FTD-001
Frontotemporal Dementia · Pick Body / TDP-43 / FUS Engine · VIZASL v1
MEBICAL · EOSE Fleet · TRB-MEBICAL-HEALTH-DOMAIN-001 · Day 90 · Real data · Cited · Sorries marked
MEBICAL · NEURO ← RESEARCH
Pick bodies (tau type III)
TDP-43 aggregates (types A/B/C)
Frontal lobe atrophy
Von Economo neurons (dying)
γ₁ floor anchor
PHASES
RX
BIOMARKERS
EEG
NPs
3 Proteins · 3 Variants · 3 Genes
bvFTD — Behavioural Variant (Most Common)
Disinhibition (socially inappropriate), apathy, compulsive/perseverative behaviour, loss of empathy, hyperorality. Frontal > temporal. Early personality change, late memory. Age <65 common. Rascovsky 2011 diagnostic criteria require 3 of 6 features.
Rascovsky et al. 2011 Brain (international consensus criteria)
Semantic Dementia (SD)
Word meaning loss. Fluent, effortless speech but meaningless (anomia, semantic paraphasia). Recognises objects but can't name category. Left temporal pole predominant. "What's a giraffe?" — "I don't know what that is."
Neary et al. 1998 Neurology (FTD consensus classification)
PNFA — Progressive Non-Fluent Aphasia
Effortful, halting speech. Agrammatism (sentence structure errors). Motor speech disorder. Comprehension relatively preserved early. Left perisylvian / Broca area predominant.
Neary et al. 1998
3 Proteins at Autopsy
(1) Tau: Pick bodies (tau type III), globose tangles, PSP-tau, CBD-tau. (2) TDP-43: Types A, B, C — each with different clinical correlation. Type A = bvFTD/PNFA; Type B = ALS-FTD; Type C = SD. NOTE: TDP-43 type B in ALS is different from FTD type B. (3) FUS: rarest, early onset, severe bvFTD.
Cairns et al. 2007 (TDP-43 subtypes) · Baker et al. 2006 Brain (GRN)
Genetics: GRN / MAPT / C9orf72
GRN (progranulin): loss-of-function → TDP-43 type A. MAPT: tau mutations → various tau pathologies. C9orf72 hexanucleotide repeat: most common genetic FTD+ALS cause. 40% of familial FTD. All autosomal dominant.
Baker et al. 2006 Brain (GRN) · DeJesus-Hernandez 2011 (C9orf72) · MAPT mutations: Hutton 1998
Von Economo Neurons — SORRY: Causality Unclear
Large spindle-shaped projection neurons. Found only in anterior insula + anterior cingulate cortex. Proposed substrate of social awareness, empathy, interoception. Severely depleted early in bvFTD. But whether VEN loss is cause or consequence of disease — UNCLEAR.
Seeley et al. 2006 Ann Neurol (VEN in bvFTD) · SORRY: causality not established
Disease-Modifying NONE APPROVED
No Approved DMT for FTD
SORRY: Despite clear genetic causes (MAPT, GRN, C9orf72), no disease-modifying treatment approved. The heterogeneity (3 proteins, 3 variants, multiple genetic causes) makes trials extremely difficult. Cannot recruit homogeneous populations.
SORRY: Trial failures include AL001 (progranulin precursor) Phase 3, tau ASOs Phase 2 ongoing
Symptomatic
SSRIs for Disinhibition
Sertraline, fluvoxamine, paroxetine. Modest benefit for disinhibition, compulsive behaviour, irritability in bvFTD. Not consistently shown to improve cognition. Better than nothing but effect size small.
Swartz et al. 1997 · Ikeda et al. 2004 (serotonergic hypothesis)
Trazodone for Agitation
Low dose (50–150mg). Serotonin modulator. Reduces agitation and irritability. Better side effect profile than antipsychotics. Empirical use widely accepted.
Lebert et al. 2004
No ChEIs — May Worsen
Cholinesterase inhibitors NOT indicated for FTD. Cholinergic system less affected than in AD. Some evidence of worsening disinhibition. CONTRAINDICATED by most guidelines.
Moretti et al. 2004 (no benefit) · Boxer 2012 (ChEIs not recommended)
Tau-Targeted Trials (MAPT carriers)
BIIB080 (tau ASO) Phase 2. JNJ-63733657 (anti-p-tau mAb) Phase 2. Primarily in tauopathy/MAPT mutation carriers. TDP-43 and FUS targets still early preclinical stage.
SORRY: No tau drug approved for FTD as of 2026
Imaging
MRI atrophyFrontal + temporal atrophy. "Knife-blade" atrophy of frontal/temporal gyri in advanced FTD. Right frontal (bvFTD), left temporal (SD), left perisylvian (PNFA). PROVEN
FDG-PETFrontal hypometabolism. Differentiates from AD (temporoparietal). Can be positive before MRI atrophy visible. STRONG
Blood / CSF
NfL STRONGNeurofilament light. Fastest-rising NfL = most aggressive progression in FTD. Tracks disease course. Elevated pre-symptom in genetic FTD (MAPT/GRN/C9orf72 carriers).
GFAP↑Elevated plasma GFAP in FTD. Less specific than in AD. Astrocyte activation. Research biomarker.
GRN/MAPT/C9orf72Genetic testing. Blood sample. Family history guides. C9orf72 repeat expansion: Southern blot or repeat-primed PCR. PROVEN for familial
TDP-43 typeSORRY: TDP-43 types A/B/C cannot be distinguished clinically or by any current biomarker. Only at autopsy. This prevents targeted trials.
Open Sorries
SORRY-1: TDP-43 type A/B/C indistinguishable in vivo — autopsy only. Prevents targeted therapy design.
SORRY-2: 3-protein/3-variant/3-genetic cause heterogeneity makes clinical trials extremely hard — no homogeneous cohort.
SORRY-3: VEN loss causality unclear — may be consequence, not cause, of bvFTD.
SORRY-4: No approved DMT despite clear genetic causes with 100% penetrance.
EEG in FTD
Frontal slowingDelta/theta excess in frontal leads. Reflects frontal lobe degeneration. Dominant EEG finding in bvFTD.
Frontal alpha ↓Reduced frontal alpha power. Frontal executive network disruption.
Posterior preservedUNLIKE AD: posterior rhythm (alpha) relatively preserved in FTD. Differentiates FTD from AD on EEG. AD shows posterior alpha loss; FTD shows frontal delta/theta with preserved posterior.
EEG non-specificSORRY: EEG relatively non-specific for FTD. Cannot distinguish bvFTD from other frontal disorders. MRI/FDG-PET remain primary. Useful to exclude epilepsy (common differential).
Novel Patterns (8)
PROVENNP-FTD-001 · 3 proteins (tau/TDP-43/FUS) × 3 variants (bvFTD/SD/PNFA) × 3 genes (GRN/MAPT/C9orf72) = heterogeneity crisis in trials
PROVENNP-FTD-002 · FTD is the most common dementia under 65 — often misdiagnosed as psychiatric illness due to behavioural features
PROVENNP-FTD-003 · C9orf72 hexanucleotide expansion: 40% of familial FTD AND familial ALS — same mutation causes both. TDP-43 links them.
PROVENNP-FTD-004 · NfL fastest-rising biomarker in FTD — tracks progression better than in AD or LBD. Can predict onset in presymptomatic genetic carriers.
PROVENNP-FTD-005 · No ChEIs in FTD — may worsen disinhibition. Opposite of AD management. Critical clinical error if applied incorrectly.
OPENNP-FTD-006 · Von Economo neuron loss as empathy substrate — early depletion in bvFTD but causality vs consequence unresolved
OPENNP-FTD-007 · Tau ASO trials in MAPT carriers: first disease-stage intervention in genetic FTD — if successful, first DMT in the spectrum
SORRYNP-FTD-008 · TDP-43 A/B/C invisible in vivo · no DMT · heterogeneity blocks trials · ChEI contraindicated · VEN causality unclear
⚠ OPEN SORRIES · FTD-001
SORRY-1 · TDP-43 typing impossible in vivo
TDP-43 types A, B, and C have different clinical correlations but cannot be distinguished by any current imaging, blood, or CSF biomarker. Only autopsy reveals the subtype. This is a fundamental barrier to targeted drug trials.

SORRY-2 · Trial heterogeneity
3 proteins × 3 clinical variants × multiple genetic causes = no homogeneous cohort. Every FTD trial struggles with inclusion criteria. The field has not solved how to run adequately powered studies.

SORRY-3 · Von Economo neuron causality
VEN depletion correlates beautifully with the empathy/social behaviour loss in bvFTD. But whether VEN loss is the cause of bvFTD or a consequence of frontal degeneration from another mechanism is unresolved.

SORRY-4 · No DMT despite clear genetics
GRN, MAPT, and C9orf72 mutations cause 100% penetrant FTD. The targets are known. Yet no drug has been approved. AL001 (progranulin precursor) failed Phase 3 in 2024. The biology-to-drug gap in FTD is as wide as in AD.
FTD-001 · 3 PROTEINS · 3 VARIANTS · 3 GENES · NO ChEIs · NfL FASTEST TRACKER · NO DMT
γ₁ = 14.134725141734693