Dementia Associated with Lewy Body and Parkinson’s Disease

1. Dementia Associated with Lewy Body and Parkinson’s Disease Karen Mullins, D.O. University of Tennessee Knoxville Neurology Clinic

2. 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

3. 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

4. Clinical Presentation Of LBD • Visual hallucinations • Delusions • REM sleep behavior disorder • Impaired excecutive function, visuospatial function (Stroop, digit span backwards)

5. 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

6. 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

7. Diagnostic CriteriaDementia 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;13:242-254.

8. PD Dementia • Typically dementia occurs later in disease • Must meet criteria for PD first • Tremor • Rigidity • Akinesia/bradykinesia • Postural instability

9. 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.

10. 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.

11. 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.

12. PD DementiaDiagnostic 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.

13. 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

14. Neuropsychological Deficits in PDD • Executive • 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

15. 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

16. 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

17. 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

18. 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

19. Imaging in PD DementiaAmyloid 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.

20. Clinicopathologic Spectrum of Dementia Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242-254.

21. Cognitive Impairment in PDCholinesterase 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;13:242-254.

22. Cognitive Impairment in PDTreatment 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.

23. Cognitive Impairment in PDTreatment 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.

24. Cognitive Impairment in PDTreatment 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.

25. Mild Cognitive Impairment in PDAtomoxetine • 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.

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

27. Cognitive Impairment in PDTreatment Kurtz AL et al., Curr Treat Opt Neuro, 2011;13:242-254.

28. Treatment Options LBDD • Acetylcholinesterase Inhibitors • Atypical neuroleptics • Antidepressants • Dopaminergic agents • Agonists • Carbidopa/levodopa

29. Treatment Options LBDD • Benzodiazepines • Antiepileptics • Gingko baloboa

30. Nonpharmacologic Options LBDD/PAD • No approved surgery (DBS) • Keep routine • Door alarms/chimes • Geropsychiatric evaluation/home health

31. Nonpharmacologic Treatment PAD/LBDD • Exercise?? • Music therapy • Yoga/tai chi • Cognitive exercises • Adequate nutrition

32. 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

33. PD DementiaVisual 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.

34. 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

35. Caregiver Support • Local support groups • Websites: • wemove.org • pda.org • lbda.org • clincialtrials.gov • Home physical therapy, nursing etc. • Strong social support group

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

37. 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