Brains Behaving Badly: Frontotemporal Dementia

Brandy R. Matthews, MDDepartment of Neurology

Indiana University School of Medicine

Geriatrics Grand Rounds 2011

Learning Objectives Evaluate, diagnose, and manage select cognitive and

behavioral symptoms in patients with FrontotemporalDementia Competencies Addressed: Patient Care, Medical Knowledge, Practice-

Based Learning and Improvement, Interpersonal and Communication Skills

Discuss the relationship between cognitive and behavioral symptoms in Frontotemporal Dementia and relevant neuroanatomy with reference to known clinicopathological correlations Competencies Addressed: Medical Knowledge, Practice-Based

Learning and Improvement

“Morning Report” Style Presentation Clinical History Localization based on History Hypothesis testing with Examination Differential Diagnosis Generation Diagnosis Confirmation with Additional

Studies Treatment Approaches

66 year old right-handed man: “memory problems” Referred for neuropsychological evaluation

by community neurologist based on clinical history

Referred to Neurobehavioral Clinic based on neuropsychological testing results and interview

Pertinent Clinical History General Medical

History Hypertension Hyperlipidemia Untreated, moderate

obstructive sleep apnea

“asthma”

Neurological History Migraine ?TIA 2009: 20 min

speech arrest and slurring Work up unremarkable

Psychiatric History ? reactive depression ‘80s

Pertinent Social History Education: 13 yrs Vocation: RT X 16 yrs; equip repair/ maint

Work became challenging at age 59

Tobacco use age 14-40 1.5 ppd EtOH: currently 1.5 L whiskey per week;

no prior abuse hx

Pertinent Family History Irish-Swedish-English

3 half-brothers 2 adult sons from 1st marriage 2 adult daughters from current marriage (31 yrs)

+ migraine

NO other neuropsychiatric illnesses

Pertinent Diagnostic History 2008 Provisional diagnosis

Alzheimer Disease age 64

Tried & “failed” FDA approved medications self-restricted driving

Retrospectively attributes current presentation to his “bucket list”

The Bucket List (Rob Reiner 2007)

LocalizationBased on Clinical History:

Informant1st sx

Temporal profile

Localization: The Frontal Lobes Dorsolateral prefrontal

cortex Set shifting multi-tasking complex decision-

making Ventromedial/Orbital

Inhibition Reward/ aversion

Anterior Cingulate Motivation Grasp reflex

Localization: The Frontal Lobes L hemisphere

language motivation

R hemisphere social behavior introspection/self-

monitoring

Diagnostic Hypothesis Generation

Based on localization-relatedawareness of neuropathology

Frontotemporal Lobar Degeneration: Neary Criteria 1998 Frontotemporal dementia (FTD/bvFTD)

Core Diagnostic Features: dx requires ALL Insidious onset, gradual progression Early decline in social interpersonal conduct Early impairment in regulation of personal

conduct Early emotional blunting Early loss of insight

Frontotemporal Lobar Degeneration: Neary Criteria 1998 Supportive Behavioral Diagnostic Features

Decline in personal hygiene Mental rigidity Distractibility Hyperorality and Dietary changes Stereotyped behavior Utilization behavior

Frontotemporal Dementia:Epidemiology 250,000 in US 8 yrs duration of

illness 6.7/100,000 person

years in US http://memory.ucsf.edu/Education

/Disease/ftd.html

4-20% incidence in memory clinics

Grossman, 2002

8-17% autopsies w/ dementia <70

Bird et al, 2003

13% prevalence in dementia(age 30-64) Sampson, Warren & Rossor, 2004

More common than AD if <60 Knopman et al, 2004

3.5/100,000 person years incidence in 45-64 yo in Cambridge

Mercy et al, 2008

Frontotemporal Lobar Degeneration: Neary Criteria 1998 Frontotemporal dementia (FTD/bvFTD/fvFTD)

Behavioral variant Semantic Dementia (SD/tvFTD)

“Fluent” aphasic variant Loss of object knowledge Anomia Right and Left variants

Progressive Nonfluent Aphasia (PNFA) “Nonfluent” aphasic variant Motor speech disorder +/- apraxia of speech

Frontotemporal Lobar Degeneration:Epidemiology Johnson et al, 2005

3 sites; n=353 bvFTD

Mean age of onset 57.5 yrs M>F

SD Mean age of onset 59.3 yrs M>F

PNFA Mean age of onset 63 yrs F>M

bvFTDSDPNFA19%

25%

57%

Frontotemporal Dementia:Historical Perspectives Arnold Pick 1892

71 yo M with 2 yr h/o behavioral change Childish Aphasia Post-mortem profound“knife-edge” atrophyesp L temporal

1904 3 additional cases with behavioral and language symptoms

and frontotemporal atrophy

Frontotemporal Dementia:Historical Perspectives Alois Alzheimer 1911

56 yo M aphasia, echolalia, hyperorality Cortical dementia Pick Body: argyrophilic intraneuronal inclusion

3R Tau + 2010 International FTD Conference Indianapolis

Genes: PGRN, tau, CHMP2B, VCP Cells: von Economo neurons Proteins: Tau, TDP-43 & FUS

Hypothesis TestingNeurobehavioral Status Exam

Informant Interview

Frontotemporal Dementia:Neuropsychological TestingExecutive Function Testing

Wisconsin Card Sorting Task (WCST) Trail Making Test (TMT) Stroop Test Controlled Oral Word Association Test

(COWAT) Frontal Assessment Battery (FAB)

These measures are often normal in patients with early fvFTD

Eslinger & Damasio, 1985; Neary et al, 1988; Gregory et al, 1999

Neuropsychological Testing Summary: Uniform Data Set (+) MMSE 28/30 Geriatric Depression

Scale 7/15 Verbal recall superior Visual recall high

average Word list learning

average Confrontational naming

high average

Verbal fluency average (COWAT)

Attention average Sequential tracking

average (TMT)

WCST conceptual reasoning average

Stroop response inhibition WNL

Frontal Assessment Battery (FAB)1. Similarities 3 categories (conceptualisation)2. Lexical fluency >9/ min (mental flexibility)3. Motor series 6 consecutive (programmation)4. Conflicting instructions 0/10 errors (sensitivity to

interference)5. Go-No Go 0/10 errors (inhibitory control)6. Prehension behavior (environmental autonomy)

18 total points possible12 points & below correlates with FTD>AD

sensitivity 77% specificity 87%Slachevsky et al, 2004

Frontotemporal Dementia:Behavioral Measures

Neuropsychiatric Inventory (NPI) Structured interview

Caregiver Quantitative rating Research & clinical utility

Cummings et al, Neurology, 1997

12 dementia-related behaviors Delusions Hallucinations Agitation Depression Anxiety Elation Apathy Disinhibition Irritability Aberrant motor behavior Sleep disturbances Eating disturbances

NPI in FTD Apathy Disinhibition Elation Aberrant Motor

Behavior Eating Disturbance

Significant difference in caregiver report of these NPI items in patients with FTD versus AD

Liu et al, 2004

NPI in FTD Rosen et al, 2005

Avg effect: apathy, disinhibition, aberrant motor behavior, eating disorderFTD/ SD

NPI in FTD Rosen et al, 2005

NPI 11/12 behaviors endorsed Mild

Elation/euphoria Irritability/lability Appetite/eating Hallucinations

Musical Associated with

hearing loss Did not tolerate hearing

aids

Moderate Agitation/aggression Depression/dysphoria Anxiety Disinhibition

Severe Apathy/indifference Motor disturbance Nighttime behaviors

Neuroanatomy of EmpathyRankin et al, 2006

Empathic Concern (emotional) “If the patient sees someone

being taken advantage of they feel protective towards them”

Interpersonal Reactivity Index; Davis 1983

Caregiver Measure

Perspective Taking (cognitive) “The patient believes there are

two sides to every question and tries to look at them both”

R hemisphere: Anterior temporal, ACC, OFC, caudate, subgenual cingulate

Loss of Self-conscious EmotionSturm et al, 2006

FTLD patients have preserved defensive startle Pontine reflex Characteristic facial

expression & posture FTLD patients have

markedly reduced self-conscious behavior following startle Medial prefrontal cortex

Theory of Mind

Developmental psychology 18-24 mos. pretend play 3-4 yrs false belief recognition (epistemic) 6-7 yrs represent mental states (intentionality) 9-11 yrs recognize faux pas (affective) Adolescence recognize complex emotions/ facial expression

interpretation

Dissociates from executive functionRowe et al, 2001; Stone et al, 2003; Lough & Hodges, 2002; Adenzato et al, 2010

Faux Pas Task Stone et al, 1998

Did anyone say something they shouldn’t have said or something awkward?

1. Yes2. No

Theory of Mind: Faux Pas Task Recognition of 2 mental states

Person saying does not know they should not say it Person hearing will be hurt or insulted

10 control and 10 experimental stories containing faux pas with corresponding memory control questions for all 20 stories

Normal controls: 89-95% fp correctStone et al, 2003; Gregory et al, 2002

fvFTD: 67% fp correct; 88% memory correct AD: 88% fp correct; 77% memory correct

Gregory et al, 2002

OFC v. DLPFC: fp errors v. memory errorsStone, Baron-Cohen, Knight, 1998

SD with few memory errors (names) & NO fp errors on short version

Reading the Mind in the EyesAdult Version

1. Joking2. Flustered3. Desire4. Convinced

Reading the Mind in the EyesAdult Version

1. Joking2. Insisting3. Amused4. Relaxed

Reading the Mind in the Eyes 28 photographs of eye region presented

along with 4 mental state terms—affective mental states

Gender determination of photos as control Adult versus Child’s version

language prohibitive?

Normal control adults: 72-83% correctBaron-Cohen et al, 2001; Stone et al, 2003; Richell et al, 2003 ; Gregory at al, 2002

Normal control children(10-12): 71-75%Baron-Cohen et al, 2001

Fv FTD: 64% correct AD: 79% correctGregory et al, 2002

SD 92% score exceeded“normal” performance

Reading the Mind in the Eyes:A Digression“ The Autism-Spectrum Quotient: Evidence from

Asperger Syndrome/High-Functioning Autism, Males and Females, Scientists and Mathematicians”

Baron-Cohen, et al, 2001 “I prefer to do things the same way over and over again” “I would rather go to a library than a party” “I notice patterns in things all the time” “I tend to notice details that others do not”

Scientists score higher than normal controlsmathematics>computer science>medicine>biological science

InvestigationsConfirmatory (History & Behavioral Measures)

vsExploratory (Young Onset Dementia)

Patient Neuroimaging: T1 axial

Patient Neuroimaging

Time to reconsider…

Young Onset Dementia <65 yo @ 1st symptoms

Cognitive/behavioral decline resulting in social and occupational dysfunction

More likely to be misdiagnosed More likely to have a reversible cause More likely to have a delay in diagnosis More likely to be referred to a specialist

Papageorgiou et al, 2009

Young Onset Dementia: Narrowing the Differential Pattern of Deficits Temporal Profile of Illness Family History Other Systemic Symptoms/Signs Social History (exposure, use/abuse)

Other Neurological Symptoms/Signs

For detailed review see: Ridha & Josephs, 2006

Neurological Examination: Revisited No “frontal release” signs Bilateral mild hearing loss: ?occupational Bilateral postural UE tremor (high frequency,

low amplitude, no family history): ?EtOH Diffusely diminished, symmetric MSR Pes cavus with skin color changes in bilateral

distal LE Only 2-3 steps in tandem

Early Age of Onset Dementia: Rational Approach to Initial Investigations

MRI Pattern of atrophy

Alzheimer Disease, FTD, Semantic Dementia

White matter dz Vascular Dementia, HIV, PML, SSPE, CADASIL, Cerebral

Amyloid Angiopathy, adult-onset leukodystrophies

Basal Ganglia Fahr, HD, Wilson, prion

Early Age of Onset Dementia: Rational Approach to Initial Investigations

CBC Thyroid Function

Tests B12 cascade Creatinine Liver Function Tests Ca2+ Mg2+

Fasting Lipids Hgb A1c Sedimentation Rate Syphilis Screen Chest Xray EKG

Additional Data: Normal Routine

CBC/CMP TSH/ Free T4 Vit B12/Mehtylmalonic

acid/homocysteine High risk?

HIV RPR Liver Function

Tests/NH3

Vascular Lipids: treated Hgb A1c Sedimentation Rate Anti-Nuclear Abs Antiphospholipid Abs

Early Age of Onset Dementia: Rational Approach to Initial Investigations

CSF

Cell count Protein Glucose

PCR JC virus Whipple

Proteins Tau Abeta 42

Knopman et al, 2001 (US); Waldemar et al, 2000 (Europe)

CSF ProteinData

Abeta 42 ( AD) 368.9 pg/mL

Ttau ( AD) 155.5 pg/mL

Ptau ( AD) 29.85 pg/mL

ATI 0.87 ATI: AB42=240+1.18 Ttau

ATI<1 AD Sensitivity 85-94% Specificity 83-89%

Ptau >61 pg/mL AD Sensitivity 72-85% Specificity 74-85%

Laboratory testing performed /interpreted by Athena Diagnostics

Additional Imaging:Gadolinium & Gradient Echo

Stable moderate diffuse cerebral volume loss stable and patchy, confluent T2 hyperintensity centrum semiovale & periventricular regionsNo contrast/GRE/ DWI changes

Additional Imaging & Reports

MRA No clear Pcoms or Acom R vertebral tiny vs absent No irregularities or premature

terminations

Additional Studies

EEG: diffuse-slowing

Frontally predominant theta

Chromosome 17 PRGN: no identifiable

mutation Tau: no identifiable

mutation

CADASIL: no NOTCH 3 mutation

Binswanger Disease 1894 Subcortical vascular

dementia 40% of VaD M>F 60-70’s HTN 80% Behavioral-

dysexecutive phenotype common

Dysarthria Gait changes

Parkinsonism Ataxia

Stroke risk Lacunes 93% Cortical infarcts in 1/3

Bowler, 2005

Progressive Subcortical Gliosisof Neumann 1949 Adult-onset

Leukoencephalopathy with Neuroaxonal Spheroids (ALENAS)

Onset 50-60’s Duration 5-15 yrs Sporadic or familial FTD phenotype

Swerdlow et al, 2009

Dementia-plus algorithm:Behavioral Syndrome + White Matter Disease

Imaging Angiogram (vasculitis) PIB-PET (mixed AD-VaD) DTI (demyelination)

PML, SSPE, MS

Ophthalmology exam Cherry red spot vasculopathy

Skin biopsy Neimann Pick type C

Filipin staining

Neuronal Ceroid Lipofuscinosis Granular osmiophilic

deposits

Adult Polyglucosan Body Disease Axillary polyglucosan

bodies

Dementia-plus algorithm:Behavioral Syndrome + White Matter Disease

Leukodystrophies Adreno- VLCFA GM2 Gangliosidosis:

Hexosaminidase A Metachromatic:

Arylsulfatase A

the great masqueraders Neurosarcoidosis CNS lymphoma

Dementia-plus algorithm:White Matter Disease +/- Peripheral Neuropathy

EMG/ NCV Classify PN

HIV EtOH related Neuroacanthocytosis

Peripheral smear

Mitochondrial d/o Ragged red fibers Respiratory chain enzymes

Sialidosis Alpha-N-acetyl-neuraminidase

Fabry disease Alpha-galactosidase A

Krabbe disease Galactosyl-B-galactosidase

SCA 3 Porphyria

Urine porphyrins

Cerebrotendinous xanthomatosis Cholestanol

Dementia-plus algorithm:White Matter Disease +/- Peripheral Neuropathy

? Ataxia

Neuronal Ceroid Lipofuscinosis/ Kuf’s

Neimann-Pick type C Superficial siderosis

MRI, CSF Alexander Disease

GFAP gene test Whipple Disease

CSF PCR or jejunal bx

Paraneoplastic disorders Ab testing

SCAs 2, 12, 17 Gene tests

Fragile X associated ataxia syndrome Gene test

Dementia-plus algorithm:White Matter Disease +/- Peripheral Neuropathy

? Ataxia ? Hearing loss

mitochondrial disease sialidosis superficial siderosis

alpha mannosidosis

Treatment & Interventions

Symptomatic:No cholinergic deficit in FTD: avoid AChEI due to agitation SSRI for repetitive behaviors (off-label) memantine for VaD or bvFTD +/- (off-label) vascular risk factor management (ASA, pravastatin,

lisinopril, diltiazem) reduce EtOH supervision (meals, meds, money) caregiver support

Take Home Points Informant measures & age of onset of first

symptoms are keys to diagnosis in behavior predominant neurodegenerative disorders

bvFTD is a disorder of frontal>temporal, R-hemisphere>L-hemisphere deficits with dysfunctional neuroanatomy predicted by clinical signs & symptoms

Neuroimaging is a valuable diagnostic tool in the differential diagnosis of young onset dementia (YOD)

Take Home Points Using a “dementia-plus” strategy rationally

guides investigation in YOD Early diagnosis & neuropathological

prediction is especially important in YOD due to higher frequency of “treatable” conditions & higher incidence of genetic disorders

Caregiver burden is unique in YOD due to unexpected loss of financial productivity & younger families

Questions? Comments?

Selected References FTD EpidemiologyBird T, Knopman D, VanSweiten J, et al. Epidemiology and genetics of frontotemporal

dementia/Pick’s disease. Ann Neurol 2003;54(suppl 5):S29-S31 Grossman, M. Frontotemporal dementia: A review. J Int Neuropsychol Soc 2002;8: 566-583. :752-

64Johnson JK, Diehl J, Mendez MF, et al. Frontotemporal lobar degeneration: Demographic

characteristics of 353 patients. Arch Neurol 2005; 62:925-30.Knopman DS, Petersen RC, Edland SD, et al., The incidence of frontotemporal lobar degeneration in

Rochester, Minnesota, 1990 through 1994. Neurology 2004; 62(3):506-508. Mercy L, Hodges JR, Dawson K, et al. Incidence of early-onset dementias in Cambridgeshire.

Neurology 2008;71:1496-99.

Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: aconsensus on clinical diagnostic criteria. Neurology; 1998: 51:1546-54.

Selected References FTD NeuropsychologyCummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The

Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44(12):2308-14.

Eslinger P, Damasia A. Severe disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR. Neurology 1985; 35:1731-42.

Gregory CA, Serra-Mestres J, Hodges JR. Early diagnosis of the frontal variant of frontotemporal dementia: How sensitive are standard neuroimaging and neuropsychological tests? Neuropsychiatry Neuropsychol Behav Neurol 1999; 12:128-35

Morris JC, Weintraub S, Chui HC, Cummings J, Decarli C, Ferris S, et al. The Uniform Data Set (UDS): clinical and cognitive variables and descriptive data from Alzheimer Disease Centers. Alzheimer Dis Assoc Disord 2006;20(4):210-6.

Neary D, Snowden JS, Northen B, Goulding P. Dementia of frontal lobe type. J Neurol Neurosurg Psychiatry 1988; 51:353-61.

Slachevsky A, Pillon B, Litvan I, Dubois B. A bedside frontal assessment battery (FAB). Neurology 1998; 50: A 406

Selected References FTD BehaviorsLiu W, Miller BL, Kramer JH, et al. Behavioral disorders in the frontal and temporal variants of

frontotemporal dementia. Neurology 2004; 62: 742-48.Rankin KP, Gorno-Tempini ML, Allison SC, et al. Structural anatomy of empathy in

neurodegenerative disease. Brain 2006; 129:2945-56.Rosen HJ, Allison SC, Schauer GF, et al. Neuroanatomical correlates of behavioral disorders in

dementia. Brain 2005; 128:2612-25.Sturm VE, Rosen HJ, Allison SC, et al. Self-conscious emotion deficits in frontotemporal lobar

degeneration. Brain 2006; 129:2508-16.Woolley JD, Gorno-Tempini ML, Seeley WW, et al. Binge eating is associated with right orbitofrontal-

insular-striatal atrophy in frontotemporal dementia. Neurology 2007;69(14):1424-33.

Selected References Theory of MindAdenzato M, Cavallo M, Enrici I. Theory of Mind ability in the behavioral variant of frontotemporal dementia: An

analysis of the neural, cognitive, and social levels. Neuropsychologia 2010; 48(1):2-12.Baron-Cohen, S, et al (2001). Reading of the Mind in the Eyes test. Journal of Child Psychology and Psychiatry. 42:

241-252.Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The Autism-Spectrum Quotient: Evidence from

Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. Journal of Autism and Dev Disorders 2001; 31 (1): 5-17.

Gregory C, Lough S, Stone V, Erzinclioglu S, Martin L, Baron-Cohen S, Hodges J. Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer’s disease: theoretical and practical implications. Brain 2002; 125

Lough S, Hodges JR. Measuring and modifying abnormal social cognition in frontal variant frontotemporal dementia. J Psychsomatic Research 2002; 53:639-46

Richell RA, Mitchell DGV, Newman C, Leonard A, Baron-Cphen S, Blair RJR. Theory of Mind and psychopathy: can psychopathic individuals read the ‘language of the eyes’? Neuropsychologia 2003; 41:523-526

Rowe AD, Bullock PR, Polkey CE, Morris RG. ‘Theory of mind’ impairments and their relationship to executive functioning following frontal lobe excisions. Brain 2001; 124:600-16.

Stone VE, Baron-Cohen S, Calder A, Keane J, Young A. Acquired theory of mind impairments in indviiduals with bilateral amygdala lesions. Neuropsychologia 2003; 41: 209-20.

Stone, VE, Baron-Cohen, S & Knight, RT (1998). Frontal Lobe contributions to theory of mind. Journal of Cognitive Neuroscience, 10:640-656.

Selected ReferencesBowler JV. Vascular cognitive impairment. J Neurol Neurosurg Psychiatry 2005; 76: v35-v44.Swerdlow RW, Miller BB, Lopes MB, et al. Autosomal dominant subcortical gliosis presenting as

frontotemporal dementia. Neurology 2009; 72:260-7.

Young Onset DementiaKelley BJ, Boeve BF, Josephs, KA. Young-onset dementia: demographic and etiologic characteristics

of 235 patients. Arch Neurol 2008;65:1502-08.Papageorgiou SG, Kontaxis T, Bonakis A, et al., Frequency and causes of early-onset dementia in a

tertiary referral center in Athens. Alzheimer Dis Assoc Disord 2009; 23(4):347-351.Ridha, B, Josephs KA. Young-onset dementia: A practical approach to diagnosis. The Neurologist

2006; 12(1):2-13.Rossor MN, Fox NC, Mummery CJ, et al., The diagnosis of young-onset dementia. Lancet Neurol

2010; 9(8):793-806.Sampson EL, Warren JD, Rossor MN. Young onset dementia. Postgrad Med J 2004;80:125-139