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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