Young-Onset Dementias Forensic Implications AAPL 2009 Presented by: Ryan C.W. Hall, M.D. and Brian S. Appleby, M.D.

Disclosures Co-Investigator of a multi-center trial of memantine for the treatment of frontotemporal dementia (Forest Laboratories) Honoraria from the CJD Foundation

Co-Investigator of a multi-center trial of memantine for the treatment of frontotemporal dementia (Forest Laboratories)

Honoraria from the CJD Foundation

Objectives Demonstrate the differential diagnosis for young-onset dementias Describe the neuropsychiatric complications of young-onset dementias Understand the management and legal complications of young-onset dementias

Demonstrate the differential diagnosis for young-onset dementias

Describe the neuropsychiatric complications of young-onset dementias

Understand the management and legal complications of young-onset dementias

Dementia Cognitive impairment Intact consciousness Functional impairment

Cognitive impairment

Intact consciousness

Functional impairment

Cognition Short-term memory Language Praxis Visuospatial skills Executive Functioning Emotion and personality

Definition Cognitive and functional impairment in individuals <65 years of age Further classification : Early-onset: <65 years of age Young-onset: <45 years of age Kelley BJ, et al. Arch Neurol , 2008

Cognitive and functional impairment in individuals <65 years of age

Further classification :

Early-onset: <65 years of age

Young-onset: <45 years of age

Cognitive Symptoms Memory Clinic, <60 years of age: -55%, no cognitive deficits -13%, mild cognitive complaints -17%, selective cognitive deficits -15%, demented Vraamark Elberling T, et al. Neurology , 2002

Memory Clinic, <60 years of age:

-55%, no cognitive deficits

-13%, mild cognitive complaints

-17%, selective cognitive deficits

-15%, demented

No Cognitive Deficits

Epidemiology (45-64 years of age) Incidence: 11.5 per 100,000 individuals Prevalence: 98.1 per 100,000 individuals Mercy L, et al . Neurology, 2009 Harvey RJ, et al . J Neurol Neurosurg Psychiatry 2003

Incidence: 11.5 per 100,000 individuals

Prevalence: 98.1 per 100,000 individuals

Epidemiology Harvey RJ, et al. J Neurosurg Neurol Psychiatry , 2003 Age Range Prevalence rate (per 100,000) Male Female Total 30-64 62.6 45.5 54.0 45-64 119.8 76.5 98.1

October 30, 2009 Causes of young-onset dementia Alzheimer disease Cerebrovascular disease Frontotemporal dementias Metabolic disorders Traumatic brain injury HIV/AIDS dementia Alcohol-related dementia Huntington disease Prion dementias Multiple sclerosis Autoimmune illnesses

Fujihara S, et al. Arq Neuropsiquiatr , 2004

Papageorgiou SG, et al ., Alzheimer Dis Assoc Disord, 2009 AD FTD

<45 years of age Kelley BJ, et al . Arch Neurol, 2008

Challenges Diagnosis Occupational Financial Social Family-spouse and children Behavioral issues Better overall health and mobility Disease specific-FTD, fAD, CJD

Diagnosis

Occupational

Financial

Social

Family-spouse and children

Behavioral issues

Better overall health and mobility

Disease specific-FTD, fAD, CJD

ZBI=Zarit Burden Interview Johns Hopkins FTD/YOD Clinic

Delany N, et al. Int J Ger Psych , 1995 Sperlinger D, et al. Int J Ger Psych , 1994

Appleby BS, et al. [In Press]

Velakoulis D, et al . BJP 2009 The solid curve shows the percentage of patients with frontotemporal dementia presenting with schizophrenia-like psychosis; the dashed curve shows the cumulative number of patients with frontotemporal dementia

Appleby BS, et al . J Neuropsychiatry Clin Neurosci, 2007

Delayed Presentation From onset to initial evaluation 3 years (Fujihara S, et al. Arq Neuropsiquiatr , 2004) 3 years (Papageorgiou SG, et al. Alzheimer Dis Assoc Disord , 2009) 2 years (Kelley BJ, et al. Dement Geriatr Cogn Disord , 2009)

From onset to initial evaluation

3 years (Fujihara S, et al. Arq Neuropsiquiatr , 2004)

3 years (Papageorgiou SG, et al. Alzheimer Dis Assoc Disord , 2009)

2 years (Kelley BJ, et al. Dement Geriatr Cogn Disord , 2009)

Creutzfeldt-Jakob disease Appleby, B. S. et al. Arch Neurol 2009;66:208-215. (Log-rank test, χ 2 = 18.35, P = 0.003) Mean age=59.7

Referral Patterns Newens AJ, et al. Br J Gen Pract , 1994 Neurologist-> 63% Psychiatrist-> 27% Other physician->9%

Work-up Patterns

Why Psychiatrists? High prevalence of behavioral disorders Frequently taking psychotropic meds 41% on neuroleptics High degree of strain and psychiatric morbidity in caregivers Need for education Baldwin RC. Psychiatr Bull , 1994 Kelley BJ, et al. Dement Geriatr Cogn Disord , 2009 Delany N & Rosenvinge H. Int J Ger Psychiatry , 1995

High prevalence of behavioral disorders

Frequently taking psychotropic meds

41% on neuroleptics

High degree of strain and psychiatric morbidity in caregivers

Need for education

We are already seeing them! Newens AJ, et al. Br J Gen Pract , 1994

Diagnosis History Course of illness Pattern of cognitive deficit Family history Other neurological signs/symptoms Other systemic illness Social/Drug history Ridha B & Josephs KA. The Neurologist , 2006

Course of illness

Pattern of cognitive deficit

Family history

Other neurological signs/symptoms

Other systemic illness

Social/Drug history

Preliminary work-up CBC Coagulation studies CMP TFT’s Vitamin B12 & folate Fasting lipid panel RPR ESR & CRP Urine toxicology Brain MRI Neuropsych testing

CBC

Coagulation studies

CMP

TFT’s

Vitamin B12 & folate

Fasting lipid panel

RPR

ESR & CRP

Urine toxicology

Brain MRI

Neuropsych testing

Expanded work-up Antibody screen Ceruloplasmin Iron studies Heavy metal screen SPEP/UPEP Homocysteine NH4 Genetic testing Brain PET scan EEG LP Whole body PET

Antibody screen

Ceruloplasmin

Iron studies

Heavy metal screen

SPEP/UPEP

Homocysteine

NH4

Genetic testing

Brain PET scan

EEG

LP

Whole body PET

Alzheimer’s disease (AD) Most prevalent dementia Presents differently in younger patients Posterior cortical atrophy Driving concerns Familial illness (<1%) Pre-senilin-1&2 Amyloid precursor protein Tang-Wai DF, et al. Neurology, 2004

Most prevalent dementia

Presents differently in younger patients

Posterior cortical atrophy

Driving concerns

Familial illness (<1%)

Pre-senilin-1&2

Amyloid precursor protein

Case 57-year-old man with AD Initial symptoms were visuospatial impairment and acalculia Police contact for suspicions of driving while intoxicated

57-year-old man with AD

Initial symptoms were visuospatial impairment and acalculia

Police contact for suspicions of driving while intoxicated

Frontotemporal Lobar Degeneration Frontotemporal Dementia Progressive Non-fluent Aphasia Semantic Dementia Neary D, et al. Neurology, 1998

FTD Core Diagnostic Features Insidious onset, gradual progression Early decline in social interpersonal conduct Early impairment in regulation of personal conduct Early emotional blunting Early loss of insight Neary D, et al. Neurology, 1998

Insidious onset, gradual progression

Early decline in social interpersonal conduct

Early impairment in regulation of personal conduct

Early emotional blunting

Early loss of insight

FTD Supportive diagnostic features Behavioral disorder Speech and language disorder Physical symptoms Investigational findings Neuropsychological testing EEG Brain imaging Neary D, et al. Neurology, 1998

Behavioral disorder

Speech and language disorder

Physical symptoms

Investigational findings

Neuropsychological testing

EEG

Brain imaging

@ Primitive reflexes and drives Rational thought, inhibition Illustration from Wider Than The Sky: The Phenomenal Gift Of Consciousness by Gerald Edelman

Phineas Gage

Case 55-year-old gentleman with FTD First presentation at airplane security Multiple family stressors Social Occupational Financial Spouse displays positive coping skills in advocacy Solution : Travel letters

55-year-old gentleman with FTD

First presentation at airplane security

Multiple family stressors

Social

Occupational

Financial

Spouse displays positive coping skills in advocacy

Solution : Travel letters

Case 59-year-old women with cortical basal degeneration Expressive aphasia and acalculia Hands blank checks to clerks Young children, ages 9 and 14 Solution: Pre-paid credit/debit cards and online video communication

59-year-old women with cortical basal degeneration

Expressive aphasia and acalculia

Hands blank checks to clerks

Young children, ages 9 and 14

Solution: Pre-paid credit/debit cards and online video communication

Traumatic Brain Injury Cognitive and neuropsychiatric effects Coup/contre-coup preferentially affect frontal lobe nerve fibers Often associated with alcohol use Chicken/Egg scenario

Cognitive and neuropsychiatric effects

Coup/contre-coup preferentially affect frontal lobe nerve fibers

Often associated with alcohol use

Chicken/Egg scenario

N Appleby BS, et al. Dement Geriatr Cogn Disord , 2008

Creutzfeldt-Jakob disease Prion disease Rapidly progressive dementia Symptoms Dementia Cerebellar impairment Vision impairment Pyramidal/Extrapyramidal symptoms Mean age of onset=62 Mean survival time=4-6 months

Prion disease

Rapidly progressive dementia

Symptoms

Dementia

Cerebellar impairment

Vision impairment

Pyramidal/Extrapyramidal symptoms

Mean age of onset=62

Mean survival time=4-6 months

Creutzfeldt-Jakob disease (CJD)

Definite CJD Histology Immunohistochemistry

Histology

Immunohistochemistry

Probable CJD Two symptoms: Cerebellar and/or visual impairment Myoclonus Akinetic mutism Pyramidal and/or Extrapyramidal symptoms Diagnostic Investigations Electroencephalogram (EEG) Cerebrospinal 14-3-3 protein Brain MRI

Two symptoms:

Cerebellar and/or visual impairment

Myoclonus

Akinetic mutism

Pyramidal and/or Extrapyramidal symptoms

Diagnostic Investigations

Electroencephalogram (EEG)

Cerebrospinal 14-3-3 protein

Brain MRI

EEG Period sharp wave complexes

Brain MRI DWI/FLAIR Cortical ribbon Basal ganglia

Case #4 57-year-old man with sCJD Social stressors Lack of support Curiosity Social construction (e.g. mad-cow disease) Solution : Family gives vague explanation (e.g. neurodegenerative illness)

57-year-old man with sCJD

Social stressors

Lack of support

Curiosity

Social construction (e.g. mad-cow disease)

Solution : Family gives vague explanation (e.g. neurodegenerative illness)

King S. Lancet , 2008

Huntington’s disease Trinucleotide repeat (CAG) disorder Genetic anticipation Atrophy of the caudate nucleus Movement (e.g. chorea), cognitive, and psychiatric symptoms Increased risk of suicide

Trinucleotide repeat (CAG) disorder

Genetic anticipation

Atrophy of the caudate nucleus

Movement (e.g. chorea), cognitive, and psychiatric symptoms

Increased risk of suicide

Case 40-year-old male with moderate dementia and psychosis from HD attacks a medical student during an examination. Risk assessment Consent for treatment

40-year-old male with moderate dementia and psychosis from HD attacks a medical student during an examination.

Risk assessment

Consent for treatment

CASE PRESENTATIONS

Case #1 64 y.o. Caucasian female Problems remembering dates and conversations, would repeat self Gradual progression with some daily fluctuations ↑ irritability, ↑ fatigue, ↓ functioning Social withdrawal, suspicious at times

64 y.o. Caucasian female

Problems remembering dates and conversations, would repeat self

Gradual progression with some daily fluctuations

↑ irritability, ↑ fatigue, ↓ functioning

Social withdrawal, suspicious at times

Brain MRI

Case #2 51 y.o. Caucasian male Trouble focusing, prioritizing, organizing Increase frequency and severity of angry outbursts Loss of empathy Rigid and resistant to change Mini-mental state exam=30/30

51 y.o. Caucasian male

Trouble focusing, prioritizing, organizing

Increase frequency and severity of angry outbursts

Loss of empathy

Rigid and resistant to change

Mini-mental state exam=30/30

Brain MRI

Case #3 39 y.o. Jordanian male Painful paresthesias of his feet (Aug) Depression (Sept) Forgetful (Nov) Inability to dress self (Jan) Worsening gait, incontinence, myoclonus (Feb)

39 y.o. Jordanian male

Painful paresthesias of his feet (Aug)

Depression (Sept)

Forgetful (Nov)

Inability to dress self (Jan)

Worsening gait, incontinence, myoclonus (Feb)

Brain MRI

Case #4 41 y.o. Caucasian female Following birth of child in her 30’s became anergic, depressed, and distractable Progressed to impulsivity and more distractability (12 car accidents/5 yrs) Periods of exhilaration and irritability with poor sleep

41 y.o. Caucasian female

Following birth of child in her 30’s became anergic, depressed, and distractable

Progressed to impulsivity and more distractability (12 car accidents/5 yrs)

Periods of exhilaration and irritability with poor sleep

Head CT

Case #5 43 y.o. Caucasian male History of alcohol, benzo, opioid abuse Found in respiratory distress, obtunded with pinpoint pupils Developed depression, apathy, disinhibition, MMSE=20/30

43 y.o. Caucasian male

History of alcohol, benzo, opioid abuse

Found in respiratory distress, obtunded with pinpoint pupils

Developed depression, apathy, disinhibition, MMSE=20/30

MRI , 8 months after inhalation

MRI , 16 months after acute phase

Thank you Johns Hopkins FTD/YOD Clinic: Chiadi Onyike Mary Anne Wylie Rebecca Rye Kate Hicks Peter Rabins Kostas Lyketsos

Johns Hopkins FTD/YOD Clinic:

Chiadi Onyike

Mary Anne Wylie

Rebecca Rye

Kate Hicks

Peter Rabins

Kostas Lyketsos