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Clinicopathological ClassificationsClinicopathological ClassificationsClinicopathological Classifications Clinicopathological Classifications of FTD and Related Disordersof FTD and Related Disorders

Keith A. Josephs, MST, MD, MSKeith A. Josephs, MST, MD, MSAssociate Professor & Consultant of NeurologyAssociate Professor & Consultant of Neurology

Mayo ClinicMayo ClinicMayo ClinicMayo Clinic

I do not have any disclosuresI do not have any disclosures

Learning ObjectivesLearning Objectivesg jg j

•• To be able to recognize 3 clinical FTDTo be able to recognize 3 clinical FTD•• To be able to recognize 3 clinical FTD To be able to recognize 3 clinical FTD syndromes & differentiate them from syndromes & differentiate them from Alzheimer’s dementiaAlzheimer’s dementiaAlzheimer s dementiaAlzheimer s dementia

•• To understand how and why FTD is To understand how and why FTD is related to progressi e s pran clearrelated to progressi e s pran clearrelated to progressive supranuclear related to progressive supranuclear palsy, corticobasal degeneration and palsy, corticobasal degeneration and motor neuron diseasemotor neuron diseasemotor neuron disease motor neuron disease

OutlineOutline

•• Three clinical FTD syndromesThree clinical FTD syndromes•• Behavioral variant FTDBehavioral variant FTD•• Semantic DementiaSemantic Dementia•• Progressive nonProgressive non--fluent aphasiafluent aphasia

•• Three related disordersThree related disorders•• Three related disordersThree related disorders•• Progressive supranuclear palsyProgressive supranuclear palsy

C ti b l d tiC ti b l d ti•• Corticobasal degenerationCorticobasal degeneration•• Motor neuron diseaseMotor neuron disease

Frontotemporal Dementia (FTD) Frontotemporal Dementia (FTD) p ( )p ( )vs. Alzheimer’s Disease (AD)vs. Alzheimer’s Disease (AD)

FTDFTD ADADFTDFTD ADAD

ClinicalClinical PersonalityPersonality Episodic memoryEpisodic memoryClinicalClinical Personality Personality and languageand language

Episodic memoryEpisodic memory

NeuropsychologyNeuropsychology Executive & Executive & Recall & Recall & p y gyp y gylanguage language dysfunctiondysfunction

spatial/perceptualspatial/perceptual

ImagingImaging Frontal &Frontal & Mesial temporalMesial temporalImagingImaging Frontal & Frontal & anterior anterior temporal lobestemporal lobes

Mesial temporal Mesial temporal lobe & lobe & temporoparietal temporoparietal

P th lP th l TDPTDP 43 t43 t B tB t l idl idPathologyPathology TDPTDP--43 or tau43 or tau BetaBeta--amyloidamyloid

FTDFTD

•• OverOver arching term that encompassesarching term that encompasses•• OverOver--arching term that encompasses arching term that encompasses 3 syndromes:3 syndromes:

•• Behavioral variant FTD (bvFTD)Behavioral variant FTD (bvFTD)•• Behavioral variant FTD (bvFTD)Behavioral variant FTD (bvFTD)•• Semantic Dementia (SD)Semantic Dementia (SD)

P iP i fl t h ifl t h i•• Progressive nonProgressive non--fluent aphasia fluent aphasia (PNFA)(PNFA)

•• Characterized by varying degree of Characterized by varying degree of personality & behavioral changes and personality & behavioral changes and language impairmentlanguage impairment

Neary et al. Neurology 1998

bvFTD ClinicalbvFTD Clinical

•• Insidious onset & gradual progressionInsidious onset & gradual progression•• Personality and behavioral changesPersonality and behavioral changes

•• Impairment in personal conductImpairment in personal conductp pp p•• Loss of emotional responsesLoss of emotional responses•• Mental rigidityMental rigidityMental rigidityMental rigidity•• Apathy or disinhibitionApathy or disinhibition•• Reduced attention & easilyReduced attention & easily•• Reduced attention & easily Reduced attention & easily

distractibledistractible•• Hyperoral and dietary changesHyperoral and dietary changes•• Hyperoral and dietary changesHyperoral and dietary changes•• Utilization behaviorUtilization behavior

Miller et al. Neurology 2007

bvFTD ClinicalbvFTD Clinical

•• Language impairment can occurLanguage impairment can occur•• Language impairment can occur Language impairment can occur (dynamic aphasia), less prominent and (dynamic aphasia), less prominent and occurs later in the disease courseoccurs later in the disease courseoccurs later in the disease courseoccurs later in the disease course

•• Stereotypies occur in up to 60% of Stereotypies occur in up to 60% of patients ith b FTDpatients ith b FTDpatients with bvFTDpatients with bvFTD

•• Compulsive type behaviors can be a Compulsive type behaviors can be a yypresenting feature in up to 40% of presenting feature in up to 40% of bvFTD patientsbvFTD patients

Mendez et al. J Geriatr Psy N 1997; Josephs et al. Neurobiol Aging 2008

bvFTD Imaging (MRI)bvFTD Imaging (MRI)g g ( )g g ( )

bvFTD Imaging (FDG PET)bvFTD Imaging (FDG PET)g g ( )g g ( )

Porter et al. Eur J of Neurol 2007

bvFTD NeuropsychologybvFTD Neuropsychologyp y gyp y gy

•• Poor performance on test ofPoor performance on test of•• Poor performance on test of Poor performance on test of executive function and behaviorexecutive function and behavior

•• Better performance on tests of Better performance on tests of episodic memory (especially episodic memory (especially recognition t pe tests)recognition t pe tests)recognition type tests)recognition type tests)

•• Relatively normal performance on Relatively normal performance on yytest of visuospatial/perceptual test of visuospatial/perceptual functionfunction

SD ClinicalSD Clinical

•• Insidious onset & gradual progressionInsidious onset & gradual progression•• Insidious onset & gradual progressionInsidious onset & gradual progression•• Fluent spontaneous somewhat empty Fluent spontaneous somewhat empty

speech speech •• Loss of word meaning manifested byLoss of word meaning manifested byLoss of word meaning manifested by Loss of word meaning manifested by

impaired naming and comprehensionimpaired naming and comprehension•• Semantic paraphasias (banana forSemantic paraphasias (banana for•• Semantic paraphasias (banana for Semantic paraphasias (banana for

peach)peach)•• Surface dyslexia (is land for island)Surface dyslexia (is land for island)

SD ClinicalSD Clinical

•• Behavioral changes can occur butBehavioral changes can occur but•• Behavioral changes can occur but Behavioral changes can occur but tend to be later in the disease course tend to be later in the disease course and are more common when the rightand are more common when the rightand are more common when the right and are more common when the right anterior temporal lobe is affected.anterior temporal lobe is affected.

•• Loss of object and face recognitionLoss of object and face recognition•• Loss of object and face recognition Loss of object and face recognition also can occur especially when right also can occur especially when right temporal lobe is affectedtemporal lobe is affectedtemporal lobe is affectedtemporal lobe is affected

SD Imaging (MRI)SD Imaging (MRI)g g ( )g g ( )

SD Imaging (FDG PET)SD Imaging (FDG PET)g g ( )g g ( )

64 y.o. woman presented with loss 64 y.o. woman presented with loss y py pof recognition of familiar facesof recognition of familiar faces

SD NeuropsychologySD Neuropsychologyp y gyp y gy

•• Poor performance on test of namingPoor performance on test of naming•• Poor performance on test of naming Poor performance on test of naming with failure to recognize the object with failure to recognize the object even when target words are giveneven when target words are giveneven when target words are giveneven when target words are given

•• Relatively better performance on Relatively better performance on tests of episodic memortests of episodic memortests of episodic memory tests of episodic memory

•• Relatively normal performance on Relatively normal performance on yytest of spatial/perceptual functiontest of spatial/perceptual function

PNFA ClinicalPNFA Clinical

•• Insidious onset & gradual progressionInsidious onset & gradual progression•• Insidious onset & gradual progression Insidious onset & gradual progression •• Agrammatism (I am gone house now for Agrammatism (I am gone house now for

the wife) and telegraphic speech (get the wife) and telegraphic speech (get passport, need for trip)passport, need for trip)

•• Majority will also have a motor speech Majority will also have a motor speech impairment (apraxia of speech) with impairment (apraxia of speech) with ( )( )sound based errors and a nonsound based errors and a non--fluent fluent speech outputspeech output

PNFA Imaging (MRI)PNFA Imaging (MRI)g g ( )g g ( )

PNFA Imaging (FGD PET)PNFA Imaging (FGD PET)g g ( )g g ( )

PNFA NeuropsychologyPNFA Neuropsychologyp y gyp y gy

•• Poor performance on test of naming Poor performance on test of naming however the patient will recognize the however the patient will recognize the target words when giventarget words when given

•• Difficulty recognizing syntactically Difficulty recognizing syntactically complex sentencescomplex sentencespp

•• Relatively better performance on Relatively better performance on tests of episodic memorytests of episodic memorytests of episodic memory tests of episodic memory

•• Relatively normal performance on Relatively normal performance on test of spatial/perceptual functiontest of spatial/perceptual functiontest of spatial/perceptual functiontest of spatial/perceptual function

Summary of FTDSummary of FTDyy

•• FTD different from ADFTD different from AD•• FTD different from ADFTD different from AD•• Three clinical syndromesThree clinical syndromes

•• bvFTD (personality change)bvFTD (personality change)•• SD (loss of meaning for words)SD (loss of meaning for words)( g )( g )•• PNFA (speech output is not fluent)PNFA (speech output is not fluent)

•• Classification is based on dominantClassification is based on dominant•• Classification is based on dominant Classification is based on dominant feature, but features do overlap somefeature, but features do overlap some

FTD PathologiesFTD Pathologiesgg

bvFTD SD PNFA

TDP-43 Tau

FTD complexFTD complexpp

bvFTD SD PNFA

TDP-43

PSP

Tau

MND FTLD

Pick’s CBD

FTD complexFTD complexpp

bvFTD SD PNFA

TDP-43

Pick

Tau

MND FTLD

PSP CBD

FTD-MND CBDPSP

Related DisordersRelated Disorders

•• Progressive supranuclear palsyProgressive supranuclear palsy•• Progressive supranuclear palsy Progressive supranuclear palsy (PSP)(PSP)

•• Corticobasal degeneration (CBD)Corticobasal degeneration (CBD)•• Motor neuron disease (MND)Motor neuron disease (MND)Motor neuron disease (MND)Motor neuron disease (MND)

Clinical features associated with PSPClinical features associated with PSP

•• Reptilian stareReptilian starepp•• Difficulty looking up or downDifficulty looking up or down•• Stiffness of neck and trunk musclesStiffness of neck and trunk muscles•• Poor balance with lots of fallsPoor balance with lots of fallsPoor balance with lots of falls Poor balance with lots of falls •• Some patients also have apathy, mild Some patients also have apathy, mild

behavioral changesbehavioral changesbehavioral changesbehavioral changes•• Subtype present with apraxia of Subtype present with apraxia of

speechspeechJosephs et al., Brain 2007

PSP Imaging (FDG PET) PSP Imaging (FDG PET) g g ( )g g ( )

Clinical features associated with CBDClinical features associated with CBD

•• Difficulty moving one arm or leg due toDifficulty moving one arm or leg due to•• Difficulty moving one arm or leg due to Difficulty moving one arm or leg due to stiffness (rigidity) and dystoniastiffness (rigidity) and dystonia

•• Limb apraxia & myoclonus Limb apraxia & myoclonus •• Trouble controlling movement of limb,Trouble controlling movement of limb,Trouble controlling movement of limb, Trouble controlling movement of limb,

i.e., the limb behaves as if it has a mind i.e., the limb behaves as if it has a mind of its own (soof its own (so--called alien limb)called alien limb)(( ))

•• Behavioral changes can be prominentBehavioral changes can be prominent•• Present as PNFA initiallyPresent as PNFA initially

CBD Imaging (FDG PET)CBD Imaging (FDG PET)g g ( )g g ( )

FTD & MNDFTD & MND

•• A subset of patients with bvFTDA subset of patients with bvFTD likelike•• A subset of patients with bvFTDA subset of patients with bvFTD--like like features also have clinical and features also have clinical and pathological features of MNDpathological features of MNDpathological features of MNDpathological features of MND

•• Predominance of lower MND findingsPredominance of lower MND findings•• Fasciculations (twitching of muscles)Fasciculations (twitching of muscles)•• Muscle weaknessMuscle weakness•• Muscle wastingMuscle wasting•• Flaccid dysarthria (breathy speech)Flaccid dysarthria (breathy speech)y ( y p )y ( y p )

Mackenzie, et al JNEN 2005

MNDMND

•• Upper motor neuron disease findingsUpper motor neuron disease findingsUpper motor neuron disease findings Upper motor neuron disease findings also occur and can occur in isolation also occur and can occur in isolation –– so call FTD/PLS (can mimic PSP)so call FTD/PLS (can mimic PSP)( )( )

•• Clinical findingsClinical findings•• Bulbar signs (spastic dysarthriaBulbar signs (spastic dysarthria•• Bulbar signs (spastic dysarthria Bulbar signs (spastic dysarthria --

strained speech)strained speech)•• Limb spasticityLimb spasticity•• Limb spasticityLimb spasticity•• Babinski sign Babinski sign

Josephs et al. Neurology 2007

MNDMND

•• If lower motor neuron disease isIf lower motor neuron disease is•• If lower motor neuron disease is If lower motor neuron disease is present, average disease duration present, average disease duration about 2 3 years (FTD without MND =about 2 3 years (FTD without MND =about 2.3 years (FTD without MND about 2.3 years (FTD without MND 77--15 years)15 years)

•• If isolated pper motor ne ronIf isolated pper motor ne ron•• If isolated upper motor neuron If isolated upper motor neuron disease, disease duration about 4 disease, disease duration about 4 yearsyearsyears years

•• Therefore, important to diagnose Therefore, important to diagnose th MND i tth MND i tthese MND variantsthese MND variants

Josephs et al. Neurology 2006 & 2007

bvFTD vs. FTDbvFTD vs. FTD--MNDMND

bvFTD

FTD-MND

Final SummaryFinal Summaryyy

•• There is overlapping clinical & There is overlapping clinical & th l i l f t b t FTDth l i l f t b t FTDpathological features between FTD pathological features between FTD

(bvFTD, SD and PNFA) and (PSP, CBD & (bvFTD, SD and PNFA) and (PSP, CBD & MND)MND)MND)MND)

•• This suggest that these diseases share This suggest that these diseases share i l i f l d ibli l i f l d iblcortical regions of loss and possibly cortical regions of loss and possibly

mechanism of neurodegenerationmechanism of neurodegeneration•• It remains important to keep them It remains important to keep them

separate if important treatment and separate if important treatment and genetic discoveries are to be made.genetic discoveries are to be made.