Down Syndrome. Overview. Developmental Disabilities and Dementia. Down Syndrome and Dementia. History of Down Syndrome. James B. Leverenz, M.D.

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1 Developmental Disabilities and Dementia James B. Leverenz, M.D. VA Northwest Network Parkinson Disease and Mental Illness Research Education and Clinical Centers Departments of Neurology and Psychiatry and Behavioral Sciences, University of Washington School of Medicine Pacific Northwest Udall Center UW Alzheimer s s Disease Research Center and Dementia James B. Leverenz, M.D. VA Northwest Network Parkinson Disease and Mental Illness Research Education and Clinical Centers Departments of Neurology and Psychiatry and Behavioral Sciences, University of Washington School of Medicine Pacific Northwest Udall Center UW Alzheimer s s Disease Research Center Overview Down syndrome overview» history and genetics Dementia» definitions, Alzheimer s s disease Dementia in Down syndrome» increased risk of Alzheimer s s disease and why» unique symptoms» medical management History of : John Langdon Down Physical characteristics Recognition as a distinct entity Reversion to primitive racial type: mongolian idiocy Proof that racial differences were not specific History of Fraser and Mitchell (1886)» 62 individuals with DS» Short life-span, similar appearance of individuals Wilmarth (1890)» Report on 100 brains Lejeune and colleagues (1959)» Persons with DS have extra chromosome 21

2 Genetics 101 Genetics Trisomy 21 Genetics 103 Chromosome 21 Cumulative rates of Down syndrome per 1000 live births for older mothers New York Sweden Massachusetts A ll A ll Dementia A ll A ll

3 Dementia A syndrome Progressive loss of intellectual abilities» interferes with social, occupational functioning Impairment of memory, abstract thinking, and judgment Prevalence of Alzheimer s s Disease Alzheimer s s Disease (%) Number (in millions) of DAT patients in the US Age (years) Adapted from Hebert LE, et al. JAMA. 1995;273:

4 History of Alzheimer s s Disease Auguste D. History - Alzheimer s Disease Auguste Autopsy: evenly affected atrophic brain Bielschowsky stain: very characteristic changes in the neurofibrils fibrils arranged parallel a tangled bundle of fibrils Dispersed over the entire cortex,miliary foci sites of deposition of a peculiar substance Alzheimer's Disease- Pathology Alzheimer's Disease- Pathology Silver Stain: Plaques & Tangles Normal AD Alzheimer's Disease- Pathology Alzheimer's Disease- Pathology Silver Stain: Neuritic Plaques Aβ Immunostain

5 Signs and Symptoms of Alzheimer s s Disease Early Stage Middle Stage Advanced Stage (years 0-4) (years 5-8) (years 8-12) memory loss* memory loss memory loss executive dysfunction* executive dysfunction executive dysfunction apathy apathy apathy depression (variable) depression (variable) poor insight poor insight poor insight aphasia* aphasia aphasia apraxia* apraxia apraxia disruptive agitation disruptive agitation psychosis psychosis Death rate of Down syndrome in California institutions to age 2.5 Dementia in cohort Death rate (cohort size cohort Death rate (cohort size Age in Years % (70) 1.1% (187) 1.7% (59) 2.2% (184) 1.8% (58) 0.6% (180) 1.8% (57) 0.0% (179) 5.5% (56) 0.0% (179) History of and Alzheimer s Disease Strowe (1929), plaques in 37 y.o. Bertrand and Koffas (1946), plaques in 34 y.o. Jervis (1948), 3 cases, first association DS/AD Melamud (1946), all 20 cases > 37 y.o. Whalley (1982) and Wisniewski et al. (1985), 91/93 over age 30 History of and Alzheimer s Disease Since mongoloid patients show a marked tendency to develop this type of reaction, it is suggested that the study of it offers some information which may contribute to a better understanding of the causes of senile dementia Jervis (1948)

6 Dementia in A connection is not evident, and it is a rather startling surprise to the initiate that a relationship has been reported to exist. Owens et al. (1971) Alzheimer s s Disease Pathology in Aβ deposition prior to NFT Early Aβ predominantly 1-42/431 Excess soluble AβA present at birth Paucity of patho-anatomic anatomic studies in under 30 years Leverenz and Raskind, Exp Neurol, 1998 Early AβA Deposition in Down Syndrome Early AβA Deposition in 42 cases DS under age 40 Hippocampus/parahippocampus Aβ immunohistochemistry and Bielschowsky silve strain Quantitative image analysis 12.5% 30% 75% 100% Leverenz and Raskind, Exp Neurol, 1998 Leverenz and Raskind, Exp Neurol, 1998 AGE Sex ITG/P CA-1 CA 2-4 DM HG 8 M F M F F F F M M M M M M * M M F * M * M Old DS (55.3) AD (76.1) Aβ Burden (% cortical area) in Hippocampal/ Parahippocampal Formation Early AβA Deposition in - 8 y.o. DS Silver stain Leverenz and Raskind, Exp Neurol, 1998 Aβ immunostain

7 Early AβA Deposition in Early AβA Deposition in PHG - diffuse plaques CA-1/Subiculum - neuritic plaques Leverenz and Raskind, Exp Neurol, 1998 Leverenz and Raskind, Exp Neurol, 1998 Early AβA Deposition in Down Syndrome Genetics Trisomy 21 Age dependent increase in AβA deposition Marked differences in AβA deposition within age groups Stereotypic deposition: PHG/ITG > CA-1/DM > CA 2-42 Earliest neuritic plaques in CA-1/Subiculum Gender independent Chromosome 21

8 Signs and Symptoms of Alzheimer s s Disease Early Stage Middle Stage Advanced Stage (years 0-4) (years 5-8) (years 8-12) memory loss* memory loss memory loss executive dysfunction* executive dysfunction executive dysfunction apathy apathy apathy depression (variable) depression (variable) poor insight poor insight poor insight aphasia* aphasia aphasia apraxia* apraxia apraxia disruptive agitation disruptive agitation psychosis psychosis Dementia in : Lai and Williams 89 84% of demented individuals with seizure disorder (10% in general AD population) 20% developed clinical Parkinsonism 14% with myoclonus 12 autopsied cases, all with AD changes, only one with Lewy bodies Dementia in : Lai and Williams 89 Stages of Dementia in DS: Memory loss, temporal disorientation, reduced verbal output, apathy reduced social interaction Loss ADL s, slowed gait, seizures Non-ambulatory, incontinent, frontal release signs Dementia in : Dalton et al available clinical/pathological studies: 58% - seizures 46% - personality change 36% - apathy/ inactivity 30% - impairment of ADL 21% - gait disturbance 18% - memory loss Behavioral Disturbances in? Frequency in non-demented DS Dementia» early personality change» apathy» agitation» psychosis Psychosis in 0.2 to 31.6% prevalence reported Little detail on characteristics Case reports» Depression» Basal ganglia calcifications

9 Psychosis in Psychosis in Case series from behavioral neurology clinic and Aging in Down Syndrome study Fifty cases All adults at time of assessment 24 males/26 females Twenty four with neuropsychiatric inventory (NPI) Six with autopsy Majority non-institutionalized Caucasian Twenty-two two with dementia (28 without) Twenty with psychosis (hallucinations and/or delusions) Psychosis in Psychosis in Psychotic Group» 67% female» Mean age 49.2 (vs years)» 60% with dementia (vs. 33%) Neuropsychiatric Inventory (NPI)» Twenty-four assessed» Psychotic Mean = 24.4 (vs. 9.8)» For all groups 71% agitation 46% depression or anxiety Psychosis in Neuropsychiatric Inventory» Psychotic Increased irritability and total scores Only mild increase in depression (1.8 vs. 0.8) A trend for higher psychosis scores for non- demented vs. demented (12.5 vs. 5.3) Psychosis in Treatment response» 85% of psychotics receiving psychotropics» Multiple agents associated with younger age» 40% positive response rate

10 Psychosis in : Conclusions Data on prevalence of psychosis in DS needs to be improved Psychosis in DS is observed in both non-demented and demented individuals Demented psychotics have less severe and more responsive disease Psychosis with early onset may have a different etiology with more severe disease Medical Mangement of Dementia Acetylcholine Rivastigmine H 3C Mechanism: AChE/BuChE-I O H 3CO C H 3 CO Donepezil Mechanism: AChE-I Cholinesterase Inhibitors H 3C + O CH N 3 H 3C CH O 3 N CH 3 CH 3 CH 3 O N CH 3 H 3C N H 2 N C H2 O O OCH 3 HO Galantamine Mechanism: AChE-I Behavior Cholinergic Drug Therapy in DS Activities of Daily Living Cognition Physicians Desk Reference 2003, 57th ed. Montvale, NJ: Medical Economics Company; November 2002 Managing Behavioral Disturbances: Depression Most common in PDD and DLB early in non-lewy body diseases true depression responds to antidepressants Behavioral management» activity (get out of the house!) Managing Behavioral Disturbances: Disruptive Agitation Complex problem that may involve more than one behavior» irritability» pacing» psychosis» aggression

11 Managing Behavioral Disturbances: Disruptive Agitation - irritability Reactive irritability» stimulus induced ( shower( shower )» antidepressants (sertraline my favorite)» caregiver education it s s the dementia (nothing personal) pick your fights distraction Managing Behavioral Disturbances: Psychosis Components» hallucinations» delusion (false beliefs) Antipsychotics» black box warning» quetiapine (low EPS, sedating) Don t t treat if not disturbing Managing Behavioral Disturbances: Disruptive Agitation - aggression Search for origin/source» irritability sertraline, distraction, etc.» psychosis antipsychotic» environmental move patient Other Disabilities & Dementia Very limited data» small numbers of cases» no clear relationships Aging disorders» Werner syndrome Werner Syndrome & Dementia Werner Syndrome & Dementia Mutation Chromome 8» DNA repair enzyme Aging disorder» short stature» premature graying» cataracts» diabetes» cancer»? dementia

12 Werner Syndrome & Dementia Werner Syndrome & Dementia 51 and 57 y.o. Werner syndrome sisters No clear dementia Brain pathology» amyloid deposition» limited neurofibrillary pathology Werner Syndrome & Dementia Questions? Amyloid Deposits Neurofibrillary tangles

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