AAPL 2009

Young-Onset Dementias

Forensic Implications

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

Objectives

I. Demonstrate the differential diagnosis for young-onset dementias

II. Describe the neuropsychiatric complications of young-onset dementias

III. Understand the management and legal complications of young-onset dementias

Dementia

1. Cognitive impairment

2. Intact consciousness

3. Functional impairment

CognitionShort-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 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

No Cognitive Deficits

Vraamark Elberling T, et al. Neurology, 2002

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, 2009Harvey RJ, et al. J Neurol Neurosurg Psychiatry 2003

Epidemiology

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

Harvey RJ, et al. J Neurosurg Neurol Psychiatry, 2003

April 12, 2023 11

Causes of young-onset dementia

Alzheimer diseaseCerebrovascular diseaseFrontotemporal dementiasMetabolic disordersTraumatic brain injuryHIV/AIDS dementia

Alcohol-related dementiaHuntington diseasePrion dementiasMultiple sclerosisAutoimmune 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

ZBI=Zarit Burden Interview Johns Hopkins FTD/YOD Clinic

17Delany N, et al. Int J Ger Psych, 1995Sperlinger 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 evaluation3 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)

Appleby, B. S. et al. Arch Neurol 2009;66:208-215.

Creutzfeldt-Jakob disease(Log-rank test, χ2= 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, 1994Kelley BJ, et al. Dement Geriatr Cogn Disord, 2009

Delany N & Rosenvinge H. Int J Ger Psychiatry, 1995

We are already seeing them!

Newens AJ, et al. Br J Gen Pract, 1994

DiagnosisHistory

• 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

Preliminary work-up

• 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

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

Case• 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

SemanticDementia

Neary D, et al. Neurology, 1998

FTD Core Diagnostic Features

A. Insidious onset, gradual progression

B. Early decline in social interpersonal conduct

C. Early impairment in regulation of personal conduct

D. Early emotional blunting

E. Early loss of insight

Neary D, et al. Neurology, 1998

FTDSupportive diagnostic features

A. Behavioral disorder

B. Speech and language disorder

C. Physical symptoms

D. Investigational findings1. Neuropsychological testing

2. EEG

3. Brain imaging

Neary D, et al. Neurology, 1998

@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

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

Traumatic Brain Injury

• 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

Creutzfeldt-Jakob disease(CJD)

Definite CJD

Histology Immunohistochemistry

Probable CJD

I. Two symptoms:A. Cerebellar and/or visual impairment

B. Myoclonus

C. Akinetic mutism

D. Pyramidal and/or Extrapyramidal symptoms

II. Diagnostic InvestigationsA. Electroencephalogram (EEG)

B. Cerebrospinal 14-3-3 protein

C. Brain MRI

EEGPeriod sharp wave complexes

Brain MRIDWI/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)

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

Case

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

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

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)

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

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

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