Pathophysiology of Parkinsons disease Jeremy Cosgrove Consultant - - PowerPoint PPT Presentation

Pathophysiology of Parkinson’s disease

Jeremy Cosgrove Consultant Neurologist, Leeds Teaching Hospitals

Outline

• Who gets Parkinson’s and why?
• What is Parkinson’s?
• How can we link changes in the brain with the symptoms of

Parkinson’s?

• What is Parkinson’s disease dementia and how is that

different to dementia with Lewy bodies?

Population Incidence Prevalence England 55,997,686 15,465 121,927 UK 66,465,641 18,461 145,519

Epidemiology

Population Incidence Prevalence 2025 68,929,547 21,451 168,582 2065 76,898,078 32,303 256,609

https://www.parkinsons.org.uk/professionals/resources/inci dence-and-prevalence-parkinsons-uk-report

Epidemiology

• 0.2% of all UK population
• 1% of 65 year olds
• 4% of 80 year olds
• 22 people in a GP practice of 10,000

• Advancing age
• Male > female 3:2
• Caucasians > Asians and

Africans

• Family history

Risk factors

Kalia and Lang, 2015

Deng et al, 2018

What is Parkinson’s? - Clinical

Diagnosis Prodrome – before diagnosis ‘Easy’ ‘Hard’

Kalia and Lang, 2015

Pathological hallmarks:

1) Early degeneration and death of dopaminergic neurons within the substantia nigra pars compacta of the basal ganglia 2) α-syn - Lewy body (cell body) and Lewy neurite (axons)

Mechanisms causing cell dysfunction

Irwin et al., 2013

Mechanisms causing cell dysfunction

Dexter & Jenner, 2013

What is Parkinson’s - Pathological

Braak et al, 2003

• Stage 1: Medulla
• Stage 2: Pontine

tegmentum

• Stage 3: Midbrain
• Stage 4:

Prosencephalon and mesocortex

• Stage 5 & 6: Neocortex

“Gut-brain axis”

Houser & Tansey, 2017

Neurotransmitter pathways

Dopaminergic Noradrenergic Serotonergic Cholinergic Haliday at al., 2014

Linking pathology with symptoms

Parietal cortex Occipital cortex Pons Frontal cortex Medulla Cerebellum Mid-brain Prodrome Motor symptoms Loss of smell RBD, EDS, Low mood Mild cognitive impairment (MCI) Dementia Hallucinations ? ? ? Constipation? Increased heart rate? Autonomic changes?

Reid et al., 2011 Hely et al., 2008

Age, hallucination and dementia

Events heralding the palliative stage

Cogni&ve)impairment) Visual)hallucina&ons) Residen&al)care) Falls) Number)of)cases) Age)at)onset)

Kempster et al., 2010

Dual syndrome hypothesis

Williams-Gray et al., 2009 Kehagia et al. 2013

Complexity of cognitive change in PD

Cosgrove et al., 2015 Aarsland et al., 2017

PDD

• Impairment in more than one cognitive

domain

• Representing a decline from premorbid

level

• Deficits severe enough to impair daily

life (social, occupational, or personal care), independent of the impairment ascribable to motor or autonomic symptoms

DLB

What is PDD and what is DLB?

Emre et al., 2007 https://www.lbda.org/go/lbd-spectrum

Pathological spectrum of PDD and DLB

Berg et al,. 2014

Conclusions

• Alpha-syn is the major pathological driver of PD
• Braak model of caudo-rostral spread can link pathology to symptoms
• Neurotransmitter dysfunction is common in PD and relates to non-

motor symptoms

• DLB and PDD are similar entities clinically and part of a disease

spectrum

Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015 Aug 29;386(9996):896-912. Deng H ,Wang P, Jankovic J. The genetics of Parkinson disease. Ageing Research

• Reviews. 2018 42: 72-85

Irwin D, Lee V, Trojanowski J. Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nature Reviews Neuroscience. 2013;14(9):626-636 Dexter DT & Jenner P. Parkinson disease: from pathology to molecular disease

• mechanisms. Free Radical Biology and Medicine. 2013 62: 132-44

Braak H, Del Tredici K, Rüb U, de Vos R, Jansen Steur E, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiology of Aging. 2003;24(2):197- 211 Houser MC & Tansey MG. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? npj Parkinson’s Disease (2017)3:3 ; doi:10.1038/s41531- 016-0002-0 Halliday GM, Leverenz JB, Schneider JS, Adler CH. The neurobiological basis of cognitive impairment in Parkinson's disease. Movement disorders 2014;29(5):634-650. Reid WG, Hely MA, Morris JG, Loy C, Halliday GM. Dementia in Parkinson's disease: a 20- year neuropsychological study (Sydney Multicentre Study). Journal of neurology, neurosurgery, and psychiatry. 2011;82(9):1033-1037. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years. Movement disorders : official journal of the Movement Disorder Society. 2008;23(6):837-844. Kempster P, O'Sullivan S, Holton J, Revesz T, Lees A. Relationships between age and late progression of Parkinson's disease: a clinico-pathological study. Brain. 2010;133(6):1755- 1762. Williams-Gray CH, Evans JR, Goris A, et al. The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. Brain. 2009;132(Pt 11):2958-2969. Kehagia AA, Barker RA, Robbins TW. Cognitive impairment in Parkinson's disease: the dual syndrome hypothesis. Neuro-degenerative diseases. 2013;11(2):79-92. Aarsland D, Creese B, Politis M, et al. Cognitive decline in Parkinson disease. Nature reviews Neurology. 2017;13(4):217-231. Cosgrove J, Alty JE, Jamieson S. Cognitive impairment in Parkinson's disease. Postgraduate medical journal. 2015;91(1074):212-220. Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Movement disorders 2007;22(12):1689-1707; quiz 1837. Berg D et al. Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease. Movement disorders. 2014: 29(4) DOI: 10.1002/mds.25844

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