Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous group of neurodegenerative diseases characterized by selective degeneration of the frontal and temporal lobes. The clinical phenotypes range from behavioral variant frontotemporal dementia (bvFTD) to the primary progressive aphasias (nfvPPA, svPPA, lvPPA) to motor neuron disease overlap (FTD-MND/ALS). The underlying neuropathology divides FTLD into three major categories based on the protein that aggregates: tau (FTLD-tau), TDP-43 (FTLD-TDP), and FUS/EWS/TAF15 (FTLD-FET). This page covers the FTLD-tau subtypes; FTLD-TDP/FUS is covered separately.

The FTLD Framework

Clinical Syndromes

• Behavioral variant FTD (bvFTD): disinhibition, apathy, loss of empathy, dietary changes, compulsive behaviors.
• Semantic variant PPA (svPPA): loss of semantic knowledge; anterior temporal atrophy.
• Nonfluent/agrammatic PPA (nfvPPA): effortful, agrammatic speech, apraxia of speech.
• Logopenic PPA (lvPPA): usually AD pathology; word retrieval difficulty.
• FTD-MND/ALS: cognitive/behavioral plus motor neuron disease.
• Progressive supranuclear palsy (PSP): tauopathy with vertical gaze palsy + axial rigidity (see PSP/CBD page).
• Corticobasal syndrome (CBS): asymmetric apraxia + alien limb + parkinsonism (see PSP/CBD page).

Pathologic Categories of FTLD

• FTLD-tau (40-45%): tau aggregation. Includes Pick disease (3R-tau), PSP, CBD, AGD, GGT (4R-tau predominant).
• FTLD-TDP (45-50%): TDP-43 aggregation. Subtypes A, B, C, D, E.
• FTLD-FET (5-10%): FUS, EWS, or TAF15 aggregation. Rare.
• FTLD-UPS (rare): ubiquitin-proteasome system; rare.

FTLD-Tau Subtypes

Pick Disease (FTLD-Tau, 3R Predominant)

• Macroscopy: severe focal atrophy of frontal and temporal lobes, often asymmetric; “knife-edge” atrophy with sharp gyral edges; relative sparing of posterior gyri.
• Pick bodies: round, well-defined, eosinophilic intracytoplasmic inclusions; positive for 3R tau (Bielschowsky and tau IHC).
• Pick cells: enlarged, ballooned neurons with displaced nuclei.
• Distribution: prefrontal cortex, anterior temporal cortex, hippocampus (dentate), brainstem.

Clinical: bvFTD or svPPA most common.

Progressive Supranuclear Palsy (PSP)

Discussed in PSP/CBD page. 4R-tau predominant.

Corticobasal Degeneration (CBD)

Discussed in PSP/CBD page. 4R-tau.

Argyrophilic Grain Disease (AGD)

• Late-onset; often coexisting with other pathology.
• Spindle-shaped argyrophilic grains in neuropil, especially CA1-2 and amygdala.
• 4R tau predominant.
• Often mild cognitive impairment; sometimes more prominent.

Globular Glial Tauopathy (GGT)

• Tau aggregates in oligodendrocytes (globular astrocytic inclusions) and globular astrocytic inclusions.
• Three subtypes (I-III) based on distribution and clinical features.
• Can present as bvFTD, PSP-like, or motor neuron disease overlap.

Age-Related Tau Astrogliopathy (ARTAG)

• Late-onset tau astrocytic pathology.
• Often mild cognitive impairment.
• Thorn-shaped astrocytes and granular fuzzy astrocytes.

Familial FTLD-Tau

• MAPT mutations: tau gene on chromosome 17. Autosomal dominant. Variable phenotype: bvFTD, PPA, parkinsonism, often PSP-like.
• Pathology variable depending on mutation: 3R, 4R, or both isoforms predominant.

Behavioral Variant FTD (bvFTD)

Clinical (Rascovsky 2011 Criteria)

Three of six core features:

• Disinhibition.
• Apathy or inertia.
• Loss of sympathy or empathy.
• Perseverative / compulsive behavior.
• Hyperorality and dietary changes.
• Executive dysfunction with relative sparing of memory and visuospatial.

Plus functional decline and supportive imaging (frontal/temporal atrophy or hypometabolism).

Pathology

• 50-60% FTLD-TDP.
• 30-40% FTLD-tau (Pick disease, PSP-like).
• 5-10% FTLD-FET.

Imaging

• Frontal and anterior temporal atrophy.
• Often asymmetric.
• FDG-PET shows frontal and temporal hypometabolism.

Semantic Variant PPA (svPPA)

Clinical

• Fluent but empty speech.
• Loss of semantic knowledge (word meaning, object identity, person identity).
• Surface dyslexia (regular pronunciation of irregular words).
• Preserved grammar, syntax, repetition early.

Pathology

Overwhelmingly FTLD-TDP type C (90%+). Bilateral anterior temporal atrophy (left often more severe).

Nonfluent/Agrammatic PPA (nfvPPA)

Clinical

• Effortful, halting, agrammatic speech.
• Apraxia of speech (phonetic errors, prosody disturbance).
• Preserved single-word comprehension; impaired complex syntax.

Pathology

• FTLD-tau (50-60%), especially PSP-like.
• FTLD-TDP (30-40%).
• Dominant frontal/insular atrophy.

Logopenic PPA (lvPPA)

Clinical

• Word retrieval difficulty.
• Impaired repetition (especially sentences).
• Phonemic paraphasic errors.

Pathology

• Usually Alzheimer disease pathology (70-80%) — not classical FTLD!
• Atypical AD with temporoparietal predominant tau and Aβ.
• Some cases FTLD-TDP.

FTD-MND (FTD-ALS)

Overlap of frontotemporal dementia with motor neuron disease (ALS). Almost always FTLD-TDP pathology. C9orf72 expansion is the most common cause.

Familial FTLD

• C9orf72 hexanucleotide repeat expansion: most common; FTD, ALS, FTD-MND. RNA foci, dipeptide repeat protein inclusions, plus TDP-43.
• GRN (progranulin): FTLD-TDP type A; haploinsufficiency.
• MAPT (tau): FTLD-tau; variable phenotype.
• VCP, CHMP2B, TARDBP, FUS: rare causes.

Clinical-Pathologic Correlations

Clinical Approach

• Careful behavioral, language, and motor examination.
• MRI for atrophy pattern (frontal/temporal asymmetry).
• FDG-PET for hypometabolism pattern.
• Genetic testing in suspected familial cases (C9orf72, GRN, MAPT).
• CSF / biomarker testing to exclude AD or DLB pathology.
• Tau PET imaging (emerging).

Treatment

• No disease-modifying therapy.
• Symptomatic management of behavioral symptoms (SSRIs, trazodone).
• Caregiver support is paramount.
• Anti-tau and anti-TDP-43 therapies in development.

🔍 Did You Know?

The classical “knife-edge” atrophy of Pick disease — severe, sharp-bordered focal atrophy of frontal and temporal gyri with relative preservation of posterior cortex — was first described in the early 1900s by Arnold Pick and his colleagues. The atrophy is so dramatic and so localized that it was visible to early neurologists at autopsy without the help of any imaging. Pick described patients with progressive language and behavioral changes, and his examination of their brains revealed cortical thinning that could be felt as well as seen — gyri that, when palpated, had edges sharp enough to “knife-edge” against the examining finger. The pathologic correlate is severe neuronal loss with reactive astrogliosis in the affected cortex, plus the characteristic Pick bodies (3R-tau intracellular inclusions) in surviving neurons. The clinical correlate is the syndrome that Pick described and that we still call by his name when it has this pathology: progressive behavioral or language disorder with this focal pattern. Modern molecular classification has shown that “Pick disease” is one specific tauopathy (3R-tau predominant), distinct from PSP (4R-tau) and CBD (4R-tau). The clinical presentation, the radiographic atrophy pattern, and the molecular pathology now all align in modern diagnostic frameworks. The lesson: focal cortical atrophy — when severe, asymmetric, and respecting the boundary between affected and preserved gyri — points strongly to FTLD. Imaging that shows this pattern in a patient with behavioral or language change can lead directly to family counseling, prognostic discussion, and inclusion in disease-modifying trials.

Pitfalls and Pearls

• FTLD = clinical/genetic/pathologic spectrum: bvFTD, svPPA, nfvPPA, FTD-MND, PSP, CBS.
• Pathologic categories: FTLD-tau (Pick disease, PSP, CBD) / FTLD-TDP (4 subtypes) / FTLD-FET (FUS).
• Pick bodies: 3R-tau intracytoplasmic inclusions.
• Knife-edge atrophy: classic Pick disease gross feature.
• bvFTD: 50-60% TDP, 30-40% tau, 5-10% FUS.
• svPPA: ~90% FTLD-TDP type C; anterior temporal atrophy.
• nfvPPA: ~50-60% FTLD-tau (PSP-like); apraxia of speech.
• lvPPA: usually AD pathology (atypical AD).
• FTD-MND: FTLD-TDP; C9orf72 most common familial cause.
• C9orf72 hexanucleotide expansion: most common genetic FTD/ALS; RNA foci + dipeptide repeats + TDP-43.
• GRN: FTLD-TDP type A.
• MAPT: FTLD-tau; variable phenotype including PSP-like.
• Rascovsky bvFTD criteria: 3 of 6 core features + functional decline.
• Loss of empathy: highly suggestive of bvFTD.
• No disease-modifying therapy yet; trials of anti-tau, anti-TDP-43 underway.

References

1. Love S, Budka H, Ironside JW, Perry A, eds. Greenfield’s Neuropathology. 9th ed. CRC Press; 2015.
2. Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of FTLD: an update. Acta Neuropathol. 2010;119(1):1-4.
3. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(9):2456-2477.
4. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014.
5. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245-256.
6. Mackenzie IR, Neumann M. Reappraisal of TDP-43 pathology in FTLD-U subtypes. Acta Neuropathol. 2017;134(1):79-96.