1 / 62

Dementia with Lewy Bodies: What is it and how do I treat it ?

Dementia with Lewy Bodies: What is it and how do I treat it ?. James B. Leverenz, M.D. Departments of Neurology and Psychiatry and Behavioral Sciences University of Washington School of Medicine and

angelina-ebrill
Download Presentation

Dementia with Lewy Bodies: What is it and how do I treat it ?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Dementia with Lewy Bodies:What is it and how do I treat it ? 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 Centers

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

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

  4. Clinical Symptoms in Parkinson’s Disease • Tremor (resting) • Rigidity • Bradykinesia • Postural instability

  5. Parkinson’s Disease

  6. Parkinson’s Disease

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

  8. Lewy Body Inclusions • Characteristic 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) • In substantia nigra it is cytoplasmic, round, eosinophilic with clear halo • In cortex less distinct appearance, best visualized with alpha-synuclein immunohistochemistry

  9. Pathology in Parkinson’s Disease

  10. Pathology in Parkinson’s Disease

  11. Pathology in Parkinson’s Disease

  12. History of Dementia with Lewy Bodies 1961 First report of cortical LB’s in dementia (Okazaki et al) 1974 Start of clinical reports of parkinsonism in AD 1986 High 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)

  13. 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

  14. 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 …”

  15. 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 poor predictor of the absence of Lewy body pathology - low negative predictive value

  16. Lewy Body Frequency in Alzheimer’s Disease 1986 28% of AD (Leverenz and Sumi) 1987 55% of AD (Ditter and Mirra) 1995 21% in CERAD registry (Hulette et al) 1998 23% in community based series (Lim et al) 1996 Dementia with Lewy bodies, largest pathological subgroup after pure AD (Consortium on DLB)

  17. Lewy Body Frequency in Alzheimer’s Disease • 1998 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

  18. Lewy Body Frequency in Alzheimer’s Disease • 2003 • 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 pathology

  19. Consensus Criteria for Dementia with Lewy Bodies Pathology • Essential for diagnosis of DLB • Lewy bodies • Associated 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

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

  21. Pathology in Dementia with Lewy Bodies Substantia nigra

  22. Pathology in Dementia with Lewy Bodies Substantia nigra

  23. Pathology in Dementia with Lewy Bodies Cerebral Cortex

  24. Pathology in Dementia with Lewy Bodies Hippocampal CA-2 Neurites

  25. Pathology in Dementia with Lewy Bodies Amygdala

  26. The Clinical Diagnosis of Dementia with Lewy Bodies

  27. 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

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

  29. Clinical Signs and Symptoms in DLB • Cognition • Short-term memory loss • Cortical dysfunction • Greater insight • Neuroleptic sensitivity

  30. Clinical Signs and Symptoms in DLB • Examination • Gait evaluation (arm swing, posture, postural stability • Frontal release signs (snout, glabellar, palmomental) • Testing • standard dementia w/u

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

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

  33. Treatment of Dementia with Lewy Bodies:Cholinesterase Inhibitors

  34. Major Changes in the CholinergicSystem in Alzheimer’s Disease • Depletion of acetylcholine (ACh) • Decline in choline acetyltransferase (ChAT) activity • Loss of cholinergic neurons •  Acetylcholinesterase (AChE) •  Butyrylcholinesterase (BuChE) • Alterations in nicotinic/muscarinic receptors

  35. Cholinergic System Innervates Areas Associated With Memory and Learning PC FC OC S B H 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.

  36. Cholinergic Enhancement Strategies • Analogous to dopaminergic enhancement strategies for Parkinson's disease • Cholinesterase inhibitor therapy • inhibits AChE (BuChE-tacrine/rivastigmine), degradative enzyme for acetylcholine • results in increase of acetylcholine available to postsynaptic neurons • increases cholinergic neurotransmission

  37. ACh Normal Cholinergic Function Acetyl CoA Astrocyte Presynaptic neuron + Choline Choline BuChE ChAT BuChE Synaptic cleft ACh Choline + AChE Postsynapticneuron Acetate AChE Cholinergic receptor ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A. Adapted from Adem A. Acta Neurol Scand. 1992;85(suppl 139):69-74.

  38. Effect of Tacrine on Cognition:ADAS-Cog* –3 Improve † –2 –1 Mean Change from Baseline  4.1‡ 0 Baseline 160 mg/d (n=238) 120 mg/d (n=174) 80 mg/d (n=60) Placebo (n=181) 1 2 Decline 3 Baseline 6 12 18 24 30 Weeks *Alzheimer’s Disease Assessment Scale–Cognitive Subscale †P<0.001 vs placebo; ‡Observed mean treatment difference. Evaluable patients at week 30 = 263. Knapp MJ, et al, for the Tacrine Study Group. JAMA. 1994;271:985-991.

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

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

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

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

  43. Cholinesterase Inhibitors:Treatment of DLB • 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.”

  44. Rivastigmine International Lewy Body Dementia Trial: Behavioural Changes (NPI) NPI 10-item Score–Mean Change from Baseline (OC) * -8 Rivastigmine -7 Placebo -6 -5 Improvement -4 -3 -2 -1 0 Week 20 Baseline Week 12 *P<0.01 vs placebo (ANOVA/ANCOVA) McKeith IG, et al. American Academy of Neurology 52nd Annual Meeting. April 29-May 6, 2000. San Diego, California.

  45. Treatment of Dementia with Lewy Bodies:Behavioral Disturbances

  46. Treating Behavioral Disturbances in DLB • Cholinesterase inhibitors • apathy, psychosis in rivastigmine study • Lack of Treatment trials • agitation • psychosis

  47. 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

More Related