Presentation made by Dr. Matt Barrett at the April 3, 2014 Live Webinar on PDD hosted by the AlzPossible at www.alzpossible.org

1. Parkinson’s Disease Dementia
Matthew J. Barrett, MD, MSc
Assistant Professor of Neurology
University of Virginia
Charlottesville, Virginia USA

2. Question #1
• Have you previously worked with patients who have
Parkinson disease with dementia?
1. Yes, in the last year.
2. Yes, more than a year ago.
3. Never.
4. Unsure.

3. Objectives
Define
Parkinson's
disease
dementia
Review
characteristics
of Parkinson's
disease
dementia
Differentiate
Parkinson's
disease
dementia from
other causes
of dementia
Review
management
of Parkinson's
disease
dementia

4. Case Presentation
• 76 year old man with change in handwriting (micrographia) and
walking 14 years ago.
• Diagnosed with Parkinson's disease and responded to levodopa.
• Within first few years he noted mild difficulty with word-finding
while speaking.
• Motor symptoms progressed very slowly over time and levodopa
was increased.

5. Worsening
cognition and
dependence on
aides to point of
needing 24 hour
care.
Hallucinations
at night;
worse with
quetiapine, currently
on aripiprazole
Insomnia
Anxiety and
depressed mood
Freezing of gait
76 year old man

6. Allergies:
None
Medications
• Carbidopa/levodopa 25/100 #2
three times daily
• Aripiprazole 5mg daily
• Clonazepam 0.5mg prn
• Levothyroxine
• Meclizine prn
• Tylenol PM acetaminophen/
diphenhydramine) prn
76 year old man

7. MRI brain:
Interval increase in global
cortical atrophy. Chronic
right lacunar infarct.
Physical Exam:
• Not oriented to place or
date.
• Could not perform serial 7‟s.
• Significant delay in verbal
responses.
• Bilateral bradykinesia and
rigidity.
• Mild dystonic dyskinesias of
limbs and trunk.
• Shuffling gait and reduced
arm swing with freezing of
gait on initiation and turns.
76 year old man
Bradykinesia = slowness of movement
Dyskinesia = involuntary muscle movements associated with
PD treatment
Dystonic = sustained involuntary postures

8. Affects >1% of those older than age 60.
PARKINSON’S
DISEASE
Movement disorder
• Bradykinesia
• Rigidity
• Rest tremor
• Postural Instability
Non-motor symptoms
• Neuropsychiatric
• Disorders of sleep and
wakefulness
• Autonomic symptoms

9. Cognition in PD
• MCI is present in 15-20% PD patients at diagnosis (Aarsland,
2009).
• Cognitive decline is insidious.
• Typical profile:
• Impaired attention
• Deficits in memory (recall not encoding)
• Impaired visuospatial function
• Impaired executive function.
• There is heterogeneity in cognitive profile.

10. PDD Epidemiology
80%
LIFETIME PREVALENCE
(Hely, 2008; Aarsland, 2003).
OF DEMENTIA PATIENTS
(Aarsland, 2005)
3-4% 1/3 of all PD
patients in clinic-
based studies
(Aarsland, 2005)
10%
PERCENTAGE OF PD PATIENTS
WHO DEVELOP DEMENTIA
ANNUALLY
(Emre, 2007)
PD ONSET OF
DEMENTIA
~10 years
(Aarsland, 2003; Hughes, 2000)

11. PDD Epidemiology
• No studies evaluating racial/ethnic differences in PDD
specifically
• In PD, one study found that African-Americans had
reduced incidence of PD compared to whites. Incidence
of PD in Hispanics was not significantly different.
(Dahodwala, 2009)
• For Medicare beneficiaries with PD, frequency of
dementia was 78.2% in Blacks, 73.1% in Hispanics, 69% in
Whites, and 66.8% in Asians. (Willis, 2012)

12. PDD Diagnostic Criteria
(Emre, et al. 2007)
Core
Features
Diagnosis of PD
(UK Brain Bank Criteria)
Dementia syndrome with
insidious onset and slow
progression, developing in the
context of established PD,
diagnosed by:
Impairment in more than one
cognitive domain
Representing a decline from
premorbid level
Deficits severe enough to impair
daily life (social, occupational, or
personal care), independent of the
impairment attributable to motor
or autonomic symptoms.

13. (Emre, et al. 2007)
Associated Clinical
Features
• Cognitive features
• Behavioral/neuro-
psychiatric symptoms
Features that make
diagnosis uncertain
• Co-existence of
abnormality which may
by itself cause
cognitive impairment,
e.g. vascular disease
• Time between motor
and cognitive
symptoms unknown
Features suggesting
other conditions or
diseases
• Acute confusion due
to systemic disease or
drugs
• Major depression
• Probable vascular
dementia
PDD Diagnostic Criteria

14. Probable
PDD
(Emre, et al. 2007)
Core
features:
Both must
be present
Associated clinical
features
• Typical cognitive profile (2/4
core cognitive domains)
• Impaired attention which may
fluctuate
• Impaired executive function,
• Impairment in visuospatial
function
• Impaired free recall which usually
improves with cueing
• Presence of at least one
behavioral symptom
• Apathy
• Depressed or anxious mood
• Hallucinations / Delusions
• Excessive daytime sleepiness
No features that
make diagnosis
uncertain
No features that
suggest other
diagnosis

15. Possible
PDD
(Emre, et al. 2007)
Core features:
Both must be
present
Associated clinical features
• Atypical cognitive profile in
one or more cognitive
domains, e.g.
• prominent fluent aphasia,
• pure encoding-failure amnesia (no
improvement with cueing) with
preserved attention.
• Behavioral symptoms may or
may not be present
One or more features
that make diagnosis
uncertain
No features
that suggest
other diagnosis

16. PDD Cognitive Profile
ATTENTION:
• Impaired and may
fluctuate
MEMORY:
• Visual and verbal memory
impaired but less than AD.
Retrieval more impaired
than encoding.
EXECUTIVE
FUNCTION:
• Impaired, typically
more than AD
VISUOSPATIAL
FUNCTION:
• Significant impairment, more
than AD
LANGUAGE:
• Less impairment than AD
(Emre, et al. 2007)

17. PDD Cognitive profile
• Cognitive profile can be used for diagnosis but does not
conclusively differentiate diagnoses.
(Emre, et al. 2007)

18. PDD Neuropsychiatric Symptoms
Psychotic
symptoms
Hallucinations
45-65%
Visual>Auditory
More common in
PDD/DLB than AD
Delusions
25-30%
Paranoid, “phantom
boarder,”
misidentification

19. PDD Neuropsychiatric Symptoms
Mood
disorder
Depression
40-60%
Anxiety
30-50%
Apathy 25-50%

20. PDD Sleep Disorders
• More REM sleep behavior disorder than AD
• May precede onset of dementia in PD (Postuma 2009)
• Increased daytime sleepiness
• Insomnia

21. PDD Motor Symptoms
• Advanced motor symptoms.
• Greater axial rigidity and postural instability.
• Increased falls.

22. Question #2
• Of patients with PD and dementia which of the
following would meet criteria for probable PDD?
Choose 1 or more.
1. Significantly impaired language and attention, hallucinations
2. Significantly impaired attention and visuospatial function,
depression
3. Significantly impaired attention and memory deficit
(encoding), apathy
4. Significantly impaired executive function and attention,
anxiety

23. Differential Diagnosis
• Dementia with Lewy bodies (DLB)
• 1-year rule
• 3rd report of DLB consortium:
“DLB should be diagnosed when dementia occurs before or
concurrently with Parkinsonism, and PD-D should be used to
describe dementia that occurs in the context of well-established
PD. In research studies in which distinction is made between
DLB and PD-D, the 1-year rule between the onset of
dementia and Parkinsonism for DLB should be used.”

24. Differential Diagnosis
• AD with late Parkinsonism
• Parkinsonism and dementia of other disorders
• Frontotemporal Dementia
• Vascular parkinsonism/dementia
• NPH

25. Risk factors for dementia in PD
• Greater age
• More severe Parkinsonism
• rigidity, postural instability, and gait disturbance
• Mild cognitive impairment at baseline.
• Inconsistent results:
• Greater age at onset
• Male gender
• Education
• Depression
• Visual hallucinations
• Other clinical features.

26. PDD Genetics
• Genetic associations with increased risk of dementia in
Parkinson's disease.
• APOE 4 allele (Huang, 2006; Morley 2012)
• MAPT H1/H1 (Williams-Gray, 2009)
• Heterozygous GBA mutations (Seto-Salvia, 2012)
• SNCA mutations
• Dementia is less common in PD patients with PRKN mutations.

27. Pathology of PD dementia
• Lewy body pathology in cortex and limbic structures.
• Hallucinations are indicator of Lewy body pathology
(Williams, 2008)
• AD pathology frequently present
• Cerebrovascular pathology

28. 76 year old man
• Assessment
• Advanced Parkinson's disease with dementia (PDD)
• Major issues of dementia, insomnia, anxiety, and freezing of gait

29. Question #3
What about this patient‟s history is inconsistent with
dementia with Lewy bodies?
1. Visual hallucinations
2. Presence of depressive symptoms and anxiety
3. Parkinsonism preceding dementia by >1 year
4. History of improvement in motor symptoms with levodopa
treatment.

30. Treatments – Dementia
• Cholinesterase inhibitors
• Donepezil (Aricept)
• Galantamine (Razadyne)
• Rivastigmine (Exelon)
• NMDA-receptor antagonist
• Memantine (Namenda)
• Movement Disorders Task Force (Seppi, 2011) concluded
rivastigmine is clinically useful and evidence for
donepezil, galantamine, and memantine was insufficient.

31. Treatments – Dementia
• 2012 Cochrane Review concluded that evidence supports use of
cholinesterase inhibitors for Parkinson's disease dementia
(Rolinski, 2012)
• Rivastigmine is the only cholinesterase inhibitor with FDA indication for
PDD.
• Evidence from clinical trials do not support the use of
memantine (Namenda).

32. Treatments – Dementia
• Donepezil
• 5mg (½-10mg) tablet daily in AM for one week
• Then 10mg tablet daily in AM
• If GI side effects, then…
• Exelon patch
• 4.6mg patch q24 hours for 1 month
• Then 9.5mg patch q24 hours
• While higher doses of each approved, little increased benefit with
greater side effects.
• These medications may improve psychosis and other behavioral
symptoms.

33. Treatment - Psychosis
• Reduction in dopaminergic medications
• Elimination of other possible contributory medications –
anticholinergics, benzodiazepines
• Rule out metabolic causes of delirium

34. Treatment - Psychosis
• Atypical antipsychotics with least likelihood of worsening
Parkinsonism.
• Clozapine
• Only treatment recommended for treatment of
psychosis in PD. (Seppi, 2011)
• Inconvenience of regular blood monitoring for
agranulocytosis limits usage.
• Quetiapine
• Both have FDA black box warning for increased
risk of sudden cardiac death. (Ray, 2009)
• Avoid all other antipsychotic medications.

35. Treatment - Psychosis
• Reduction in dopaminergic medications, transition toward
levodopa-only regimen
• Assess for other causative medications
• Assess causes of delirium
• Labs, head CT, infection
• Add cholinesterase inhibitor if dementia present.
• Quetiapine 12.5mg, increase as needed unless limited by sedation.
• Clozapine 12.5mg increase as needed.
• Pimavanserin? – Serotonin inverse agonist

36. Treatment
• Depression
• SSRI/SNRIs
• REM sleep behavior disorder
• Environmental modification
• Benzodiazepines

37. Movement disorder
• Levodopa primary treatment
• More effective for bradykinesia and rigidity.
• Not for apraxia
• Less side effects
• Medications to avoid
• Anticholinergic drugs – trihexyphenidyl
• Amantadine
• Dopamine agonists
• MAO inhibitors

38. 76 year old man
• Assessment
• Advanced Parkinson's disease with dementia (PDD)
• Major issues of dementia, insomnia, anxiety, and freezing of gait

39. Allergies:
None
Medications
• Carbidopa/levodopa 25/100 #2
three times daily
• Aripiprazole 5mg daily
• Clonazepam 0.5mg prn
• Levothyroxine
• Meclizine prn
• Tylenol PM acetaminophen/
diphenhydramine) prn
76 year old man

40. Question #4
What is the best first intervention to address freezing
of gait in this patient?
A. Increase each levodopa dose.
B. Add additional levodopa dose and reduce time between
doses.
C. Stop aripiprazole
D. Add pramipexole, a dopamine agonist, to reduce „off‟
periods

41. Question #5
• What is the best intervention for treatment of dementia
in PDD?
A. There is no good evidence to support any pharmacological
intervention.
B. Add memantine.
C. Add cholinesterase inhibitor
D. Both B. and C.

42. Question #6
If after stopping aripiprazole and starting a cholinesterase
inhibitor, psychotic symptoms continued and were
disabling, what would be a reasonable treatment option?
A. Retry quetiapine.
B. Initiate clozapine.
C. Initiate olanzapine.
D. A or B
E. A, B, or C.

43. 76 year old man
• Plan
Dementia
• Cholinesterase inhibitor
for dementia and possibly
hallucinations to reduce
need for antipsychotic.
Parkinsonism/
Freezing
• No antipsychotics
• Determine if freezing
occurs at end of dose –
would consider 4 times a
day dosing
Insomnia/Anxiety
/Depressed mood
• Mirtazapine
• No diphenhydramine
(No Tylenol PM)
Anxiety
• Anti-depressant
• Consider low-dose
benzodiazepines (fall risk)

44. 1. Aarsland D, Bronnick K, Larsen JP et al. Cognitive impairment in incident, untreated parkinson
disease: The norwegian ParkWest study. Neurology 2009;72(13):1121-1126.
2. Emre M, Aarsland D, Brown R et al. Clinical diagnostic criteria for dementia associated with
parkinson's disease. Mov Disord 2007;22(12):1689-707; quiz 1837.
3. Postuma RB, Gagnon JF, Vendette M, Montplaisir JY. Idiopathic REM sleep behavior disorder in
the transition to degenerative disease. Mov Disord 2009;24(15):2225-2232.
4. Aarsland D, Zaccai J, Brayne C. A systematic review of prevalence studies of dementia in
parkinson's disease. Mov Disord 2005;20(10):1255-1263.
5. Hely MA, Morris JG, Reid WG, Trafficante R. Sydney multicenter study of parkinson's disease:
Non-L-dopa-responsive problems dominate at 15 years. Mov Disord 2005;20(2):190-199.
6. Aarsland D, Andersen K, Larsen JP et al. Prevalence and characteristics of dementia in parkinson
disease: An 8-year prospective study. Arch Neurol 2003;60(3):387-392.
7. Hughes TA, Ross HF, Musa S et al. A 10-year study of the incidence of and factors predicting
dementia in parkinson's disease. Neurology 2000;54(8):1596-1602.
8. Dahodwala N, Siderowf A, Xie M et al. Racial differences in the diagnosis of parkinson's disease.
Mov Disord 2009;24(8):1200-1205.
9. Willis AW, Schootman M, Kung N et al. Predictors of survival in patients with parkinson disease.
Arch Neurol 2012;69(5):601-607.
10. McKeith IG, Dickson DW, Lowe J et al. Diagnosis and management of dementia with lewy
bodies: Third report of the DLB consortium. Neurology 2005;65(12):1863-1872.
References

45. 11. Huang X, Chen P, Kaufer DI et al. Apolipoprotein E and dementia in parkinson disease: A meta-
analysis. Arch Neurol 2006;63(2):189-193.
12. Morley JF, Xie SX, Hurtig HI et al. Genetic influences on cognitive decline in parkinson's disease.
Mov Disord 2012;27(4):512-518.
13. Williams-Gray CH, Evans JR, Goris A et al. The distinct cognitive syndromes of parkinson's
disease: 5 year follow-up of the CamPaIGN cohort. Brain 2009;132(Pt 11):2958-2969.
14. Seto-Salvia N, Pagonabarraga J, Houlden H et al. Glucocerebrosidase mutations confer a greater
risk of dementia during parkinson's disease course. Mov Disord 2012;27(3):393-399.
15. Williams DR, Warren JD, Lees AJ. Using the presence of visual hallucinations to differentiate
parkinson's disease from atypical parkinsonism. J Neurol Neurosurg Psychiatry 2008;79(6):652-655.
16. Seppi K, Weintraub D, Coelho M et al. The movement disorder society evidence-based medicine
review update: Treatments for the non-motor symptoms of parkinson's disease. Mov Disord 2011;26
Suppl 3:S42-80.
17. Rolinski M, Fox C, Maidment I, McShane R. Cholinesterase inhibitors for dementia with lewy
bodies, parkinson's disease dementia and cognitive impairment in parkinson's disease. Cochrane
Database Syst Rev 2012;3:CD006504.
18. Ray WA, Chung CP, Murray KT et al. Atypical antipsychotic drugs and the risk of sudden cardiac
death. N Engl J Med 2009;360(3):225-235.
References

46. LBD
Vision
• A cure for Lewy body
dementias and quality
support for those still
living with the disease.
Mission
• Through
outreach, education and
research, we support
those affected by Lewy
body dementias
Family Services
• LBD Caregiver Link
(800.539.9767)
• Caregiver support groups
• An active online community
Educational Resources
• Free publications, for families and
professionals
• Webinars
• Lewy Body Digest (e-newsletter)
• www.lbda.org
Download free diagnostic
and comprehensive
symptom checklists from
LBDA.org
Order print copies of this 40
page booklet from NIA’s
Alzheimer’s Disease
Education & Referral Center

47. Questions?