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The Lancet. Neurology May 2021Parkinson's disease is the second most common neurodegenerative disease and its prevalence has been projected to double over the next 30 years. An accurate diagnosis of... (Review)
Review
Parkinson's disease is the second most common neurodegenerative disease and its prevalence has been projected to double over the next 30 years. An accurate diagnosis of Parkinson's disease remains challenging and the characterisation of the earliest stages of the disease is ongoing. Recent developments over the past 5 years include the validation of clinical diagnostic criteria, the introduction and testing of research criteria for prodromal Parkinson's disease, and the identification of genetic subtypes and a growing number of genetic variants associated with risk of Parkinson's disease. Substantial progress has been made in the development of diagnostic biomarkers, and genetic and imaging tests are already part of routine protocols in clinical practice, while novel tissue and fluid markers are under investigation. Parkinson's disease is evolving from a clinical to a biomarker-supported diagnostic entity, for which earlier identification is possible, different subtypes with diverse prognosis are recognised, and novel disease-modifying treatments are in development.
Topics: Diagnosis, Differential; Disease Progression; Humans; Magnetic Resonance Imaging; Parkinson Disease; Symptom Assessment
PubMed: 33894193
DOI: 10.1016/S1474-4422(21)00030-2 -
Clinics in Geriatric Medicine Feb 2020Parkinson disease is a complex, age-related, neurodegenerative disease associated with dopamine deficiency and both motor and nonmotor deficits. Many environmental and... (Review)
Review
Parkinson disease is a complex, age-related, neurodegenerative disease associated with dopamine deficiency and both motor and nonmotor deficits. Many environmental and genetic factors influence Parkinson disease risk, with different factors predominating in different patients. These factors converge on specific pathways, including mitochondrial dysfunction, oxidative stress, protein aggregation, impaired autophagy, and neuroinflammation. Ultimately, treatment of Parkinson disease may focus on targeted therapies for pathophysiologically defined subtypes of Parkinson disease patients.
Topics: Aged; Genetic Predisposition to Disease; Health Status Indicators; Humans; Metabolism; Neuroimmunomodulation; Parkinson Disease; Patient Care Management
PubMed: 31733690
DOI: 10.1016/j.cger.2019.08.002 -
Journal of Neural Transmission (Vienna,... May 2020The substantial contributions of Dr. Gerald Stern to past and current treatments for Parkinson's disease patients are reviewed, which form the foundation for an... (Review)
Review
The substantial contributions of Dr. Gerald Stern to past and current treatments for Parkinson's disease patients are reviewed, which form the foundation for an evaluation of future options to control symptoms and halt progression of the disease. These opportunities will depend on a greater understanding of the relative contributions of the environment, genetic and epigenetic influences to disease onset, and promise to emerge as strategies for improving mitochondrial function, halting accumulation of synuclein and neuromelanin, in addition to refinement of stem cell and gene therapies. Such advances will be achieved through deployment of improved models for the disease.
Topics: History, 20th Century; History, 21st Century; Humans; Neurology; Parkinson Disease
PubMed: 32172471
DOI: 10.1007/s00702-020-02167-1 -
Acta Medica Portuguesa Oct 2019Parkinson's disease is the second most common neurodegenerative disorder, and a significant increase in its prevalence in the past three decades has been documented.... (Review)
Review
Parkinson's disease is the second most common neurodegenerative disorder, and a significant increase in its prevalence in the past three decades has been documented. Environmental and genetic factors contribute to the pathophysiology of this disease, and 5% - 10% of cases have a monogenic cause. The diagnosis relies on clinical findings, supported by adequate testing. There is no absolute method to diagnose Parkinson's disease in vivo, except for genetic testing in specific circumstances, whose usefulness is limited to a minority of cases. New diagnostic criteria have been recently proposed with the aim of improving diagnostic accuracy, emphasizing findings that might point to other causes of parkinsonism. The available therapeutic options are clinically useful, as they improve the symptoms as well as the quality of life of patients. After the introduction of levodopa, deep brain stimulation emerged as the second therapy with an important symptomatic impact in the treatment of Parkinson's disease. Non-motor symptoms and motor complications are responsible for a large proportion of disability, so these should be identified and treated. Current scientific research is focused on the identification of disease biomarkers allowing correct and timely diagnosis, and on creating more effective therapies, thus fulfilling current clinical unmet needs. This paper presents an updated review on Parkinson's disease, guiding the readership through current concepts, and allowing their application to daily clinical practice.
Topics: Antiparkinson Agents; Biomarkers; Deep Brain Stimulation; Diagnosis, Differential; Humans; Levodopa; Parkinson Disease; Symptom Assessment
PubMed: 31625879
DOI: 10.20344/amp.11978 -
Annual Review of Pathology Jan 2023Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected... (Review)
Review
Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson's syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central and peripheral nervous systems, the distribution varies and other pathologies commonly modify PD or trigger similar manifestations. Nearly all PD is genetically influenced. More than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common and rare genetic variants. Despite its complex architecture, insights from experimental genetic dissection coalesce to reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms of pathogenesis. This emerging understanding of Parkinson's syndrome, coupled with advances in biomarkers and targeted therapies, presages successful precision medicine strategies.
Topics: Humans; Parkinson Disease; Mitochondria; Mutation
PubMed: 36100231
DOI: 10.1146/annurev-pathmechdis-031521-034145 -
Journal of Parkinson's Disease 2022Fueled by aging populations and continued environmental contamination, the global burden of Parkinson's disease (PD) is increasing. The disease, or more appropriately... (Review)
Review
Fueled by aging populations and continued environmental contamination, the global burden of Parkinson's disease (PD) is increasing. The disease, or more appropriately diseases, have multiple environmental and genetic influences but no approved disease modifying therapy. Additionally, efforts to prevent this debilitating disease have been limited. As numerous environmental contaminants (e.g., pesticides, metals, industrial chemicals) are implicated in PD, disease prevention is possible. To reduce the burden of PD, we have compiled preclinical and clinical research priorities that highlight both disease prediction and primary prevention. Though not exhaustive, the "PD prevention agenda" builds upon many years of research by our colleagues and proposes next steps through the lens of modifiable risk factors. The agenda identifies ten specific areas of further inquiry and considers the funding and policy changes that will be necessary to help prevent the world's fastest growing brain disease.
Topics: Humans; Parkinson Disease; Pesticides
PubMed: 34719434
DOI: 10.3233/JPD-212922 -
Journal of Parkinson's Disease 2022Early-onset parkinsonism (EO parkinsonism), defined as subjects with disease onset before the age of 40 or 50 years, can be the main clinical presentation of a variety... (Review)
Review
Early-onset parkinsonism (EO parkinsonism), defined as subjects with disease onset before the age of 40 or 50 years, can be the main clinical presentation of a variety of conditions that are important to differentiate. Although rarer than classical late-onset Parkinson's disease (PD) and not infrequently overlapping with forms of juvenile onset PD, a correct diagnosis of the specific cause of EO parkinsonism is critical for offering appropriate counseling to patients, for family and work planning, and to select the most appropriate symptomatic or etiopathogenic treatments. Clinical features, radiological and laboratory findings are crucial for guiding the differential diagnosis. Here we summarize the most important conditions associated with primary and secondary EO parkinsonism. We also proposed a practical approach based on the current literature and expert opinion to help movement disorders specialists and neurologists navigate this complex and challenging landscape.
Topics: Diagnosis, Differential; Humans; Middle Aged; Neurologists; Parkinson Disease; Parkinsonian Disorders
PubMed: 34569973
DOI: 10.3233/JPD-212815 -
Genes Jun 2021The genetic landscape of Parkinson's disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants... (Review)
Review
The genetic landscape of Parkinson's disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design.
Topics: Genetic Predisposition to Disease; Humans; Mutation; Parkinson Disease; Penetrance; Polymorphism, Single Nucleotide
PubMed: 34208795
DOI: 10.3390/genes12071006 -
Journal of Parkinson's Disease 2021Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson's disease (PD). Initially originating from... (Review)
Review
Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson's disease (PD). Initially originating from the observation that mitochondrial toxins cause PD, findings from genetic PD supported a contribution of mitochondrial dysfunction to the disease. Here, proteins encoded by the autosomal recessively inherited PD genes Parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 are involved in mitochondrial pathways. Additional evidence for mitochondrial dysfunction stems from models of autosomal-dominant PD due to mutations in alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2). Moreover, patients harboring alterations in mitochondrial polymerase gamma (POLG) often exhibit signs of parkinsonism. While some molecular studies suggest that mitochondrial dysfunction is a primary event in PD, others speculate that it is the result of impaired mitochondrial clearance. Most recent research even implicated damage-associated molecular patterns released from non-degraded mitochondria in neuroinflammatory processes in PD. Here, we summarize the manifold literature dealing with mitochondria in the context of PD. Moreover, in light of recent advances in the field of personalized medicine, patient stratification according to the degree of mitochondrial impairment followed by mitochondrial enhancement therapy may hold potential for at least a subset of genetic and idiopathic PD cases. Thus, in the second part of this review, we discuss therapeutic approaches targeting mitochondrial dysfunction with the aim to prevent or delay neurodegeneration in PD.
Topics: Animals; Humans; Mitochondrial Diseases; Parkinson Disease
PubMed: 33074190
DOI: 10.3233/JPD-201981 -
Neurobiology of Disease Feb 2020Parkinson's disease (PD) is a neurodegenerative disease with a 200 year-long research history. Our understanding about its clinical phenotype and pathogenesis remains... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease with a 200 year-long research history. Our understanding about its clinical phenotype and pathogenesis remains limited, although dopaminergic replacement therapy has significantly improved patient outcomes. Autonomic dysfunction is an essential category of non-motor phenotypes that has recently become a cutting edge field that directs frontier research in PD. In this review, we initially describe the epidemiology of dysautonomic symptoms in PD. Then, we perform a meticulous analysis of the pathophysiology of autonomic dysfunction in PD and propose that the peripheral autonomic nervous system may be a key route for α-synuclein pathology propagation from the periphery to the central nervous system. In addition, we recommend that constipation, orthostatic hypotension, urinary dysfunction, erectile dysfunction, and pure autonomic failure should be viewed as prodromal dysautonomic markers in PD prediction and diagnosis. Finally, we summarize the strategies currently available for the treatment of autonomic dysfunction in PD and suggest that high-quality, better-designed, randomized clinical trials should be conducted in the future.
Topics: Animals; Autonomic Nervous System; Autonomic Nervous System Diseases; Humans; Mice; Parkinson Disease
PubMed: 31809788
DOI: 10.1016/j.nbd.2019.104700