1. What is Dementia with Lewy Bodies? James B. Leverenz, M.D. Departments of Neurology and Psychiatry and Behavioral Sciences University of Washington School of Medicine and VA Northwest Network Mental Illness and Parkinson’s Disease Research, Education, and Clinical Center VA Northwest Network Mental Illness and Parkinson’s Disease Research, Education, and Clinical Centers

4. History of Parkinson’s Disease 138-201 Galen describes resting tremor 1817Initial description of disease by James Parkinson 1859/68Trousseau describes intellectual decline 1861-95Charcot and Brissaud emphasize rigidity, bradykinesia and “psychic troubles”

5. Clinical Symptoms in Parkinson’s Disease Tremor (resting)Tremor (resting) RigidityRigidity BradykinesiaBradykinesia Postural instabilityPostural instability

6. Parkinson’s Disease

8. Pathology in Parkinson’s Disease Clinical history of parkinsonismClinical history of parkinsonism Neuronal loss and Lewy body inclusions in the substantia nigra, locus coeruleus, basal forebrain and cerebral cortexNeuronal loss and Lewy body inclusions in the substantia nigra, locus coeruleus, basal forebrain and cerebral cortex

9. Lewy Body Inclusions Characteristic inclusions in substantia nigra neurons of patients with Parkinson’s diseaseCharacteristic inclusions in substantia nigra neurons of patients with Parkinson’s disease Immunoreactive for neurofilaments, ubiquitin and alpha- synuclein, but not tau (NFT are tau and ubiquitin positive)Immunoreactive for neurofilaments, ubiquitin and alpha- synuclein, but not tau (NFT are tau and ubiquitin positive) In substantia nigra it is cytoplasmic, round, eosinophilic with clear haloIn substantia nigra it is cytoplasmic, round, eosinophilic with clear halo In cortex less distinct appearance, best visualized with alpha-synuclein immunohistochemistryIn cortex less distinct appearance, best visualized with alpha-synuclein immunohistochemistry

10. Pathology in Parkinson’s Disease

13. History of Dementia with Lewy Bodies 1961First report of cortical LB’s in dementia (Okazaki et al) 1974Start of clinical reports of parkinsonism in AD 1986High frequency of LB in AD patients (Leverenz & Sumi) 1990“Lewy body variant” proposed (Hansen et al) 1990“Diffuse Lewy body disease” (Crystal et al) 1996“Dementia with Lewy bodies” (Consortium on DLB)

14. Consensus Criteria for Dementia with Lewy Bodies 1. Progressive cognitive decline with loss of normal social and occupational function: loss of memory, attention, frontal subcortical skills, visuospatial ability 2. Two of the following: a. fluctuating cognition, attention, alertness b. visual hallucinations c. motor features of parkinsonism 3. Supportive features: falls, syncope, LOC, neuroleptic sensitivity, delusions, non-visual hallucinations

15. Consensus Criteria for Dementia with Lewy Bodies “It is suggested that if dementia occurs within 12 months of the onset of extrapyramidal motor symptoms, the patient should be assigned a primary diagnosis of possible DLB … “ “If the clinical history of parkinsonism is longer than 12 months, PD with dementia … will usually be a more appropriate diagnostic label …”

16. Consensus Criteria for Dementia with Lewy Bodies Criteria good predictor of Lewy body pathology (with or without concomitant AD pathology) - high positive predictive value Criteria good predictor of Lewy body pathology (with or without concomitant AD pathology) - high positive predictive value Criteria poor predictor of the absence of Lewy body pathology - low negative predictive value Criteria poor predictor of the absence of Lewy body pathology - low negative predictive value

17. Lewy Body Frequency in Alzheimer’s Disease 198628% of AD (Leverenz and Sumi) 198755% of AD (Ditter and Mirra) 199521% in CERAD registry (Hulette et al) 1998 23% in community based series (Lim et al) 1996Dementia with Lewy bodies, largest pathological subgroup after pure AD (Consortium on DLB)

18. Lewy Body Frequency in Alzheimer’s Disease 1998 to 20001998 to 2000 »Using ASN immunohistochemistry and amygdala sampling »63% PS-1/APP mutation AD »50% of Down syndrome »61% of “sporadic” AD »64% PS-2 mutation AD

20. Lewy Body Frequency in Alzheimer’s Disease 20032003 »33 % of AD cases in a community- based sample  alpha-synuclein staining  amygdala sampling There appears to be a sampling- bias in the frequency of LB pathologyThere appears to be a sampling- bias in the frequency of LB pathology

21. Consensus Criteria for Dementia with Lewy Bodies Pathology Essential for diagnosis of DLBEssential for diagnosis of DLB » Lewy bodies Associated but not essentialAssociated but not essential » Lewy-related neurites » Plaques (all morphologic types) » Neurofibrillary tangles » Regional neuronal loss (substantia nigra, locus coeruleus, basal forebrain) » Microvacuolation and synapse loss » Neurochemical abnormalities and neurotransmitter deficits

22. Pathology in Dementia with Lewy Bodies Neuronal loss and LB’s in substantia nigraNeuronal loss and LB’s in substantia nigra Cortical LB’s and CA-2 ubiquitinated fibersCortical LB’s and CA-2 ubiquitinated fibers Full AD pathology (SP/NFT), ~ 80%Full AD pathology (SP/NFT), ~ 80% Restricted AD pathology (diffuse SP and restricted NFT distribution), ~ 20%Restricted AD pathology (diffuse SP and restricted NFT distribution), ~ 20%

23. Pathology in Dementia with Lewy Bodies Substantia nigra

24. Pathology in Dementia with Lewy Bodies Substantia nigra

25. Pathology in Dementia with Lewy Bodies CerebralCortex

26. Hippocampal CA-2 Neurites

27. Pathology in Dementia with Lewy Bodies Amygdala

28. The Clinical Diagnosis of Dementia with Lewy Bodies

29. Consensus Criteria for Dementia with Lewy Bodies 1. Progressive cognitive decline with loss of normal social and occupational function: loss of memory, attention, frontal subcortical skills, visuospatial ability 2. Two of the following: a. fluctuating cognition, attention, alertness b. visual hallucinations c. motor features of parkinsonism 3. Supportive features: falls, syncope, LOC, neuroleptic sensitivity, delusions, non-visual hallucinations

30. Clinical Signs and Symptoms in DLB Early psychiatric symptomsEarly psychiatric symptoms »Visual hallucinations, complex delusions ParkinsonismParkinsonism »Early gait and posture/stance difficulties »Tremor less frequent »May never be clinically evident

31. Clinical Signs and Symptoms in DLB CognitionCognition »Short-term memory loss »Cortical dysfunction »Greater insight Neuroleptic sensitivityNeuroleptic sensitivity

32. Clinical Signs and Symptoms in DLB ExaminationExamination »Gait evaluation (arm swing, posture, postural stability »Frontal release signs (snout, glabellar, palmomental) TestingTesting »standard dementia w/u

33. Diagnostic Accuracy in a Community-Based Sample of DLB

35. Treatment of Dementia with Lewy Bodies: Cholinesterase Inhibitors

36. Major Changes in the Cholinergic System in Alzheimer’s Disease Depletion of acetylcholine (ACh)Depletion of acetylcholine (ACh) Decline in choline acetyltransferase (ChAT) activityDecline in choline acetyltransferase (ChAT) activity Loss of cholinergic neuronsLoss of cholinergic neurons  Acetylcholinesterase (AChE)  Acetylcholinesterase (AChE)  Butyrylcholinesterase (BuChE)  Butyrylcholinesterase (BuChE) Alterations in nicotinic/muscarinic receptorsAlterations in nicotinic/muscarinic receptors

37. FC = Frontal cortex PC = Parietal cortex OC = Occipital cortex H = Hippocampus B = Nucleus basalis S = Medial septal nucleus Adapted from Coyle JT, et al. Science. 1983;219:1184-1190. Cholinergic System Innervates Areas Associated With Memory and Learning FC PC B H OC S

38. Is There a Cholinergic Deficit in DLB ? Depletion of acetylcholine (ACh) ?Depletion of acetylcholine (ACh) ? Decline in choline acetyltransferase (ChAT) activity Decline in choline acetyltransferase (ChAT) activity  Loss of cholinergic neurons Loss of cholinergic neurons   Acetylcholinesterase (AChE) ?  Acetylcholinesterase (AChE) ?  Butyrylcholinesterase (BuChE) ?  Butyrylcholinesterase (BuChE) ? Alterations in nicotinic/muscarinic receptors Alterations in nicotinic/muscarinic receptors 

39. Is There a Cholinergic Deficit in DLB ? Samuel et al (JNEN 1997)Samuel et al (JNEN 1997) »30% reduction of ChAT in AD »75% reduction of ChAT in DLB Tiraboschi et al (Arch Psychiat 2002)Tiraboschi et al (Arch Psychiat 2002) »ChAT preserved in mild AD »ChAT significantly lower in early DLB

40. Cholinesterase Inhibitors: Treatment of DLB Multiple positive open-label trials (tacrine, donepezil, rivastimine)Multiple positive open-label trials (tacrine, donepezil, rivastimine) McKeith et al (Lancet 2000)McKeith et al (Lancet 2000) »Double-blinded, 120 patients »Rivastigmine up to 12 mg/d »Focus on behavioral symptoms using NPI

41. Cholinesterase Inhibitors: Treatment of DLB McKeith et al (Lancet 2000)McKeith et al (Lancet 2000) »NPI – Positive - apathy, indifference, anxiety, delusions, hallucinations and aberrant motor behavior – No change - depression, agitation/aggression, irritability, sleep

42. Cholinesterase Inhibitors: Treatment of DLB McKeith et al (Lancet 2000)McKeith et al (Lancet 2000) »MMSE trend positive (p = 0.07) »Individual cognitive data all “significantly favoured rivastigmine.” and “...will be described more fully elsewhere.”

43. Rivastigmine International Lewy Body Dementia Trial: Behavioural Changes (NPI) NPI 10-item Score–Mean Change from Baseline (OC) -8 -7 -6 -5 -4 -3 -2 0 Baseline Week 12 Week 20 Rivastigmine Placebo Improvement *P<0.01 vs placebo (ANOVA/ANCOVA) McKeith IG, et al. American Academy of Neurology 52 nd Annual Meeting. April 29-May 6, 2000. San Diego, California. *

44. Treatment of Dementia with Lewy Bodies: Behavioral Disturbances

45. Treating Behavioral Disturbances in DLB Cholinesterase inhibitorsCholinesterase inhibitors »apathy, psychosis in rivastigmine study Lack of Treatment trialsLack of Treatment trials »agitation »psychosis

46. Pharmacologic Approaches to Agitation in AD Anti-epileptics (mood stabilizers) »valproic acid (Depakote) »carbamazepine (Tegretol) CNS-active beta-blockers »propranolol Other approaches »trazodone »antiandrogens/estrogens

47. Antipsychotic Medications Avoid typical antipsychoticsAvoid typical antipsychotics Consider lowering dopaminergic agentsConsider lowering dopaminergic agents Atypical agentsAtypical agents

48. Agents for Psychotic Symptoms AgentHaloperidolThioridazineRisperidoneOlanzapineQuetiapineClozapine Starting Dose 0.5 mg/day 10-25 mg/day 0.5-1.0 mg/day 2.5 mg/day 25-50 mg/day 6.25 mg/day Maximal Dose 2-5 mg/day 50-100 mg/day 2-6 mg/day 2.5-15 mg/day 400 mg/day 50 mg/day

49. Treatment of Dementia with Lewy Bodies: Motor Symptoms

50. Antiparkinsonian Medications No prospective treatment trialsNo prospective treatment trials Generally less responsive (non- dopaminergic motor symptoms)Generally less responsive (non- dopaminergic motor symptoms) Can elect not to treatCan elect not to treat L-dopa preferred to agonistsL-dopa preferred to agonists

51. Pharmacologic Approaches to DLB Cholinesterase inhibitors Atypical antipsychotics Limited dopaminergic agents Other approaches »? AD agitation medications »? Vitamin E »? Estrogens, NSAIDS, vaccine, BACE inhibitors

52. DLB: Research Directions Improvement in clinical diagnosisImprovement in clinical diagnosis »imaging, electrophysiology Clinical trialsClinical trials »cognition, behavior, motor Clinical-pathologic studiesClinical-pathologic studies BiochemistryBiochemistry »ACh, DA, NE, 5HT GeneticsGenetics »familial DLB, risk factors

53. How do you define a “disease” ? Genetics > Pathology > Clinical ? Genetics > Pathology > Clinical ? » mutation causes pathology leading to the clinical presentation What about known pathogens ? What about known pathogens ? » e.g. syphilis, mad cow disease (exposure superimposed on genetic risk). Becoming difficult to define “a disease” Becoming difficult to define “a disease”

54. Summary What is Dementia with Lewy bodies ?What is Dementia with Lewy bodies ? »Variant of Alzheimer’s disease »Variant of Parkinson’s disease »Clinical syndrome with unique clinical presentation and management issues »Common pathology in dementia (30 to 60%) »Additional study needed to fully characterize this “second-leading” cause of dementia