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KEY FACTS

Terminology
- Frontotemporal dementia (FTD): Progressive neurodegenerative disorder of frontal/anterior temporal lobes
Imaging
- F-18 FDG PET - Helps differentiate between FTD and other causes of dementia - Glucose hypometabolism - Initially in frontal lobes progressing to temporal lobes - Anterior cingulate also commonly hypometabolic - Left-sided asymmetry could suggest underlying primary progressive aphasia (PPA) - Hypometabolism within motor strip (precentral gyrus) could suggest motor neuron disease FTD (FTD-MND)
- Perfusion SPECT - Similar pattern of frontal hypoperfusion as F-18 FDG PET - Potentially less sensitive than F-18 FDG PET
Clinical Issues
- Progressive changes in behavior, language, or motor function depending upon subtype
- Memory is less dominant clinical feature in FTDs
- No current disease-modifying treatment for FTD, only symptomatic therapy
Diagnostic Checklist
- Clinical therapy decisions depend on proper diagnosis - FTD important to distinguish from Alzheimer disease (AD) because AD medications do not slow progression of FTD and can worsen symptoms - Amyloid-targeting therapies (ATTs) have no role in treating FTDs
- Image analysis - If hypometabolism is anterior-predominant (e.g., frontal, anterior temporal, anterior cingulate), this favors FTD - Amyloid PET can also help exclude AD pathology

TERMINOLOGY

Abbreviations
- Frontotemporal dementia (FTD)
- Alzheimer disease (AD)
Definitions
- Progressive neurodegenerative disorder of frontal/anterior temporal lobes - Typically subdivided into categories based on underlying molecular aggregates [TDP-43 (50%), tauopathy without amyloid (40%), and FET protein family (10%)] and main functional deficit (cognitive and behavior, language, or motor) - Behavioral variant FTD (bvFTD) (formerly Pick disease) - Commonly characterized by behavioral disinhibition, apathy, loss of sympathy, hyperorality, executive deficits - Most commonly seen with TDP-43 aggregation, initially described with intracellular τ inclusions (Pick bodies) - Prosopagnosia (inability to recognize familiar faces) has been described with right temporal variant FTD - Language variant FTD [FTD-primary progressive aphasia (PPA)] - Includes 2/3 subtypes of PPA, semantic variant PPA (svPPA) and nonfluent agrammatic variant PPA (nfvPPA) - svPPA is predominantly seen with TDP-43 pathology and nfvPPA with τ pathology - Other PPA variant, logopenic variant (lvPPA), is atypical AD variant (amyloid and τ positive) - Motor neuron disease FTD (FTD-MND) - Includes amyotrophic lateral sclerosis (FTD-ALS; 95% TDP-43) as well as atypical parkinsonian syndromes of progressive supranuclear palsy (PSP; tauopathy) and corticobasal degeneration (CBD; tauopathy) - ALS classically presents with both upper motor neuron signs (spasticity, rigidity, hyperreflexia), lower motor neuron signs (muscle fasciculations, muscle atrophy), and nonmotor signs (behavioral disturbances), as seen with bvFTD (30% of cases) - PSP usually presents with bradykinesia, rigidity, vertical gaze palsy, dysphagia, dysarthria - CBD presents with parkinsonism, dystonia, apraxia, executive dysfunction, aphasia, "alien limb" phenomenon

IMAGING

Nuclear Medicine Findings
- F-18 FDG PET/CT - Glucose hypometabolism initially in frontal lobes with progression to include regions of temporal/parietal lobes - Anterior cingulate cortex, frontal insula, caudate nuclei, thalamus may also have hypometabolism bilaterally - Relative sparing of motor cortex, except in FTD-MNDs, specifically ALS and CBD, which can show hypometabolism - Hemispheric metabolic asymmetry may be present - Hypometabolism occurs before atrophy visually evident on CT/MR - Most sensitive diagnostic tool currently available - Glucose hypometabolism worsens with disease progression - May be used to distinguish between FTD and AD - AD often shows hypometabolism in posterior cingulate/temporoparietal regions, spared with FTD - 50% of patients with behavioral or dysexecutive AD variant do not show typical parietal and posterior cingulate hypometabolism - Amyloid PET can be helpful in this situation if considering amyloid-targeting therapies (ATTs) - Attenuation correction CT can show - Preferential atrophy of frontal/temporal lobes - Increased CSF space surrounding medial temporal lobes - Enlargement of lateral ventricles
- Perfusion SPECT - Pattern is similar to F-18 FDG PET with decreased radiotracer activity in frontal/temporal lobes - SPECT generally has less sensitivity and quantitative potential compared to PET - More sensitive than structural MR in detecting early changes
Imaging Recommendations
- Best imaging tool
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- F-18 FDG PET helps to differentiate between FTD and other causes of dementia, e.g., AD and Lewy body dementia (LBD)
        - Correlates with disease progression
- Amyloid PET can help exclude AD variants that can mimic FTDs, such as lvPPA
- I-123 ioflupane scan can help in cases of suspected PSP or CBD, which will show decreased/abnormal uptake
- CT/MR documents atrophy of mainly frontal/temporal lobe structures
        - Look for reversible causes of dementia, e.g., normal-pressure hydrocephalus
        - Motor band sign with T2* hypointensity of precentral gyri or T2/FLAIR hyperintensity of corticospinal tracts in ALS
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- F-18 FDG PET - Patient preparation - Patient should fast, stop IV fluids containing dextrose, and stop parenteral feeding for 4-6 hours - Blood sugar should be < 150-200 (mg/dL) - Patient should be placed in quiet, dimly lit room prior to and after injection (30 min) - Radiopharmaceutical: F-18 FDG - Dose: 5-20 mCi (185-740 MBq) - Dosimetry: Urinary bladder receives largest dose - Image acquisition: Image 30-60 min after injection
- SPECT - 2nd-line study if F-18 FDG PET is not available/reimbursed - Patient preparation - Patient should be placed in quiet, dimly lit room prior to and after injection (30 min)
- Radiopharmaceutical - Tc-99m exametazime (HMPAO) - Tc-99m ethyl cysteinate dimer (ECD)
- Dose: 15-30 mCi (555 MBq to 1.1 GBq)
- Dosimetry - Tc-99m HMPAO: Kidneys receive highest dose - Tc-99m ECD: Bladder wall receives highest dose
- Image acquisition - Optimal imaging time for Tc-99m HMPAO: 90 min post injection - Optimal imaging time for Tc-99m ECD: 45 min post injection
Artifacts and Quality Control
- Immobilize patient's head to decrease motion, attenuation correction artifacts

DIFFERENTIAL DIAGNOSIS

Alzheimer Disease
- Most common cause of dementia generally leading to impairments in episodic memory and other cognitive domains
- Related to aggregation of amyloid-β and τ proteins; therefore, positive on amyloid PET
- Behavioral and dysexecutive variants of AD - Clinical presentation with less memory impairment and more behavioral disinhibition/loss of executive function - Can be clinically indistinguishable from bvFTD - 50% of cases show F-18 FDG hypometabolism in precuneus and posterior cingulate gyrus (similar to classic AD); 50% show frontal hypometabolism with parietal sparing similar to FTD - Must consider amyloid PET in these cases; prerequisite for ATTs
- lvPPA - Predominant language loss with spared memory that can mimic other PPAs - Sentence repetition and single-word meaning usually preserved - Often have mild cognitive impairments outside of language (more than seen with svPPA or nfvPPA) - F-18 FDG hypometabolism shows more parietal involvement than other PPAs; amyloid PET can be helpful if considering ATTs
Limbic-Predominant Age-Related TDP-43 Encephalopathy
- Newly recognized neurodegenerative disease with predominant memory deficits related to hippocampal dysfunction
- Typically in patients > 80 years
- Often slower decline than AD, though can commonly be comorbid with AD, accelerating disease progression
- F-18 FDG PET shows marked hippocampal hypometabolism with less severe involvement of precuneus and posterior cingulate
- MR often shows marked hippocampal sclerosis
Vascular Dementia
- 2nd most common cause of dementia
- Caused by impaired blood supply to brain regions
- Global atrophy with diffuse white matter lesions (infarcts)
- Lesions generally correlate with cognitive symptoms
Lewy Body Dementia
- Commonly presents with hallucinations, sleep disturbances, and parkinsonian motor features
- F-18 FDG PET hypometabolism in occipital cortex
- Cardiac MIBG demonstrates sympathetic denervation (CBD and PSP do not demonstrate denervation)
- Positive α-synuclein skin test (CBD and PSP are tauopathies)
Psychiatric Illness
- Bipolar disorder, schizophrenia, obsessive compulsive disorder
Reversible Dementias
- Mass lesions (brain tumor), head trauma, normal-pressure hydrocephalus, vitamin B12 deficiency, hypothyroidism, infections (neurosyphilis, Lyme disease)

PATHOLOGY

General Features

Etiology

- Heterogeneous pathologic and clinical subtypes
        - Resulted from disease naming related to clinical presentation, before etiology/pathology was well understood
- Pathologic subtypes of FTD are classified based upon pattern of protein accumulation in groups encompassing disorders of frontotemporal lobar degeneration
- Etiology uncertain but associated with 3 major protein aggregates
        - τ (microtubule-associated protein)
        - TDP-43 (transactive response DNA binding protein of 43kD)
        - FET protein family, including FUS (tumor-associated protein; fused in sarcoma)

Genetics

- Autosomal dominant inheritance in 10-25% of FTD cases
        - c9orf72 most common genetic mutation in familial FTD and familial ALS
        - *SOD1*(superoxide dismutase) gene mutation in 10% of familial ALS with specific treatment, intrathecal tofersen
- Positive family history of FTD is only known risk factor
        - 30-50% of individuals with bvFTD have positive family history

CLINICAL ISSUES

Presentation

Most common signs/symptoms

- Progressive changes in behavior, personality, language, &/or motor function, depending upon clinical subtype
        - Disinhibition, apathy, loss of sympathy, hyperorality, dysexecutive behaviors
        - Bradykinesia, rigidity, tremor, spasticity, hyperreflexia, fasciculations, muscle atrophy in motor subtypes
        - Loss of language comprehension, including word meaning or agrammatism in language subtypes

Clinical profile

- FTD is composed of 3 main clinical subtypes
        - bvFTD
                  - Most common, accounting for ~ 1/2 of cases
                  - Progressive decline in social function with personality changes, often with disinhibition
        - Language presentation (PPA)
                  - Including variants svPPA and nfvPPA
        - Motor presentation
                  - ALS, PSP, CBD

Demographics

Age

- Mean of onset: 50-60 years
- ~ 10% > 70 years
- Younger onset than AD, which is generally > 65 years

Natural History & Prognosis
- Insidious onset of behavioral and cognitive dysfunction
- More significant behavioral, language, executive functioning impairment than memory
- Slowly progressive with eventual functional impairment
- Median survival ~ 8-10 years after diagnosis; varies widely based upon underlying pathology
- Median survival in ALS is 2-5 years
Treatment
- No current disease-modifying treatment for FTD
- ALS with SOD1mutation can be treated with intrathecal tofersen (6.5-month increase in median survival at 3 years)

DIAGNOSTIC CHECKLIST

Consider
- FTD important to distinguish from AD because AD medications do not slow progression of FTD and can worsen symptoms - FTDs are not amenable to ATTs due to lack of underlying amyloid pathology
Image Interpretation Pearls
- When analyzing images, use surface projections and normative dataset comparison to increase sensitivity

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References

Selected References

Images

Selected Images

Axial F-18 FDG PET shows findings associated with frontotemporal dementia (FTD), predominantly frontal and temporal lobe hypometabolism. Functional changes may occur prior to CT or MR changes.

Axial CT shows classic morphologic changes of FTD. Note advanced bilateral frontal lobe atrophy . In this case, there is also advanced bilateral temporal lobe atrophy (not shown).

Axial F-18 FDG PET shows findings associated with FTD, predominantly frontal and temporal lobe hypometabolism, the latter not shown.

Axial fused F-18 FDG PET/CTs in the same patient show predominantly frontal hypometabolism in purple/blue areas , signifying regions with a z-score > -2, or 2 standard deviations less than expected in normal controls.

Sagittal F-18 FDG PET in a patient with FTD shows predominantly frontal hypometabolism .

F-18 FDG PET shows reference maps (1st row), healthy older person map of glucose metabolism (2nd row), and patient's glucose metabolism (3rd row), which demonstrates strikingly diminished metabolism in the frontal and temporal lobes. Z-score map (4th row) illustrates areas of hypometabolism (compared to normal controls) in the frontal and temporal lobe . (Courtesy University of Utah Medical Center.)

Axial fused FDG PET/MR in a 61-year-old man with apathy, disinhibition, and lack of empathy shows subtle decreased metabolism in the medial frontal lobes . Not pictured is decreased activity in the right temporal lobe.

Surface projection in the same patient corroborates mild regional hypometabolism within the medial frontal lobes and the bilateral temporal lobes with preservation of the precuneus. This is suggestive of early FTD.

Axial fused FDG PET/MR shows L > R frontal hypometabolism as well as left parietal hypometabolism in a 51-year-old woman with severe frontal dysexecutive features.

Surface projection in the same patient shows focal hypometabolism within the L > R precuneus and parietal lobes as well as L > R frontal and temporal lobes , most consistent with early-onset dysexecutive Alzheimer disease (AD), rather than FTD.

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KEY FACTS

Terminology

Imaging

Clinical Issues

Diagnostic Checklist

TERMINOLOGY

Abbreviations

Definitions

IMAGING

Nuclear Medicine Findings

Imaging Recommendations

Best imaging tool

Artifacts and Quality Control

DIFFERENTIAL DIAGNOSIS

Limbic-Predominant Age-Related TDP-43 Encephalopathy

Vascular Dementia

Lewy Body Dementia

Psychiatric Illness

Reversible Dementias