Dementia Associated with Lewy Body and Parkinson’s Disease

Karen Mullins, D.O.University of Tennessee

Knoxville Neurology Clinic

Lecture ObjectivesDescribe clinical presentations of Lewy Body

and Parkinson’s Associated Dementia(PAD)Describe pathophysiological mechanisms

associated with Lewy Body Dementia (LBDD) and PAD

Review both pharmacologic and nonpharmacologic treatments for LBDD and PAD

Clinical Presentation Of LBDFluctuations in cognitive functionVarying levels of alertness and attentionExcessive daytime drowsiness or daytime

sleep >2 hoursEpisodes of staring off into spaceEpisodes of disorganized speech

Clinical Presentation Of LBDVisual hallucinationsDelusionsREM sleep behavior disorderImpaired excecutive function, visuospatial

function (Stroop, digit span backwards)

Clinical Presentation of LBDParkinsonism

Appears early in course of diseaseMay not be enough to meet full criteria for PDLess frequent rest tremorMay see myoclonusOrthostatic hypotension

Clinical Presentation LBDCapgras syndrome: delusion that people in

the environment are not themselves but actually doubles

Also see passive personality traits- decreased emotional responsivity, lack of interest in hobbies, increasing apathy , purposeless hyperactivity

Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242-254.

Diagnostic CriteriaDementia with Lewy Bodies (DLB)Consensus diagnostic criteria for DLB were first

established in 1996Dementia accompanied by ≥ 1 of three core symptoms

Fluctuating cognition, visual hallucinations, and motor parkinsonism

Criteria were expanded in 2005 Neuroleptic sensitivity and RBD Specific imaging findings on dopamine SPECT imaging

or MIBG cardiac scintigraphy Dementia with progressive cognitive deficits that

result in social and occupational dysfunction must be present for either probable or possible DLB

PD DementiaTypically dementia occurs later in diseaseMust meet criteria for PD first

TremorRigidityAkinesia/bradykinesiaPostural instability

Manifestations at PD OnsetTremor at restBradykinesiaRigidityMicrographiaHypophoniaMasked faceStooped, shuffling gaitSlowing of activities of daily livingDecreased arm swing when walking

Barbosa et al. Psychiatr Clin North Am. 1997;20:769-90. Playfer. Postgrad Med. 1997;73:257-64.

Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.

Early Deficits in PDFronto-striatal Syndrome

Cognitive flexibility

Planning

Working memory

Learning

Prodrome to dementia?

Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.

Mild Cognitive Impairment in PD20% - 57% of patients are affected in 3-5 years of PD

diagnosis

PD as a fronto-striatal syndromeDeficits clear when patients need to act based on

internal rather than external cues

DA DependentFlexibility, switching between known tasks, working

memory

DA IndependentMental rotation, verbal memory

Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.

PD DementiaDiagnostic CriteriaPDD associated with mortalityLongitudinal estimates of its cumulative

prevalence are 75% to 90%PD patients are three to five times more

likely to develop dementia compared with healthy individuals

Closely related to dementia with Lewy bodiesBoth are distinguishable from ADLewy bodies, plaques, and vascular changes

are present in bothDifferent temporal profiles

Diagnostic Criteria for PDDDiagnosis of PD by the Queen Square brain bank

criteriaPD precedes dementia onsetMMSE score of <26Severe cognitive dysfunction that interferes with daily

livingImpairment on at least tow

Three-word recall (MMSE) Overlapping pentagons (MMSE) Months reverse or sevens backward (MMSE) Lexical fluency Clock drawing

Absence of major depression, delirium, or other abnormalities that obscure diagnosis

Neuropsychological Deficits in PDDExecutive

Wisconsin card sorting test; Stroop performance; Odd-Man-Out, verbal fluency

Working Memory Digit and spatial span

Memory Free and cued recall, auditory verbal learning

Visuospatial Abilities Clock drawing, Benton line orientation, face

recognition, fragmented letters

Key Points : LBDD vs PADLBDD presents with dementia early on in the

diseaseLBDD are more likely to have hallucinations,

delusions early on in disease courseLBDD have fewer Parkinsonian symptomsPAD must meet criteria for PD, dementia

occurs later in disease course

Pathophysiology LBDDLewy Bodies- eosinophilic inclusion bodiesPresent in brainstem and cerebral cortexSee changes in basal ganglia>>reduction in

# of cholinergic projections to thalamic reticular nucleus>> reduction in cholinergic neurotransmission

Specific to LBD: correlation between hallucinations, staring spells and decreased cholinergic function

Pathophysiology LBDDNagahama et al found SPECT scan studies of

145 DLB patients revealed:Visual hallucinations- hypoperfusion of

parietal-occipital association corticesMisidentifications- hypoperfusion of the limbic-

paralimbic structuresDelusions- hypoperfusion of the frontal cortices

Pathophysiology of PADSee loss of pedunculopontine cholinergic

neurons>>loss of dopamine, norepinephrine or acetylcholine neurotransmitters

May see inability of ACH transporting ions to bind to receptors

Als0 see presence of abnormal tau genes

Silbert LC et al., Brain Path, 2010;20:646-653.

Imaging in PD DementiaAmyloid ImagingCortical amyloid deposition is significantly

increased in DLB Amyloid burden in PDD and PD-ND similar

PDD subjects shown to have significantly decreased PiB binding compared to AD or DLB with similar dementia severity

Occipital cortex Severely compromised in DLB, PDD and PD-ND Relative sparing in AD

Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242-254.

Clinicopathologic Spectrum of Dementia

Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242-254.

Cognitive Impairment in PDCholinesterase InhibitorsStudied in DLB and PDD

Provide benefit in treating cognitive and neuropsychiatric symptoms

Types:Rivastigmine approved in 2006Donepezil Galantamine

Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.

Cognitive Impairment in PDTreatment Strategies

RivastigmineDual acetylcholinesterase and

butyrylcholinesterase inhibitionImproved apathy, anxiety, delusions

nad hallucinations in DLB patientsImproved ADL in PDD relative to

baselineOnly stabilize AD patients

Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.

Cognitive Impairment in PDTreatment Strategies

DonepezilAcetylcholinesterase inhibitionTested in smaller studiesImprove cognition as measured by MMSEDid not exacerbate parkinsonism

Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.

Cognitive Impairment in PDTreatment Strategies

MemantineOriginally tested as a PD

treatmentGlutamatergic compoundNon-competitive antagonist of

nicotinic acetylcholine receptors

2009 test in PDD and DLB Improved MMSE and global

change score Ameliorated cognition in PDD

May have differential therapeutic responsivity

Burn DJ et al., Brain Path, 2010;20:672-678.

Mild Cognitive Impairment in PDAtomoxetine

Norepinephrine reuptake inhibitor

Recent open-label studyImprovements in clinicians global impression

of change and executive functionAEs included gastrointestinal disturbanceOne patient exhibited hypermania

Further studies are needed

Burn DJ et al., Brain Path, 2010;20:672-678.

Mild Cognitive Impairment in PDSafinamide

Dopaminergic and glutamatergic properties

Undergoing evaluation in early and late PD

Preliminary study suggest some benefit on executive dysfunction in early PD

Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242-254.

Cognitive Impairment in PDTreatment

Treatment Options LBDDAcetylcholinesterase InhibitorsAtypical neurolepticsAntidepressantsDopaminergic agents

AgonistsCarbidopa/levodopa

Treatment Options LBDDBenzodiazepinesAntiepilepticsGingko baloboa

Nonpharmacologic Options LBDD/PADNo approved surgery (DBS)Keep routineDoor alarms/chimesGeropsychiatric evaluation/home health

Nonpharmacologic Treatment PAD/LBDD

Exercise??Music therapyYoga/tai chiCognitive exercisesAdequate nutrition

Disease Course PADMore predictable than DLBD as dementia

occurs later in disease courseIf cognitive issues are due to medication side

effects then often controllable or even reversibleAdjust PD medsExclude underlying infectionTreat with atypical antipsychotic

Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.

PD DementiaVisual HallucinationsPredict rapid cognitive deterioration and

dementia onsetAssociated with cortical Lewy bodies Temporal regionsHippocampal atrophy associated with verbal

learning deficits in PDD patients having hallucinations

Patients with visual hallucinations also have frontal hypermetabolism and orbitofrontal atrophy that correlates with visual memory deficits

Disease Course in LBDDDisease symptoms fluctuateHarder to controlMore sensitive to medicationsAs dementia occurs earlier on in illness, pts

often require assistive care earlier

Caregiver SupportLocal support groupsWebsites:

wemove.org pda.orglbda.orgclincialtrials.gov

Home physical therapy, nursing etc.Strong social support group

Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242-254.

Defining Characteristics

Take Home PointsBoth LBDD and PAD patients should be on an

acetylcholinesterase inhibitor early on- TREAT EARLY!

Providing the caregiver with support is essential

Further research is needed to identify biomarkers to distinguish PAD from DLBD

Earlier diagnosis of PD may delay onset of PAD