Parkinson's Disease Dementia


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

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  • Note the major issues are not the motor symptoms.
  • Note the major issues are not the motor symptoms.
  • Note the major issues are not the motor symptoms.
  • 3rd – In study using Medicare data, Blacks with PD were more likely to develop dementia than whites. Hispanics were also more likely to develop dementia. Asians were less likely to have dementia/cognitive impairment.
  • Movement Disorder Society Task Force
  • 34. Huang X, Chen P, Kaufer DI, Troster AI, Poole C. Apolipoprotein E and dementia in Parkinson's disease: a meta-analysis. Arch Neurol 2006;63(2):189-193.35. Morley JF, Xie SX, Hurtig HI, Stern MB, Colcher A, Horn S, Dahodwala N, Duda JE, Weintraub D, Chen-Plotkin AS, Van Deerlin V, Falcone D, Siderowf A. Genetic influences on cognitive decline in Parkinson's's disease. MovDisord 2012;27(4):512-518.36. Williams-Gray CH, Evans JR, Goris A, Foltynie T, Ban M, Robbins TW, Brayne C, Kolachana BS, Weinberger DR, Sawcer SJ, Barker RA. The distinct cognitive syndromes of Parkinson's's disease: 5 year follow-up of the CamPaIGN cohort. Brain 2009;132(Pt 11):2958-2969.Seto-Salvia N, Pagonabarraga J, Houlden H, Pascual-Sedano B, Dols-Icardo O, Tucci A, Paisan-Ruiz C, Campolongo A, Anton-Aguirre S, Martin I, Munoz L, Bufill E, Vilageliu L, Grinberg D, Cozar M, Blesa R, Lleo A, Hardy J, Kulisevsky J, Clarimon J. Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's's disease course. MovDisord 2012;27(3):393-399.
  • Note the major issues are not the motor symptoms.
  • Parkinson's Disease Dementia

    1. 1. Parkinson’s Disease Dementia Matthew J. Barrett, MD, MSc Assistant Professor of Neurology University of Virginia Charlottesville, Virginia USA
    2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 17. PDD Cognitive profile • Cognitive profile can be used for diagnosis but does not conclusively differentiate diagnoses. (Emre, et al. 2007)
    18. 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. 19. PDD Neuropsychiatric Symptoms Mood disorder Depression 40-60% Anxiety 30-50% Apathy 25-50%
    20. 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. 21. PDD Motor Symptoms • Advanced motor symptoms. • Greater axial rigidity and postural instability. • Increased falls.
    22. 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. 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. 24. Differential Diagnosis • AD with late Parkinsonism • Parkinsonism and dementia of other disorders • Frontotemporal Dementia • Vascular parkinsonism/dementia • NPH
    25. 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. 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. 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. 28. 76 year old man • Assessment • Advanced Parkinson's disease with dementia (PDD) • Major issues of dementia, insomnia, anxiety, and freezing of gait
    29. 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. 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. 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. 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. 33. Treatment - Psychosis • Reduction in dopaminergic medications • Elimination of other possible contributory medications – anticholinergics, benzodiazepines • Rule out metabolic causes of delirium
    34. 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. 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. 36. Treatment • Depression • SSRI/SNRIs • REM sleep behavior disorder • Environmental modification • Benzodiazepines
    37. 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. 38. 76 year old man • Assessment • Advanced Parkinson's disease with dementia (PDD) • Major issues of dementia, insomnia, anxiety, and freezing of gait
    39. 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. 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. 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. 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. 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. 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. 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. 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) • Download free diagnostic and comprehensive symptom checklists from Order print copies of this 40 page booklet from NIA’s Alzheimer’s Disease Education & Referral Center
    47. 47. Questions?