Frontotemporal dementia talk

8/11/2019 Frontotemporal dementia talk

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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.
http://upload.wikimedia.org/wikipedia/commons/f/ff/Pick.gif


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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.jpg


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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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Semantic dementia (SD) Progressive nonfluent aphasia (PNFA)







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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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Progressive nonfluent aphasia

(PNFA) Progressive Supranuclear Palsy (PSP)





P i fl t
http://en.wikipedia.org/wiki/File:Maurice_Ravel_1912.jpg


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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)
http://en.wikipedia.org/wiki/File:Maurice_Ravel_1912.jpg


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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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Progressive Supranuclear Palsy (PSP) Corticobasal degeneration (CBD)





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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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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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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
http://www.neuropathologyweb.org/chapter9/images9/9-pick.jpg


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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
http://www.neuropathologyweb.org/chapter9/images9/9-9.jpg


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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
http://www.neuropathologyweb.org/chapter9/images9/9-9.jpghttp://www.neuropathologyweb.org/chapter9/images9/9-9.jpg


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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
http://en.wikipedia.org/wiki/File:Maurice_Ravel_1912.jpghttp://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpg


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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)
http://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpg


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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
http://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpg


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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.
http://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpghttp://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpghttp://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpghttp://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpghttp://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpghttp://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpghttp://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpghttp://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpghttp://stewartdesignweb.com/wp-content/uploads/2009/04/unravelingbolero.jpg

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