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Dementia Associated with Lewy Body and Parkinson’s Disease

Dementia Associated with Lewy Body and Parkinson’s Disease. Karen Mullins, D.O. University of Tennessee Knoxville Neurology Clinic. Lecture Objectives. Describe clinical presentations of Lewy Body and Parkinson’s Associated Dementia(PAD)

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Dementia Associated with Lewy Body and Parkinson’s Disease

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  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

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