1. 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 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;13:242- 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 PD Fronto-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 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.

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 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.

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

21. 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;13:242- 254.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. Cognitive Impairment in PD Treatment 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 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.

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