Brian S. Appleby, M.D.Associate Professor

Department of Neurology

Young-Onset Dementia An Overview

Objectives

• Describe epidemiological characteristics of young-onset dementia (YOD)

• Discuss the differential diagnoses and evaluation of YOD

• Understand unique patient and caregiver challenges in YOD

Definition

Cognitive and functional impairment in individuals <65 years of age

Further classification:Early-onset: <65 years of ageYoung-onset: <45 years of age

Kelley BJ, Arch Neurol 2008

Cognitive Symptoms

Memory Clinic, <60 years of age:-55%, no cognitive deficits-17%, selective cognitive deficits-15%, demented -13%, not classified

Vraamark Elberling T, Neurology 2002

Patients with Dementia

Vraamark Elberling T, Neurology 2002

No Cognitive Deficits

Vraamark Elberling T, Neurology 2002

EpidemiologyAge Range Prevalence rate (per 100,000)

Male Female Total30-64 62.6 45.5 54.045-64 119.8 76.5 98.1

Harvey RJ, J Neurosurg Neurol Psychiatry 2003Garre-Olmo J, Neurology 2010

Age Range Prevalence rate (per 100,000)Male Female Total

30-64 13.0 13.9 13.4

50-64 - - 18

Demographics of YOD

Baldwin, 1994 Harvey, 2003 Fujihara, 2004 Papageorgiou, 2009 Garre-Olmo, 2010

N 43 185 141 114 144Mean Age 59 58 53 59 58.1Male 28 (65%) 107(58%) 86 (61%) 55 (48%) 73 (50.7%)

Papageorgiou S, Alzheimer Dis Assoc Disord 2009

Fujihara S, Arq Neuropsiquiatr 2004

Kelley BJ, Arch Neurol 2008

Kelley BJ, Dement Geriatr Cogn Disord 2009

Dementia Types

Alzheimer’s disease• Most prevalent YOD• Presents differently in younger patients

– 33% have non-memory symptoms– Visuospatial impairment– Apraxia

• Pathogenetic etiology (<1%)– Presenilins 1&2– Amyloid precursor protein– APOE4 effect

Tang-Wai DF, Neurology 2004Koedam EL, J Alzheimers Dis 2010

Frontotemporal Lobar Degeneration

• Frontotemporal Dementia

• Primary progressive aphasia

• Semantic dementia

• Progressive non-fluent aphasia

• Logopenic aphasia• Progressive

supranuclear palsy• Corticobasal

degeneration

Creutzfeldt-Jakob disease(CJD)

Genetic CJDFatal familial insomniaGerstmann-Sträussler-Scheinker

KuruIatrogenic CJDVariant CJD

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

Caregiver Burden

ZBI=Zarit Burden Interview From: Johns Hopkins FTD/YOD Clinic

Delany N, Int J Ger Psych 1995Sperlinger D, Int J Ger Psych 1994

Atypical Presentation

Ebner L, Alzheimer’s and Dementia 2010

Frontotemporal dementiaSchizophrenia-like psychosis

Velakoulis D, Br J Psychiatry 2009

Late Onset C9ORF72 Carriers

• Mostly FTD phenotype• Differences:

– initial cognitive impairment (memory)– Late onset psychosis

Galimberti D, Biological Psychiatry 2013

Appleby BS, J Clin Neurosci Neuropsychiatry 2007

Delayed Presentation

From onset to initial evaluation3.9 years (Garre-Olmo J, Neurology 2010)

3 years (Fujihara S, Arq Neuropsiquiatr 2004)

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

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

Appleby BS, Arch Neurol 2009

Sporadic CJD Time to Presentation(Log-rank test, χ2= 18.35, P = .003)

Mean age=59.7

Referral Patterns

Newens AJ, Br J Gen Pract 1994

Neurologist-> 63%

Psychiatrist-> 27%

Other physician->9%

Work-up Patterns

Newens AJ, 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• CMP• TSH• Vitamin B12, D3, folate• RPR• ESR• HIV

• Brain MRI w/wo

Expanded work-up

• Antibody screen• Ceruloplasmin• Iron studies• Heavy metal screen• SPEP/UPEP• Homocysteine• NH3• Genetic testing

• Brain PET scan• EEG• LP• Whole body CT

Case presentations

Case #1• 60 y.o. WF with h/o rheumatic fever, GERD,

vit D def, osteopenia, and liver/brain hemangiomas

• 1 yr h/o progressive strabismus with diplopia (repaired with return 1 mo later), parkinsonism, dysarthria, and short-term amnesia, fatigue, anxiety, panic attacks

Exam Speech: hypophonic, sparse, dysarthricThought Process: bradyphrenicAffect: stable, flat without brighteningMMSE: 7/30UPDRS II: 43Neuro: vertical gaze impairment, choppy saccades, hypomimia, axial rigidity

Case #2• 58 y.o. AAM attorney with h/o dyslexia with

a 2 yr h/o cognitive decline and personality change

• Distracted, poor concentration, low mood, fatigued

• Only reads comic books and watches cartoons, often the same ones repeatedly

Exam

General: Asked to leave room several times to walk around. Buccal stereotypies (i.e., blowing)Speech: Sparse, poverty of contentAffect: Flat, no brighteningMMSE: 19/30Brain MRI: Mild generalized atrophy

Further Work-up

Case 3

• 61 y.o. MWF, R-handed• Insidious onset, gradual progression x 1 year• Initial sx’s of effortful speech, skips nouns,

semantic paraphrasic errors• Later developed concentration difficulties,

fatigue, easily overwhelmed

Exam

• MMSE: 25/30 (-4 calc, -1 read/obey)• 3MS: 83/100• Mild L hand resting tremor• Glabellar sign

Diagnostics

• EEG: diffuse slowing• CSF: RBC=32, WBC=2, pro=25, glu=57, 14-3-3

neg, tau=354• Body FDG-PET: B thyroid lobe activity• Two brain MRI w/ cortical hyperintensity on

DWI, no ADC changes, and no changes in btwn studies

Case #4

• 50 y.o. female from Spain with 4 yr h/o gradual executive dysfxn, short-term amnesia, progressive non-fluent aphasia, parkinsonism, and myoclonus

• Paces frequently, apathetic, crying when frustrated, seen responding to internal stimuli, and sometimes thinks others are stealing from her

ExamGait: slow, shuffling, leans to leftSpeech: Effortful, paraphrasic errorsMMSE: 5/303MS: 17/100Clock: 1/5UPDRS II: 44• Myoclonus with speech and action• Left-sided neglect, finger agnosia

Exam

Pentagons Clock

Case #5

• 74 y.o. MWF with no past neuropsych history• Two family members had ALS• Presents with couple year history of profound

anxiety and compulsion to call her friends• Worried that if she does not call them,

something bad will happen to her family

Exam and Work-Up

• Extremely tense and anxious, emotionally labile• Accuses husband of mistreating her• Cognitive screening was most indicative of

impairment in delayed recall• Elevated anti-thryoglobulin/thyroperoxidase Ab,

no improvement on IV steroids• Genetic testing demonstrated C9ORF72

mutation

University Hospitals Case Medical Center Studies

• SNIFF (intranasal insulin for MCI and AD)• A4 (treatment in asymptomatic AD)• Isotretinoin (AD)• ADNI (Neuroimaging in AD)• TauRx (frontotemporal dementia)• FDA diagnostic study for sCJD (sCJD, AD, FTD)• FDG-PET neuroimaging in prion disease• Art therapy in prion disease• Determinants of initial diagnosis of prion disease• Cataracts in dementia