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Cells Feb 2023Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and the aggregation of Lewy bodies in the basal ganglia,... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and the aggregation of Lewy bodies in the basal ganglia, resulting in movement impairment referred to as parkinsonism. However, the etiology of PD is not well known, with genetic factors accounting only for 10-15% of all PD cases. The pathogenetic mechanism of PD is not completely understood, although several mechanisms, such as oxidative stress and inflammation, have been suggested. Understanding the mechanisms of PD pathogenesis is critical for developing highly efficacious therapeutics. In the PD brain, dopaminergic neurons degenerate mainly in the basal ganglia, but recently emerging evidence has shown that astrocytes also significantly contribute to dopaminergic neuronal death. In this review, we discuss the role of astrocytes in PD pathogenesis due to mutations in α-synuclein (PARK1), DJ-1 (PARK7), parkin (PARK2), leucine-rich repeat kinase 2 (LRRK2, PARK8), and PTEN-induced kinase 1 (PINK1, PARK6). We also discuss PD experimental models using neurotoxins, such as paraquat, rotenone, 6-hydroxydopamine, and MPTP/MPP+. A more precise and comprehensive understanding of astrocytes' modulatory roles in dopaminergic neurodegeneration in PD will help develop novel strategies for effective PD therapeutics.
Topics: Humans; Parkinson Disease; Astrocytes; Parkinsonian Disorders; Lewy Bodies; Dopamine; Mutation
PubMed: 36831289
DOI: 10.3390/cells12040622 -
Neuroscience Bulletin Oct 2017Olfactory dysfunction is common in Parkinson's disease (PD) and often predates the diagnosis by years, reflecting early deposition of Lewy pathology, the histologic... (Review)
Review
Olfactory dysfunction is common in Parkinson's disease (PD) and often predates the diagnosis by years, reflecting early deposition of Lewy pathology, the histologic hallmark of PD, in the olfactory bulb. Clinical tests are available that allow for the rapid characterization of olfactory dysfunction, including tests of odor identification, discrimination, detection, and recognition thresholds, memory, and tests assessing the build-up of odor intensity across increasing suprathreshold stimulus concentrations. The high prevalence of olfactory impairment, along with the ease and low cost of assessment, has fostered great interest in olfaction as a potential biomarker for PD. Hyposmia may help differentiate PD from other causes of parkinsonism, and may also aid in the identification of "pre-motor" PD due to the early pathologic involvement of olfactory pathways. Olfactory function is also correlated with other non-motor features of PD and may serve as a predictor of cognitive decline. In this article, we summarize the existing literature on olfaction in PD, focusing on the potential for olfaction as a biomarker for early or differential diagnosis and prognosis.
Topics: Cognitive Dysfunction; Diagnosis, Differential; Humans; Olfaction Disorders; Parkinson Disease; Prognosis
PubMed: 28831680
DOI: 10.1007/s12264-017-0170-x -
Journal of Parkinson's Disease 2018In vivo gene therapy for neurodegenerative disorders has turned out to be a formidable challenge. It is a field not much older than twenty years, but we were many who... (Review)
Review
In vivo gene therapy for neurodegenerative disorders has turned out to be a formidable challenge. It is a field not much older than twenty years, but we were many who would have predicted a much easier path towards the clinic using this treatment modality. For Parkinson's disease patients, this has meant a frustrating wait, seeing many promising therapies being forgotten after a few pre-clinical proof-of-concept studies. The reasons for this are both scientific and economical. However, this is slowly but surely changing and over the next two decades we will see a very exciting development in this field. In a foreseeable future, gene therapy will be a very natural component of many clinical therapies, not least in Parkinson's disease.
Topics: Brain; Genetic Therapy; Humans; Parkinson Disease
PubMed: 30584164
DOI: 10.3233/JPD-181485 -
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 -
Neuroscience Bulletin Oct 2017Typical Parkinsonian symptoms consist of bradykinesia plus rigidity and/or resting tremor. Some time later postural instability occurs. Pre-motor symptoms such as... (Review)
Review
Typical Parkinsonian symptoms consist of bradykinesia plus rigidity and/or resting tremor. Some time later postural instability occurs. Pre-motor symptoms such as hyposmia, constipation, REM sleep behavior disorder and depression may antecede these motor symptoms for years. It would be ideal, if we had a biomarker which would allow to predict who with one or two of these pre-motor symptoms will develop the movement disorder Parkinson's disease (PD). Thus, it is interesting to learn that biopsies of the submandibular gland or colon biopsies may be a means to predict PD, if there is a high amout of abnormally folded alpha-synuclein and phosphorylated alpha-synuclein. This would be of relevance if we would have available means to stop the propagation of abnormal alpha-synuclein which is otherwise one of the reasons of this spreading disease PD.
Topics: Constipation; Depression; Early Diagnosis; Humans; Olfaction Disorders; Parkinson Disease; REM Sleep Behavior Disorder
PubMed: 28776303
DOI: 10.1007/s12264-017-0159-5 -
International Journal of Molecular... Aug 2022Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease, globally. Dopaminergic neuron degeneration in substantia nigra... (Review)
Review
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease, globally. Dopaminergic neuron degeneration in substantia nigra pars compacta and aggregation of misfolded alpha-synuclein are the PD hallmarks, accompanied by motor and non-motor symptoms. Several viruses have been linked to the appearance of a post-infection parkinsonian phenotype. Coronavirus disease 2019 (COVID-19), caused by emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has evolved from a novel pneumonia to a multifaceted syndrome with multiple clinical manifestations, among which neurological sequalae appear insidious and potentially long-lasting. Exosomes are extracellular nanovesicles bearing a complex cargo of active biomolecules and playing crucial roles in intercellular communication under pathophysiological conditions. Exosomes constitute a reliable route for misfolded protein transmission, contributing to PD pathogenesis and diagnosis. Herein, we summarize recent evidence suggesting that SARS-CoV-2 infection shares numerous clinical manifestations and inflammatory and molecular pathways with PD. We carry on hypothesizing that these similarities may be reflected in exosomal cargo modulated by the virus in correlation with disease severity. Travelling from the periphery to the brain, SARS-CoV-2-related exosomal cargo contains SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that could operate as promoters of neurodegenerative and neuroinflammatory cascades, potentially leading to a future parkinsonism and PD development.
Topics: COVID-19; Cell Communication; Humans; Neurodegenerative Diseases; Parkinson Disease; Parkinsonian Disorders; RNA, Viral; SARS-CoV-2; alpha-Synuclein
PubMed: 36077138
DOI: 10.3390/ijms23179739 -
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 -
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 -
Journal of Parkinson's Disease 2017The MDS-UPDRS (Movement Disorders Society - Unified Parkinson's Disease Rating Scale) is the most widely used scale for rating impairment in PD. Subscores measuring... (Review)
Review
BACKGROUND
The MDS-UPDRS (Movement Disorders Society - Unified Parkinson's Disease Rating Scale) is the most widely used scale for rating impairment in PD. Subscores measuring bradykinesia have low reliability that can be subject to rater variability. Novel technological tools can be used to overcome such issues.
OBJECTIVE
To systematically explore and describe the available technologies for measuring limb bradykinesia in PD that were published between 2006 and 2016.
METHODS
A systematic literature search using PubMed (MEDLINE), IEEE Xplore, Web of Science, Scopus and Engineering Village (Compendex and Inspec) databases was performed to identify relevant technologies published until 18 October 2016.
RESULTS
47 technologies assessing bradykinesia in PD were identified, 17 of which offered home and clinic-based assessment whilst 30 provided clinic-based assessment only. Of the eligible studies, 7 were validated in a PD patient population only, whilst 40 were tested in both PD and healthy control groups. 19 of the 47 technologies assessed bradykinesia only, whereas 28 assessed other parkinsonian features as well. 33 technologies have been described in additional PD-related studies, whereas 14 are not known to have been tested beyond the pilot phase.
CONCLUSION
Technology based tools offer advantages including objective motor assessment and home monitoring of symptoms, and can be used to assess response to intervention in clinical trials or routine care. This review provides an up-to-date repository and synthesis of the current literature regarding technology used for assessing limb bradykinesia in PD. The review also discusses the current trends with regards to technology and discusses future directions in development.
Topics: Biomedical Technology; Extremities; Humans; Hypokinesia; Neurology; Parkinson Disease
PubMed: 28222539
DOI: 10.3233/JPD-160878 -
Parkinsonism & Related Disorders Jan 2016Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1% of the worldwide population. Despite... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1% of the worldwide population. Despite considerable progress in understanding PD pathophysiology, including genetic and biochemical causes, diagnostic approaches lack accuracy and interventions are restricted to symptomatic treatments. PD is a complex syndrome with different clinical subtypes and a wide variability in disorder course. In order to deliver better clinical management of PD patients and discovery of novel therapies, there is an urgent need to find sensitive, specific, and reliable biomarkers. The development of biomarkers will not only help the scientific community to identify populations at risk, but also facilitate clinical diagnosis. Furthermore, these tools could monitor progression, which could ultimately deliver personalized therapeutic strategies. The field of biomarker discovery in PD has attracted significant attention and there have been numerous contributions in recent years. Although none of the parameters have been validated for clinical practice, some candidates hold promise. This review summarizes recent advances in the development of PD biomarkers and discusses new strategies for their utilization.
Topics: Animals; Biomarkers; Disease Progression; Humans; Neuroimaging; Parkinson Disease
PubMed: 26439946
DOI: 10.1016/j.parkreldis.2015.09.048