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Movement Disorders : Official Journal... Feb 2020Objective assessments of movement impairment are needed to support clinical trials and facilitate diagnosis. The objective of the current study was to determine if a...
BACKGROUND
Objective assessments of movement impairment are needed to support clinical trials and facilitate diagnosis. The objective of the current study was to determine if a rapid web-based computer mouse test (Hevelius) could detect and accurately measure ataxia and parkinsonism.
METHODS
Ninety-five ataxia, 46 parkinsonism, and 29 control participants and 229,017 online participants completed Hevelius. We trained machine-learning models on age-normalized Hevelius features to (1) measure severity and disease progression and (2) distinguish phenotypes from controls and from each other.
RESULTS
Regression model estimates correlated strongly with clinical scores (from r = 0.66 for UPDRS dominant arm total to r = 0.83 for the Brief Ataxia Rating Scale). A disease change model identified ataxia progression with high sensitivity. Classification models distinguished ataxia or parkinsonism from healthy controls with high sensitivity (≥0.91) and specificity (≥0.90).
CONCLUSIONS
Hevelius produces a granular and accurate motor assessment in a few minutes of mouse use and may be useful as an outcome measure and screening tool. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ataxia; Child; Child, Preschool; Computers; Disease Progression; Female; Humans; Male; Middle Aged; Parkinson Disease; Parkinsonian Disorders; Young Adult
PubMed: 31769069
DOI: 10.1002/mds.27915 -
Neuroscience and Biobehavioral Reviews Jan 2022Understanding the pathophysiological mechanism of Parkinson's disease (PD) in the subthalamic nucleus (STN) has become a critical issue since deep brain stimulation... (Review)
Review
Understanding the pathophysiological mechanism of Parkinson's disease (PD) in the subthalamic nucleus (STN) has become a critical issue since deep brain stimulation (DBS) in this region has been proven as an effective treatment for this disease. The STN possesses a special ability to switch from the spike to the burst firing mode in response to dopamine deficiency in parkinsonism, and this STN burst is considered an electrophysiological signature of the cortico-basal ganglia circuit in the brains of PD patients. This review focuses on the role of STN burst firing in the pathophysiology of PD and during DBS. Here, we review existing literature on how STN bursts originate and the specific factors affecting their formation; how STN burst firing causes motor symptoms in PD and how interventions can rescue these symptoms. Finally, the similarities and differences between the two electrophysiological hallmarks of PD, STN burst firing and beta-oscillation, are discussed. STN burst firing should be considered as a pathophysiological target in PD during treatment with DBS.
Topics: Basal Ganglia; Deep Brain Stimulation; Humans; Parkinson Disease; Parkinsonian Disorders; Subthalamic Nucleus
PubMed: 34856222
DOI: 10.1016/j.neubiorev.2021.11.044 -
Multiple Sclerosis and Related Disorders Jun 2022Rare cases of coexisting multiple sclerosis and parkinsonism have been reported in the literature. However, the true prevalence, clinical characteristics, and causal... (Observational Study)
Observational Study
BACKGROUND
Rare cases of coexisting multiple sclerosis and parkinsonism have been reported in the literature. However, the true prevalence, clinical characteristics, and causal relation between the two entities have not been systematically evaluated.
OBJECTIVE
To evaluate the prevalence of parkinsonism in patients with multiple sclerosis and examine the causal relationship, if any.
METHODS
Consecutive patients referred to the multiple sclerosis clinic were evaluated by a neurologist with double training in both neuroimmunology and movement disorders. All patients were specifically screened for movement disorders via a movement disorder survey and a focused exam. Video samples were independently rated by two blinded movement disorder raters. Pre-specified criteria were developed for five potential clinical scenarios: incidental idiopathic Parkinson's disease, incidental Parkinson-plus syndrome, drug-induced parkinsonism, acute symptomatic parkinsonism, and chronic symptomatic parkinsonism.
RESULTS
From 2016 to 2021, 336 patients were evaluated. Of those, 12 patients (3.6%) had clinical parkinsonism (average age 68 years, 66% females). Nine patients (75%) were deemed to have incidental Parkinson's disease, 2 (17%) had drug-induced parkinsonism, and 1 (8.3%) was deemed to have demyelination-related chronic symptomatic parkinsonism. The latter presented with gradual and progressive parkinsonism without prodromal symptoms. Both blinded raters agreed with the parkinsonism phenomenology. In addition to typical enhancing and non-enhancing demyelinating lesions, the patient had lesions bilaterally in the basal ganglia. She had positive oligoclonal bands in the cerebrospinal fluid. DAT scan was normal. She was diagnosed with PPMS with activity and progression manifesting solely with secondary parkinsonism. Her disease stabilized with ocrelizumab. There were no cases of acute symptomatic parkinsonism or co-existing Parkinson-plus syndrome over the five-year duration of the study. Three of the incidental idiopathic Parkinson's disease cases had radiologically isolated syndrome.
CONCLUSION
Parkinsonism in MS is rare and most cases are incidental. However, clinicians need to recognize the entity of demyelination-related chronic symptomatic parkinsonism in patients with progressive MS phenotypes and demyelinating lesions in the basal ganglia and/or upper midbrain. Parkinsonism may be the sole clinical presentation of progressive MS and the only indication for DMT initiation or escalation. There is an over-representation of radiologically isolated syndrome in patients with presumptive incidental demyelination and idiopathic Parkinson's disease. Prospective studies utilizing high-field MRI and longitudinal DAT scans are needed to better characterize the complex relationship between demyelination and parkinsonism.
Topics: Demyelinating Diseases; Female; Humans; Male; Multiple Sclerosis; Parkinson Disease; Parkinson Disease, Secondary; Parkinsonian Disorders; Prospective Studies; Syndrome
PubMed: 35428029
DOI: 10.1016/j.msard.2022.103796 -
Movement Disorders : Official Journal... Dec 2023Parkin RBR E3 ubiquitin-protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in...
BACKGROUND
Parkin RBR E3 ubiquitin-protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants.
OBJECTIVES
To identify complex structural variants in PRKN using long-read sequencing.
METHODS
We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read sequencing. We assessed the presence and frequency of complex inversions overlapping PRKN using whole-genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP-PD) and United Kingdom (UK)-Biobank datasets.
RESULTS
Multiple ligation probe amplification identified a heterozygous exon three deletion in PRKN and long-read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN expression.
CONCLUSIONS
This is the first report describing a large 7 Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long-read sequencing for structural variant analysis in unresolved young-onset PD cases. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Topics: Humans; Heterozygote; Mutation; Parkinson Disease; Parkinsonian Disorders; Ubiquitin-Protein Ligases
PubMed: 37926948
DOI: 10.1002/mds.29610 -
Seminars in Neurology Feb 2023Neuroimaging is an important adjunct to the clinical assessment of Parkinson disease (PD). Parkinsonism can be challenging to differentiate, especially in early disease...
Neuroimaging is an important adjunct to the clinical assessment of Parkinson disease (PD). Parkinsonism can be challenging to differentiate, especially in early disease stages, when it mimics other movement disorders or when there is a poor response to dopaminergic therapies. There is also a discrepancy between the phenotypic presentation of degenerative parkinsonism and the pathological outcome. The emergence of more sophisticated and accessible neuroimaging can identify molecular mechanisms of PD, the variation between clinical phenotypes, and the compensatory mechanisms that occur with disease progression. Ultra-high-field imaging techniques have improved spatial resolution and contrast that can detect microstructural changes, disruptions in neural pathways, and metabolic and blood flow alterations. We highlight the imaging modalities that can be accessed in clinical practice and recommend an approach to the diagnosis of clinically uncertain parkinsonism.
Topics: Humans; Parkinsonian Disorders; Parkinson Disease; Neuroimaging; Disease Progression; Molecular Imaging
PubMed: 36878467
DOI: 10.1055/s-0043-1764228 -
Movement Disorders : Official Journal... May 2021Parkinson's disease (PD) is a genetically complex neurodegenerative disease with ~20 genes known to contain mutations that cause PD or atypical parkinsonism. Large-scale...
BACKGROUND
Parkinson's disease (PD) is a genetically complex neurodegenerative disease with ~20 genes known to contain mutations that cause PD or atypical parkinsonism. Large-scale next-generation sequencing projects have revolutionized genomics research. Applying these data to PD, many genes have been reported to contain putative disease-causing mutations. In most instances, however, the results remain quite limited and rather preliminary. Our aim was to assist researchers on their search for PD-risk genes and variant candidates with an easily accessible and open summary-level genomic data browser for the PD research community.
METHODS
Sequencing and imputed genotype data were obtained from multiple sources and harmonized and aggregated.
RESULTS
In total we included a total of 102,127 participants, including 28,453 PD cases, 1650 proxy cases, and 72,024 controls.
CONCLUSIONS
We present here the Parkinson's Disease Sequencing Browser: a Shiny-based web application that presents comprehensive summary-level frequency data from multiple large-scale genotyping and sequencing projects https://pdgenetics.shinyapps.io/VariantBrowser/. Published © 2021 This article is a U.S. Government work and is in the public domain in the USA. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: DNA; Humans; Mutation; Neurodegenerative Diseases; Parkinson Disease; Parkinsonian Disorders
PubMed: 33497488
DOI: 10.1002/mds.28488 -
Neurology Aug 2023
Topics: Humans; Lewy Body Disease; Parkinsonian Disorders; Parkinson Disease
PubMed: 37344229
DOI: 10.1212/WNL.0000000000207572 -
Seminars in Neurology Feb 2023In this manuscript, we review the epidemiology of movement disorders including Parkinson's disease (PD), atypical parkinsonism, essential tremor, dystonia, functional... (Review)
Review
In this manuscript, we review the epidemiology of movement disorders including Parkinson's disease (PD), atypical parkinsonism, essential tremor, dystonia, functional movement disorders, tic disorders, chorea, and ataxias. We emphasize age-, sex-, and geography-based incidence and prevalence, as well as notable trends including the rising incidence and prevalence of PD. Given the growing global interest in refining clinical diagnostic skills in recognizing movement disorders, we highlight some key epidemiological findings that may be of interest to clinicians and health systems tasked with diagnosing and managing the health of patients with movement disorders.
Topics: Humans; Movement Disorders; Parkinson Disease; Parkinsonian Disorders; Essential Tremor; Chorea; Ataxia
PubMed: 36893797
DOI: 10.1055/s-0043-1764140 -
International Journal of Molecular... Feb 2024Parkinson's disease (PD) is associated with various deficits in sensing and responding to reductions in oxygen availability (hypoxia). Here we summarize the evidence... (Review)
Review
Parkinson's disease (PD) is associated with various deficits in sensing and responding to reductions in oxygen availability (hypoxia). Here we summarize the evidence pointing to a central role of hypoxia in PD, discuss the relation of hypoxia and oxygen dependence with pathological hallmarks of PD, including mitochondrial dysfunction, dopaminergic vulnerability, and alpha-synuclein-related pathology, and highlight the link with cellular and systemic oxygen sensing. We describe cases suggesting that hypoxia may trigger Parkinsonian symptoms but also emphasize that the endogenous systems that protect from hypoxia can be harnessed to protect from PD. Finally, we provide examples of preclinical and clinical research substantiating this potential.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Parkinsonian Disorders; Dopaminergic Neurons; Hypoxia; Oxygen
PubMed: 38339038
DOI: 10.3390/ijms25031759 -
Handbook of Clinical Neurology 2023Although neuropalliative care is a relatively new field, there is increasing evidence for its use among the degenerative parkinsonian syndromes, including idiopathic... (Review)
Review
Although neuropalliative care is a relatively new field, there is increasing evidence for its use among the degenerative parkinsonian syndromes, including idiopathic Parkinson disease, progressive supranuclear palsy, multiple system atrophy, dementia with Lewy bodies, and corticobasal syndrome. This chapter outlines the current state of evidence for palliative care among individuals with the degenerative parkinsonian syndromes with discussion surrounding: (1) disease burden and needs across the conditions; (2) utility, timing, and methods for advance care planning; (3) novel care models for the provision of palliative care; and 4) end-of-life care issues. We also discuss currently unmet needs and unanswered questions in the field, proposing priorities for research and the assessment of implemented care models.
Topics: Humans; Parkinson Disease; Palliative Care; Parkinsonian Disorders; Supranuclear Palsy, Progressive; Multiple System Atrophy
PubMed: 36599503
DOI: 10.1016/B978-0-12-824535-4.00017-3