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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Question 1NeurologyEasy
A 65-year-old man has a 6-month history of personality change, behavioral disinhibition, and executive dysfunction that preceded any memory loss. His family reports socially inappropriate behavior and apathy. MRI of the brain shows frontal and temporal lobe atrophy. Which of the following is the most likely diagnosis?
- AFrontotemporal dementia
- BVascular dementia
- CDementia with Lewy bodies
- DAlzheimer's disease
Reveal answer & full explanation
Correct answer: A — Frontotemporal dementia
- AFrontotemporal dementia✓
- BVascular dementia
- CDementia with Lewy bodies
- DAlzheimer's disease
Why frontotemporal dementia is correct
- Behavioral-variant frontotemporal dementia (FTD) presents with early personality change, disinhibition, apathy, and executive dysfunction that precede memory loss — the reverse of Alzheimer's disease
- Onset is typically younger (often before age 65)
- MRI shows focal frontal and temporal lobe atrophy, matching this patient
- Management is supportive; no disease-modifying therapy exists
Why the others are wrong
- Vascular dementia — produces stepwise decline tied to cardiovascular risk factors with cortical/subcortical infarcts on imaging, not isolated frontotemporal atrophy or behavior-first onset; the buzzword-match trap of labeling any older-adult dementia vascular
- Dementia with Lewy bodies — features fluctuating cognition, visual hallucinations, parkinsonism, and REM sleep behavior disorder, none described here; the confused-with-FTD trap when early non-memory symptoms appear
- Alzheimer's disease — begins with prominent short-term memory loss and shows temporoparietal/hippocampal atrophy, not behavior-first decline with frontotemporal atrophy; the premature-closure pick because it is the most common dementia
Question 2NeurologyMedium
A 58-year-old man is brought in by his wife for 14 months of personality change. He has become socially disinhibited, makes crude comments to strangers, and shows little empathy for family members. He has developed a craving for sweets and eats compulsively. He is unconcerned about these changes, and bedside memory and visuospatial testing are relatively preserved. Routine labs including TSH, B12, RPR, and HIV are unremarkable. An MRI of the brain is obtained. Which of the following findings would best support the suspected diagnosis?
- ACortical ribboning on diffusion-weighted imaging
- BAsymmetric frontal and anterior temporal atrophy
- CSymmetric hippocampal and medial temporal atrophy
- DConfluent periventricular white matter changes
Reveal answer & full explanation
Correct answer: B — Asymmetric frontal and anterior temporal atrophy
- ACortical ribboning on diffusion-weighted imaging
- BAsymmetric frontal and anterior temporal atrophy✓
- CSymmetric hippocampal and medial temporal atrophy
- DConfluent periventricular white matter changes
Why Asymmetric frontal and anterior temporal atrophy is correct
- Disinhibition, loss of empathy, hyperorality with a new sweet tooth, lack of insight, and preserved memory and visuospatial function fit behavioral-variant frontotemporal dementia (Rascovsky 2011: at least 3 of 6 behavioral features plus functional decline).
- The supportive imaging signature of FTD is selective, often asymmetric atrophy of the frontal and/or anterior temporal lobes, with matching frontotemporal hypometabolism on FDG-PET; this distinguishes it from the midlife mimics.
Why the others are wrong
- Symmetric hippocampal and medial temporal atrophy is the classic pattern of Alzheimer disease, which is memory-dominant and points away from this frontal-predominant, memory-sparing picture.
- Confluent periventricular white matter changes reflect small-vessel ischemic disease seen in vascular dementia, which causes stepwise decline and focal deficits rather than an insidious behavioral syndrome.
- Cortical ribboning on diffusion-weighted imaging is the hallmark of Creutzfeldt-Jakob disease, which progresses rapidly (under a year) with myoclonus, not a 14-month behavioral course.
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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).