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Dementia with Lewy Bodies

Sarah B. Berman, M.D., Ph.D.

Associate Professor

Department of Neurology

Director of DLB Programs

Alzheimer Disease Research Center

Pittsburgh Institute for Neurodegenerative Diseases

University of Pittsburgh

October 29, 2020

Outline

• What is Dementia with Lewy Bodies?

– How it differs from Alzheimer’s disease

– How it differs from Parkinson’s disease

• Diagnosis

• Treatment strategies

– Multi-faceted

• Research/Future directions

Dementia with Lewy Bodies

• Second most common neurodegenerative

dementia

– Second only to Alzheimer’s disease

• Prevalence

– About 5% (1-25%) of all dementias

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Lewy Body Diseases

• Dementia with Lewy Bodies (DLB)

• Parkinson’s Disease and

Parkinson’s Disease Dementia

• Multiple Systems Atrophy (MSA)

• All have Lewy Body pathology

– Abnormal protein aggregates; contain

ubiquitin and a-synuclein

– DLB: in cortical and brainstem neurons

– Also termed ‘Synucleinopathies’

– Very common for people with DLB to

also have Alzheimer’s pathology Spillantini et al., Nature 1997

Lewy Bodies

Clinical Features

• DLB has both cognitive and motor signs

– can be confused with both Alzheimer’s and

Parkinson’s disease

– Will focus on how to differentiate each one

1) cognitive changes

2) motor changes

Dementia with Lewy Bodies

Dementia

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Prominent Patterns of Cognitive Changes

DLB

• Executive Function

• Visuospatial

• Memory usually later

Other features

• Fluctuating consciousness

• Hallucinations

– Usually well-formed

(people, animals)

– Illusions also

Alzheimer’s disease

• Memory

• Language, executive

function

Hallucinations, fluctuations

less common

Dementia with Lewy Bodies

Cognitive Changes

Dementia

Hallucinations

Changes in alertness

Parkinsonism

“Motor” Symptoms:• Rest tremor

• Bradykinesia (Slowness of

movement)

• Rigidity

• In DLB, usually symmetric

• Balance difficulty

• Shuffling gait

• Stooped posture

• Softer voice; less facial

expression

• Smaller writing

Rest tremor

Turning ‘en bloc’

Stooped posture

Medlink Neurology

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Postural instability

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Freezing of gait

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Signs can be subtle- Rest tremor

- Bradykinesia

Nutt JG and Wooten GF. Diagnosis and

Initial Management of Parkinson's

Disease. N Engl J Med

2005;353(10):1021-7.

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Dementia with Lewy Bodies

Cognitive Changes

Dementia

Hallucinations

Fluctuating

consciousness

Parkinsonism

REM sleep disorder

REM Sleep Behavior Disorder (RBD)

• During REM sleep, when dreams occur, the

body is normally paralyzed (atonia)

• In RBD, the paralysis doesn’t occur

– Acting out dreams

– Talking in sleep

– Can be violent

Dementia with Lewy Bodies

Cognitive Changes

Dementia

Hallucinations

Fluctuating

consciousness

Parkinsonism

REM sleep disorder

Supportive Features

• Autonomic insufficiency

• Hyposmia

• Delusions

• Anxiety/depression

• Sensitivity to

antipsychotic

medications

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DLB DiagnosisMcKeith et al, 2017 Consensus Criteria

Dementia

2+ Core Features

• Parkinsonism

• Visual Hallucinations

• REM sleep disorder

• Fluctuating

consciousness

Dementia should start within 1

year of Parkinsonian motor

signs

• or else classified as Parkinson’s

disease dementia

Dementia

One Core Feature

• Parkinsonism

• Hallucinations

• REM sleep disorder

• Fluctuating

consciousness

Positive Biomarker

DLB DiagnosisMcKeith et al, 2017 Consensus Criteria

Biomarkers

Used in diagnosis

• Dopamine transporter SPECT (DaTscan)

– Motor symptoms of DLB due to loss of dopamine neurons

– Measures loss of striatal dopamine axons

• Cardiac MIBG scintigraphy

– Measures loss of sympathetic innervation

• Polysomnography

– Documents RBD (REM sleep without atonia)

Supportive but not used in diagnosis

• Diminished occipital metabolism (PET or SPECT scan)

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Brain Imaging in DLB

Modified from McKeith et al. Neurology 2017;89:88-100

Copyright © 2017 The Author(s). Published by Wolters Kluw er Health, Inc. on behalf of the

American Academy of Neurology.

My-ms.org

Figure 3 Polysomnographic (PSG) recordings

Ian G. McKeith et al. Neurology 2017;89:88-100

Copyright © 2017 The Author(s). Published by Wolters Kluw er Health, Inc. on behalf of the

American Academy of Neurology.

Modified from McKeith et al. Neurology 2017;89:88-100

Copyright © 2017 The Author(s). Published by Wolters Kluw er Health, Inc. on behalf of the American Academy of Neurology.

Brain Imaging in DLB

PET Imaging: Metabolic activity

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Dementia with Lewy Bodies

Dementia

Core Features

• Parkinsonism

• Hallucinations

• REM sleep disorder

• Fluctuating

consciousness

Biomarkers

Supportive Features

• Autonomic insufficiency

• Hyposmia

• Delusions

• Anxiety/depression

• Sensitivity to

antipsychotic

medications

Treatment Strategies

• Multifactorial and individualized

– No disease-modifying therapy available

– Address specific symptoms

• Complexities of treatment interactions

Treatment Strategies

Cognitive changes

• Acetylcholinesterase inhibitors

– Donepezil

– Rivastigmine (oral or transdermal)

– Galantamine

(Modified from Parsons et al.,

Neurotox Res, 2013)

X

XOften more noticeable

benefit in DLB than in AD

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Treatment Strategies

Psychosis (hallucinations, delusions)

• Cholinesterase inhibitors might be helpful

• AVOID typical antipsychotics (e.g., haloperidol)

• If necessary, the atypical antipsychotic quetiapine is a

better choice

– Less parkinsonism, better tolerated

– Or clozapine (but requires monitoring)

• Future targets?

– Serotonin-targeting medications

• Pimavanserin (Nuplazid) - Approved for PD psychosis, under review

by FDA for dementia-related psychosis

Treatment Strategies

Parkinsonism (motor symptoms)

• PT/OT/Speech/Exercise programs

• Levodopa

– How it works

– Risks in DLB

X

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Dopamine metabolism

L-DOPA DOPAMINE

3,4-DOPAC

3-Methoxytyramine

HVA

Dopamine metabolism

L-DOPA DOPAMINE

3,4-DOPAC

3-Methoxytyramine

HVABlood-brain barrier

DOPAMINE

Dopamine metabolism

L-DOPA DOPAMINE

3,4-DOPAC

3-Methoxytyramine

HVABlood-brain barrier

carbidopa

SINEMET®: L-DOPA + CarbidopaDOPAMINE

X

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Carbidopa/Levodopa

• Can help with

– Slowness

– Stiffness

– Shuffling walk/freezing

– Tremor

• Not as useful as in Parkinson’s disease

– Potential side effects

• Worsening hallucinations

DLB Complexities

Dopamine-related treatments

Levodopa

Quetiapine

Other anti-psychotics

DOPAMINE LEVELS

Parkinsonian motor sx

Hallucinations, Delusions

Treatment Strategies

Sleep Disturbance

• REM sleep behavior disorder (RBD)

– Melatonin, Low-dose clonazepam

Depression/Anxiety• SSRIs

– e.g., sertraline, escitalopram

• SNRIs

– e.g., venlafaxine

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Treatment Strategies

Apathy• Can be disabling and very difficult to treat

• SSRIs

• Cholinesterase inhibitors

• Stimulants?

• Dopaminergic medications

Treatment Strategies

Autonomic disturbances

• Orthostatic hypotension

– Conservative and Pharmacologic measures:

compression stockings, fludrocortisone, midodrine

• Urinary incontinence

– Try to avoid anti-cholinergics for urinary symptoms

• Constipation

– Diet, miralax or other agents

Treatments to AVOID

• Dopamine antagonists– Such as MOST antipsychotics (haloperidol, risperidone)

– If needed, consider Clozaril or Seroquel

– Includes anti-emetics Reglan, Compazine

• Anticholinergics– Such as Benadryl, over the counter sleep aids

• Dopamine agonists– Pramipexole, ropinirole, rotigotine

– Frequently worsen hallucinations, can cause encephalopathy,

behavioral changes

– Frequently used if misdiagnosed as Parkinson’s disease

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• We can ONLY treat the symptoms

• We don’t know how to stop or even slow

the disease

Neuroprotective therapies

– What causes the pathology?

– How do we stop the progression?

Therapeutic Challenges

Research/Future Directions

• Basic research studies

– Genetics

– Animal models

– Etiology of neuropathology and underlying mechanisms

• Clinical studies

– Multiple studies underway to characterize clinical progression

and biomarkers

– Critical for outcomes for future neuroprotective therapy trials

• Goals:

– Develop effective neuroprotective therapies to slow/prevent

progression

– Develop better symptomatic therapies

Lewy Body Disease Local

Research Opportunities

• Dementia with Lewy Bodies Consortium (DLBC) study: o Longitudinal study at Pitt ADRC and 8 other sites, with matching clinical and

imaging and CSF/blood biomarker data

o Goal: Support clinical research to discover biomarkers that will improve efficiency and outcome of Phase II clinical trials for DLB

o If interested in referring potential participants for evaluation:

o Donna Simpson, CRNP, MPH, Clinical Research Coordinator, ADRC

Phone: (412) 692-2717

• Mito-PET Brain Imaging Studyo MJFF-funded pilot study of a new PET brain imaging tracer

o May be a biomarker in DLB, PD, and PD dementia

o Goal is to develop biomarkers of early changes in the brain that can be used to

monitor therapeutic trials

o If interested in referring potential participants for evaluation:

o Patricia McGeown, RN, BSN, Clinical Research Coordinator, ADRC

Phone: (412) 692-2722

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