Chiadi U. Onyike, MD, MHS Johns Hopkins Neuropsychiatry

Disclosure: PI, Baltimore site of multicenter trial of memantine for

behavioral frontotemporal dementia ▪ Results published: The Lancet Neurology, 12(2), 149–156.

PI, Baltimore site of multicenter trial of LMTM for behavioral frontotemporal dementia

Content: Spectrum of non-Alzheimer neurodegenerative diseases Their features Their management

A teacher of 58 developed dysnomia and decline in spelling ability, comprehension of reading and conversation, and singing ability. Attention, planning/organization and self care were impaired, and he exhibited child-like behavior and loss of etiquette (eating some meals with his fingers). He developed anxiety. Two years into the illness, a neurologist suspected dementia. MMSE score was 27 points and the neurological exam was normal. Brain MRI showed temporal lobe atrophy.

Neuropsychological testing 3 years later showed MMSE = 28, and impaired memory and learning, marked dysnomia, and poor word knowledge with paraphasias and regularization spelling errors. Behavior was impulsive and obstinate. Eating was gluttonous. A year later MMSE = 29. Further decline in word and object knowledge was noted…

High prevalence 682 with MCI (n=138) or

dementia (n=270)

43% of MCI ▪ 20% depression ▪ 15% apathy ▪ 15% irritability

75% of dementia patients ▪ 35% apathy ▪ 32% depression ▪ 30% agitation/aggression

Incidence N (%), N = 61 Mean severity score (SD)

Delusions 17 (27.9) 4.1 (3.6)

Apathy 13 (21.3) 5.6 (3.6)

Aberrant motor behavior 13 (21.3) 3.7 (2.5)

Irritability 12 (19.7) 3.8 (4.0)

Depression 11 (18.0) 4.7 (3.2)

Hallucinations 10 (16.4) 2.9 (1.3)

Agitation/aggression 10 (16.4) 6.4 (3.8)

Anxiety 9 (14.8) 3.6 (2.6)

Disinhibition 6 (9.8) 2.0 (0.9)

Elation 0 (0) N/A

Is it “memory loss”?

Is it just cognition?

What about? Depression/anxiety Paranoia and delusions Hallucinations Abnormalities of judgment

and social conduct Compulsions

Alzheimer disease, AD Most common cause

Cerebrovascular disease, CVD Genetic varieties particularly

Frontotemporal degeneration, FTD 1:1 or greater ratio FTD:AD below age 50

Lewy body disease Uncommon before age 65

Traumatic brain injury, TBI

HIV/AIDS dementia Prevalence decreased since HAART

Alcohol-related dementia Controversial; due to nutritional deficiency?

Huntington disease, HD Among the commonest below age 35

Prion dementias, e.g., CJD Fulminant progression

Multiple sclerosis, MS

Normal Pressure Hydrocephalus

Left: The Prague Asylum, with a view of the tower of St. Catharine Monastery. Right: Arnold Pick (1851-1924); Professor of Psychiatry and Neuropathology and Chair of Neuropsychiatry in Prague (1887-1921). He described the presenile focal dementias and aphasias that would became known as ‘Pick’s disease’.

Source: Kertesz and Kavlach, 1996

Historical timeline

“It’s hallmarks are progressive decline in

[conduct]: coarsening of temperament, dispositions, judgment, and comportment; dysregulation of emotions, drives and self-control; and disintegration of language and communication… Aphasia syndromes and motor syndromes are also well recognized”

1896 – case study: primary aphasia

1911 – “Pick” bodies

1923/26 – “Picks disease”

1974/75 – Types A, B and C

1975 – Semantic aphasia

1982 – Primary progressive aphasia

1986 – 1st conference, Lund, Sweden

1994 & 98 – Lund-Manchester criteria

1998 – 1st genetic locus (MAPT)

2006 & 09 – TDP43 & FUS discovery

2011 – International criteria

2011 – 7th genetic locus (C9orf72)

Definition

Onyike et al., 2011

Insidious deterioration

Behavioral disinhibition and asocial behavior

Inertia and apathy

Loss of empathy/sympathy

Perseveration, stereotypies and compulsions

Hyperorality, hyperphagia and/or stereotyped eating habits

Executive dysfunction

Focal abnormality on brain imaging

Causal mutation

Peak age of onset 53 – 58; range 21 – 75…

Prevalence: 18 – 38 per 100,000

Incidence: 3 – 4 per 100,000

Life expectancy: 8 –10 years; ~3 years for FTD-ALS

M>>F in most reports

AD:FTD ratio <2 below age 65

Familial in >40%; hereditary in 10-20%

Phenotypic heterogeneity reflects biologic heterogeneity

Syndrome to disease (phenotype:pathology) correlation is imperfect

Syndrome to genotype correlation is also imperfect

Syndromes not shown include affective and psychotic presentations

Gender Onset Clinic Death Features FamHx Tau Ubiq TDP43 Diagnosis

Case 1 F 21 22 25 DEP, COGIMP None + - N FTD17

Case 2 M 28 33 37 SCHIZ None - + + FTD-MND

Case 3 M ? 37 46 APATH/DISIN ? - - ? DLDH

Case 4 M 34 39 41 BIPOLAR None - + N FTD-U

Case 5 M 35 39 43 SCHIZ None - + + FTD-MND

Case 6 M 37 40 44 DEP/APATH YOD - + + FTD-U (PGRN)

Case 7 M 38 43 45 SCHIZ FTD-MND - + ? FTD-ID

Case 8 M 45 46 49 APATH FTD17 + + FTD17

Case 9 M 43 49 61 COGIMP None - + + FTD-ID

Case 10 F ? 50 63 COGIMP YOD + - N FTD17

Case 11 M 45 50 63 COGIMP/APATH MND* - + ? FTD-U

Case 12 M ? 51 62 COGIMP FTD17 + - N FTD17

Case 13 F 50 53 64 COGIMP LOD - + ? FTD-U

Case 14 F 49 55 66 COGIMP None - + + FTD-ID

Case 15 M 56 57 59 COGIMP/PSP AD + - N PSP

Case 16 M 58 59 60 DISIN/COGIMP None - + + FTD-ID

Case 17 F 59 62 65 COGIMP None - + + FTD-MND

Implications for clinical syndromes

Different clinical syndromes may represent the same disease state

Memory is not necessarily a central characteristic of dementia

Thus arise questions about: Dementia definitions How clinical phenomena relate to

diseases Traditional professional boundaries (i.e.,

cognitive vs. behavioral; “organic” vs. “non-organic”)

“I wish it would dawn upon engineers that, in order to be an engineer, it is not enough to be an engineer”

Jose Ortega y Gasset (Toward a Philosophy of History, 1941)

History:

Unusual age at onset

Puzzling “atypical” features

Family history of dementia,

parkinsonism, motor disorder

Unusual prodrome, e.g., sleep problem

Rapid progression

Mental state:

Poor insight

Apathy/indifference

Compulsions without obsessions

Early hallucinations and/or paranoia

Cognitive state

Predominance of abnormal speech

Unusually pronounced loss of skills

Visual complaints (other than

hallucinations)

Motor examination

Abnormal posture and movement

Frequent falls at early stage

Frequent jerking

Progressive motor weakness

Poor coordination

Left-right asymmetry

Disease/disorder Phenotype Onset Features

AD Apathy, depression, anxiety, amnesia, dysexecutive

65+ cognition; global atrophy; diffuse EEG slowing

FTD conduct, impulsive, dysexecutive, aphasia

45+ cognition; focal EEG slowing; focal atrophy

Vascular dementia Dysexecutive, affective disorder, psychomotor slowing, CVD

>60 cognition; neurological signs; infarcts and gliosis on MRI

DLB Hallucinations, paranoia, amnesia, parkinsonism

>70 cognition; global atrophy; diffuse EEG slowing

Major depression Intermittent depression with apathy and anhedonia

<30 Normal cognition; normal EEG; no atrophy

OCD Obsessions, compulsions and anxiety

<30 Normal insight, cognition, EEG; no atrophy

Bipolar disorder Intermittent mania and depression

<35 Normal cognition; no atrophy

Schizophrenia Intermittent or chronic psychosis <30 Youth onset; chronic status; stable cognition; no atrophy

Personality disorder Sociopathic; compulsive behavior <18 Lifelong (+/- developmental); stable cognition; variable EEG; no atrophy

History

Clinical examination

“Bedside” scales

Laboratory tests

Neuropsychology assessment

Blood/serum assays

EEG

Brain MRI

Brain SPECT

Brain PET

Genetic analysis

Jun 2008 Oct 2008 Jan 2009 Mar 2009 Jun 2009 Sep 2009

MMSE 29 30 27 28 27 30

3MS 90 98 91 -- -- --

CDR 1.0 1.0 -- 1.0 1.0 1.0

Sep 2009: Poor CVLT Category-cued fluency = 5 Digit span (reverse) = 4 BNT (15-item) = 10 CGIC: “Mild decline”

Problem Role Intervention

Disease/disorder Diagnose Provide evaluation, direct investigation, make referrals

Distressing or offensive symptom(s)

Provide relief Make prescriptions

Handicaps, crises Solve problems Manage crises and psychosocial/rehabilitative care

Demoralization, stress Guidance Provide clarification, support and direction

The Alzheimer Association at www.alz.org or www.alz.org/maryland for the local chapter

Association for Frontotemporal dementias at www.ftd-picks.org

Websites at JHH, Columbia, UCSF, the Mayo Clinics, U of Pennsylvania…

BOOKS: The 36 Hour Day - Nancy Mace and Peter Rabins What if it is not Alzheimer’s: A Caregiver’s Guide to Dementia - Lisa and Gary

Radin, editors The Banana Lady and Other Stories of Curious Behavior - Andrew Kertesz The Family That Couldn’t Sleep: A Medical Mystery - D.T. Max

Drug(s)

Pluripotent cells Drosophila C. Elegans Zebra fish Mouse

Clinical trials

Stratified by: AB42/tau Tau TDP-43 FUS

Cases & cohorts

Recruitment of centers & regional networks

Cohort(s)

Data and tissue capture in registry & biobank

Onyike CU, 2014. Strategies for increasing global research in familial FTLD. International EFE fFTLD conference lecture, San Francisc0. Nov. 2014.

Cases & cohorts

Recruitment of centers & regional networks

Cohort(s)

Data and tissue capture in registry & biobank

Enrollment Registration

Known Known

New

New

New

Cohort

Case identification

Onyike CU. EFE fFTLD conference lecture, San Francisc0. Nov. 2014.

Neuropsychiatry: Peter Rabins, MD Campbell Sullivan, PhD Mary Anne Wylie, RN Rebecca Rye, RN Kate Hicks, MPH Kelly Sloane, MS-III Kalyani Kansal Alexa Minc

Cognitive Neurology: Argye Hillis, MD Marilyn Albert, PhD

Neuropathology Juan Troncoso, MD Olga Pletnikova, MD

Neuroscience Phil Wong, PhD

Packard Center for ALS Bryan Traynor, MD, PHD Jeff Rothstein, MD, PhD Nick Maragakis, MD Lora Clawson, RN Richard Kimball, RN