Advisory Council July 2015 Meeting Presentation: Lewy Body Dementias

Monday, July 27, 2015

The Lewy Body Dementias

James B. Leverenz, MD
Chair, Scientific Advisory Council
Lewy Body Dementia Association

Cleveland Lou Ruvo Center for Brain Health
Neurological Institute
Cleveland Clinic

What is Lewy Body Dementia?

Overview

• What is a Lewy body?
• What are the Lewy body dementias?
• How common is Lewy body dementia?
• What are the needs moving forward?

What is a Lewy Body?

Frederick Lewy

Parkinson’s Disease

• Tremor (resting)
• Rigidity
• Bradykinesia
• Postural instability

Pathology in Parkinson’s Disease

• Clinical history of parkinsonism
• Neuronal loss and Lewy body inclusions in the substantia nigra, locus coeruleus, basal forebrain and cerebral cortex

Pathology in Parkinson’s Disease

Substantia Nigra

Lewy Body Pathology

H&E Stain

• Mutations in alpha-synuclein gene linked to Parkinson’s disease
• Duplications of alpha-synuclein gene linked to Parkinson’s disease and dementia with Lewy bodies
• All Lewy bodies have alpha-synuclein protein
• Increased ability to detect Lewy body changes in brain studies

a-synuclein IHC

Neuropathology of a Community Based Dementia Sample

 

 

The Lewy Body Dementias

Dementia with Lewy Bodies
Parkinson’s Disease Dementia

Consensus Criteria for Dementia with Lewy Bodies (DLB)

1. …progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function… (“dementia”)
2. Core features (2 = “probable”, 1 = “possible”)
   1. fluctuating cognition, attention, alertness
   2. recurrent visual hallucinations
   3. spontaneous features of parkinsonism
3. Suggestive features (plus one core = “probable” DLB)
   1. REM sleep behavior disorder
   2. severe neuroleptic sensitivity
   3. low dopamine transporter uptake (PET/SPECT)
4. One year rule for DLB vs. Parkinson’s Disease Dementia

McKeith I, et al. Neurology 2005

Formed Visual Hallucinations

Dementia in Parkinson’s Disease

Aarsland D et al. Mov Disord. 2003;20:1255-1263. Robbins JM et al. PARC Working Paper Series. 2001. University of Pennsylvania, Philadelphia

Pathology of Parkinson’s Disease Dementia

• 140 autopsied cases
• Links to dementia
  • Lewy pathology
  • APOE e4
  • AD (~ 30%)

Irwin DJ, et al. Ann Neurol 2012

Dementia with Lewy Bodies

• Criteria good predictor of Lewy body pathology (with or without concomitant AD pathology) - high positive predictive value
• Criteria poor predictor of the absence of Lewy body pathology - low negative predictive value
• Pathology in DLB identical to PDD except for higher coexiting AD pathology

Lewy Body Pathology in Alzheimer’s Disease

• High frequency in AD
  • Using ASN immunohistochemistry and amygdala sampling
  • 63% PS-1/APP mutation AD
  • 50% of Down syndrome
  • 61% of “sporadic” AD
  • 64% PS-2 mutation AD

Leverenz et al, Arch Neurol, 1986; Ditter et al, Neurology, 1987; Hamilton, Brain Path, 2000,
Lippa, Lippa et al, AJP, 1998; Lippa et al Ann Neurol, 1999; Leverenz et al, Arch Neurol, 2006

Leverenz et al, Arch Neurol, 2006

DLB, PDD and Alzheimer’s Disease

• Is DLB just a variant of PD/PDD?
  • Similar Lewy body pathology
  • Some shared genetics (e.g., GBA)
• Is DLB just a variant of AD?
  • Frequent AD pathology in DLB
  • Some shared genetics (e.g., APOE)
• We don’t know
  • Likely shared risks contribute to the clinical and pathological picture

National Plan to Address Alzheimer's Disease: 2015 Update

Goals as Building Blocks for Transformation

Achieving the vision of elminating the burden of ADRD starts with concrete goals. Below are the five that form the foundation of this National Plan:

1. Prevent and Effectively Treat Alzheimer's Disease by 2025.
2. Enhance Care Quality and Efficiency.
3. Expand Supports for People with Alzheimer's Disease and their Families.
4. Enhance Public Awareness and Engagement.
5. Track Progress and Drive Improvement.

    

Lewy Body Dementias -- Positive

• Increasing recognition of dementia in PD
  • Focus of two NINDS sponsored Udall Centers
  • Increasing funding from other sources (MJFF)
• First international DLB meeting in 10 years
• NIA sponsored DLB module
• Increasing interest from industry
• Lewy Body Dementia Association
  • Expanding programs, “Lewy Who”

Lewy Body Dementias – Negative

• 1.4 Million Americans
  • DLB, PDD, and LBV-AD
• Clinical care
  • Multiple visits before diagnosis, misdiagnosis
  • Inappropriate care (e.g., antipsychotics)
  • Patient and family distress
  • Access to long term care
• Research
  • Consistent and coordinated research and funding (DLB)

Thank You