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KEY FACTS

Terminology
- Clinical subtypes - Behavioral variant frontotemporal dementia (bvFTD) - Primary progressive aphasia syndromes (PPA) - Semantic variant (sv-PPA): Previously known as semantic dementia - Nonfluent/agrammatic variant (nfv-PPA): Previously known as progressive nonfluent aphasia - Logopenic variant (lv-PPA) - Frontotemporal dementia with motor symptoms
Imaging
- Early - PET shows frontotemporal ↓ glucose metabolism
- Late: Frontotemporal atrophy with knife-like gyri on MR
- Subtypes have characteristic cortical atrophy patterns
Top Differential Diagnoses
- Alzheimer dementia (AD)
- Vascular dementia
- Corticobasal ganglionic degeneration (CBD)
- Dementia with Lewy bodies (DLB)
Clinical Issues
- Clinical syndromes (some overlap) - bvFTD: Disinhibition, apathy & loss of empathy, hyperorality, & compulsive behavior - sv-PPA: Impaired single-word comprehension & object naming with preserved fluency, repetition, & grammar - nfv-PPA: Effortful speech production of phonemes (linguistic units of sound) & orofacial apraxia - lv-PPA: Impaired word finding & repetition with errors in speech & naming
- Younger age group than AD
- FTLD most common cause of early-onset (< 65 years) dementia
- Median survival: 6-11 years from symptom onset & 3-4 years from diagnosis

TERMINOLOGY

Abbreviations
- Frontotemporal lobar degeneration (FTLD)
- Clinical subtypes - Behavioral variant frontotemporal dementia (bvFTD) - Primary progressive aphasia syndromes (PPA) - Semantic variant (sv-PPA): Previously known as semantic dementia - Nonfluent/agrammatic variant (nfv-PPA): Previously known as progressive nonfluent aphasia - Logopenic variant**(lv-PPA)**: Has Alzheimer pathology & is not included as 1 of 3 clinical FTD syndromes
- Frontotemporal dementia (FTD) with motor symptoms - Corticobasal degeneration (CBD) - Progressive supranuclear palsy (PSP) - FTD with motor neuron disease - FTD with amyotrophic lateral sclerosis (ALS)
Synonyms
- Pick disease no longer used - Referred to pathologic variant with Pick bodies
Definitions
- Heterogeneous family of neurodegenerative disorders characterized by focal lobar degeneration of frontal &/or temporal lobes

IMAGING

General Features

Best diagnostic clue

- Structural & functional imaging are supportive but not diagnostic of FTD
- PET showing frontotemporal ↓ glucose metabolism
- Anterior frontotemporal atrophy with knife-like gyri

Location

- Anterior temporal/frontal lobes, orbitofrontal cortex, medial temporal region
- Relative sparing of parietooccipital lobes

Morphology

- Knife blade appearance of atrophic gyri
- ± marked asymmetry
        - May have worst atrophy in dominant hemisphere

CT Findings

NECT

- Frontal lobe atrophy often most prominent feature
        - ↑ size of frontal horns (larger than rest of lateral ventricles)

MR Findings
- T1WI
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- Atrophy of frontal & temporal lobes, often asymmetric
- Knife-like gyri with normal signal
- Dilated frontal sulci reflecting atrophy
- Relative sparing of parietooccipital lobes
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- T2WI
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- ± hyperintensity in frontotemporal white matter (WM)
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- FLAIR
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- ± hyperintensity in frontotemporal WM
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- MRS
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- ↓ NAA glutamate + glutamine (neuronal loss), ↑ myoinositol (↑ glial content) in frontal lobes
        - ↓ NAA in posterior cingulate gyri
        - Reflects ↓ neuronal population, viability
- ± lactate peak in frontal lobes
```
- MR voxel-based morphometry - Subtypes have characteristic cortical atrophy patterns - Frontal vs. temporal, left vs. right help discriminate - bvFTD: Atrophy of frontal & temporal lobes - Anterior insula, anterior cingulate, orbitofrontal cortex, & amygdala (early changes occur in right hemisphere) - sv-PPA: Typically anterior temporal lobe atrophy (asymmetric to left) - Entire temporal lobe can be involved - Ventromedial & superior frontal lobes - Right temporal atrophy as disease progresses - nfv-PPA: Selective left posterior frontoinsular region - lv-PPA: Predominant atrophy of left posterior temporal cortex & parietal lobe
- DTI - Widespread damage to WM tracts reported - bvFTD: Uncinate fasciculus, inferior longitudinal fasciculus, & anterior commissural fibers - sv-PPA: Inferior longitudinal & uncinate fasciculi - nfv-FTD: Left superior longitudinal fasciculus - lv-PPA: Widespread dorsal & ventral WM tracts
Nuclear Medicine Findings
- PET
```
- Functional imaging more sensitive than MR in early-stage disease
- FDG PET: ↓ metabolic activity in frontotemporal cortex
- Amyloid PET helps differentiate FTLD from Alzheimer disease (AD)
```
- HMPAO-SPECT - Sensitive technique for early detection of FTD - Occurs before atrophy is evident - bvFTD: ↓ perfusion frontal & anterior temporal lobes - Asymmetric, left or right dominant - sv-PPA: Prominent anterior temporal hypoperfusion, left > right - nfv-PPA: Asymmetric frontal hypoperfusion often involving insular cortex - lv-PPA: ↓ perfusion in left parietal inferior lobule & posterolateral temporal lobe
- SPECT perfusion deficits predominantly in frontal & anterior temporal lobes with preserved perfusion posteriorly - Helps distinguish FTD from AD
- Reduced frontal perfusion is not specific to FTD but also occurs in some cases of schizophrenia, depression, HIV encephalopathy, Creutzfeldt-Jakob disease, AD

Imaging Recommendations

Best imaging tool

- PET/SPECT; MR voxel-based morphometry

Protocol advice
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- Routine T1WI, T2WI, coronal T2WI MR
```

DIFFERENTIAL DIAGNOSIS

Alzheimer Disease
- Parietal & temporal cortical atrophy with disproportionate hippocampal volume loss
- Increased rate of atrophy in FTD compared to AD
- Often coexisting microvascular disease, WM hyperintensities, microhemorrhages
- Amyloid imaging (11C-labeled Pittsburgh Compound-B) helps to differentiate AD from other dementias
Vascular Dementia
- 2nd most common dementia (15-30%)
- WM & deep gray lacunae
- Hyperintense lesions on T2WI & focal atrophy is suggestive of chronic infarcts
Corticobasal Degeneration
- Prominent extrapyramidal, cortical symptoms
- Severe frontoparietal atrophy contralateral to more severely affected clinically
- Atrophy of paracentral structures
Dementia With Lewy Bodies
- Hypometabolism of entire brain, especially visual cortex
- Visual & auditory hallucinations, paranoid delusions

PATHOLOGY

General Features

Etiology

- Tau protein (hyperphosphorylated microtubular protein) or TDP-43 (TAR DNA-binding protein-43)
- Rare cases change on fused-in-sarcoma (FUS) protein

Genetics

- FTD is highly heritable without clear inheritance pattern
- 25-40% of FTD is familial, > 50% of bvFTD is autosomal dominant
- Mutations in following 3 genes together constitute 15% of FTD cases
        - Most common: Hexanucleotide expansion in chromosome 9 open reading frame 72 (*C9orf72*) gene
        - Microtubule-associated protein tau (*MAPT*) gene
        - Granulin precursor (*GRN*) gene

Staging, Grading, & Classification
- Histopathologic classification of FTLD based on abnormal inclusions - FTLD-tau: Tau inclusion (hyperphosphorylated tau protein)/Pick bodies - FTLD-TDP: Tau-negative & TDP-43-positive inclusions (subtypes: Type A, B, C, & D) - FTLD-FUS: Tau-/TDP-negative & FUS-positive inclusions - FTLD-ALS/dipeptide repeats (DPR): TDP-negative DPR protein aggregates - FTLD-ni: No inclusions
- FTD clinical syndromes correlate with brain atrophy patterns & not with pathologic subtypes
Gross Pathologic & Surgical Features
- Gross atrophy of frontal &/or anterior temporal lobes
- Firm cortical gray matter (gliosis) &/or basal ganglia atrophy
- Soft, retracted subcortical WM
Microscopic Features
- Loss of pyramidal neurons & microvacuolar degeneration in layer II & III of frontal & temporal cortex
- Subjacent WM shows axonal & myelin loss
- FTLD-related tauopathies - Pick disease: Prototypical tauopathy of FTLD - Characterized by Pick bodies: Solitary, round or oval, argyrophilic inclusions in cytoplasm of neurons - Commonly found in dentate gyrus of hippocampus, amygdala, frontal & temporal neocortex

CLINICAL ISSUES

Presentation

Most common signs/symptoms

- Personality, behavior, & language changes
- Memory loss, confusion, cognitive & speech dysfunction, apathy, & abulia

Clinical profile

- **bvFTD**: Disinhibition, apathy & loss of empathy, hyperorality, & compulsive behavior
        - 15-20% may develop concomitant motor neuron disease (MND)
- **sv-PPA**: Impaired single-word comprehension & object naming with preserved fluency, repetition, & grammar
- **nfv-PPA**: Effortful speech production of phonemes (linguistic units of sound) & orofacial apraxia
- **lv-PPA**: Impaired word finding & repetition with errors in speech & naming

Demographics

Age

- More common cause of early-onset (midlife) dementia
        - Mean age of onset is 58 years; rare < 40 & > 75 years
        - Peak incidence 45-65 years

Sex

- bvFTD & sv-FTD: Male preponderance
- nfv-PPA: Female predominance

Ethnicity

- Familial forms of Pick complex dementias particularly common in people of Scandinavian origin

Epidemiology

- FTLD more common cause of early-onset (< 65 years) dementia
- Age > 65 years account for 20-25% of cases of FTLD
- Prevalence: 3.5-15/100,000 person-years
- FTLD accounts for ~ 5% of all pathologic diagnoses in patients with dementia

Natural History & Prognosis
- Insidious onset of behavioral & cognitive dysfunction
- Speech & language disturbance are often more profound than memory disorder
- Median survival 6-11 years from symptom onset & 3-4 years from diagnosis
- Currently no FDA-approved disease-modifying drugs available for treatment of FTD
- Some patients develop artistic talents during course of dementia (disinhibition of "creative" brain areas)

DIAGNOSTIC CHECKLIST

Consider
- Other common forms of dementia (AD, dementia with Lewy bodies)
Image Interpretation Pearls
- Bilateral frontal lobe atrophy should make one consider diagnosis of FTD
- Bilateral asymmetric anterior temporal lobe atrophy: sv-PPA
Reporting Tips
- Report pattern of cortical volume loss

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References

Selected References

Tables

Imaging Features for Various Clinical Subtypes of Frontotemporal Dementia

Clinical Subtypes	Imaging Features
bvFTD	MR: Atrophy of frontal & temporal lobes; asymmetric right frontal &/or temporal lobe atrophy may occur NM: Decreased perfusion & metabolism in frontal &/or temporal lobes, usually asymmetric to right side
sv-PPA	MR: Typically atrophy of left anterior & inferior temporal lobe; right temporal lobe atrophies as disease progresses NM: Decreased perfusion & metabolism in anterior temporal lobes (L > > R)
nfv-PPA	MR: Selective left perisylvian & frontal atrophy NM: Asymmetric decreased perfusion & metabolism in frontal lobes (L > > R) often involving insular cortex
lv-PPA	MR: Prominent atrophy of left angular & middle temporal gyri NM: Decreased perfusion & metabolism in left parietal inferior lobule & posterolateral temporal lobe

Images

Selected Images

Graphic depicts the classic disproportionate frontal lobe atrophy of late-stage frontotemporal dementia (FTD). The sulci are widened & gyri are knife-like . Parietooccipital lobes are spared. Gyri around the central sulcus are normal.

Coronal NECT MPR through the frontal lobes of a 62-year-old man with behavioral variant frontotemporal dementia (bvFTD) shows asymmetric atrophy of right frontal lobe with relatively preserved left frontal lobe volume .

Coronal T2WI MR of a 55-year-old woman with nfv-PPA shows diffuse brain parenchymal atrophy, which is more pronounced in the left perisylvian region due to atrophy of adjacent inferior & lateral temporal convexity and frontal operculum .

Parasagittal T1WI MR through left (top) & right (bottom) temporal lobes of a 55-year-old man with sv-PPA shows asymmetric temporal lobe atrophy on left vs. right . Also note relatively preserved frontal lobe volume.

FDG PET raw data & 3D-SSP images of a 59-year-old man with sv-PPA demonstrate decreased metabolic activity in the anterior & medial left temporal lobe & to a lesser degree in anterior & medial temporal lobe . (Courtesy M. Matesan, MD.)

Axial T2WI MR in a patient with classic FTD shows predominantly frontal lobar atrophy with knife-like gyri . In this case, an associated region of hyperintense white matter is present.

Axial FDG PET of a 55-year-old woman with sv-PPA (clinical subtype of FTD) shows decreased metabolic activity in the left temporal lobe & to a lesser degree in the right temporal lobe . Note relative sparing of parietal & occipital lobes .

Axial FLAIR MR in the same patient shows asymmetric atrophy of bilateral temporal lobes (left > right) with knife-like gyri . (Courtesy M. Matesan, MD.)

Axial color-coded FDG PET in a 65-year-old man with apathy & slowly progressive behavioral changes with clinical diagnosis of bvFTD shows decreased metabolic activity in bilateral anterior & medial temporal lobes with relative sparing of bilateral parietooccipital lobes .

Sagittal reformat of color-coded FDG PET in the same patient shows decreased metabolic activity in the frontal lobe . (Courtesy J. Singh, MD.)

Additional Images

Sagittal T1WI MR demonstrates marked atrophy of the frontal lobe in a patient with FTD.

Coronal T1WI MR in a patient with FTD shows prominent atrophy of both frontal lobes, which appears more pronounced on the left side.

Axial NECT demonstrates predominantly frontal lobe volume loss from FTD.

Axial T2WI MR in a patient with FTD shows marked frontal lobe atrophy.

Axial FLAIR MR shows frontal lobe volume loss as well as associated hyperintense signal in white matter.

Axial T2WI MR in a patient with FTD demonstrates marked volume loss as well as associated hyperintense signal within bilateral temporal lobes.

FDG PET in a patient with FTD & dementia depicts glucose hypometabolism (green regions in the cortex) in the frontal lobes. (Courtesy N. Foster, MD & the University of Michigan PET Center.)

FDG PET in the same patient shows a decreased rate of glucose metabolism in the frontal & temporal lobes, consistent with FTD. (Courtesy N. Foster, MD & the University of Michigan PET Center.)

Axial T2WI MR in a 57-year-old woman with probable FTD shows temporal lobe atrophy with knife-like gyri . The parietal & occipital lobes are relatively well preserved.

FDG PET in a patient with FTD shows marked hypometabolism in the frontal & temporal lobes. There is relative preservation of glucose metabolism in the occipital & parietal lobes .

Sagittal SSP FDG PET scan in a 72-year-old man with FTD shows a normal elderly control map (2nd row), the patient's glucose metabolism (3rd row), & Z-score statistical map (bottom row). The frontal lobes are strikingly hypometabolic. The temporal lobes are somewhat less severely affected.

Coronal T1WI MR in the same patient shows focal atrophy of the olfactory gyri . This finding was initially overlooked & the patient was given the imaging diagnosis of Alzheimer disease. Review & subsequent clinical evaluation confirmed FTD.

Axial FDG PET in a patient with FTD shows decreased glucose metabolism in frontal & temporal lobes. The parietal & occipital lobes are spared.

Sagittal FDG PET in the same patient with FTD depicts glucose hypometabolism in the frontal lobes . The occipital lobes are normal.

Coronal FDG PET in a patient with FTD exhibits glucose hypometabolism in frontal and temporal lobes .

Axial T2WI MR in a patient with semantic dementia subtype of FTLD shows marked atrophy of anterolateral temporal lobes . Note the relative preservation of the hippocampi .

Axial NECT in a 78-year-old patient diagnosed with late-stage FTD through the upper lateral ventricles shows striking frontal lobar atrophy with classic knife-like gyri characteristic of FTD. In contrast, the parietal & occipital lobes appear relatively spared.

Axial FLAIR MR in a patient with early findings of FTD shows relatively mild frontal lobe volume loss compared to the normal appearance of the parietal lobes.

Axial FLAIR MR shows atrophy of both the frontal & temporal lobes. Note compensatory enlargement of the temporal horns due to temporal lobe volume loss.

Sagittal T1WI MR shows predominantly frontal & temporal lobe atrophy. Some gyri demonstrate a classic knife-like appearance () reflecting severe atrophy of a gyrus.

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KEY FACTS

Terminology

Imaging

Top Differential Diagnoses

Clinical Issues

TERMINOLOGY

Abbreviations

Synonyms

Definitions

IMAGING

General Features

Best diagnostic clue

Location

Morphology

CT Findings

NECT

MR Findings

T1WI

T2WI

FLAIR

MRS

Nuclear Medicine Findings

PET

Imaging Recommendations

Best imaging tool

Protocol advice

DIFFERENTIAL DIAGNOSIS

PATHOLOGY

General Features

Etiology

Genetics

Staging, Grading, & Classification

Gross Pathologic & Surgical Features

Microscopic Features

CLINICAL ISSUES

Presentation

Most common signs/symptoms

Clinical profile

Demographics

Age

Sex

Ethnicity

Epidemiology

Natural History & Prognosis

DIAGNOSTIC CHECKLIST

Consider

Image Interpretation Pearls

Reporting Tips

References

Selected References

Tables

Imaging Features for Various Clinical Subtypes of Frontotemporal Dementia

Images

Selected Images

Additional Images

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