-
Cold Spring Harbor Perspectives in... Aug 2012Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variable associated extrapyramidal signs and symptoms, is accompanied by degeneration of... (Review)
Review
Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variable associated extrapyramidal signs and symptoms, is accompanied by degeneration of the nigrostriatal dopaminergic system, with neuronal loss and reactive gliosis in the substantia nigra found at autopsy. Parkinsonism is pathologically heterogeneous, with the most common pathologic substrates related to abnormalities in the presynaptic protein α-synuclein or the microtubule binding protein tau. In idiopathic Parkinson's disease (PD), α-synuclein accumulates in neuronal perikarya (Lewy bodies) and neuronal processes (Lewy neurites). The disease process is multifocal and involves select central nervous system neurons and peripheral autonomic nervous system neurons. The particular set of neurons affected determines nonmotor clinical presentations. Multiple system atrophy (MSA) is the other major α-synucleinopathy. It is also associated with autonomic dysfunction and in some cases with cerebellar signs. The hallmark histopathologic feature of MSA is accumulation of α-synuclein within glial cytoplasmic inclusions (GCI). The most common of the Parkinsonian tauopathies is progressive supranuclear palsy (PSP), which is clinically associated with severe postural instability leading to early falls. The tau pathology of PSP also affects both neurons and glia. Given the population frequency of PD, α-synuclein pathology similar to that in PD, but not accompanied by neuronal loss, is relatively common (10% of people over 65 years of age) in neurologically normal individuals, leading to proposed staging schemes for PD progression. Although MSA-like and PSP-like pathology can be detected in neurologically normal individuals, such cases are too infrequent to permit assessment of patterns of disease progression.
Topics: Brain; Diagnosis, Differential; Head Injuries, Closed; Humans; Inclusion Bodies; Lewy Bodies; Multiple System Atrophy; Nerve Degeneration; Neuroglia; Parkinson Disease; Parkinsonian Disorders; Supranuclear Palsy, Progressive; TDP-43 Proteinopathies
PubMed: 22908195
DOI: 10.1101/cshperspect.a009258 -
Current Neurology and Neuroscience... Apr 2021There has been an exponential growth in functional connectomics research in neurodegenerative disorders. This review summarizes the recent findings and limitations of... (Review)
Review
PURPOSE OF REVIEW
There has been an exponential growth in functional connectomics research in neurodegenerative disorders. This review summarizes the recent findings and limitations of the field in Parkinson's disease (PD) and atypical parkinsonian syndromes.
RECENT FINDINGS
Increasingly more sophisticated methods ranging from seed-based to network and whole-brain dynamic functional connectivity have been used. Results regarding the disruption in the functional connectome vary considerably based on disease severity and phenotypes, and treatment status in PD. Non-motor symptoms of PD also link to the dysfunction in heterogeneous networks. Studies in atypical parkinsonian syndromes are relatively scarce. An important clinical goal of functional connectomics in neurodegenerative disorders is to establish the presence of pathology, track disease progression, predict outcomes, and monitor treatment response. The obstacles of reliability and reproducibility in the field need to be addressed to improve the potential of the functional connectome as a biomarker for these purposes in PD and atypical parkinsonian syndromes.
Topics: Connectome; Humans; Multiple System Atrophy; Parkinson Disease; Parkinsonian Disorders; Reproducibility of Results; Supranuclear Palsy, Progressive
PubMed: 33817766
DOI: 10.1007/s11910-021-01111-4 -
Neurotherapeutics : the Journal of the... Jul 2023Ferroptosis is a programmed cell death pathway that is recently linked to Parkinson's disease (PD), where the key genes and molecules involved are still yet to be...
Ferroptosis is a programmed cell death pathway that is recently linked to Parkinson's disease (PD), where the key genes and molecules involved are still yet to be defined. Acyl-CoA synthetase long-chain family member 4 (ACSL4) esterifies polyunsaturated fatty acids (PUFAs) which is essential to trigger ferroptosis, and is suggested as a key gene in the pathogenesis of several neurological diseases including ischemic stroke and multiple sclerosis. Here, we report that ACSL4 expression in the substantia nigra (SN) was increased in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated model of PD and in dopaminergic neurons in PD patients. Knockdown of ACSL4 in the SN protected against dopaminergic neuronal death and motor deficits in the MPTP mice, while inhibition of ACSL4 activity with Triacsin C similarly ameliorated the parkinsonism phenotypes. Similar effects of ACSL4 reduction were observed in cells treated with 1-methyl-4-phenylpyridinium (MPP) and it specifically prevented the lipid ROS elevation without affecting the mitochondrial ROS changes. These data support ACSL4 as a therapeutic target associated with lipid peroxidation in PD.
Topics: Animals; Mice; Apoptosis; Dopaminergic Neurons; Lipids; Mice, Inbred C57BL; Parkinson Disease; Parkinsonian Disorders; Phenotype; Reactive Oxygen Species; Humans
PubMed: 37133631
DOI: 10.1007/s13311-023-01382-4 -
Journal of Neurology Dec 2021In March 2020, WHO declared Covid-19 outbreak pandemic. There has been increasing evidence that frail, old, multi-pathological patients are at greater risk of developing... (Review)
Review
In March 2020, WHO declared Covid-19 outbreak pandemic. There has been increasing evidence that frail, old, multi-pathological patients are at greater risk of developing severe Covid-19 infection than younger, healthy ones. Covid-19's impact on Parkinson's Disease (PD) patients could be analysed through both the influence on PD patients' health and their risk of developing severe Covid-19, and the consequences of lockdown and restrictive measures on mental and cognitive health on both patients and caregivers. Moreover, there are critical issues to be considered about patients' care and management through an unprecedented time like this. One important issue to consider is physiotherapy, as most patients cannot keep exercising because of restrictive measures which has profoundly impacted on their health. Lastly, the relationship between PD and Sars-Cov2 may be even more complicated than it seems as some studies have hypothesized a possible Covid-19-induced parkinsonism. Hereby, we review the state of the art about the relationship between Covid-19 and Parkinson's Disease, focusing on each of these five points.
Topics: COVID-19; Communicable Disease Control; Humans; Parkinson Disease; RNA, Viral; SARS-CoV-2
PubMed: 34313818
DOI: 10.1007/s00415-021-10721-4 -
Journal of Parkinson's Disease 2017
Topics: Animals; Biomedical Research; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Parkinson Disease
PubMed: 28282817
DOI: 10.3233/JPD-179008 -
Tidsskrift For Den Norske Laegeforening... Sep 2008The dopamine deficiency syndrome Parkinson's disease (PD) is characterized by tremor, rigidity, bradykinesia and reduced postural reflexes. Conditions with similar... (Review)
Review
BACKGROUND
The dopamine deficiency syndrome Parkinson's disease (PD) is characterized by tremor, rigidity, bradykinesia and reduced postural reflexes. Conditions with similar symptoms but other causes than PD (about 1/3 of cases) are called atypical parkinsonism. From a neuropathological perspective, PD is associated with loss of nigro-striatal dopaminergic neurons (related to motor symptoms) and accumulation of alpha-synuclein-containing Lewy bodies in the mid-brain. Nigro-striatal pathways may also be involved in atypical parkinsonism, but lesions in other parts of the brain/basal ganglions dominate. Parkinsonism may also be related to chronic cerebrovascular disease or use of drugs with extrapyramidal side effects.
MATERIAL AND METHODS
Articles retrieved from PubMed were reviewed to examine current knowledge on diseases other than PD that can induce parkinsonism.
RESULTS AND INTERPRETATION
Diseases with atypical parkinsonism usually start more symmetric than PD and tremor is either not present or differs from the typical rest tremor seen in PD. An exception is corticobasal degeneration with very asymmetric symptoms. Other (plus-) symptoms in atypical parkinsonism are (early) falling tendency, dizziness upon change of position, coordination difficulties or early cognitive decline. The article describes the clinical characteristics of atypical parkinsonism, possibilities of improved diagnostics with supplementary examinations and alternative treatment strategies.
Topics: Brain; Diagnosis, Differential; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Multiple System Atrophy; Parkinson Disease; Parkinsonian Disorders; Prognosis; Supranuclear Palsy, Progressive
PubMed: 18846125
DOI: No ID Found -
Journal of Parkinson's Disease 2021Parkinson's disease (PD) is thought to be caused by a combination of genetic and environmental factors. Bacterial or viral infection has been proposed as a potential... (Review)
Review
Parkinson's disease (PD) is thought to be caused by a combination of genetic and environmental factors. Bacterial or viral infection has been proposed as a potential risk factor, and there is supporting although not entirely consistent epidemiologic and basic science evidence to support its role. Encephalitis caused by influenza has included parkinsonian features. Epidemiological evidence is most compelling for an association between PD and hepatitis C virus. Infection with Helicobacter pylori may be associated not only with PD risk but also response to levodopa. Rapidly evolving knowledge regarding the role of the microbiome also suggests a role of resident bacteria in PD risk. Biological plausibility for the role for infectious agents is supported by the known neurotropic effects of specific viruses, particular vulnerability of the substantia nigra and even the promotion of aggregation of alpha-synuclein. A common feature of implicated viruses appears to be production of high levels of cytokines and chemokines that can cross the blood-brain barrier leading to microglial activation and inflammation and ultimately neuronal cell death. Based on multiple avenues of evidence it appears likely that specific bacterial and particularly viral infections may increase vulnerability to PD. The implications of this for PD prevention requires attention and may be most relevant once preventive treatments for at-risk populations are developed.
Topics: Bacterial Infections; Gastrointestinal Microbiome; Humans; Parkinson Disease; Virus Diseases
PubMed: 33361610
DOI: 10.3233/JPD-202279 -
Journal of Parkinson's Disease 2023Little is known about the burden of parkinsonism and Parkinson's disease (PD) in Latin America. Better understanding of health service use and clinical outcomes in PD is...
BACKGROUND
Little is known about the burden of parkinsonism and Parkinson's disease (PD) in Latin America. Better understanding of health service use and clinical outcomes in PD is needed to improve its prognosis.
OBJECTIVE
The aim of the study was to estimate the burden of parkinsonism and PD in six Latin American countries.
METHODS
12,865 participants aged 65 years and older from the 10/66 population-based cohort study were analysed. Baseline assessments were conducted in 2003-2007 and followed-up 4 years later. Parkinsonism and PD were defined using current clinical criteria or self-reported diagnosis. Logistic regression models assessed the association between parkinsonism/PD with baseline health service use (community-based care or hospitalisation in the last 3 months) and Cox proportional hazards regression models with incident dependency (subjective assessment by interviewer based on informant interview) and mortality. Separate analyses for each country were combined via fixed effect meta-analysis.
RESULTS
At baseline, the prevalence of parkinsonism and PD was 7.9% (n = 934) and 2.6% (n = 317), respectively. Only parkinsonism was associated with hospital admission at baseline (OR 1.89, 95% CI 1.30-2.74). Among 7,296 participants without dependency at baseline, parkinsonism (HR 2.34, 95% CI 1.81-3.03) and PD (2.10, 1.37-3.24) were associated with incident dependency. Among 10,315 participants with vital status, parkinsonism (1.73, 1.50-1.99) and PD (1.38, 1.07-1.78) were associated with mortality. The Higgins I2 tests showed low to moderate levels of heterogeneity across countries.
CONCLUSIONS
Our findings show that older people with parkinsonism or PD living in Latin America have higher risks of developing dependency and mortality but may have limited access to health services.
Topics: Aged; Humans; Cohort Studies; Latin America; Parkinson Disease; Parkinsonian Disorders; Patient Acceptance of Health Care
PubMed: 37742660
DOI: 10.3233/JPD-230114 -
Journal of Neural Transmission (Vienna,... Sep 2022To date, the diagnoses of Parkinson syndromes are based on clinical examination. Therefore, these specific diagnoses are made, when the neuropathological process is... (Review)
Review
To date, the diagnoses of Parkinson syndromes are based on clinical examination. Therefore, these specific diagnoses are made, when the neuropathological process is already advanced. However, disease modification or neuroprotection, is considered to be most effective before marked neurodegeneration has occurred. In recent years, early clinical or prodromal stages of Parkinson syndromes came into focus. Moreover, subtypes of distinct diseases will allow predictions of the individual course of the diseases more precisely. Thereby, patients will be enrolled into clinical trials with more specific disease entities and endpoints. Furthermore, novel fluid and imaging biomarkers that allow biochemical diagnoses are under development. These will lead to earlier diagnoses and earlier therapy in the future as consequence. Furthermore, therapeutic approaches will take the underlying neuropathological process of neurodegenerative Parkinson syndromes more specific into account. Specifically, future therapies will target the aggregation of aggregation-prone proteins such as alpha-synuclein and tau, the degradation of pathological aggregates, and the spreading of pathological protein aggregates throughout the brain. Many of these approaches are already in (pre)clinical development. In addition, anti-inflammatory approaches are in development. Furthermore, drug-repurposing is a feasible approach to shorten the developmental process of new drugs.
Topics: Biomarkers; Brain; Humans; Parkinson Disease; Parkinsonian Disorders; Supranuclear Palsy, Progressive
PubMed: 35695938
DOI: 10.1007/s00702-022-02520-6 -
Nature Communications Nov 2023The degenerative process in Parkinson's disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in...
The degenerative process in Parkinson's disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in neuronal susceptibility warrants an amenable PD model that, in comparison to post-mortem human specimens, controls for environmental and genetic differences in PD pathogenesis. Here we generated high-quality profiles for 250,173 cells from the substantia nigra (SN) and putamen (PT) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian macaques and matched controls. Our primate model of parkinsonism recapitulates important pathologic features in nature PD and provides an unbiased view of the axis of neuronal vulnerability and resistance. We identified seven molecularly defined subtypes of nigral DaNs which manifested a gradient of vulnerability and were confirmed by fluorescence-activated nuclei sorting. Neuronal resilience was associated with a FOXP2-centered regulatory pathway shared between PD-resistant DaNs and glutamatergic excitatory neurons, as well as between humans and nonhuman primates. We also discovered activation of immune response common to glial cells of SN and PT, indicating concurrently activated pathways in the nigrostriatal system. Our study provides a unique resource to understand the mechanistic connections between neuronal susceptibility and PD pathophysiology, and to facilitate future biomarker discovery and targeted cell therapy.
Topics: Animals; Humans; Mice; Parkinson Disease; Parkinsonian Disorders; Substantia Nigra; Dopaminergic Neurons; Macaca; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37980356
DOI: 10.1038/s41467-023-43213-2