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6/13/2012
Karen Mullins, D.O.
University of Tennessee
Knoxville Neurology Clinic
Lecture Objectives
Describe 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 LBD
Fluctuations in cognitive function
Varying levels of alertness and attention
Excessive daytime drowsiness or daytime sleep >2
hours
Episodes of staring off into space
Episodes of disorganized speech
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Clinical Presentation Of LBD
Visual hallucinations
Delusions
REM sleep behavior disorder
Impaired excecutive function, visuospatial function
(Stroop, digit span backwards)
Clinical Presentation of LBD
Parkinsonism
Appears early in course of disease
May not be enough to meet full criteria for PD
Less frequent rest tremor
May see myoclonus
Orthostatic hypotension
Clinical Presentation LBD
Capgras 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
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Diagnostic Criteria
Dementia with Lewy Bodies (DLB)
Consensus diagnostic criteria for DLB were first established in
1996
Dementia 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
Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242254.
PD Dementia
Typically dementia occurs later in disease
Must meet criteria for PD first
Tremor
Rigidity
Akinesia/bradykinesia
Postural instability
Manifestations at PD Onset
Tremor at rest
Bradykinesia
Rigidity
Micrographia
Hypophonia
Masked face
Stooped, shuffling gait
Slowing of activities of daily living
Decreased arm swing when walking
Barbosa et al. Psychiatr Clin North Am. 1997;20:769-90.
Playfer. Postgrad Med. 1997;73:257-64.
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Early Deficits in PD
Fronto-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 PD
20% - 57% of patients are affected in 3-5 years of PD diagnosis
PD as a fronto-striatal syndrome
Deficits clear when patients need to act based on internal rather
than external cues
DA Dependent
Flexibility, switching between known tasks, working memory
DA Independent
Mental rotation, verbal memory
Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.
PD Dementia
Diagnostic Criteria
PDD associated with mortality
Longitudinal 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 bodies
Both are distinguishable from AD
Lewy bodies, plaques, and vascular changes are present
in both
Different temporal profiles
Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.
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Diagnostic Criteria for PDD
Diagnosis of PD by the Queen Square brain bank criteria
PD precedes dementia onset
MMSE score of <26
Severe cognitive dysfunction that interferes with daily living
Impairment 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 PDD
Executive
Wisconsin card sorting test; Stroop performance; Odd-ManOut, 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 PAD
LBDD presents with dementia early on in the disease
LBDD are more likely to have hallucinations, delusions
early on in disease course
LBDD have fewer Parkinsonian symptoms
PAD must meet criteria for PD, dementia occurs later
in disease course
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Pathophysiology LBDD
Lewy Bodies- eosinophilic inclusion bodies
Present in brainstem and cerebral cortex
See 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 LBDD
Nagahama et al found SPECT scan studies of 145 DLB
patients revealed:
Visual hallucinations- hypoperfusion of parietal-
occipital association cortices
Misidentifications- hypoperfusion of the limbic-
paralimbic structures
Delusions- hypoperfusion of the frontal cortices
Pathophysiology of PAD
See 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
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Imaging in PD Dementia
Amyloid Imaging
Cortical 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
Silbert LC et al., Brain Path, 2010;20:646-653.
Clinicopathologic Spectrum of
Dementia
Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242254.
Cognitive Impairment in PD
Cholinesterase Inhibitors
Studied in DLB and PDD
Provide benefit in treating cognitive and
neuropsychiatric symptoms
Types:
Rivastigmine approved in 2006
Donepezil
Galantamine
Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242254.
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Cognitive Impairment in PD
Treatment Strategies
Rivastigmine
Dual acetylcholinesterase and
butyrylcholinesterase inhibition
Improved apathy, anxiety, delusions nad
hallucinations in DLB patients
Improved ADL in PDD relative to baseline
Only stabilize AD patients
Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.
Cognitive Impairment in PD
Treatment Strategies
Donepezil
Acetylcholinesterase inhibition
Tested in smaller studies
Improve cognition as measured by MMSE
Did not exacerbate parkinsonism
Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.
Cognitive Impairment in PD
Treatment Strategies
Memantine
Originally tested as a PD treatment
Glutamatergic compound
Non-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
Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.
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Mild Cognitive Impairment in PD
Atomoxetine
Norepinephrine reuptake inhibitor
Recent open-label study
Improvements in clinicians global impression of change
and executive function
AEs included gastrointestinal disturbance
One patient exhibited hypermania
Further studies are needed
Burn DJ et al., Brain Path, 2010;20:672-678.
Mild Cognitive Impairment in PD
Safinamide
Dopaminergic and
glutamatergic properties
Undergoing evaluation in
early and late PD
Preliminary study suggest
some benefit on executive
dysfunction in early PD
Burn DJ et al., Brain Path, 2010;20:672-678.
Cognitive Impairment in PD
Treatment
Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242254.
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Treatment Options LBDD
Acetylcholinesterase Inhibitors
Atypical neuroleptics
Antidepressants
Dopaminergic agents
Agonists
Carbidopa/levodopa
Treatment Options LBDD
Benzodiazepines
Antiepileptics
Gingko baloboa
Nonpharmacologic Options
LBDD/PAD
No approved surgery (DBS)
Keep routine
Door alarms/chimes
Geropsychiatric evaluation/home health
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Nonpharmacologic Treatment
PAD/LBDD
Exercise??
Music therapy
Yoga/tai chi
Cognitive exercises
Adequate nutrition
Disease Course PAD
More predictable than DLBD as dementia occurs later
in disease course
If cognitive issues are due to medication side effects
then often controllable or even reversible
Adjust PD meds
Exclude underlying infection
Treat with atypical antipsychotic
PD Dementia
Visual Hallucinations
Predict rapid cognitive deterioration and dementia
onset
Associated with cortical Lewy bodies
Temporal regions
Hippocampal 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
Kehagia AA et al., Lancet Neurol, 2010;9:1200-1213.
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Disease Course in LBDD
Disease symptoms fluctuate
Harder to control
More sensitive to medications
As dementia occurs earlier on in illness, pts often
require assistive care earlier
Caregiver Support
Local support groups
Websites:
wemove.org
pda.org
lbda.org
clincialtrials.gov
Home physical therapy, nursing etc.
Strong social support group
Defining Characteristics
Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242254.
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Take Home Points
Both 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
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