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Add comprehensive articles on Vascular Dementia and Wallerian Degeneration

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- Created a detailed article for Vascular Dementia covering key facts, terminology, imaging findings, differential diagnoses, pathology, clinical issues, and diagnostic checklist.
- Developed an extensive article on Wallerian Degeneration including key facts, terminology, imaging features, differential diagnoses, pathology, clinical issues, and diagnostic checklist.
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---
title: "Frontotemporal Dementia"
docid: "9f9eda8c-7e3c-4292-9861-4b8abc2c6474"
breadcrumbs:
- "Nuclear Medicine"
- "Central Nervous System"
- "Neurodegeneration"
- "Frontotemporal Dementia"
---
# 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
- 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
- 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](/document/alzheimer-disease/2aad3ac4-44fd-43e5-8e50-a86987483af3)
- 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 *SOD1*mutation 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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