Prevalence of mixed pathologies in dementia and movement disorders - - PowerPoint PPT Presentation

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Prevalence of mixed pathologies in dementia and movement disorders - - PowerPoint PPT Presentation

Aug 07, 2023 184 likes •516 views

Prevalence of mixed pathologies in dementia and movement disorders Edward B. Lee, M.D., PhD. Clinicopathologic Correlation Neuropathologic Classification: Clinical Syndromes: Alzheimers disease (low, intermediate, high)

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Prevalence of mixed pathologies in dementia and movement disorders

Edward B. Lee, M.D., PhD.

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Clinicopathologic Correlation

Neuropathologic Classification:

  • Alzheimer’s disease (low, intermediate, high)
  • Cerebrovascular disease
  • Lewy body disease (brainstem, limbic,

amygdala, neoctx)

  • FTLD-TDP (A, B, C, D, E)
  • FTLD-Tau (Pick’s, PSP, CBD)
  • Prion disease
  • Cerebral amyloid angiopathy
  • Amyotrophic lateral sclerosis
  • Agyrophilic grain disease
  • Chronic traumatic encephalopathy
  • Hippocampal sclerosis
  • Multiple system atrophy
  • Primary age-related tauopathy (PART)
  • Aging –related tau astrogliopathy (ARTAG)

Clinical Syndromes:

  • Alzheimer’s type dementia
  • Vascular dementia
  • Mild Cognitive Impairment
  • Parkinson’s disease
  • Parkinson’s disease dementia
  • Lewy body dementia
  • Frontotemporal degeneration

How common are comorbid neurodegenerative disease pathologies across diverse autopsy cohorts? Do comorbid pathologies affect clinical phenotype?

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Center for Neurodegenerative Disease Brain Bank Autopsy Series

  • Tertiary medical center (University of Pennsylvania)
  • >1800 brain autopsy cases with frozen and fixed tissues
  • Cases recruited from the ADC Clinical Core, Parkinson’s

Disease and Movement Disorders Center, Penn FTD Center, Penn Comprehensive ALS Center

  • Current analysis includes study of 12-15 CNS regions

using H&E and immunohistochemistry for β-amyloid, phospho-tau, α-synuclein, phospho-TDP-43 performed

  • n every region.
  • How common are comorbid neuropathologies across

neurodegenerative disease conditions?

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  • 766 autopsies individuals across the spectrum of

neurodegenerative diseases (from 2000-20016)

  • AD (n=247), tauopathies (n=95),

synucleinopathies (n=164), TDP-43 proteinopathies (n=188), minimal pathology (n=72)

Robinson JL, et al., Brain 141: 2181-2193, 2018

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β-amyloid Pathology Across Neurodegenerative Diseases

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Tau Pathology Across Disease Subtypes

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Tau β-amyloid Alzheimer’s Disease Neuropathologic Change

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α-Syn Across Disease Subtypes

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TDP-43 Across Disease Subtypes

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Comorbid Pathology in AD

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Comorbid Pathology in LBD

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  • AD pathology in Lewy body disease is

associated with: more α-syn pathology shorter motor to dementia interval shorter survival (disease duration)

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Conclusions Part 1

  • Comorbid pathologies are highly prevalent

across most neurodegenerative diseases

  • Analysis does not include vascular pathology
  • Potential selection bias given tertiary center

cohort

  • Perhaps similar to a clinical trial population?

What is seen in other autopsy cohorts???

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Comorbidities in ADNI

  • Alzheimer’s Disease Neuroimaging Initiative
  • Public/private, multi-institutional collaboration
  • Uniform data collection (neuroimaging,

biomarkers, etc.)

  • Clinical trial population
  • From 2005-20015, 45 autopsies from 78 deaths

(autopsy rate 58%)

  • Nigel Cairns, M.D. (Washington University)
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Comorbidities in ADNI

Neuropathologic Diagnosis Total AD 14 AD + DLB 9 AD + TDP 2 AD + DLB + TDP 2 AD + DLB + TDP + AGD 1 AD + ALB + TDP 1 AD + AGD 1 AD + ALB 2 AD + HS + AGD 1 AD + HS + TDP + AGD 1 AD + TDP + infarcts 1 AGD 1 AD + DLB + AGD 1

Franklin EE, et al. Alzheimers Dement 11(7): 815-22, 2015 N=45

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Comorbidities in ADNI

AD AD + DLB AD + TDP AD + DLB + TDP AD + DLB + TDP + AGD AD + ALB + TDP AD + AGD AD + ALB AD + HS + AGD AD + HS + TDP + AGD AD + TDP + infarcts AGD AD + DLB + AGD

AD

  • nly

AD + DLB

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Autopsy Cohorts

✓Specialized tertiary center autopsy cohort ✓Multi-institutional research cohort Perhaps not reflective of the general population?

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Population Based Neuropathology Cohort

  • Religious Orders Study (1994)
  • Rush Memory and Aging Project (1997)
  • Julie A. Schneider, M.D. (Rush University)
  • 3414 participants as of end of 2017
  • 72.6% female, 88.2% non-Latino white, 6.3% African American,

5.5% Latino, mean age 78.3 years, mean education 16.9 years

  • Annual follow up rate >90 %
  • Autopsy rate 87.7% (1506 out of 1717 deaths)

– 67.2% femal, 94.5% non-Latino White, 89.1 years old, 16.9 years education – 31.0% normal cognition, 23.0% MCI, 41.4% AD dementia, 4.5% other dementia

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Comorbidities in ROSMAP

Kapasi A, DeCarli C and Schneider JA. Acta Neuropathologica 134: 171-186, 2017

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Cerebrovascular Disease and Risk for AD Dementia

Arvanitakis Z et al., Lancet Neurology 15(9): 934-943, 2016

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α-Synuclein and Risk for AD Dementia

Schneider J.A., et al., Brain 135:3005-3014, 2012

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Hippocampal Sclerosis

Nag S., et al., Annals of Neurology 77(6): 942-52, 2015

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Hippocampal Sclerosis and Risk for AD Dementia

Nag S., et al., Annals of Neurology 77(6): 942-52, 2015

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Combinatorial Neuropathology

  • 1079 autopsy cases
  • 236 different combinations of neuropathology

AD DLB TDP-43 HS Atherosclerosis Arteriolosclerosis CAA Macroinfarcts Microinfarcts

Boyle PA, et al., Ann Neurol 83(1):74-83, 2018

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Top 10 Combinations of Neuropathology

Neuropathology n % AD only 64 5.9 None 62 5.8 AD + CAA 41 3.8 AD + CAA + TDP 26 2.4 Gross Infarcts 24 2.2 Atherosclerosis 22 2.0 AD + TDP 18 1.7 TDP-43 only 17 1.6 AD + atherosclerosis 17 1.6 Microinfarcts 16 1.5 Boyle PA, et al., Ann Neurol 83(1):74-83, 2018 n=1079

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Cognitive Loss & Neuropathologies

Boyle PA, et al., Ann Neurol 83(1):74-83, 2018

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Autopsy Cohorts

✓Specialized tertiary center autopsy cohort ✓Multi-institutional research cohort ✓Community-based cohort Perhaps one can select a “pure” genetic cohort?

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Comorbid Pathology in Genetic AD: Dominantly Inherited Alzheimer Network

Cairns NJ et al., Neuropathology 35: 390-400, 2015

50% of DIAN autopsies showed comorbid Lewy body disease.

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Comorbid LBD Across Genotypes

Cairns NJ et al., Neuropathology 35: 390-400, 2015

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Contursi Kindred: SNCA A53T

Duda JE et al., Acta Neuropathologica 104: 7-11, 2002.

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Contursi Kindred: Tau Pathology

Duda JE et al., Acta Neuropathologica 104: 7-11, 2002.

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Summary of Comorbid Pathologies in Diverse Autopsy Cohorts

✓ UPenn: specialized tertiary center cohort (across neurodegenerative diseases) ✓ ADNI: Multi-institutional research cohort ✓ ROSMAP: Community-based cohort ✓ Dominantly inherited forms of AD and PD

  • How common are comorbid neurodegenerative disease

pathologies across diverse autopsy cohorts? Comorbid neurodegenerative disease pathologies are common regardless of cohort characteristics

  • Do comorbid pathologies affect clinical phenotype?

Comorbid neurodegenerative disease pathologies contribute to clinical phenotype