New Brains Behaving Badly: Frontotemporal 2012. 9. 25.¢  Geriatrics Grand Rounds 2011. Learning Objectives

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  • Brains Behaving Badly: Frontotemporal Dementia

    Brandy R. Matthews, MD Department 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 Frontotemporal Dementia  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)

  • Localization Based on Clinical History:

    Informant 1st 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-related awareness 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

  • 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

    bvFTD SD PNFA19%

    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” atrophy esp 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 Testing Neurobehavioral Status Exam

    Informant Interview

  • Frontotemporal Dementia: Neuropsychological Testing Executive 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 possible 12 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 disorder FTD/ 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 Empathy Rankin 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 Emotion Sturm 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

     Developm