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title: "Frontotemporal Lobar Degeneration"
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docid: "49510d0e-acf7-45cb-9eb1-53f8193b0b6d"
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breadcrumbs:
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- "Brain"
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- "Diagnosis"
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- "Pathology-Based Diagnoses"
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- "Acquired Toxic/Metabolic/Degenerative Disorders"
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- "Dementias and Degenerative Disorders"
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- "Frontotemporal Lobar Degeneration"
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---
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# KEY FACTS
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- ## Terminology
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- Clinical subtypes
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- Behavioral variant frontotemporal dementia **(bvFTD)**
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- Primary progressive aphasia syndromes **(PPA)**
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- Semantic variant **(sv-PPA)**: Previously known as semantic dementia
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- Nonfluent/agrammatic variant **(nfv-PPA)**: Previously known as progressive nonfluent aphasia
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- Logopenic variant **(lv-PPA)**
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- Frontotemporal dementia with motor symptoms
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- ## Imaging
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- Early
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- PET shows frontotemporal ↓ glucose metabolism
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- Late: Frontotemporal atrophy with knife-like gyri on MR
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- Subtypes have characteristic cortical atrophy patterns
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- ## Top Differential Diagnoses
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- Alzheimer dementia (AD)
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- Vascular dementia
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- Corticobasal ganglionic degeneration (CBD)
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- Dementia with Lewy bodies (DLB)
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- ## Clinical Issues
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- Clinical syndromes (some overlap)
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- **bvFTD**: Disinhibition, apathy & loss of empathy, hyperorality, & compulsive behavior
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- **sv-PPA**: Impaired single-word comprehension & object naming with preserved fluency, repetition, & grammar
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- **nfv-PPA**: Effortful speech production of phonemes (linguistic units of sound) & orofacial apraxia
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- **lv-PPA**: Impaired word finding & repetition with errors in speech & naming
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- Younger age group than AD
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- FTLD most common cause of early-onset (< 65 years) dementia
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- Median survival: 6-11 years from symptom onset & 3-4 years from diagnosis
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# TERMINOLOGY
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- ## Abbreviations
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- Frontotemporal lobar degeneration (FTLD)
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- Clinical subtypes
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- Behavioral variant frontotemporal dementia **(bvFTD)**
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- Primary progressive aphasia syndromes **(PPA)**
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- Semantic variant **(sv-PPA)**: Previously known as semantic dementia
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- Nonfluent/agrammatic variant **(nfv-PPA)**: Previously known as progressive nonfluent aphasia
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- Logopenic variant**(lv-PPA)**: Has Alzheimer pathology & is not included as 1 of 3 clinical FTD syndromes
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- Frontotemporal dementia (FTD) with motor symptoms
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- Corticobasal degeneration (CBD)
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- Progressive supranuclear palsy (PSP)
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- FTD with motor neuron disease
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- FTD with amyotrophic lateral sclerosis (ALS)
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- ## Synonyms
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- Pick disease no longer used
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- Referred to pathologic variant with Pick bodies
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- ## Definitions
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- Heterogeneous family of neurodegenerative disorders characterized by focal lobar degeneration of frontal &/or temporal lobes
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# IMAGING
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- ## General Features
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- ### Best diagnostic clue
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- Structural & functional imaging are supportive but not diagnostic of FTD
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- PET showing frontotemporal ↓ glucose metabolism
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- Anterior frontotemporal atrophy with knife-like gyri
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- ### Location
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- Anterior temporal/frontal lobes, orbitofrontal cortex, medial temporal region
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- Relative sparing of parietooccipital lobes
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- ### Morphology
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- Knife blade appearance of atrophic gyri
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- ± marked asymmetry
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- May have worst atrophy in dominant hemisphere
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- ## CT Findings
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- ### NECT
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- Frontal lobe atrophy often most prominent feature
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- ↑ size of frontal horns (larger than rest of lateral ventricles)
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- ## MR Findings
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- ### T1WI
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- Atrophy of frontal & temporal lobes, often asymmetric
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- Knife-like gyri with normal signal
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- Dilated frontal sulci reflecting atrophy
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- 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
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- ↓ NAA in posterior cingulate gyri
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- Reflects ↓ neuronal population, viability
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- ± lactate peak in frontal lobes
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- MR voxel-based morphometry
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- Subtypes have characteristic cortical atrophy patterns
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- Frontal vs. temporal, left vs. right help discriminate
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- **bvFTD**: Atrophy of frontal & temporal lobes
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- Anterior insula, anterior cingulate, orbitofrontal cortex, & amygdala (early changes occur in right hemisphere)
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- **sv-PPA**: Typically anterior temporal lobe atrophy (asymmetric to left)
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- Entire temporal lobe can be involved
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- Ventromedial & superior frontal lobes
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- Right temporal atrophy as disease progresses
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- **nfv-PPA**: Selective left posterior frontoinsular region
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- **lv-PPA**: Predominant atrophy of left posterior temporal cortex & parietal lobe
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- DTI
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- Widespread damage to WM tracts reported
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- **bvFTD**: Uncinate fasciculus, inferior longitudinal fasciculus, & anterior commissural fibers
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- **sv-PPA**: Inferior longitudinal & uncinate fasciculi
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- **nfv-FTD**: Left superior longitudinal fasciculus
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- **lv-PPA**: Widespread dorsal & ventral WM tracts
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- ## Nuclear Medicine Findings
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- ### PET
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- Functional imaging more sensitive than MR in early-stage disease
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- FDG PET: ↓ metabolic activity in frontotemporal cortex
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- Amyloid PET helps differentiate FTLD from Alzheimer disease (AD)
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- HMPAO-SPECT
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- Sensitive technique for early detection of FTD
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- Occurs before atrophy is evident
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- **bvFTD**: ↓ perfusion frontal & anterior temporal lobes
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- Asymmetric, left or right dominant
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- **sv-PPA**: Prominent anterior temporal hypoperfusion, left > right
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- **nfv-PPA**: Asymmetric frontal hypoperfusion often involving insular cortex
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- **lv-PPA**: ↓ perfusion in left parietal inferior lobule & posterolateral temporal lobe
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- SPECT perfusion deficits predominantly in frontal & anterior temporal lobes with preserved perfusion posteriorly
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- Helps distinguish FTD from AD
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- Reduced frontal perfusion is not specific to FTD but also occurs in some cases of schizophrenia, depression, HIV encephalopathy, Creutzfeldt-Jakob disease, AD
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- ## Imaging Recommendations
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- ### Best imaging tool
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- PET/SPECT; MR voxel-based morphometry
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- ### Protocol advice
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- Routine T1WI, T2WI, coronal T2WI MR
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# DIFFERENTIAL DIAGNOSIS
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- [Alzheimer Disease](/document/alzheimer-disease/f71f5cf5-b1af-4c6d-b145-b4c10eec7b58)
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- Parietal & temporal cortical atrophy with disproportionate hippocampal volume loss
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- Increased rate of atrophy in FTD compared to AD
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- Often coexisting microvascular disease, WM hyperintensities, microhemorrhages
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- Amyloid imaging (11C-labeled Pittsburgh Compound-B) helps to differentiate AD from other dementias
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- [Vascular Dementia](/document/vascular-dementia/f59dab57-c511-4369-8fcc-592421a4b8d1)
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- 2nd most common dementia (15-30%)
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- WM & deep gray lacunae
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- Hyperintense lesions on T2WI & focal atrophy is suggestive of chronic infarcts
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- [Corticobasal Degeneration](/document/corticobasal-degeneration/23f97d4e-8724-4229-b9f8-08f63906ebd8)
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- Prominent extrapyramidal, cortical symptoms
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- Severe frontoparietal atrophy contralateral to more severely affected clinically
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- Atrophy of paracentral structures
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- [Dementia With Lewy Bodies](/document/dementia-with-lewy-bodies/e8e46d1d-46d2-4e5a-880f-f025a84c5871)
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- Hypometabolism of entire brain, especially visual cortex
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- Visual & auditory hallucinations, paranoid delusions
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# PATHOLOGY
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- ## General Features
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- ### Etiology
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- Tau protein (hyperphosphorylated microtubular protein) or TDP-43 (TAR DNA-binding protein-43)
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- Rare cases change on fused-in-sarcoma (FUS) protein
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- ### Genetics
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- FTD is highly heritable without clear inheritance pattern
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- 25-40% of FTD is familial, > 50% of bvFTD is autosomal dominant
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- Mutations in following 3 genes together constitute 15% of FTD cases
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- Most common: Hexanucleotide expansion in chromosome 9 open reading frame 72 (*C9orf72*) gene
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- Microtubule-associated protein tau (*MAPT*) gene
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- Granulin precursor (*GRN*) gene
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- ## Staging, Grading, & Classification
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- Histopathologic classification of FTLD based on abnormal inclusions
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- FTLD-tau: Tau inclusion (hyperphosphorylated tau protein)/Pick bodies
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- FTLD-TDP: Tau-negative & TDP-43-positive inclusions (subtypes: Type A, B, C, & D)
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- FTLD-FUS: Tau-/TDP-negative & FUS-positive inclusions
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- FTLD-ALS/dipeptide repeats (DPR): TDP-negative DPR protein aggregates
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- FTLD-ni: No inclusions
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- FTD clinical syndromes correlate with brain atrophy patterns & not with pathologic subtypes
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- ## Gross Pathologic & Surgical Features
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- Gross atrophy of frontal &/or anterior temporal lobes
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- Firm cortical gray matter (gliosis) &/or basal ganglia atrophy
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- Soft, retracted subcortical WM
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- ## Microscopic Features
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- Loss of pyramidal neurons & microvacuolar degeneration in layer II & III of frontal & temporal cortex
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- Subjacent WM shows axonal & myelin loss
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- FTLD-related tauopathies
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- Pick disease: Prototypical tauopathy of FTLD
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- Characterized by Pick bodies: Solitary, round or oval, argyrophilic inclusions in cytoplasm of neurons
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- Commonly found in dentate gyrus of hippocampus, amygdala, frontal & temporal neocortex
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# CLINICAL ISSUES
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- ## Presentation
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- ### Most common signs/symptoms
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- Personality, behavior, & language changes
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- Memory loss, confusion, cognitive & speech dysfunction, apathy, & abulia
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- ### Clinical profile
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- **bvFTD**: Disinhibition, apathy & loss of empathy, hyperorality, & compulsive behavior
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- 15-20% may develop concomitant motor neuron disease (MND)
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- **sv-PPA**: Impaired single-word comprehension & object naming with preserved fluency, repetition, & grammar
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- **nfv-PPA**: Effortful speech production of phonemes (linguistic units of sound) & orofacial apraxia
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- **lv-PPA**: Impaired word finding & repetition with errors in speech & naming
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- ## Demographics
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- ### Age
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- More common cause of early-onset (midlife) dementia
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- Mean age of onset is 58 years; rare < 40 & > 75 years
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- Peak incidence 45-65 years
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- ### Sex
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- bvFTD & sv-FTD: Male preponderance
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- nfv-PPA: Female predominance
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- ### Ethnicity
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- Familial forms of Pick complex dementias particularly common in people of Scandinavian origin
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- ### Epidemiology
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- FTLD more common cause of early-onset (< 65 years) dementia
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- Age > 65 years account for 20-25% of cases of FTLD
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- Prevalence: 3.5-15/100,000 person-years
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- FTLD accounts for ~ 5% of all pathologic diagnoses in patients with dementia
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- ## Natural History & Prognosis
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- Insidious onset of behavioral & cognitive dysfunction
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- Speech & language disturbance are often more profound than memory disorder
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- Median survival 6-11 years from symptom onset & 3-4 years from diagnosis
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- Currently no FDA-approved disease-modifying drugs available for treatment of FTD
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- Some patients develop artistic talents during course of dementia (disinhibition of "creative" brain areas)
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# DIAGNOSTIC CHECKLIST
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- ## Consider
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- Other common forms of dementia (AD, dementia with Lewy bodies)
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- ## Image Interpretation Pearls
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- Bilateral frontal lobe atrophy should make one consider diagnosis of FTD
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- Bilateral asymmetric anterior temporal lobe atrophy: sv-PPA
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- ## Reporting Tips
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- Report pattern of cortical volume loss
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69c47a04-dd7a-4a23-a55b-21542ccce82a
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