FTLD and the Tauopathies
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Direct answer
Frontotemporal lobar degeneration (FTLD) is the pathological umbrella beneath the clinical frontotemporal dementia syndromes — behavioural variant, semantic variant and nonfluent-agrammatic primary progressive aphasia — classified by the deposited protein: FTLD-tau in about 40-45% of cases, FTLD-TDP-43 in about half, and FTLD-FUS in a small residue. Within FTLD-tau, the isoform discriminates diseases: Pick disease deposits three-repeat (3R) tau as rounded argyrophilic Pick bodies with ballooned achromatic neurons; progressive supranuclear palsy and corticobasal degeneration deposit four-repeat (4R) tau with tufted astrocytes and astrocytic plaques respectively; MAPT mutations on chromosome 17q21.3 drive the familial forms. On the TDP-43 side, subtypes A-E correlate loosely with genes — GRN with type A, C9orf72 expansion with type B — and the C9orf72 hexanucleotide repeat expansion is the single commonest genetic cause of both FTD and amyotrophic lateral sclerosis.
What you must remember
- Protein-first classification: FTLD-tau, FTLD-TDP and FTLD-FUS — the clinical syndrome does not predict the protein, which is why the pathological label carries the disease name.
- Pick body properties: spherical, tau- and p62-positive, argyrophilic (silver-staining) cytoplasmic inclusions, mildly tau-3 positive and tau-4 negative — 3R-selective, accompanied by ballooned "Pick cells" and knife-edge frontotemporal atrophy.
- 4R tau pair: PSP (tufted astrocytes, globose subcortical tangles, subthalamic and nigral degeneration) versus CBD (astrocytic plaques, thread pathology, asymmetric frontoparietal involvement with ballooned neurons).
- MAPT: the tau gene at 17q21.3; missense and splice-site mutations cause familial FTLD-tau, including the classic exon 10 splice mutations that raise 4R tau.
- TDP-43 subtypes: type A (compact inclusions, GRN linkage, semantic or agrammatic presentations), type B (numerous neuronal cytoplasmic inclusions, C9orf72 and FTD-MND), type C (long dystrophic neurites, semantic dementia) — morphology-gene correlations examiners quote.
- C9orf72 expansion: G4C2 hexanucleotide repeat on chromosome 9, detected by repeat-primed PCR; produces p62-positive, TDP-43-negative dipeptide-repeat inclusions notably in cerebellum and hippocampal dentate granule cells.
- GRN haploinsufficiency: progranulin mutations cause type A FTLD-TDP with earlier onset and prominent aphasia; plasma progranulin levels can screen carriers.
- Indian context: young-onset dementia workups in Indian neurology centres increasingly request genetic panels, but C9orf72 testing access remains limited outside metropolitan referral laboratories.
How a pathology report sorts an FTD brain
A 62-year-old with disinhibition, hyperoralia and apathy dies after six years; the brain shows circumscribed frontotemporal atrophy sparing the posterior cortex — the "knife-edge" anterior temporal and frontal slicing. The first diagnostic move is a tau stain. Diffuse tau-positive rounded cytoplasmic inclusions in granule neurons of the dentate gyrus and cortical pyramidal cells, argyrophilic on silver stain and negative on 4R-selective tau: Pick bodies, FTLD-tau, three-repeat type. The report then completes the classification: TAR DNA-binding protein 43 immunostain is negative in inclusions (no TDP-43 pathology), fused-in-sarcoma negative, and the clinicopathological synthesis reads frontotemporal dementia, behavioural variant, with Pick disease pathology.
Had the tau stain shown only thread-and-tuft architecture in white matter with astrocytic tufts, the same clinical syndrome would conclude as PSP pathology; an astrocytic plaque pattern would render CBD. Had tau been negative but TDP-43 strongly positive with long dystrophic neurites, type C FTLD-TDP would accompany a semantic-variant history the family never emphasised. One clinical syndrome, four molecular destinations — the working demonstration that FTD is a clinical sign-out and FTLD a pathological one.
High-yield viva angles
Three questions dominate. Which inclusion is argyrophilic and 3R — the Pick body, distinct from the Lewy body it superficially resembles on haematoxylin-eosin (no halo, tau positive, synuclein negative). Which two diseases share 4R tau but differ in astrocyte — tufted (PSP) versus plaque (CBD), a one-word discriminator worth a mark. And what links FTD to motor neuron disease — the TDP-43 protein and the C9orf72 expansion, which produce the FTD-ALS continuum; roughly a tenth to a fifth of FTD patients develop ALS features. Indian viva practice adds the resource question: without autopsy or genetic panels, antemortem FTD subtyping relies on clinical plus MRI plus, increasingly, CSF and plasma biomarker panels available in referral centres.
Frequently asked questions
What is a Pick body?
A spherical, argyrophilic, tau- and p62-positive cytoplasmic inclusion of three-repeat tau in cortical and dentate neurons, defining Pick disease within FTLD-tau.
Which tau isoform defines PSP and CBD?
Four-repeat tau — the two diseases differ astrocytically in tufted astrocytes (PSP) versus astrocytic plaques (CBD).
Which genetic finding most commonly links FTD and ALS?
The C9orf72 G4C2 hexanucleotide repeat expansion — the commonest genetic cause of both diseases, producing p62-positive dipeptide-repeat inclusions.
Which gene causes familial FTLD-tau?
MAPT on chromosome 17q21.3, by missense or splicing mutations including those increasing 4R tau production.
Which TDP-43 subtype associates with GRN mutations?
Type A — compact neuronal cytoplasmic inclusions with dystrophic neurites, typically presenting with progressive aphasia and earlier onset.