease Fatigue Scale (PFS-16). Results Twenty (40.8%) showed probable sarcopenia. Eight (16%) had fatigue, and 8 (19%) were at risk of malnutrition. No significant differences in sarcopenia indicators were found between groups, but those with fatigue had lower physical performance (CST, p = 0.033; TUG, p = 0.011), slower gait speed ( p = 0.050), and poorer appetite ( p = 0.003). Conclusion A substantial proportion of de novo PD presented probable sarcopenia. Fatigue was associated with poorer physical performance and appetite but not sarcopenia. Whether fatigue increases risk of future malnutrition/sarcopenia is unclear due to cross-sectional study design. It should be further explored using a longitudinal study design.

Abnormal α-synuclein binds to synaptotagmin 13, impairing extracellular vesicle release in synucleinopathies

2025-06-23
Yasuo Miki , Shuji Shimoyama , Makoto T Tanaka +7 more | Translational Neurodegeneration
Despite increasing in vitro research, direct evidence of how abnormal α-synuclein (α-Syn) dysregulates vesicular transport and synaptic function in the human brain is lacking. We performed a transcriptome analysis using 
 Despite increasing in vitro research, direct evidence of how abnormal α-synuclein (α-Syn) dysregulates vesicular transport and synaptic function in the human brain is lacking. We performed a transcriptome analysis using brain tissues from a multiple system atrophy (MSA) mouse model, which develops human α-Syn-positive glial cytoplasmic inclusion-like structures and neuronal cytoplasmic inclusion-like structures after tamoxifen injection. We then performed histologic and biochemical analyses using brain samples from 71 human cases (Parkinson's disease, n = 10; dementia with Lewy bodies [DLB], n = 19; MSA, n = 15; control: n = 27), a human blood sample (control: n = 1), and cultured cells. Based on the transcriptome of the MSA mouse model, we identified 10 vesicular transport proteins, including synaptotagmin 13 (SYT13), that might interact with α-Syn. Immunohistochemistry using human brain samples demonstrated that of the 10 vesicular transport proteins identified in the transcriptome analysis, only SYT13 was incorporated into both Lewy bodies and glial cytoplasmic inclusions. Proximity ligation assays revealed that SYT13 exhibited a higher degree of interactions with phosphorylated α-Syn than with endogenous α-Syn. Immunoprecipitation confirmed that SYT13 bound predominantly to phosphorylated α-Syn, SYT1, and the soluble N-ethylmaleimide-sensitive attachment protein receptor (SNARE) complexes. Filter trap assays revealed interactions between SYT13 and soluble toxic ÎČ-sheet-rich α-Syn oligomers. Furthermore, fraction analysis showed a significant increase of SYT13 protein levels at the synapses in DLB and MSA. Notably, a correlation was observed between the levels of SYT13 and aggregated α-Syn at the synapses. SYT13 was observed to regulate extracellular vesicle release in association with SYT1 and the SNARE complexes in SH-SY5Y cells. SYT13 overexpression in SH-SY5Y cells impaired extracellular vesicle release. Consistently, the numbers of extracellular vesicles were significantly reduced in the brain homogenates of DLB and MSA cases compared with those in controls. Abnormal α-Syn impairs extracellular vesicle release through interactions with SYT13 in synucleinopathies. Our findings provide insights into therapeutic strategies for alleviating dysregulations of vesicular transport and synaptic function in patients with synucleinopathies.

Feasibility and preliminary efficacy of an online home-based functional exercise program for Parkinson's disease: a pilot study

2025-06-23
Hyungwoo Lee , Hunyoung Ha , Heehyun Shin +5 more | Frontiers in Neurology
Background Parkinson's disease (PD) leads to motor and non-motor impairments, contributing to sarcopenia and reduced functional independence. While functional strength exercises can help manage these symptoms, adherence remains challenging, particularly 
 Background Parkinson's disease (PD) leads to motor and non-motor impairments, contributing to sarcopenia and reduced functional independence. While functional strength exercises can help manage these symptoms, adherence remains challenging, particularly in home-based setting. Objective This pilot exercise intervention study aimed to evaluate the feasibility and efficacy of an 8-week Online Home-Based Exercise Program (OHEP), which provides easy-to-follow functional strength exercises for PD patients, enabling them perform these exercises safely and effectively at home. Methods Fifteen patients with early-stage PD (Hoehn and Yahr Stage 1–2) participated in an 8-week exercise intervention, consisting of a 2-week in-person training followed by a 6-week online home-based exercise session using Zoom. The exercise regimen included softball, bodyweight, elastic band, and step box exercises targeting muscle strength, balance, and mobility. Feasibility was assessed through attrition rate, adherence rate, compliance rate, and safety. Efficacy was evaluated by examining changes in motor and non-motor symptoms, body composition, and physical performance. Results Three participants withdrew from the study, resulting in an attrition rate of 20%. Feasibility was supported by a high adherence rate (median: 91%) and exercise compliance rates exceeding 93% across all exercise types. No adverse events reported. Among clinical outcomes, depressive symptoms significantly improved (Beck Depression Inventory, p = 0.011). Additionally, lower limb muscle function significantly improved, as reflected by a reduced time in the Five Times Sit-to-Stand test ( p = 0.002). However, no significant changes were observed in other clinical or physical performance measures. Conclusion These findings suggest that a short-term OHEP is feasible and safe intervention for PD patients, with potential benefits in improving depressive symptoms and physical function. However, further randomized controlled long-term studies are needed to better delineate the effects of this intervention in the management of PD. Clinical trial registration https://cris.nih.go.kr , Identifier: KCT0008302.

Common SNCA Genetic Variants and Parkinson’s Disease Risk: A Systematic Review and Meta-Analysis

2025-06-23
Raziyeh Mohammadi , M H Shirazi , Seyedeh Fatemeh Sadatmadani +7 more | International Journal of Molecular Sciences
The SNCA gene, encoding alpha-synuclein, is implicated in the pathogenesis of Parkinson’s disease (PD), with several single-nucleotide polymorphisms (SNPs) linked to increased risk. This study systematically evaluated the association between 
 The SNCA gene, encoding alpha-synuclein, is implicated in the pathogenesis of Parkinson’s disease (PD), with several single-nucleotide polymorphisms (SNPs) linked to increased risk. This study systematically evaluated the association between common SNCA polymorphisms and PD through a meta-analysis of cohort and case–control studies published before 20 November 2023. Eligible studies were identified via comprehensive searches of PubMed, Scopus, and Web of Science, and pooled odds ratios with 95% confidence intervals were calculated under allelic, dominant, and recessive models. Heterogeneity and publication bias were assessed, and subgroup and sensitivity analyses were performed. Twenty-seven studies were included. SNP rs11931074 showed consistent associations with PD across all models, with low heterogeneity and no evidence of publication bias. rs356219 and rs356165 were also significantly associated with PD, although regional differences contributed to heterogeneity. In contrast, rs2583988 showed marginal significance in the allelic model, which was lost after sensitivity analyses. No associations were found under dominant or recessive models for this SNP. These findings confirm rs11931074 as a robust PD risk variant and support the roles of rs356219 and rs356165 while suggesting weaker evidence for rs2583988. Large, multi-ethnic studies are warranted to elucidate underlying mechanisms and support precision medicine in PD.

IntervençÔes fisioterapĂȘuticas na doença de Parkinson: uma revisĂŁo sistemĂĄtica

2025-06-23
Maria Fernanda Ranghetti Peasson , M. Silva , Silvano Piovan | Brazilian Journal of Health Review
A Doença de Parkinson (DP) Ă© uma condição neurolĂłgica degenerativa, crĂŽnica e progressiva que afeta principalmente a população idosa, gerando comprometimentos motores como tremores, rigidez muscular, bradicinesia e desequilĂ­brio. A 
 A Doença de Parkinson (DP) Ă© uma condição neurolĂłgica degenerativa, crĂŽnica e progressiva que afeta principalmente a população idosa, gerando comprometimentos motores como tremores, rigidez muscular, bradicinesia e desequilĂ­brio. A fisioterapia tem se mostrado eficaz na atenuação desses sintomas e na promoção da qualidade de vida dos pacientes. Esta revisĂŁo sistemĂĄtica teve como objetivo investigar os efeitos das intervençÔes fisioterapĂȘuticas sobre o equilĂ­brio e a funcionalidade em indivĂ­duos com DP. Foram analisados 20 estudos, sendo 17 ensaios clĂ­nicos randomizados, 1 estudo observacional, 1 estudo paralelo e 1 triagem clĂ­nica. Os resultados indicam que 12 dos estudos demonstraram melhorias significativas no equilĂ­brio, marcha, tremores e qualidade de vida. Abordagens como fisioterapia convencional associada Ă  facilitação neuromuscular, realidade virtual, exercĂ­cios com movimento ocular e estimulação vestibular se destacaram como eficazes. No entanto, a heterogeneidade dos protocolos, o nĂșmero reduzido de amostras em alguns estudos e a ausĂȘncia de padronização nos desfechos clĂ­nicos limitam a generalização dos resultados. A fisioterapia individualizada e iniciada precocemente, aliada ao uso de novas tecnologias, se mostra promissora no manejo da DP.

Digital phenotyping of Parkinson’s disease via natural language processing

2025-06-23
Simona Aresta , Petronilla Battista , Cinzia Palmirotta +7 more | npj Parkinson s Disease
Frontostriatal degeneration in Parkinson's disease (PD) is associated with language deficits, which can be identified using natural language processing, a remarkable tool for digital-phenotyping. Current evidence is mostly blind to 
 Frontostriatal degeneration in Parkinson's disease (PD) is associated with language deficits, which can be identified using natural language processing, a remarkable tool for digital-phenotyping. Current evidence is mostly blind to the disorder's cognitive phenotypes. We validated an AI-driven approach to capture digital language markers of PD with and without mild cognitive impairment (PD-MCI, PD-nMCI) relative to healthy controls (HCs). Analyzing the connected speech of participants, we extracted linguistic features with CLAN software. Classification was performed using SVM and RFE. Discrimination between PD and HCs reached an AUC of 77%, with even better results for subgroup analyses (AUC: 85% PD-nMCI vs. HCs; 83% PD-MCI vs. HCs; 75% PD-nMCI vs. PD-MCI). Key linguistic features included retracing, action verb, utterance error, and verbless-utterance ratios. Despite the small sample size, which may limit statistical power and generalizability, this study highlights the foundational potential of linguistic digital markers for early diagnosis and phenotyping of PD.

A Real‐World Study on Unstable Parkinson's Disease: Levodopa Dosage Management and the Role of Nonmotor Symptoms

2025-06-23
Fabrizio Stocchi , Jaime Kulisevsky , Wolfgang H. Jost | Movement Disorders Clinical Practice
Abstract Background Parkinson's disease (PD) is a neurodegenerative disorder associated with motor and nonmotor symptoms. Objectives This study assesses levodopa dose management, the therapeutic goals of clinicians, the factors that 
 Abstract Background Parkinson's disease (PD) is a neurodegenerative disorder associated with motor and nonmotor symptoms. Objectives This study assesses levodopa dose management, the therapeutic goals of clinicians, the factors that influence clinicians' choice of therapy, and the role of nonmotor symptoms using real‐world evidence from Germany, Italy, and Spain. Methods To assess the management of unstable PD patients on levodopa‐containing regimens, neurologists were asked to complete questionnaires (n = 181) and prospective electronic patient records (EPR) were collected (n = 2687). Neurologists were asked questions about their practice and approach to unstable PD patients. EPRs were completed by neurologists after each visit with patients, and the objectives of any changes to therapy were recorded. Results Seventy‐four percent of neurologists cited “improving motor symptoms” as the main objective for increasing daily levodopa dose. This was also the main objective when starting an add‐on (50%) and the main reason for selecting a new add‐on therapy (29%). In comparison, reducing nonmotor symptoms, depression, and pain was rarely cited as either the main or secondary objective for a therapy selection (15%, 9%, and 9%, respectively) even when over 60% of unstable patients had pain or depression and 29% had both. When the importance of add‐on therapy features was rated, “improve quality of life (QoL)” had the highest average score. Improving nonmotor symptoms, pain, and depression was among the lowest‐rated therapy feature. Conclusions These findings suggest that improving motor symptoms is a key driver of therapeutic choice. In prioritizing motor symptoms, neurologists may unintentionally neglect nonmotor symptoms, despite most patients suffering from pain or depression.

Comparative Analysis of Progression Milestones Across Parkinson’s Disease Clinical, Pathological, and Data-driven Subtypes: A 10-year follow-up

2025-06-23
Ahmed Negida , Nitai D. Mukhopadhyay , Brian D. Berman +1 more | Research Square (Research Square)
<title>Abstract</title> Parkinson’s disease (PD) heterogeneity complicates disease-modification clinical trial design and lead to ambiguous results, necessitating robust subtyping frameworks to identify rapid progressors. This study compared progression milestones across previously 
 <title>Abstract</title> Parkinson’s disease (PD) heterogeneity complicates disease-modification clinical trial design and lead to ambiguous results, necessitating robust subtyping frameworks to identify rapid progressors. This study compared progression milestones across previously defined clinical (tremor-dominant [TD], postural instability/gait difficulty [PIGD], indeterminate), pathological (brain-first, body-first), and data-driven (diffuse malignant [DM], intermediate [IM], mild motor-predominant [MMP]) PD subtypes. Using data from the Parkinson’s Progression Markers Initiative (PPMI), we analyzed milestone attainment across six functional domains and performed competing risks regression. Randomized controlled trial sample size simulations evaluated the impact of subtyping on trial efficiency. Data-driven subtypes exhibited the highest progression rates, with DM patients attaining 50% of milestones, surpassing PIGD (43.0%) and body-first (42.0%) subtypes. Competing risks regression confirmed that DM patients had more than double the hazard of progression compared to MMP (SHR 2.02, 95% CI 1.49 to 2.75; P &lt; 0.001). Trial power simulations demonstrated that enrolling DM patients could reduce sample size requirements by approximately 50% using standard trial durations compared to unstratified PD cohorts. This analysis showed that data-driven subtyping, particularly the identification of the DM subtype, offers a promising strategy to optimize disease-modification trials in PD by capturing patients who meet progression milestones earlier.

Parkinson’s disease: exploring the systemic immune mechanisms through molecular investigations

2025-06-23
Maneesh Mohan , Ashi Mannan , Thakur Gurjeet Singh | Inflammopharmacology

Caregiver burden in Parkinson’s disease: a nationwide observational survey

2025-06-23
Giulia Donzuso , Paolo Brunelli , Giuseppe Milesi +5 more | Neurological Sciences
Caregivers play an important role in Parkinson's disease (PD), especially in the advanced stages. Aim of this study is to evaluate the caregiver burden of PD in an Italian sample 
 Caregivers play an important role in Parkinson's disease (PD), especially in the advanced stages. Aim of this study is to evaluate the caregiver burden of PD in an Italian sample of caregivers. An online anonymous survey was conducted among Italian caregivers funded by "Fondazione LIMPE per il Parkinson ONLUS" and "Confederazione Parkinson Italia". The survey encompassed several dimensions (i.e. caregiving, work, economic and personal health) related to caregivers' activities and patients' characteristics. The survey was completed by 478 caregivers, 361 were women (75%), and the majority had an age included between 55 and 70 years old (46.4%). The burden of assistance increased from 1 to 2 days weekly in the first period of the disease to all the weekly days with the progression of the disease. 15% of caregivers reported not working because of assistance, and among caregivers who were still working, almost 70% reported at least one working day lost monthly due to caregiving activities. Concerning health, most caregivers reported an impact on health due to the assistance, in terms of "excessive tiredness" (74.6%), and "lack of sleep" (60.5%) as the most impacting disturbances. Considering gender, women caregivers reported that they could not work due to the assistance and complained a higher impact on health than men caregivers. Caregivers of PD patients experienced and reported the presence of caregiver burden in several domains. Additionally, a gender-related pattern was present suggesting the need of a customized support to enhance awareness and minimizing caregiver burden.

Loss‐of‐function coding variants in the Ras of complex proteins/<scp>GTPase</scp> domain of leucine rich repeat kinase 2

2025-06-22
Sarah K. Butterfield , Susanne Herbst , Patrick A. Lewis | Protein Science
Abstract The LRRK2 gene is a key contributor to the genetic risk of Parkinson's disease, and a priority drug target for the disorder. Leucine Rich Repeat Kinase 2, the protein 
 Abstract The LRRK2 gene is a key contributor to the genetic risk of Parkinson's disease, and a priority drug target for the disorder. Leucine Rich Repeat Kinase 2, the protein product of LRRK2 , is a multidomain enzyme implicated in a range of cellular processes—including endolysosomal trafficking and damage response. Based on the report that truncation and structural variants resulting in loss of LRRK2 protein are observed in human populations, genomic sequence repositories were queried for coding variants affecting key catalytic residues in LRRK2—resulting in the identification of three variants (K1347E, K1347R, and T1348P) predicted to ablate the capacity of LRRK2 to bind GTP. Biochemical and cellular characterization of these variants confirmed loss of GTP binding, as well as reduced or loss of kinase activity. These data demonstrate the presence of rare coding enzymatic loss‐of‐function variants in humans, with implications for our understanding of LRRK2 as a driver of disease and as a drug target.

Nigral volume loss in prodromal, early, and moderate Parkinson’s disease

2025-06-21
Jason Langley , Kristy S Hwang , Daniel E. Huddleston +1 more | npj Parkinson s Disease
Abstract The loss of melanized neurons in the substantia nigra pars compacta (SNc) is a hallmark pathology in Parkinson’s disease (PD). Melanized neurons in SNc can be visualized in vivo 
 Abstract The loss of melanized neurons in the substantia nigra pars compacta (SNc) is a hallmark pathology in Parkinson’s disease (PD). Melanized neurons in SNc can be visualized in vivo using magnetization transfer (MT) effects. Nigral volume was extracted in data acquired with a MT-prepared gradient echo sequence in 50 controls, 90 non-manifest carriers (46 LRRK2 and 44 GBA1 nonmanifest carriers), 217 prodromal hyposmic participants, 76 participants with rapid eye movement sleep behavior disorder (RBD), 194 de novo PD patients and 26 moderate PD patients from the Parkinson’s Progressive Markers Initiative. No difference in nigral volume was seen between controls and LRRK2 and GBA1 non-manifest carriers ( F = 0.732; P = 0.483). A significant main effect in group was observed between controls, prodromal hyposmic participants, RBD participants, and overt PD patients ( F = 9.882; P &lt; 10 −3 ). This study shows that nigral depigmentation can be robustly detected in prodromal and overt PD populations.

[Autophagy Impairment in Parkinson's Disease: Approaches to Therapy].

2025-06-21
Tatiana Usenko | PubMed
Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by progressive motor impairment due to the death of dopaminergic neurons in the substantia nigra (SN) 
 Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by progressive motor impairment due to the death of dopaminergic neurons in the substantia nigra (SN) of the brain. PD affects more than 1% of the population over 60 years of age worldwide. Despite significant progress in understanding the pathogenesis of PD, including genetic and biochemical aspects, current therapy is limited to symptomatic treatments. Recent evidence suggests that impaired autophagy leads to the accumulation of abnormal proteins and, particularly, α-synuclein, aggregated forms of which are neurotoxic to dopaminergic neurons in the SN. Notably, PD is predominantly sporadic. However, monogenic PD forms have also been described. PD forms associated with mutations of the GBA1 or LRRK2 gene are among the most common PD forms with known etiology. Leucine-rich repeat kinase 2 (LRRK2), which is encoded by LRRK2, and the lysosomal enzyme glucocerebrosidase (GCase), which is encoded by GBA1, are involved in the same endolysosomal pathway. LRRK2 and GCase dysfunction reported in PD, especially in cases with mutations of the respective genes, can impair the endolysosomal pathway, the lysosomal function, and possibly autophagy. The review highlights the molecular mechanisms of autophagy and the prospects for targeted therapy of PD via induction of autophagy by influencing the key players in the process.

Formation of seeding-competent α-synuclein aggregates in parkin-deficient iPSC-derived human neurons

2025-06-21
Sissel Ida Schmidt , Justyna Okarmus , Daniel Aghaie Madsen +7 more | npj Parkinson s Disease
Loss-of-function mutations in PARK2 (parkin) cause early-onset familial Parkinson's disease (PD) and may also contribute to sporadic PD. While Lewy bodies, enriched in aggregated phosphorylated α-synuclein (α-Syn), are typical in 
 Loss-of-function mutations in PARK2 (parkin) cause early-onset familial Parkinson's disease (PD) and may also contribute to sporadic PD. While Lewy bodies, enriched in aggregated phosphorylated α-synuclein (α-Syn), are typical in PD, their presence in PARK2-mediated PD remains debated. Using human isogenic PARK2-/- induced pluripotent stem cell-derived neurons, we investigated α-Syn pathology under parkin deficiency. PARK2-/- neurons showed elevated intracellular aggregated and total α-Syn levels, increased α-Syn release, and higher levels of aggregation-inducing α-Syn seeds. These neurons also displayed more pSer129 α-Syn+ inclusions, which were further enhanced by α-Syn preformed fibril (PFF) exposure. Moreover, we identified synaptic loss in the PARK2-/- neurons, exacerbated by PFF treatment, and dysregulated Ca2+ homeostasis consistent with enhanced activity of the smooth endoplasmic reticulum Ca2+-ATPase (SERCA). Our data provide an important contribution to the debate on the role of α-Syn in the pathology of PARK2-related PD and challenge the view of PARK2-related PD as a non-synucleinopathy.

Gait analysis and Machine learning algorithms to distinguish between Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease

2025-06-20
Yi Ru , Xiangwei Zhao , Yasamin Baghersad +3 more | Biomedical Signal Processing and Control

Effect of Safinamide on Non-Motor Symptoms and Quality of Life in Parkinson’s Disease Patients According to Sex, Age, Disease Duration and Levodopa Equivalent Daily Dose

2025-06-20
Ángela Vidal , Rosa Yåñez Baña , Carmen M. Labandeira +5 more | Brain Sciences
Background and objective: Safinamide can improve the non-motor symptoms (NMSs) and quality of life (QoL) in patients with Parkinson’s disease (PD). In this post hoc analysis of the SAFINONMOTOR study, 
 Background and objective: Safinamide can improve the non-motor symptoms (NMSs) and quality of life (QoL) in patients with Parkinson’s disease (PD). In this post hoc analysis of the SAFINONMOTOR study, we analyzed the effect of safinamide on NMSs and QoL according to age, sex, disease duration (DD), and levodopa equivalent daily dose (LEDD). Patients and Methods: The change from baseline to the end of the observational period (6 months) in the Non-Motor Symptoms Scale (NMSS) and the 39-item Parkinson’s Disease Quality of Life Questionnaire (PDQ-39) was analyzed in subgroups according to sex (male vs. female), age (≀75 vs. &gt;75 years old), DD (≀10 vs. &gt;10 years) and LEDD (≀1000 vs. &gt;1000 mg). Nonparametric tests and general linear model (GLM) repeated measures were applied. Results: A total of 44 patients completed the final visit and were valid for the analysis. A significant reduction in the NMSS score was observed in all groups. Regarding QoL, a significant reduction in the PDQ-39 score was observed in females (p &lt; 0.0001) and in patients with a DD &gt; 10 years (p = 0.011) but not in males or those &gt; 75 years old or receiving an LEDD &gt; 1.000 mg. In the GLM, only LEDD at baseline influenced the degree of change in the NMSS total score (p = 0.026; F = 5.23). None of the variables influenced the change in the PDQ39. Conclusions: Safinamide improved NMSs independently of sex, age, DD, and LEDD. QoL improved independently of DD, and in females and non-elderly and very treated patients.

Constipation in a Large Online Cohort of Persons with Parkinson's Disease

2025-06-20
Adil E. Bharucha , Mohammad Ghafouri , Revati Varma +5 more | Movement Disorders Clinical Practice
Abstract Background Small studies suggest that constipation is a common symptom associated with a worse prognosis in patients with Parkinson's disease (PD). Objectives The aim was to compare the association 
 Abstract Background Small studies suggest that constipation is a common symptom associated with a worse prognosis in patients with Parkinson's disease (PD). Objectives The aim was to compare the association between constipation, motor, and other non‐motor symptoms (NMS) in PD patients at baseline and in future. Methods Using the Fox Insight database, we compared baseline characteristics, risk of progressive motor symptoms, and incidence of NMS between PD patients with versus without constipation. Results Of 20,352 participants, 16,611 (82%) reported infrequent bowel movements and/or excessive straining, 15,594 (77%) had incomplete evacuation, and 14,165 (70%) reported both symptoms. Patients with constipation were generally older, white, women, had PD &gt;5 years, and had higher NMS and comorbidity scores ( P &lt; 0.001). Constipation was significantly associated with worse motor symptoms and most NMS , especially fecal incontinence (odds ratio [ OR] = 1.65; 95% confidence interval [CI], 1.49–1.82), dysphagia ( OR = 1.20; 95% CI = 1.12–1.29), talking/moving during sleep ( OR = 1.39; 95% CI = 1.30–1.48), and urinary urgency ( OR = 1.23; 95% CI = 1.16–1.32). Constipation was associated with a small, but statistically significant increased risk of some progressive motor symptoms. At a mean median follow‐up of 2.8 years, constipation was associated with an increased risk of incident gastrointestinal, autonomic, neuropsychiatric, sleep‐related, sensory NMS , such as dysphagia (hazard ratio [ HR] = 1.43; 95% CI = 1.35–1.51), fecal incontinence ( HR = 1.87; 95% CI = 1.74–2.01), falls ( HR = 1.44; 95% CI = 1.35–1.52), hallucinations ( HR = 1.65; 95% CI = 1.52–1.79), cognitive impairment ( HR = 1.38; 95% CI = 1.30–1.47), and talking/moving during sleep ( HR = 1.65; 95% CI = 1.55–1.75). Conclusions Constipation is a common symptom associated with severity of motor and other NMS and portends a worse prognosis in persons with PD.

A community-led initiative to de-risk and advance Parkinson’s disease therapeutic targets

2025-06-20
Alexandra Vaiana , Jonathan Behr , Ryan Birol +7 more | npj Parkinson s Disease
Abstract Identifying effective therapeutic targets for Parkinson’s disease (PD) is challenging, with no current disease-modifying therapies available. To address this, The Michael J. Fox Foundation for Parkinson’s Research launched the 
 Abstract Identifying effective therapeutic targets for Parkinson’s disease (PD) is challenging, with no current disease-modifying therapies available. To address this, The Michael J. Fox Foundation for Parkinson’s Research launched the Targets to Therapies (T2T) initiative, uniting experts to prioritize and validate promising targets. T2T aims to develop validation strategies, create comprehensive target data profiles, and build tools to support drug development, ultimately accelerating the discovery of new therapies for PD patients.

Impact of an intensive outpatient rehabilitation on non-motor patients’ reported outcomes in PD: the INTENSO study

2025-06-20
Marianna Capecci , NicolĂČ Baldini , Elisa Andrenelli +5 more | npj Parkinson s Disease
Abstract Non-motor symptoms in Parkinson’s disease (PD) can reduce quality of life and increase disability. This historical cohort study investigated how rehabilitation intensity influences non-motor symptoms. The primary outcomes were 
 Abstract Non-motor symptoms in Parkinson’s disease (PD) can reduce quality of life and increase disability. This historical cohort study investigated how rehabilitation intensity influences non-motor symptoms. The primary outcomes were changes in non-motor symptoms in the short and medium term. Secondary outcomes were changes in disability burden, motor symptom severity, and freezing of gait after treatment. Measurements were taken before (T0) and after treatment (T1) and 6 ± 1 months after T1 (T2). According to total training duration, 24 patients with PD were assigned to High-Intensity Training group (HIT, 1800 min) and 24 to Low-Intensity Training (LIT, less than 900 minutes). At T1, only the HIT group showed clinically significant improvements in non-motor symptoms, which were maintained at T2. In contrast, the LIT group experienced worsening disability at follow-up. Multivariate analysis revealed training intensity and baseline disability as predictors of improvement. These findings support the benefits of high intensity exercise in PD management.

Dopamine and cortical neurons with different Parkinsonian mutations show variation in lysosomal and mitochondrial dysfunction

2025-06-20
Jessica Chedid , Yan Li , Adahir Labrador‐Garrido +7 more | npj Parkinson s Disease
Abstract Mutations causing Parkinson’s disease (PD) give diverse pathological phenotypes whose cellular correlates remain to be determined. Those with PRKN mutations have significantly earlier selective vulnerability of dopamine neurons, those 
 Abstract Mutations causing Parkinson’s disease (PD) give diverse pathological phenotypes whose cellular correlates remain to be determined. Those with PRKN mutations have significantly earlier selective vulnerability of dopamine neurons, those with SNCA mutations have increased alpha-synuclein deposition, while those with LRRK2 mutations have additional deposition of tau. Yet all three mutation types are implicated in mitochondrial and/or lysosomal dysfunction. To compare cellular dysfunctions associated with these different pathological phenotypes, an unbiased high-content imaging platform was developed to assess both lysosomal and mitochondrial dysfunction, along with alpha-synuclein and tau protein deposition using induced pluripotent stem cell (iPSC) derived cortical and ventral midbrain neurons. Different PD mutations caused cell type specific dysfunctions, likely to impact on both selective neuronal vulnerability and the pathologies observed in PD. Comparison of dopamine neurons identified that both lysosomal and mitochondrial dysfunction were predominant with PRKN lof mutations, whereas SNCA A53T and LRRK2 R1441G mutations had increased tau deposition. In contrast, cortical neurons with SNCA and LRRK2 mutations both had mitochondrial and autophagy impairments without protein deposition, with LRRK2 cells additionally showing decreased glucocerebrosidase activity and increased alpha-synuclein phosphorylation.

Clinical progression and genetic pathways in body-first and brain-first Parkinson’s disease

2025-06-20
Massimiliano Passaretti , Dåniel Veréb , Mite Mijalkov +7 more | Molecular Neurodegeneration

Parkinson's Disease and Addiction

2025-06-20
Kareem Sharif , Noreen Hassan , Ahmad Hassan +1 more | CRC Press eBooks

Optimising Parkinsons Disease Management: A Comparative Analysis of Levodopa and Dopamine Agonists

2025-06-20
Ava Guarnotta | Theoretical and Natural Science
Motor and non-motor symptoms are hallmarks of Parkinson's disease (PD), a chronic, progressive neurodegenerative illness caused by the decline of dopamine-producing neurones in the substantia nigra. Although the exact cause 
 Motor and non-motor symptoms are hallmarks of Parkinson's disease (PD), a chronic, progressive neurodegenerative illness caused by the decline of dopamine-producing neurones in the substantia nigra. Although the exact cause is still unknown, environmental variables like pesticide exposure and genetic alterations (such as SNCA, LRRK2, and PARK7) are involved in its development. Tremors, bradykinesia, stiffness, and postural instability are the hallmark motor symptoms that are caused by a dopamine deficit in the basal ganglia. Quality of life is impacted by non-motor symptoms such as mood problems, sleep disruptions, and cognitive deterioration. By restoring dopamine levels in the brain, Levodopa efficiently treats motor symptoms and is still the gold standard for treating Parkinson's disease. When combined with carbidopa to increase delivery and reduce side effects, Levodopa dramatically enhances motor function, particularly in the early and middle stages of the disease. However, problems, including dyskinesia and motor irregularities, are linked to prolonged use. Another treatment option is provided by dopamine agonists, which directly activate dopamine receptors, especially in younger or early-stage PD patients. They reduce the risk of early dyskinesia by delaying Levodopa and providing long-lasting symptom alleviation, although less effective than Levodopa. They do, however, have an increased risk of behavioural and cognitive adverse effects, including impulse control issues and hallucinations. Combination therapy maximises symptom management by utilising the advantages of both levodopa and dopamine agonists, but it necessitates close observation. Treatment plans must change as PD worsens to strike a balance between effectiveness and adverse effects. Future studies on sophisticated medication regimens and neuroprotective therapies have the potential to improve long-term results in the treatment of Parkinson's disease.

Outpatient interface challenges for drug safety in Parkinson’s disease patients: a questionnaire based cross-sectional study

2025-06-19
Stephan Greten , Clara Niesmann , Lea Krey +3 more | Frontiers in Neurology
Background Parkinson’s disease (PD) is a chronic and multifaceted disease with a variety of motor and non-motor symptoms. The safe symptomatic drug therapy of often multimorbid patients places enormous demands 
 Background Parkinson’s disease (PD) is a chronic and multifaceted disease with a variety of motor and non-motor symptoms. The safe symptomatic drug therapy of often multimorbid patients places enormous demands on the competence, communication and coordination of the treating physicians, particularly in the outpatient sector. Objectives This study aimed to explore aspects of drug safety and interdisciplinary communication in the outpatient sector of PD patients. Methods A semistructured questionnaire was designed addressing various aspects of drug safety in the outpatient setting. The questionnaire was sent to a total of 1,002 general practitioners (GP) and 1,005 neurologists (NEU). Results One hundred and forty-seven NEU and eighty-four GP answered the questionnaire. Overall, NEU treated more PD patients, while GP cared for more geriatric PD patients, especially outside of the outpatient clinic (home visits, nursing homes). Regarding the execution of recommended laboratory or technical check-ups, as well as the prescription of new medications, neither a formal agreement nor structured communication existed. Merely the identification of potential drug–drug interactions (DDI) was regularly carried out by both professions. Conclusion The inadequate interdisciplinary communication hampers therapy safety and consequently the safety of the vulnerable PD patient group. For this reason, standardized and comprehensive communication mechanisms are urgently needed. Solution approaches may include an individual protected digital health record or integrated treatment networks comprising all professionals participating in the management of PD patients.

Using prodromal non-motor symptoms to predict Parkinson’s disease onset and motor phenotype

2025-06-19
Joshua Pearson , James Badenoch , Daniel J. van Wamelen | Journal of Neurology Neurosurgery & Psychiatry
Background Non-motor symptoms are highly prevalent in prodromal Parkinson’s disease (PD); however, their impact on PD trajectory remains largely unexplored. We aimed to assess whether prevalent prodromal non-motor symptoms could 
 Background Non-motor symptoms are highly prevalent in prodromal Parkinson’s disease (PD); however, their impact on PD trajectory remains largely unexplored. We aimed to assess whether prevalent prodromal non-motor symptoms could predict future motor phenotype and time-to-PD diagnosis. Methods We studied the prodromal cohort of the ongoing Parkinson’s Progression Markers Initiative (n=958), which prospectively assesses individuals with prodromal PD features (genetic: n=361, hyposmia: n=298, rapid eye movement behaviour disorder: n=136, combination: n=163) with up to 10 years of follow-up. The presence of prevalent prodromal symptoms was defined by evidence-based cut-off scores. In unmedicated or OFF-state PD converters (total n=52), binary logistic regression models established whether these predicted non-tremor-dominant (n=35) and tremor-dominant (n=17) motor phenotypes at diagnosis. Cox proportional hazards models determined whether identified prodromal symptoms predicted a shorter time-to-phenoconversion across all PD converters (n=59) and non-converters (n=343). Both models adjusted for age and sex. Results Prodromal anxiety and hyposmia were each associated with an increased risk of subsequent non-tremor-dominant PD, compared with other motor phenotypes (adjusted OR=4.45, 95% CI 1.34 to 15.27 and adjusted OR=3.90, 95% CI 1.01 to 15.16, respectively). Concurrent prodromal anxiety and hyposmia predicted an increased risk of PD phenoconversion over time (HR=4.93, 95% CI 2.71 to 8.98). Conclusion In this exploratory analysis, individuals with prodromal hyposmia and anxiety phenoconverted to PD sooner and more often had a non-tremor-dominant phenotype, potentially reflecting more widespread pathology or specific pathophysiology underlying these symptoms. This may improve phenotyping prodromal PD and stratifying poorer prognostic trajectories for earlier and more personalised management.

A domain-based framework for cognitive profile identification in Parkinson’s disease across diverse samples

2025-06-19
Elvira AndĂșjar-Castillo , Carla Carrillo-Molina , Fernando Alonso +7 more | Frontiers in Neuroanatomy
Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms and heterogeneous cognitive impairments influenced by factors such as age, disease duration, and severity. Traditional neuropsychological assessments 
 Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms and heterogeneous cognitive impairments influenced by factors such as age, disease duration, and severity. Traditional neuropsychological assessments often fall short in capturing the multifaceted nature of PD-related cognitive dysfunction due to their reliance on single test metrics. This study provides empirical support for the implementation of domain-based cognitive assessments, structured in line with Movement Disorder Society recommendations, to provide a multidimensional evaluation of cognitive profiles in PD patients. Methods Neuropsychological and clinical data were analyzed from 316 PD patients recruited from three Spanish hospitals—Hospital Clínico San Carlos (Madrid), the University Complejo Universitario de Santiago de Compostela (Galicia), and Hospital Virgen del Rocío (Sevilla)— and a control group of 96 older individuals, whose age difference from the PD group was statistically significant. Five cognitive domains were constructed, addressing attention/working memory, executive functions, memory, visuospatial abilities, and language, using composite z-scores derived from standardized neuropsychological tests. Results Latent Cluster Analysis identified three distinct cognitive profiles: (1) a fronto-striatal profile characterized by mild deficits in executive and attention functions and intact visuospatial abilities, (2) a posterior cortical profile marked by severe memory and visuospatial impairments but strong language performance, and (3) a preserved profile displaying mild deficits across multiple domains. Comparisons between PD clusters and controls revealed significant differences in cognitive trajectories, emphasizing the value of a domain-based approach for differentiating neurodegenerative patterns from normal aging. Discussion The findings highlight the potential of domain-based assessments to unify data across diverse samples, fostering standardized cross-cohort comparisons and facilitating large-scale research initiatives. By enabling methodological consistency, this approach provides a robust framework for advancing the understanding of cognitive dysfunctions in PD and improving clinical decision-making.

Pathological α-synuclein elicits granulovacuolar degeneration independent of tau

2025-06-19
Dylan J. Dues , Madalynn Erb , Alysa Kasen +5 more | Translational Neurodegeneration

Cognitive Impairment in Patients with Parkinson’s Disease

2025-06-19
Е А ĐšĐ°Ń‚ŃƒĐœĐžĐœĐ° , A. V. Parusova , I. V. Golovanova +1 more | Neuroscience and Behavioral Physiology

C-Terminal Radical Oxidation Inhibits α-Synuclein Aggregation and Cytotoxicity via an Oxidative Oligomer-Disrupting Pathway

2025-06-18
Xiaoli Wang , Tingting Liang , Aibing Jin +5 more | Journal of the American Chemical Society
α-Synuclein (α-Syn) aggregation is a hallmark of Parkinson's disease and other neurodegenerative disorders. This study investigates the impact of controlled radical oxidation on α-Syn aggregation and associated cytotoxicity. Using a 
 α-Synuclein (α-Syn) aggregation is a hallmark of Parkinson's disease and other neurodegenerative disorders. This study investigates the impact of controlled radical oxidation on α-Syn aggregation and associated cytotoxicity. Using a microscale low-temperature plasma device for submillisecond radical oxidation, combined with native ion mobility-mass spectrometry and liquid chromatography-tandem mass spectrometry, we demonstrate radical-directed preferential oxidation of the α-Syn C-terminal region. This targeted oxidation leads to the inhibition of protein aggregation and reduced cytotoxicity in SH-SY5Y cells. Mechanistic analysis reveals that ultrafast C-terminal radical oxidation impairs α-Syn oligomerization propensity, likely by preventing conformational transitions critical for forming stable amorphous deposits and well-ordered fibers. Notably, this inhibitory effect is specific to monomer oxidation prior to aggregation rather than oxidation of preformed fibers. Our findings unveil a novel oxidative oligomerization-disrupting pathway that modulates α-Syn fibrillization behavior, offering new insights into the complex interplay between oxidative stress and protein aggregation in neurodegenerative diseases. This study challenges conventional views of the detrimental role of oxidative stress in α-Syn pathology and suggests potential neuroprotective strategies based on targeted oxidative modifications.

Imaging advances to detect non-motor prodromal markers of Parkinson’s disease and explore therapeutic translation opportunities

2025-06-18
Mathangi Palanivel , Krishna Ghosh , Madhav Mallam +4 more | npj Parkinson s Disease
Parkinson's disease (PD) is a progressive neurological disorder marked by late-emerging motor symptoms, but early non-motor signs like hyposmia and REM sleep behavior disorder may precede diagnosis by years. Identifying 
 Parkinson's disease (PD) is a progressive neurological disorder marked by late-emerging motor symptoms, but early non-motor signs like hyposmia and REM sleep behavior disorder may precede diagnosis by years. Identifying non-motor biomarkers during this prodromal phase could predict phenoconversion and enable early interventions. This narrative review outlines key prodromal non-motor symptoms, summarizes imaging technologies for early detection, and explores their translational potential in guiding timely, neuroprotective therapies for at-risk individuals.

A prospective study of cognitive impairment in Parkinson’s disease: clinical, neuropsychological, and neuroimaging correlates

2025-06-18
Ahmed A. Gaballa , Nabil H. Elagouz , A. E. Sarhan +1 more | Exploration of Medicine
Aim: Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic neuron loss, leading to motor and non-motor symptoms. Cognitive impairment in PD (PD-CI), ranging from mild cognitive deficits 
 Aim: Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic neuron loss, leading to motor and non-motor symptoms. Cognitive impairment in PD (PD-CI), ranging from mild cognitive deficits to dementia, significantly reduces quality of life and increases caregiver burden. This study aims to identify predictors of PD-CI, potentially supporting early interventions. Methods: This one-year prospective observational study included 80 idiopathic PD patients recruited from Al-Azhar University Hospitals. Inclusion followed the Movement Disorder Society (MDS) Clinical Diagnostic Criteria for PD, with evaluations conducted at baseline, 3, 6, and 12 months. Patients underwent clinical assessments [Unified Parkinson’s Disease Rating Scale, Part III (UPDRS-III), Hoehn and Yahr (H-Y), Beck Depression Inventory (BDI), and Hamilton Anxiety Rating Scale (HAM-A)], cognitive evaluations [Brief International Cognitive Assessment for MS (BICAMS) and Montreal Cognitive Assessment (MoCA)], magnetic resonance imaging (MRI), and laboratory testing. Exclusion criteria included conditions such as cerebellar abnormalities, early dementia diagnoses, and other Parkinsonism causes. Results: Cognitive impairment was observed in 41.25% of patients. Those with cognitive impairment were older, had a longer disease duration, and exhibited higher fasting blood glucose (FBS) levels and lower thyroid-stimulating hormone (TSH) levels compared to patients without cognitive impairment (p &lt; 0.05). Brain atrophy was detected in 4 (5%) patients in a subset of patients with PD, which was particularly pronounced in regions associated with cognitive function, such as the hippocampus and frontal lobe. Higher H-Y, UPDRS-III, and BDI scores correlated with cognitive decline, while lower MoCA and Symbol Digit Modalities Test (SDMT) scores predicted impairment (p &lt; 0.05). Conclusions: Cognitive impairment in PD is associated with advanced age, longer disease duration, metabolic factors, and structural brain changes. These findings suggest the potential for a predictive model to identify early cognitive decline in PD, enabling timely intervention and improved patient outcomes.

Differential pathological dynamics triggered by distinct Parkinson patient–derived α-synuclein extracts in nonhuman primates

2025-06-18
RĂ©mi Kinet , Mathieu Bourdenx , Sandra DoverĂł +7 more | Science Advances
The presence of α-synuclein (α-syn) aggregates, such as Lewy bodies in patients with Parkinson’s disease (PD), contributes to dopaminergic cell death. Injection of PD patient–derived α-syn in nonhuman primates has 
 The presence of α-synuclein (α-syn) aggregates, such as Lewy bodies in patients with Parkinson’s disease (PD), contributes to dopaminergic cell death. Injection of PD patient–derived α-syn in nonhuman primates has illustrated the exquisite vulnerability of primate dopaminergic neurons. Here, we aimed to elucidate the temporal and spatial pathological changes induced by two distinct α-syn pathogenic structures, having large or small sizes. To unravel the underlying molecular pathways, we conducted a proteomic analysis of the putamen and the entorhinal cortex, two brain regions carrying notable α-syn pathology. We demonstrate that distinct assemblies of α-syn aggregates drive unique pathogenic changes that ultimately result in a comparable extent of nigrostriatal degeneration at the level of nigral dopaminergic neuron cell bodies and striatal dopaminergic terminals. More broadly, our findings identify pathogenic trajectories associated with large or small α-syn aggregates, suggesting the existence of several possible concomitant pathogenic routes in PD.

A meta-analysis of survival and prognostic factors in multiple system atrophy

2025-06-18
Xiao Dong , Daji Chen , Linlin Wan +7 more | Journal of Neurology

Regional homogeneity differences in resting-state fMRI between Parkinson’s disease and multiple system atrophy-parkinsonian type

2025-06-18
Shihua Liu , Xudong Zhu , Hong Pu +6 more | Journal of Neural Transmission
Both Parkinson's disease (PD) and the Multiple system atrophy-parkinsonian type (MSA-P) belong to the category of α-synucleinopathies, characterized by overlapping clinical manifestations and a high risk of misdiagnosis. The aim 
 Both Parkinson's disease (PD) and the Multiple system atrophy-parkinsonian type (MSA-P) belong to the category of α-synucleinopathies, characterized by overlapping clinical manifestations and a high risk of misdiagnosis. The aim of this study is to provide objective imaging biomarkers for differentiating PD from MSA-P. We enrolled 25 patients with PD, 15 patients with MSA-P, and 20 healthy controls (HC). Resting-state functional magnetic resonance imaging (rs-fMRI) was employed to analyze regional homogeneity (ReHo) differences between PD and MSA-P groups. The discriminative capacity of ReHo values in these differential brain regions for distinguishing PD from MSA-P was subsequently evaluated. Compared to MSA-P, PD showed decreased ReHo in cerebellar lobule IX, left fusiform gyrus, and right thalamus, but increased ReHo in the right cuneus. In PD, ReHo in cerebellar lobule IX, left fusiform gyrus negatively correlated with UPDRS-III scores (r=- 0.8548, P< 0.001), while right cuneus ReHo positively correlated (r=0.6526, P=0.0004). The ReHo values in cerebellar lobule IX, left fusiform gyrus showed optimal discriminative power between PD and MSA-P groups, achieving an area under the curve (AUC) of 0.8693 (P< 0.001). Our study enhances understanding of altered neural synchronization in specific brain regions under rs-fMRI in PD and MSA-P. We established the link between ReHo changes in localized areas and PD clinical manifestations. Notably, ReHo alterations in cerebellar lobules IX and fusiform gyrus serve as potential biomarkers for differentiating PD from MSA-P.

The GLP-1 receptor agonist liraglutide inhibits necroptosis and neuroinflammation in a mouse model of Parkinson’s disease with diabetes co-morbidity

2025-06-18
Xiaomin Zhang , Pengyang Du , Bo Bai +5 more | Frontiers in Neuroscience
Objective To investigate the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide on motor function, necroptosis, and neuroinflammation in the brain in mice with diabetic Parkinson’s disease (PD) and 
 Objective To investigate the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide on motor function, necroptosis, and neuroinflammation in the brain in mice with diabetic Parkinson’s disease (PD) and its possible mechanism. Methods We prepared a diabetic model with streptozotocin, followed by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced diabetic PD model, along with liraglutide or saline intervention, and the control group with equal volume saline. After that, body weight and blood glucose of each group mice were measured, and the open field experiment and gait analysis experiment were performed to detect the motor and non-motor symptoms of mice, western blotting and immunohistochemistry experiments were performed to test the levels of necroptosis-related proteins tumor necrosis factor-α (TNF-α), receptor interacting serine/threonine kinase 1 (RIP1) and neuroinflammation-related proteins nuclear factor kappa-B p-p65 (NF-ÎșB p-p65), nuclear factor kappa-B p65 (NF-ÎșB p65), interleukin-1 beta (IL-1ÎČ), and monocyte chemoattractant protein-1 (MCP-1). Results The GLP-1 receptor agonist liraglutide inhibited necroptosis and neuroinflammation via TNF-α signaling in diabetic PD mice, decreasing blood glucose and improving motor function and mood. Compared with the control group, the blood glucose of diabetic PD mice increased, and the total distance and resting time in the central area decreased in the open field tests, stride length and overall run speed reduced in the gait analysis experiments, stance time and stride width increased, and the levels of necroptosis-related proteins such as TNF-α and RIP1, as well as neuroinflammation-related proteins including NF-ÎșB p-p65/p65, IL-1ÎČ, and MCP-1 increased. Compared with the diabetic PD mice on the 7th day, the mice in the model group on the 21st day showed reduced motor activity and more severe brain injury. After administration of liraglutide, these impairments were reversed. Conclusion In the diabetic PD model, liraglutide is neuroprotective by reducing necroptosis and neuroinflammation through the TNF-α signaling pathway.

Treadmill training for gait rehabilitation in elderly patients with mild-to-moderate Parkinson’s disease: a systematic review and meta-analysis

2025-06-18
X. Yin , PeiQiang Peng , Hongxia Zhang +3 more | Frontiers in Neurology
Background Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, leads to lower extremity dysfunction that critically contributes to falls and disability, yet effective rehabilitation remains limited. Objective Systematic assessment 
 Background Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, leads to lower extremity dysfunction that critically contributes to falls and disability, yet effective rehabilitation remains limited. Objective Systematic assessment of the effects of treadmill training on lower limb motor performance in patients with PD. Methods As of March 1, 2024, a systematic search was conducted in PubMed, Web of Science, Embase, and the Cochrane Library to gather randomized controlled trials (RCTs) that report the effects of treadmill training on patients with PD. Data on the Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III), the Timed Up and Go test (TUG), the Berg Balance Scale (BBS),6-Minute Walk Test (6MWT),10 Meter Walk Test (10MWT), and the Parkinson’s Disease Questionnaire-39 (PDQ-39) outcome metrics, as well as general characteristics of the studies, participant demographics, and details regarding the intervention and control groups, were extracted. The Cochrane Risk of Bias tool was employed to evaluate the quality of articles at risk, while the funnel plot and Egger’s test were utilized to assess publication bias. Results 16 RCTs comprising 582 participants were included. The meta-analysis indicated that treadmill training (TT) produced significantly better outcomes than conventional therapy (CT) in the post-intervention assessments of motor symptoms (UPDRS-III: SMD: -0.45; 95% CI: −0.73 to −0.17), and gait performance (6MWT: SMD 0.53; 95% CI: 0.08 to 0.97; 10MWT: 0.93; 95% CI: 0.54 to 1.32). Body Weight Supporting Treadmill (BBS) for Better Healing However, quality of life (PDQ-39: SMD: -0.35; 95% CI: −0.95 to 0.25), balance (BBS: SMD SMD: -0.35; 95% CI: −0.95 to 0.25; TUG: SMD: -0.35; 95% CI: −0.95 to 0.25), and treatment effects were comparable. Conclusion TT (especially weight-supported) vs. conventional training demonstrates superior efficacy in enhancing lower limb mobility for Parkinson’s disease, improving muscular endurance and short-term gait speed, but requires enhanced dynamic balance integration. Systematic trial registration https://www.crd.york.ac.uk/prospero/ , identifier, CRD42021256958.

The association between the incident risk of Parkinson’s disease and depression in middle-aged and older adults, and the moderating role of lifestyle: evidence from the CHARLS

2025-06-18
Wu-xiao Wei , Meng Lian , Z.F. Mao +4 more | Frontiers in Psychology
Background Parkinson’s disease (PD) and depression frequently coexist in middle-aged and older populations, potentially influencing each other. This study explores the relationship between depression and PD risk and investigates the 
 Background Parkinson’s disease (PD) and depression frequently coexist in middle-aged and older populations, potentially influencing each other. This study explores the relationship between depression and PD risk and investigates the association between lifestyle score and PD risk. Methods Data from the China Health and Retirement Longitudinal Study (CHARLS) for adults aged 45 and above were analyzed. A total of 30,347 participants were included, with 565 individuals developing PD during follow-up. PD cases were self-reported physician diagnoses. Depression was assessed using the CESD-10 scale (score ≄ 10 indicating depression). Lifestyle factors (smoking, drinking, social activity, sleep, and BMI) were scored as healthy (≄4) or unhealthy (&amp;lt;4). Cox proportional hazards models were used to analyze PD risk, and cubic spline regression was employed to evaluate the dose–response relationship between depression, lifestyle, and PD risk. Results Depression (CESD-10 ≄ 10) was significantly associated with an increased risk of PD. In the fully adjusted model (Model 4), individuals with depression had a 53% higher risk of developing PD compared to those without depression (HR = 1.53, 95% CI: 1.28–1.83). Cubic spline regression revealed a dose–response relationship: as CESD-10 scores increased, the risk of PD also increased. Unhealthy lifestyle was significantly associated with a higher risk of PD. The analysis showed that individuals with an unhealthy lifestyle had a 23.5% higher risk of developing PD than those with a healthy lifestyle. Additionally, the risk of PD varied with different lifestyle components. For example, no-smoking had a 17.9% lower risk of developing PD compared to smoking, and individuals with long sleep durations had a 36.2% lower risk of PD compared to those with short sleep durations. Conclusion Depression is significantly associated with the risk of PD in middle-aged and older populations. Our findings show a strong link between an unhealthy lifestyle and PD risk. This highlights the importance of addressing depression and avoiding unhealthy lifestyles in PD prevention.

p‐Cresol and p‐Cresyl Sulphate Boost Oxidative Stress: A Systematic Review of Recent Evidence

2025-06-18
Rinvil Renaldi , Tjhin Wiguna , Antonio M. Persico +1 more | Basic & Clinical Pharmacology & Toxicology
ABSTRACT Recent studies have emphasized the significant role of p‐cresol and its conjugated form, p‐cresyl sulphate (PCS), in enhancing oxidative stress, leading to potential detrimental effects on various biological systems. 
 ABSTRACT Recent studies have emphasized the significant role of p‐cresol and its conjugated form, p‐cresyl sulphate (PCS), in enhancing oxidative stress, leading to potential detrimental effects on various biological systems. Both p‐cresol and PCS contribute to increased production of reactive oxygen species (ROS), which can result in tissue damage, inflammation and a cascade of physiological abnormalities. Elevated p‐cresol levels have been associated with greater clinical severity in autism spectrum disorder, correlating with more severe behavioural manifestations and a history of regression. This systematic review explores the recent evidence on how these compounds promote oxidative stress and their impact on different health conditions. This review also addresses the involvement of p‐cresol and PCS in conditions such as chronic kidney disease, Parkinson's disease and other neurodegenerative disorders, where oxidative damage contributes to disease progression. Furthermore, this review highlights the need for further research to understand the precise mechanisms by which p‐cresol and PCS modulate oxidative stress and their potential as biomarkers for clinical diagnosis and disease management. Summary This focused review systematically summarizes recent evidence that oxidative stress plays an important role in the damage of biological systems produced by two uremic toxins, p‐cresol and its conjugated form, p‐cresyl sulphate (PCS). p‐cresol coming from environmental sources or produced by some gut bacterial strains, modulates various conditions, like chronic kidney disease, Parkinson's disease and autism spectrum disorder, among others. Oxidative damage and inflammation seemingly contribute to disease onset, progression and/or severity. The exact mechanism by which p‐cresol and PCS promote oxidative stress, their influence on disease trajectory and their potential role as biomarkers merit further investigation.

Effects of task-specific training on motor activity, cognitive function, and quality of life among individuals with Parkinson’s disease: a quasi-experimental pilot study

2025-06-18
Prathap Suganthirababu , Vignesh Srinivasan , Kumaresan Abathsagayam +2 more | Physiotherapy Quarterly
Introduction The second most prevalent neurological condition in adults over 50 years is Parkinson’s disease (PD). Individuals with PD(IwPD) experience motor and non-motor symptoms during disease progression. One of the 
 Introduction The second most prevalent neurological condition in adults over 50 years is Parkinson’s disease (PD). Individuals with PD(IwPD) experience motor and non-motor symptoms during disease progression. One of the most significant variables in non-motor symptoms is cognitive impairment, andthe disease may lead to dementia. Even though the cognitive impairment in IwPD is mild, there should be concern regarding its rehabilitation because there is no pharmacological management for cognitive impairment, and just a handful of studies on functional cognitive training for IwPD have been published. This raises the prospect of task-specific training among IwPD and functional rehabilitation of cognitive function. Methods Thisquasi-experimental study involved 30 participants, who were assessed and selected based on inclusion and exclusion criteria. Pre-test and post-test values were obtained using the Montreal Cognitive Assessment (MoCA), Unified Parkinson’s Disease Rating Scale (UPDRS) Part III, and Parkinson’s Disease Questionnaire (PDQ)-39. All subjects underwent task-specific training with cognitive training for 8 weeks. Results Statistical analysisshowed significant improvements in motor activity, cognitive function, and quality of life. The p-value of each outcome measure was &lt; 0.0001 after analysingpre-test and post-test data. Conclusions According to the findings ofthis study, task-specific training combined with cognitive training significantly improved motor activity, cognitive function, and quality of life among IwPD.

Comparative assessment of binding and functional differences of clinical antibodies targeting α-synuclein in cellular models of Parkinson’s disease

2025-06-18
Yuting Liu , Isin Dalkilic-Liddle , You Li +7 more | Biomedicine & Pharmacotherapy

How Do I Diagnose Multiple System Atrophy—A Videolibrary on Clinical and Imaging Features

2025-06-18
Victoria Sidoroff , Luca Baldelli , Nathaniel Bendahan +7 more | Movement Disorders Clinical Practice