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Frontotemporal
Dementia (FTD)
Monica K. Crane, MD
Associate Director
Cole Neuroscience Center, UTMCK
Clinical Assistant Professor, Dept. of Medicine
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Frontotemporal dementia
(FTD) Overview
Background and clinical definition
Prevalence
Anatomy
FTD clinical subtypes Neuropathology and genetics of
Frontotemporal lobe dementia (FTLD)
Historical cases
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FTD = a clinical neurodegenerative disease
affecting frontal & temporal lobes
Personality changes
Loss of socially
acceptable behavior &
emotions
Bizarre and compulsive
behaviors
Language dysfunction
Movement disorder
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FTD International Research Criteria:
1. Early disinhibition
2. Early apathy, loss of
motivation
3. Loss of emotional recognition
4. Perseverative, compulsive,
ritualistic behavior
5. Hyperorality/ dietary changes
6. FTD neuropsychological profile
Either #7 or #8 one
symptom from #1-6
7. Frontal and/or
anterior temporal
atrophy; other radiologicfindings
8. Presence of a known
mutation
B. L. Miller, C. Ikonte, M. Ponton, et al. Neurology 1997;48;937
ORThree of the fol lowing:
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Dementia That's Neither
Alzheimer's Nor Easy
FDG-PET images of metabolic activity: healthy controls,
AD, and FTD. Scale red (high FDG uptake)-yellow-
green-blue (low FDG uptake).
Normal Alzheimer's FTD
Photo Credit: Dr. Janet Miller, Dr. Suzanna Lee, MGH/ Harvard, Radiology Rounds April 2006
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Dementia Prevalence(% of each type seen in US)
FTD syndromes~10-15%
Alzheimers Disease (AD) ~ 50-70%
Vascular dementia~ 5-10%
Dementia with Lewy Bodies & Parkinsons
disease dementia~10%
Boxer AL, Miller BL.Alzheimer Dis Assoc Disord. 2005;19 S1:S3-6
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FTD Prevalence
FTD: Alzheimers disease (AD) ratio is 1:1 inthose aged 45-65.Ratnavalli et al, Neurology 2002.
FTD is more common that AD below age 60.Knopman et al, Neurology 2004.
FTD spectrum comprises near 15% or more
of the total FTD dementia cases.Boxer AL, Miller BL.Alzheimer Dis Assoc Disord. 2005.
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Picks disease FTD
Picks is an autopsy finding only
so do not use this term. Theclinical disease is FTD.
In 1892, Dr. Pick reported a case of a
71 year-old man with focal atrophy
and aphasia, & concluded that
progressive brain atrophy can leadto symptoms of local disturbance
through local accentuation of the
diffuse process.Dr. Arnold Pick (1851-1924)
Prof. of Psychiatry, PragueHistory of Psychiatry v. 1994, 539-547. GE Berrios , DM Girling. Classic Text No 20. Cambridge.
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From: LM Shaw LM, Korecka M, Clark CM, Lee VMY, Troganowski. Biomarkers of neurodeneration for diagnosis and monitoring
therapeutics Nature Reviews Drug Discovery. 2007;6:295-303.
Frontotemporal lobar degeneration (FTLD) =
Neuropathology of clinical FTD
Picks is a small subset of FTLD
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Heterogeneity of FTD
subtypes:
Anatomy and Clinical
presentation
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What areas of the brain are
affected in FTD?
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FTD damages 3 major networks:Dorosolateral prefrontal cortex (DLPFC)
Anterior cingulate cortex (ACC)Orbitofrontal cortex (OFC)
A ff d i FTD AD
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Areas affected in FTD versus AD
Hagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, et al. Entorhinal cortex 2009
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Clinical Presentation:
FTD Subtypes
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Frontotemporal dementia subtypes
Behavior variant (bvFTD)
Semantic dementia (SD)
Progressive nonfluent aphasia (PNFA)
Progressive Supranuclear Palsy (PSP)
Corticobasal degeneration (CBD)
FTD with motor neuron disease (FTD-MND)
ALS/CTE (Chronic Traumatic Encephalopathy)
Boxer AL, Miller BL. Clinical features of frontotemporal dementia.Alzheimer Dis AssocDisord. 2005;19 S1:S3-6
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Behavioral variant (bvFTD)
Approximately 60% of patients with any formof FTD have bvFTD.
Figure 1. Coronal pathology
section showing asymmetricright-sided atrophy (R
temporal cortices with
widening of the inferior horn
of the lateral ventral).
L R
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Clinical Features of bv-FTD
Gradual onset Impaired judgment and
planning
Apathy
Impaired insight
(anosognosia)
Loss of empathy and
emotion recognition(alexithymia)
Disinhibition Abnormal eating
behavior
Stereotypical or
ritualistic behavior
Personal neglect
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Profanity use during letter fluency tasks can
differentiate FTD from AD. Ringman JM et al. Cogn Behav Neurol2010;23:159-64
Cli i l F t FTD AD
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Clinical Features FTD AD
Age of onset Rarely >75 Increases w age
Behavior & Social
problems
Early disinhibition, +
socially inappropriate
Moderate-severe,
increases with severityLanguage Isolated language
problem
Language + memory
Visuospatial defici t Rare in mild-moderate Common
Motor signs Common UnusualMood Alexithymia, withdrawal,
verbal irritability, labile
Sadness, anhedonia
Psychotic features Somatic, religious,
bizarre delusions
Delusions increase with
disease severity
Appetite/
hunger/diet
Overeating, weight ;
carbohydrate craving
Weight loss, anorexia;
misses meals
Muangpaisan W. Geriat Aging. 2007; McKhann MG et al. Arch Neurol 2001; Muangpaisan W et al.Neuro J Thai 2003
50% f FTD bt i di d
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>50% of FTD subtypes misdiagnosed as
primary psychiatric disease
Figure. % of patients initially misdiagnosed prior to ND diagnosis
Woolley et al. J Clin Psychiatry. 201; 72(2): 126133.
Computer Self Test (CST)
http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=An%20external%20file%20that%20holds%20a%20picture%2C%20illustration%2C%20etc.%0AObject%20name%20is%20nihms257032f1.jpg%20%5BObject%20name%20is%20nihms257032f1.jpg%5D&p=PMC3&id=3076589_nihms257032f1.jpghttp://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=An%20external%20file%20that%20holds%20a%20picture%2C%20illustration%2C%20etc.%0AObject%20name%20is%20nihms257032f1.jpg%20%5BObject%20name%20is%20nihms257032f1.jpg%5D&p=PMC3&id=3076589_nihms257032f1.jpghttp://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=An%20external%20file%20that%20holds%20a%20picture%2C%20illustration%2C%20etc.%0AObject%20name%20is%20nihms257032f1.jpg%20%5BObject%20name%20is%20nihms257032f1.jpg%5D&p=PMC3&id=3076589_nihms257032f1.jpg8/11/2019 Frontotemporal dementia talk
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Dougherty JD et al.
The computerized
self test (CST): an
interactive, internet
accessible cognitivescreening test for
dementia. J
Alzheimer's Dis 2010
Apr;20:185-95.
Crane MK et al.
Distinguishing
Frontotemporal
dementia from
Alzheimers disease:
A pilot study
employing the
Computer Self-Test
(CST). Dementia
Geriatr Cogn Disord2010;30:62.
Computer Self-Test (CST)
as a diagnostic tool
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CST Cognitive pattern differentiates AD from FTD
Crane, MK et al.Neurology. 2011 Suppl(March) 76;
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VIDEO example of bvFTD
alexithymia
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VIDEO example of a
bvFTD patient with a
palmar grasp reflex
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Frontotemporal dementia subtypes
Behavior variant (bvFTD)
Semantic dementia (SD) Progressive nonfluent aphasia (PNFA)
Progressive Supranuclear Palsy (PSP)
Corticobasal degeneration (CBD)
FTD with motor neuron disease (FTD-MND)
ALS/CTE (Chronic Traumatic Encephalopathy)
Boxer AL, Miller BL.Alzheimer Dis Assoc Disord. 2005;19 S1:S3-6
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Semantic dementia (SD) or temporal variant
LEFT predominance
Language features: fluent speechbut loss of semantics (word choice)
Reading declines, numbers intact
RIGHT predominance Severe deficits inunderstanding emotions;loss of empathy
Difficulty recognizing
faces and facial expression
Eventually R-sideddisease progresses to Lwith language features,
and visa versa
SD patients developbvFTD behaviors
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VIDEO example of
semantic deficits
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Frontotemporal dementia subtypes
Behavior variant (bvFTD)
Semantic dementia (SD)
Progressive nonfluent aphasia
(PNFA) Progressive Supranuclear Palsy (PSP)
Corticobasal degeneration (CBD)
FTD with motor neuron disease (FTD-MND)
ALS/CTE (Chronic Traumatic Encephalopathy)
Boxer AL, Miller BL.Alzheimer Dis Assoc Disord. 2005;19 S1:S3-6
P i fl t
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Progressive nonfluent
aphasia (PNFA)
20% of FTD cases
Hesitant, effortful speech;stutter or return of
childhood stutter
Anomia, agrammatism,sound errors (gat for cat)
Eventually develop severemovement disorder thatoverlaps with PSP andCBD
Marcel Ravel, (1875-1937)
French composer.- in the early stages of
PNFA/FTD when
composing the orchestral
work Bolro (1928).
P i fl t h i (PNFA)
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Progressive nonfluent aphasia (PNFA)
Fig. Coronal T1 weighted MRI of mild and moderate PNFA
Case 1: mild PNFA, atrophy of temporal lobe & pars triangularis.
Case 2: moderate PNFA, global atrophy with L-sided and
perisylvian predominance.
Case 1 Case 2
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Frontotemporal dementia subtypes
Behavior variant (bvFTD)
Semantic dementia (SD)
Progressive nonfluent aphasia (PNFA)
Progressive Supranuclear Palsy (PSP) Corticobasal degeneration (CBD)
FTD with motor neuron disease (FTD-MND)
ALS/CTE (Chronic Traumatic Encephalopathy)
Boxer AL, Miller BL.Alzheimer Dis Assoc Disord. 2005;19 S1:S3-6
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Progressive supranuclear palsy (PSP)
Progressive supranuclear palsy
Deterioration of cells in the brainstem,
frontal cortex and basal ganglia
Dudley Moore 1935-2002
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Progressive
supranuclear
palsy (PSP)key features
Postural instability and falls within first year of diagnosis
Vertical supranuclear opthalmoparesis
Upward gaze paresis with abnormal saccadic eyemovements
Axial rigidity Cognitive decline
Early stage difficult to distinguish from multiple system atrophy,Parkinson disease, and small vessel diease.
Most patients with PNFA have PSP or CBD postmortem
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PSP radiologic features
Hypometabolism on FDG-PET in basal ganglia, brainstem,and frontal lobes
Midbrain
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Midbrainatrophy in
PSP
(A) Normal:convex upper
border of the
midbrain
(B) Severeatrophy of the
midbrain with
(C) concave
upper border of
midbrain
humming bird
sign.
C
A B
F t t l d ti bt
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Frontotemporal dementia subtypes
Behavior variant (bvFTD)
Semantic dementia (SD)
Progressive nonfluent aphasia (PNFA)
Progressive Supranuclear Palsy (PSP)
Corticobasal degeneration (CBD)
FTD with motor neuron disease (FTD-MND)
ALS/CTE (Chronic Traumatic Encephalopathy)
Boxer AL, Miller BL.Alzheimer Dis Assoc Disord. 2005;19 S1:S3-6
Corticobasal Degeneration (CBD) criteria
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Corticobasal Degeneration (CBD) criteria
Core Features
Cortical dysfunction Asymmetric ideomotor apraxia
Alien limb phenomenon
Visual or sensory hemineglect
Focal or asymmetric myoclonus
Non-fluent aphasia (overlap withPNFA)
Extrapyramidal dysfunction
Asymmetric rigidity lackingsustained levodopa response,and focal dystonia
Supportive Features
Lateralized cognitivedysfunction with
preserved memory
and learning
MRI with asymmetric
atrophy in parietal
and frontal cortex
FDG-PET decreased
glucose uptake in
parietal and frontal
cortex, basal ganglia
and thalamus.
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Figure. CBD. Pt1:Mild, focal atrophy of corpus callosum with mildhypometabolism in L frontoparietal cortex (arrow). Pt2:Moderate atrophy ofcorpus callosum, moderate hypometabolism in L frontoparietal cortex (arrows)
Pt3: Severe, diffuse atrophy with bilateral hypometabolism accentuated in theright frontoparietal cortex (arrows)
F t t l d ti bt
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Frontotemporal dementia subtypes
Behavior variant (bvFTD)
Semantic dementia (SD)
Progressive nonfluent aphasia (PNFA)
Progressive Supranuclear Palsy (PSP)
Corticobasal degeneration (CBD)
FTD with motor neuron disease
(FTD-MND)
ALS/CTE (Chronic Traumatic Encephalopathy Elevated levels of the TDP-43 protein have been found in CTE, a
also been identified in patients with CTE, a condition that often
mimics ALS and that has been associated with athletes who have
experienced multiple concussions and head injury.
FTD with motor neuron disease
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(FTD-MND)
FTD-MND is a CLINICAL PHENOTYPE:
15% of FTD patients also have FTD-MND FTD-MND co-occurs in patients with bvFTD but rare in
PNFA, CBD, PSP
Early cognitive and behavioral changes with MND symptoms:
slurring of speech, difficulty swallowing, choking Autonomic dysfunction
limb weakness or muscle wasting
Patients live 1.4 years after diagnosis (respiratorycomplications of bulbar symptoms as cause of death)
Most common MND is amyotrophic lateral sclerosis (ALS);older ALS patients may also have behavioral or cognitive
problems similar to those seen in FTD (FTD-ALS syndrome)
Results of MRI voxel-based morphometry analyses: behavior
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Results of MRI voxel based morphometry analyses: behavior
& language dominant FTD-MND analysis compared to control
Coon E et al. Neuro logy 2011;76:1886-1892
Both with frontotemporal gray matter loss. Behavioral variant
FTD-MND in frontal lobes. Language variant FTD-MND in
L lateral inferior temporal lobe and R putamen.
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Neuropathology
and Genetics
FTD inheritance
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FTD inheritance
Genetic (40%) Approximately 20-50% ofFTD patients have anaffected 1stdegree relative.
Familial FTD is suspectedwhen 2+ family members areaffected in 2+ generations.
Among individuals with FTD,
approximately 10% have asingle gene mutation(autosomal dominantinheritance).
Sporadic (60%) 50-80% of individualsappear to be the first
person with FTD in the
family, also called
sporadic or nonfamilial
FTD (family not at risk).
Frontotemporal Lobar Degeneration (FTLD) is
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Frontotemporal Lobar Degeneration (FTLD) is
the pathologic confirmation of clinical FTD
FTLDs are histopathologicdiagnosis with neuronalloss & gliosis, spongiosis& ballooned neurons(image below).
Abnormal protein inclusionsin neurons & glial cells.
Tauopathies: FTLD withtau+ inclusions
TDP-43 proteinopathies:FTLD with tau-, alpha-synuclein- inclusionswhich contain the proteinTDP-43 + conjugated withubiquitin+
FUS: tau-, ubiquitin+,TDP-43-, with fused insarcoma (FUS) inclusions
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Seelar H, Rohrer LD, Pijnenburg YAL, Fox NC, can Swieten JC. Clinical, genetic and pathologicalheterogeneity of frontotemporal dementia: A review. J Neurol Neurosurg Psychiatry 2010.
Tau immunopositive inclusions and neurofibrillary
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p ytangles (NFTs) in tauopathy family of FTLDs
Pick inclusion bodies:
tau-positive spherical
cytoplasmic neuronal inclusions,
composed of straight filaments
NFTs and neurit icthreads (arrow) in the
gray matter of the frontal
cortex.
Perinuclear inclusions
of (asterisk) within the
frontal cortex
Reynolds M R et al. J. Neurosci. 2006;26:10636-10645
BIGGEST ADVANCE in ALS
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and FTD
Chromosome 9 open reading frame 72
(C9ORF72) gene mutation most commoncause of familial ALS and FTD Toxic buildup of RNA
Similar to other ALS genes but not SOD1
40% of familial ALS of European descent
15% of familiar ALS SOD1 mutation
Same expansion in 12% familial FTDand 3% sporadic FTD, 4%
in sporadic ALS!
Renton A, Majounie E, Waite A, J S-S, Sara Rollinson S, Gibbs J, et al.A Hexanucleotide Repeat Expansion in C9ORF72 Is the
Cause of Chromosome 9p21-Linked ALS-FTD. Neuron. 2011;72(2):257.
Dejesus-Hernandez M, Mackenzie I, Boeve B, Boxer A, Matt Baker, Rutherford N, et a Neuron. 2011;72(2):245.
FTD and creative bursts
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Trained in mathematics, chemistry
and biology, Anne Adams, PhDdecided to leave her career in
science (1986) to care for a family
member and to take up art.
In 1994, she became fascinatedwith the music of Ravel, and thus
painted Unravelling Bolro a
work that translated the famous
musical score into visual form.
Ironically, Ravel was in early PNFA
when composing Bolro. Both
Adams and Ravel died from
complications of PNFA/FTD.
Marcel Ravel
FrenchComposer
(1875-1937)
Anne Adams,
PhD
Chemist
(1940-2007)
FTD and creative bursts
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Anne Adams, Unravelling Bolro, 1994
Each vertical figure represents a bar of music, with height corresponding to
volume. The theme repeats & builds until a change to orange/pink, representing
the key change preceding the dramatic conclusion.
Dr. Anne Adams,(2004)
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ms te rdam (2004)
At the time of this painting,
Adams was nearly mutetaking 10-15 seconds toinitiate a word and wasformally diagnosed withPNFA.
Adams then developeda shuffling gait, R limbapraxia and dystonia, andstopped all verbal
communication. She died in2007 from advanced FTDwith motor and respiratorysymptoms.
Seeley W W et al. Brain 2008;131:39-49
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Questions?Special thanks to the Cole Family Foundation for their ongoingsupport of the Cole Neuroscience Center at UTMCK, and to
the Bagby family for their willingness to share and educate
others
Special recognition goes to my clinical mentor, Dr. John
Dougherty, as well as to the neurologists and clinical team at
Cole Neuroscience Center.
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