Early-onset dementia syndromes characterized by frontal-temporal degeneration; presents as behavioral change or progressive aphasia.
Also known as: FTD, frontotemporal lobar degeneration, FTLD, Pick disease, behavioral variant FTD, primary progressive aphasia
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Risk factors
- Family history of FTD, ALS, or atypical parkinsonism
- Genetic mutations: C9orf72 hexanucleotide repeat (most common; overlaps with ALS), MAPT, GRN (progranulin)
- Younger age of onset than most neurodegenerative dementias
Pathophysiology
Selective degeneration of frontal lobes, anterior temporal lobes, and connected limbic and basal ganglia structures. Histopathology divides into FTLD-tau (Pick bodies, CBD, PSP-like), FTLD-TDP (most common, includes C9orf72 and GRN), and FTLD-FUS subtypes. Spreading of misfolded protein along network connections may underlie focal-then-generalized progression.
Clinical presentation
Symptoms
- Behavioral variant: disinhibition, apathy, loss of empathy, perseverative/compulsive behavior, hyperorality and dietary changes (sweet tooth), executive dysfunction
- Nonfluent/agrammatic PPA: effortful, halting speech with agrammatism, apraxia of speech; comprehension preserved early
- Semantic variant PPA: loss of word meaning, impaired single-word comprehension, surface dyslexia, prosopagnosia
- Overlap syndromes with ALS (FTD-ALS, often C9orf72), corticobasal syndrome, or progressive supranuclear palsy
- Memory and visuospatial function often relatively spared early
Signs / physical exam
- Frontal release signs (grasp, snout, palmomental reflexes) may appear later
- Motor neuron signs (fasciculations, weakness, hyperreflexia) suggest FTD-ALS
- Parkinsonism, vertical gaze palsy, or limb apraxia suggest overlap with PSP/CBD
- Lack of insight is characteristic — family usually brings the patient in
Classic findings
Mid-50s patient with new socially inappropriate behavior, apathy, or progressive nonfluent speech, with disproportionate frontal/temporal atrophy on MRI.
Differential diagnosis
- Alzheimer disease — Memory dominant, hippocampal atrophy on MRI, positive amyloid PET / CSF Aβ-tau profile; FTD can mimic AD when there is significant temporal involvement
- Psychiatric disorder (depression, bipolar, schizophrenia) — Personality change in midlife can resemble bvFTD — atrophy/hypometabolism on imaging argues for FTD
- Vascular dementia — Stepwise decline, focal deficits, white matter disease on MRI
- Creutzfeldt-Jakob disease — Rapid progression (<1 year), myoclonus, cortical ribboning on MRI DWI
- Autoimmune encephalitis — Subacute onset, seizures, abnormal CSF, antibodies (LGI1, CASPR2, NMDAR)
- Neurosyphilis, HIV dementia, B12 deficiency — Reversible mimics; screen routinely
- Normal pressure hydrocephalus — Gait disturbance dominant, ventriculomegaly disproportionate to atrophy
Diagnostic workup
Diagnostic criteria
Rascovsky 2011 (bvFTD): ≥3 of 6 behavioral features (disinhibition, apathy, loss of sympathy/empathy, perseverative/compulsive behavior, hyperorality, dysexecutive cognitive profile) + functional decline. Gorno-Tempini 2011 criteria for PPA variants. Imaging or genetic evidence supports diagnosis.
Labs
- TSH, B12, HIV, RPR, ANA, ceruloplasmin if young
- CSF Aβ42, t-tau, p-tau (often normal in FTD, contrasting with AD pattern)
- Genetic testing if family history or young onset: C9orf72, MAPT, GRN
Imaging
- MRI brain — frontal and/or anterior temporal atrophy (often asymmetric; left perisylvian in nfvPPA, anterior temporal in svPPA)
- FDG-PET — frontal and temporal hypometabolism
- Amyloid PET (if available) — typically negative; helps distinguish from AD
Treatment
First-line
- No disease-modifying therapy approved
- SSRIs (sertraline, citalopram, escitalopram, trazodone) — first-line for disinhibition, compulsive behaviors, irritability, and overeating
- Atypical antipsychotics (quetiapine, olanzapine) — reserved for agitation/aggression refractory to non-pharmacologic strategies; caution due to extrapyramidal sensitivity
- AVOID cholinesterase inhibitors — may worsen behavioral symptoms; not approved for FTD
- Speech and language therapy for PPA variants
- Caregiver education, structured environment, behavior management
bvFTD
- SSRIs for disinhibition, hyperorality, and compulsivity
- Trazodone modestly effective for irritability
- Safety planning: financial supervision, driving evaluation, firearm safety
Primary progressive aphasia
- Speech-language pathology for word retrieval and communication strategies
- Augmentative communication devices as disease progresses
FTD-ALS
- Multidisciplinary ALS clinic care (see ALS entry)
- Address respiratory and bulbar function aggressively
Second-line / adjunct
- Investigational therapies (e.g., progranulin replacement for GRN carriers, antisense oligonucleotides for C9orf72) — clinical trial referral
- Palliative care and hospice in advanced disease
Complications
- Loss of employment, financial mismanagement, legal difficulties early in disease
- Caregiver burnout — bvFTD imposes among the highest dementia caregiver burdens
- Falls and injury
- Aspiration pneumonia in advanced disease
- Respiratory failure in FTD-ALS
PANCE pearls
- Personality change or new socially inappropriate behavior in a middle-aged adult is FTD until proven otherwise.
- FTD often misdiagnosed as depression or psychiatric illness — look for the structural and metabolic imaging signature.
- Memory and visuospatial testing can be paradoxically preserved on bedside cognitive screens — leading to false reassurance.
- C9orf72 expansion connects FTD and ALS — ask about family history of motor neuron disease.
- Cholinesterase inhibitors do not help FTD and may worsen behavior; reserve memantine for AD.
References
- Rascovsky 2011 — Rascovsky K et al. Sensitivity of revised diagnostic criteria for the behavioural variant of FTD. Brain 2011;134:2456-2477.
- Gorno-Tempini 2011 — Gorno-Tempini ML et al. Classification of primary progressive aphasia and its variants. Neurology 2011;76:1006-1014.
- AAN 2020 — AAN Quality Measurement Set: Dementia (incl. FTD-relevant measures).
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