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Lancet (London, England) Jan 2024Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. Insights into the pathogenesis of Parkinson's... (Review)
Review
Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. Insights into the pathogenesis of Parkinson's disease have been derived from genetics and molecular pathology. Biochemical studies, investigation of transplanted neurons in patients with Parkinson's disease, and cell and animal model studies suggest that abnormal aggregation of α-synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson's disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson's disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson's disease. Although there are currently no disease-modifying treatments for Parkinson's disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.
Topics: Animals; Humans; Parkinson Disease; alpha-Synuclein; Brain; Models, Animal; Neurons
PubMed: 38245249
DOI: 10.1016/S0140-6736(23)01478-2 -
The Lancet. Neurology Feb 2024With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically... (Review)
Review
With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically based classification. Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. These three components are linked to a clinical component (C), defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features. The use of a biological classification will enable advances in both basic and clinical research, and move the field closer to the precision medicine required to develop disease-modifying therapies. We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies.
Topics: Humans; Parkinson Disease; Neuroimaging; Precision Medicine
PubMed: 38267191
DOI: 10.1016/S1474-4422(23)00404-0 -
Current Opinion in Neurology Aug 2023Our knowledge of the genetic architecture underlying Parkinson's disease has vastly improved in the past quarter century. About 5-10% of all patients suffer from a... (Review)
Review
PURPOSE OF REVIEW
Our knowledge of the genetic architecture underlying Parkinson's disease has vastly improved in the past quarter century. About 5-10% of all patients suffer from a monogenic form of Parkinson's disease.
RECENT FINDINGS
Mutations in autosomal dominant genes (e.g. SNCA, LRRK2, VPS35) or autosomal recessive genes (e.g. PRKN, PINK1, DJ-1) can cause genetic Parkinson's disease. Recessive DNAJC6 mutations can present predominantly as atypical parkinsonism, but also rarely as typical Parkinson's disease. Majority of Parkinson's disease is genetically complex. Mutation in RIC3 , a chaperone of neuronal nicotinic acetylcholine receptor subunit α-7 (CHRNA7), provides strong evidence for the role of cholinergic pathway, for the first time, in cause of Parkinson's disease. X-linked parkinsonism manifests at a young age accompanied by many (atypical) features such as intellectual disability, spasticity, seizures, myoclonus, dystonia, and have poor response to levodopa.
SUMMARY
This review article aims to provide a comprehensive overview on Parkinson's disease genetics. MAPT , which encodes the microtubule associated protein tau, TMEM230, LRP10, NUS1 and ARSA are the five new putative disease-causing genes in Parkinson's disease. The validation of novel genes and its association with Parkinson's disease remains extremely challenging, as genetically affected families are sparse and globally widespread. In the near future, genetic discoveries in Parkinson's disease will influence our ability to predict and prognosticate the disease, help in defining etiological subtypes that are critical in implementation of precision medicine.
Topics: Humans; Parkinson Disease; Membrane Proteins; Parkinsonian Disorders; Mutation; Seizures; LDL-Receptor Related Proteins; Receptors, Cell Surface
PubMed: 37366140
DOI: 10.1097/WCO.0000000000001167 -
Journal of Integrative Neuroscience Sep 2023Continuous medical progress is significantly improving the quality of health care. As a result, people are living longer than during the past century, but this has also... (Review)
Review
Continuous medical progress is significantly improving the quality of health care. As a result, people are living longer than during the past century, but this has also caused an increase of the prevalence of many neurological disorders. Parkinson's disease (PD) is the fastest growing neurological condition, with a doubling of cases reported between 1995 and 2015 and a further doubling projected by 2030. Parkinson's disease is generally associated with characteristic motor symptoms (resting tremor, rigidity, bradykinesia and postural instability). However, patients with PD also experience many non-motor symptoms that might be at least as debilitating as the motor symptoms and which significantly impact patients' quality of life (QoL). Pain is a frequent yet underrecognized symptom; the incidence in PD is much higher than in the general population and constitutes a silent disability that significantly contributes to a deterioration in QoL. Accurate identification of parkinsonian pain is important for its diagnosis and effective treatment. In this review, we provide an overview of the pathophysiology, classification, and management of pain in PD. We define the various modalities of chronic PD pain, suggesting possible explanations for its relationship with PD pathology, and discuss its management and currently recommended therapies.
Topics: Humans; Parkinson Disease; Quality of Life; Chronic Pain
PubMed: 37735139
DOI: 10.31083/j.jin2205132 -
Journal of Advanced Research Aug 2023Parkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and... (Review)
Review
BACKGROUND
Parkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and non-motor symptoms. Through the last two decades of research, there has been growing consensus that inflammation-mediated oxidative stress, mitochondrial dysfunction, and cytokine-induced toxicity are mainly involved in neuronal damage and loss associated with PD. However, it remains unclear how these mechanisms relate to sporadic PD, a more common form of PD. Both enteric and central nervous systems have been implicated in the pathogenesis of sporadic PD, thus highlighting the crosstalk between the gut and brain.
AIM
of Review: In this review, we summarize how alterations in the gut microbiome can affect PD pathogenesis. We highlight various mechanisms increasing/decreasing the risk of PD development. Based on the previous supporting evidence, we suggest how early interventions could protect against PD development and how controlling specific factors, including our diet, could modify our perspective on disease mechanisms and therapeutics. We explain the strong relationship between the gut microbiota and the brain in PD subjects, by delineating the multiple mechanisms involved inneuroinflammation and oxidative stress. We conclude that the neurodetrimental effects of western diet (WD) and the neuroprotective effects of Mediterranean diets should be further exploredin humans through clinical trials. Key Scientific Concepts of Review: Alterations in the gut microbiome and associated metabolites may contribute to pathogenesis in PD. In some studies, probiotics have been shown to exert anti-oxidative effects in PD via improved mitochondrial dynamics and homeostasis, thus reducing PD-related consequences. However, there is a significant unmet need for randomized clinical trials to investigate the effectiveness of microbial products, probiotic-based supplementation, and dietary intervention in reversing gut microbial dysbiosis in PD.
Topics: Humans; Parkinson Disease; Gastrointestinal Microbiome; Inflammation; Probiotics; Diet
PubMed: 36332796
DOI: 10.1016/j.jare.2022.10.013 -
Nature Medicine Aug 2023Parkinson's disease is a progressive neurodegenerative movement disorder with a long latent phase and currently no disease-modifying treatments. Reliable predictive...
Parkinson's disease is a progressive neurodegenerative movement disorder with a long latent phase and currently no disease-modifying treatments. Reliable predictive biomarkers that could transform efforts to develop neuroprotective treatments remain to be identified. Using UK Biobank, we investigated the predictive value of accelerometry in identifying prodromal Parkinson's disease in the general population and compared this digital biomarker with models based on genetics, lifestyle, blood biochemistry or prodromal symptoms data. Machine learning models trained using accelerometry data achieved better test performance in distinguishing both clinically diagnosed Parkinson's disease (n = 153) (area under precision recall curve (AUPRC) 0.14 ± 0.04) and prodromal Parkinson's disease (n = 113) up to 7 years pre-diagnosis (AUPRC 0.07 ± 0.03) from the general population (n = 33,009) compared with all other modalities tested (genetics: AUPRC = 0.01 ± 0.00, P = 2.2 × 10; lifestyle: AUPRC = 0.03 ± 0.04, P = 2.5 × 10; blood biochemistry: AUPRC = 0.01 ± 0.00, P = 4.1 × 10; prodromal signs: AUPRC = 0.01 ± 0.00, P = 3.6 × 10). Accelerometry is a potentially important, low-cost screening tool for determining people at risk of developing Parkinson's disease and identifying participants for clinical trials of neuroprotective treatments.
Topics: Humans; Parkinson Disease; Movement; Prodromal Symptoms; Biomarkers; Wearable Electronic Devices
PubMed: 37400639
DOI: 10.1038/s41591-023-02440-2 -
JAMA Neurology Jul 2023An increased risk of Parkinson disease (PD) has been associated with exposure to the solvent trichloroethylene (TCE), but data are limited. Millions of people in the US...
IMPORTANCE
An increased risk of Parkinson disease (PD) has been associated with exposure to the solvent trichloroethylene (TCE), but data are limited. Millions of people in the US and worldwide are exposed to TCE in air, food, and water.
OBJECTIVE
To test whether the risk of PD is higher in veterans who served at Marine Corps Base Camp Lejeune, whose water supply was contaminated with TCE and other volatile organic compounds (VOCs), compared with veterans who did not serve on that base.
DESIGN, SETTING, AND PARTICIPANTS
This population-based cohort study examined the risk for PD among all Marines and Navy personnel who resided at Camp Lejeune, North Carolina (contaminated water) (n = 172 128), or Camp Pendleton, California (uncontaminated water) (n = 168 361), for at least 3 months between 1975 and 1985, with follow-up from January 1, 1997, until February 17, 2021. Veterans Health Administration and Medicare databases were searched for International Classification of Diseases diagnostic codes for PD or other forms of parkinsonism and related medications and for diagnostic codes indicative of prodromal disease. Parkinson disease diagnoses were confirmed by medical record review.
EXPOSURES
Water supplies at Camp Lejeune were contaminated with several VOCs. Levels were highest for TCE, with monthly median values greater than 70-fold the permissible amount.
MAIN OUTCOME AND MEASURES
Risk of PD in former residents of Camp Lejeune relative to residents of Camp Pendleton. In those without PD or another form of parkinsonism, the risk of being diagnosed with features of prodromal PD were assessed individually and cumulatively using likelihood ratio tests.
RESULTS
Health data were available for 158 122 veterans (46.4%). Demographic characteristics were similar between Camp Lejeune (5.3% women, 94.7% men; mean [SD] attained age of 59.64 [4.43] years; 29.7% Black, 6.0% Hispanic, 67.6% White; and 2.7% other race and ethnicity) and Camp Pendleton (3.8% women, 96.2% men; mean [SD] age, 59.80 [4.62] years; 23.4% Black, 9.4% Hispanic, 71.1% White, and 5.5% other race and ethnicity). A total of 430 veterans had PD, with 279 from Camp Lejeune (prevalence, 0.33%) and 151 from Camp Pendleton (prevalence, 0.21%). In multivariable models, Camp Lejeune veterans had a 70% higher risk of PD (odds ratio, 1.70; 95% CI, 1.39-2.07; P < .001). No excess risk was found for other forms of neurodegenerative parkinsonism. Camp Lejeune veterans also had a significantly increased risk of prodromal PD diagnoses, including tremor, anxiety, and erectile dysfunction, and higher cumulative prodromal risk scores.
CONCLUSIONS AND RELEVANCE
The study's findings suggest that the risk of PD is higher in persons exposed to TCE and other VOCs in water 4 decades ago. Millions worldwide have been and continue to be exposed to this ubiquitous environmental contaminant.
Topics: Aged; Male; Humans; Female; United States; Middle Aged; Child, Preschool; Military Personnel; Trichloroethylene; Parkinson Disease; Cohort Studies; Environmental Exposure; Medicare
PubMed: 37184848
DOI: 10.1001/jamaneurol.2023.1168 -
Translational Neurodegeneration Jul 2023Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. More than 200 years after its first clinical... (Review)
Review
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. More than 200 years after its first clinical description, PD remains a serious affliction that affects a growing proportion of the population. Prevailing treatments only alleviate symptoms; there is still neither a cure that targets the neurodegenerative processes nor therapies that modify the course of the disease. Over the past decades, several animal models have been developed to study PD. Although no model precisely recapitulates the pathology, they still provide valuable information that contributes to our understanding of the disease and the limitations of our treatment options. This review comprehensively summarizes the different animal models available for Parkinson's research, with a focus on those induced by drugs, neurotoxins, pesticides, genetic alterations, α-synuclein inoculation, and viral vector injections. We highlight their characteristics and ability to reproduce PD-like phenotypes. It is essential to realize that the strengths and weaknesses of each model and the induction technique at our disposal are determined by the research question being asked. Our review, therefore, seeks to better aid researchers by ensuring a concrete discernment of classical and novel animal models in PD research.
Topics: Animals; Parkinson Disease; Disease Models, Animal; Neurotoxins; Mutation
PubMed: 37468944
DOI: 10.1186/s40035-023-00368-8 -
Practical Neurology Jan 2024Gait disorders are a common feature of neurological disease. The gait examination is an essential part of the neurological clinical assessment, providing valuable clues... (Review)
Review
Gait disorders are a common feature of neurological disease. The gait examination is an essential part of the neurological clinical assessment, providing valuable clues to a myriad of causes. Understanding how to examine gait is not only essential for neurological diagnosis but also for treatment and prognosis. Here, we review aspects of the clinical history and examination of neurological gait to help guide gait disorder assessment. We focus particularly on how to differentiate between common gait abnormalities and highlight the characteristic features of the more prevalent neurological gait patterns such as ataxia, waddling, steppage, spastic gait, Parkinson's disease and functional gait disorders. We also offer diagnostic clues for some unusual gait presentations, such as dystonic, stiff-person and choreiform gait, along with red flags that help differentiate atypical parkinsonism from Parkinson's disease.
Topics: Humans; Parkinson Disease; Parkinsonian Disorders; Gait; Cerebellar Ataxia; Ataxia; Gait Disorders, Neurologic
PubMed: 38135498
DOI: 10.1136/pn-2023-003917 -
Brain : a Journal of Neurology Feb 2024While Parkinson's disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease...
While Parkinson's disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease commonly consists of multiple pathologies, but it is unclear where these co-pathologies occur early in disease and whether they are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits. Motor deficits were determined on a modified and validated Unified Parkinson's Disease Rating Scale III but were insufficient in degree to diagnose Parkinson's disease. However, in our past studies, cases in this cohort had a selection bias, as both a clinical syndrome in between no motor deficits and Parkinson's disease, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in the current study, we only based inclusion on the presence of a clinical phenotype with mild motor impairment insufficient to diagnose Parkinson's disease. Then, we divided this group further based upon whether or not subjects had a synucleinopathy in the nigrostriatal system. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation and loss of the tyrosine hydroxylase-phenotype in the substantia nigra and putamen occur equally in mild motor deficit groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8 positive phosphorylated tau, a pathology not seen in the nigrostriatal system of age-matched controls. These findings were confirmed with early (tau Ser208 phosphorylation) and late (tau Ser396/Ser404 phosphorylation) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and can be tau mediated.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Parkinsonian Disorders; Synucleinopathies; Putamen; Substantia Nigra; Dopamine
PubMed: 38006313
DOI: 10.1093/brain/awad388