Parkinson Disease Epidemiology, Pathology, Genetics, and Pathophysiology.

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.

[1]  H. Braak,et al.  Neuropathological Staging of Brain Pathology in Sporadic Parkinson’s disease: Separating the Wheat from the Chaff , 2017, Journal of Parkinson's disease.

[2]  Manuel B. Graeber,et al.  PGC-1α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease , 2010, Science Translational Medicine.

[3]  A. Schapira,et al.  Glucocerebrosidase and Parkinson Disease: Molecular, Clinical, and Therapeutic Implications , 2018, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[4]  K. Marder,et al.  Pilot association study of the β‐glucocerebrosidase N370S allele and Parkinson's disease in subjects of Jewish ethnicity , 2005, Movement disorders : official journal of the Movement Disorder Society.

[5]  K. Lim,et al.  Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. , 2007, Human molecular genetics.

[6]  T. Südhof,et al.  Cell Biology and Pathophysiology of α-Synuclein. , 2018, Cold Spring Harbor perspectives in medicine.

[7]  M. Beal,et al.  Somatic mitochondrial DNA mutations in early parkinson and incidental lewy body disease , 2012, Annals of neurology.

[8]  H. Braak,et al.  Staging of brain pathology related to sporadic Parkinson’s disease , 2003, Neurobiology of Aging.

[9]  C. Tanner,et al.  Prevalence of Parkinson’s disease across North America , 2018, npj Parkinson's Disease.

[10]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[11]  C. Tanner,et al.  Concordance for Parkinson's disease in twins: A 20‐year update , 2019, Annals of neurology.

[12]  Sonja W. Scholz,et al.  Parkinson’s disease genetics: identifying novel risk loci, providing causal insights and improving estimates of heritable risk , 2018, bioRxiv.

[13]  A. Nicholas,et al.  Nonmotor symptoms in Parkinson's disease: expanding the view of Parkinson's disease beyond a pure motor, pure dopaminergic problem. , 2013, Neurologic clinics.

[14]  C. Tanner,et al.  Pre-motor features of Parkinson's disease: the Honolulu-Asia Aging Study experience. , 2012, Parkinsonism & related disorders.

[15]  K. Marder,et al.  Pooled analysis of tobacco use and risk of Parkinson disease. , 2007, Archives of neurology.

[16]  Michael Jerrett,et al.  A study of the relationships between Parkinson's disease and markers of traffic-derived and environmental manganese air pollution in two Canadian cities. , 2007, Environmental research.

[17]  C. Tanner,et al.  Dietary fat intake, pesticide use, and Parkinson's disease. , 2014, Parkinsonism & related disorders.

[18]  T. Sherer,et al.  The rotenone model of Parkinson's disease: genes, environment and mitochondria. , 2003, Parkinsonism & related disorders.

[19]  M. Tansey,et al.  The role of innate and adaptive immunity in Parkinson's disease. , 2013, Journal of Parkinson's disease.

[20]  R. Nussbaum,et al.  Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 , 2004, Science.

[21]  Lianne Sheppard,et al.  Dose-dependent progression of parkinsonism in manganese-exposed welders , 2017, Neurology.

[22]  Michael Johnson,et al.  Triggers, Facilitators, and Aggravators: Redefining Parkinson’s Disease Pathogenesis , 2019, Trends in Neurosciences.

[23]  J. Olsen,et al.  Parkinson's disease and other neurodegenerative disorders among welders: A Danish cohort study , 2012, Movement disorders : official journal of the Movement Disorder Society.

[24]  Xiang Gao,et al.  Prospective study of dietary pattern and risk of Parkinson disease. , 2007, The American journal of clinical nutrition.

[25]  T. Sherer,et al.  Nilotinib – Differentiating the Hope from the Hype , 2016, Journal of Parkinson's disease.

[26]  C. Tanner,et al.  Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases. , 2019, Neurology.

[27]  H. Berendse,et al.  Patterns of α-synuclein pathology in incidental cases and clinical subtypes of Parkinson's disease. , 2012, Parkinsonism & related disorders.

[28]  A. Reunanen,et al.  Polychlorinated biphenyls in prospectively collected serum and Parkinson's disease risk , 2012, Movement disorders : official journal of the Movement Disorder Society.

[29]  J. Jankovic,et al.  Targeting α-Synuclein in Parkinson’s Disease: Progress Towards the Development of Disease-Modifying Therapeutics , 2019, Drugs.

[30]  D. Alessi,et al.  LRRK2 kinase in Parkinson's disease , 2018, Science.

[31]  J. Nutt,et al.  Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease , 2010, Nature Genetics.

[32]  H. Shill,et al.  Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction , 2009, Acta Neuropathologica.

[33]  S. Goldman Environmental toxins and Parkinson's disease. , 2014, Annual review of pharmacology and toxicology.

[34]  Guodong Huang,et al.  Age-Dependent Dopaminergic Neurodegeneration and Impairment of the Autophagy-Lysosomal Pathway in LRRK-Deficient Mice , 2017, Neuron.

[35]  P. Brundin,et al.  Prying into the Prion Hypothesis for Parkinson's Disease , 2017, The Journal of Neuroscience.

[36]  C. Tanner,et al.  Consumption of milk and calcium in midlife and the future risk of Parkinson disease , 2005, Neurology.

[37]  P. Cobbold,et al.  Potential Role of Vitamin D in the Elderly to Resist COVID-19 and to Slow Progression of Parkinson’s Disease , 2020, Brain sciences.

[38]  C. Tanner,et al.  Rotenone, Paraquat, and Parkinson’s Disease , 2011, Environmental health perspectives.

[39]  H. Birnbaum,et al.  Direct costs and survival of medicare beneficiaries with early and advanced Parkinson's disease. , 2012, Parkinsonism & related disorders.

[40]  C. Tanner,et al.  The disease intersection of susceptibility and exposure: Chemical exposures and neurodegenerative disease risk , 2014, Alzheimer's & Dementia.

[41]  Janel O. Johnson,et al.  α-Synuclein Locus Triplication Causes Parkinson's Disease , 2003, Science.

[42]  H. Adami,et al.  Physical activity and risk of Parkinson's disease in the Swedish National March Cohort. , 2015, Brain : a journal of neurology.

[43]  B. Bloem,et al.  The Emerging Evidence of the Parkinson Pandemic , 2018, Journal of Parkinson's disease.

[44]  C. Tanner,et al.  Association of coffee and caffeine intake with the risk of Parkinson disease. , 2000, JAMA.

[45]  W. Poewe,et al.  Mortality in Parkinson's disease: A 38‐year follow‐up study , 2015, Movement disorders : official journal of the Movement Disorder Society.

[46]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[47]  C. Tanner,et al.  Solvent exposures and parkinson disease risk in twins , 2012, Annals of neurology.

[48]  Xuemei Huang,et al.  Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein , 2019, Science Signaling.

[49]  L. Sheppard,et al.  [18F]FDOPA positron emission tomography in manganese‐exposed workers , 2017, Neurotoxicology.

[50]  O. Sánchez,et al.  Role of Connexins 30, 36, and 43 in Brain Tumors, Neurodegenerative Diseases, and Neuroprotection , 2020, Cells.

[51]  Daniela Berg,et al.  Advances in markers of prodromal Parkinson disease , 2016, Nature Reviews Neurology.

[52]  T. Dawson,et al.  PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson's Disease , 2011, Cell.

[53]  S. Schneider,et al.  Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature , 2017, Movement disorders : official journal of the Movement Disorder Society.

[54]  D. Twelves,et al.  Systematic review of incidence studies of Parkinson's disease , 2003, Movement disorders : official journal of the Movement Disorder Society.

[55]  C. Tanner,et al.  Protective glove use and hygiene habits modify the associations of specific pesticides with Parkinson's disease. , 2015, Environment international.

[56]  J. Volkmann,et al.  Parkinson disease , 2017, Nature Reviews Disease Primers.

[57]  G. Di Trapani,et al.  The Multifaceted Roles of DJ-1 as an Antioxidant. , 2017, Advances in experimental medicine and biology.

[58]  A. Ascherio,et al.  The epidemiology of Parkinson's disease: risk factors and prevention , 2016, The Lancet Neurology.

[59]  A. Lees,et al.  Ageing and Parkinson's disease: substantia nigra regional selectivity. , 1991, Brain : a journal of neurology.

[60]  T. Warner,et al.  Association between diabetes and subsequent Parkinson disease , 2018, Neurology.

[61]  L. Leclair-Visonneau,et al.  Is Parkinson’s disease a chronic low-grade inflammatory bowel disease? , 2019, Journal of Neurology.

[62]  C. Adler,et al.  Does Parkinson’s disease start in the gut? , 2017, Acta Neuropathologica.

[63]  M. Hannan,et al.  Integration of risk factors for Parkinson disease in 2 large longitudinal cohorts , 2018, Neurology.

[64]  Suneil K. Kalia,et al.  Disease‐modifying strategies for Parkinson's disease , 2015, Movement disorders : official journal of the Movement Disorder Society.

[65]  D. Morens,et al.  Epidemiologic observations on Parkinson's disease , 1996, Neurology.

[66]  G. Riboldi,et al.  GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches , 2019, Cells.

[67]  N. Gray,et al.  Small-Molecule Inhibitors of LRRK2. , 2017, Advances in neurobiology.

[68]  M. Smidt,et al.  Entanglement of Genetics and Epigenetics in Parkinson’s Disease , 2019, Front. Neurosci..

[69]  Patrizia Rizzu,et al.  Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism , 2002, Science.

[70]  B. Ritz,et al.  Head injury and risk for Parkinson disease , 2015, Neurology.