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
Overview
A heterogeneous group of neurodegenerative disorders defined by progressive degeneration of frontal and/or temporal lobes. Three main clinical syndromes: behavioral variant (bvFTD), nonfluent/agrammatic primary progressive aphasia (nfvPPA), and semantic variant primary progressive aphasia (svPPA). Underlying pathology involves tau, TDP-43, or FUS protein aggregates.
Epidemiology
Second or third most common dementia in patients under 65 (rivaling early-onset AD). Mean onset 50-65 years. Equal sex distribution overall. ~30-50% have family history; up to 10-20% are caused by autosomal dominant mutations (MAPT, GRN, C9orf72).
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Question 1NeurologyMedium
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?
AAsymmetric frontal and anterior temporal atrophy
BConfluent periventricular white matter changes
CBilateral caudate atrophy with enlarged frontal horns
DCortical ribboning on diffusion-weighted imaging
ESymmetric hippocampal and medial temporal atrophy
Reveal answer & full explanation
Correct answer: A — Asymmetric frontal and anterior temporal atrophy
AAsymmetric frontal and anterior temporal atrophy✓
BConfluent periventricular white matter changes
CBilateral caudate atrophy with enlarged frontal horns
DCortical ribboning on diffusion-weighted imaging
ESymmetric hippocampal and medial temporal atrophy
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.
Bilateral caudate atrophy with enlarged frontal horns — the classic MRI pattern of Huntington disease, tempting because HD can also begin with personality change, irritability, and executive dysfunction while memory is relatively preserved; but HD is diagnosed by its motor signs, classically chorea, usually with an autosomal dominant family history, and neither is described here, whereas hyperorality and loss of empathy are core features of behavioral-variant FTD.
Question 2PsychiatryMedium
A 64-year-old man is brought in by his wife because he has become tactless with strangers, makes impulsive purchases, and can no longer plan the family trip he organized every year. He scores 29 of 30 on the Mini-Mental State Examination and recalls three of three words at 5 minutes. His gait and cranial nerve examination are normal. Which bedside examination task would best evaluate the suspected deficit?
APantomiming the use of a toothbrush on verbal command
BCopying a drawing of two intersecting pentagons
CRepeating a fist-edge-palm alternating hand sequence
DNaming uncommon objects shown in line drawings
ERecalling a short story read aloud after a delay
Reveal answer & full explanation
Correct answer: C — Repeating a fist-edge-palm alternating hand sequence
APantomiming the use of a toothbrush on verbal command
BCopying a drawing of two intersecting pentagons
CRepeating a fist-edge-palm alternating hand sequence✓
DNaming uncommon objects shown in line drawings
ERecalling a short story read aloud after a delay
Why Repeating a fist-edge-palm alternating hand sequence is correct
Disinhibition, impulsivity, and loss of planning with preserved memory point to a frontal or executive syndrome, and the Mini-Mental State Examination is nearly blind to that domain, which is why a score of 29 of 30 does not reassure.
The MMSE samples orientation, registration, attention through serial sevens, delayed recall, naming, repetition, a three-stage command, reading, writing, and pentagon copying, but it contains no true executive item.
The Montreal Cognitive Assessment was designed to fill that gap and adds an alternating trail-making task, clock drawing, phonemic fluency, and abstraction, along with a harder five-word delayed recall.
At the bedside, motor sequencing tasks such as the Luria fist-edge-palm sequence expose frontal dysfunction directly, with perseveration or loss of the sequence after a few cycles.
Repeating a fist-edge-palm alternating hand sequence — the keyed task, a direct bedside probe of frontal motor sequencing and set maintenance.
Why the others are wrong
Recalling a short story read aloud after a delay — a medial temporal memory task; his three-word recall is already intact and episodic memory is not the domain in question.
Naming uncommon objects shown in line drawings — a language task probing dominant temporal cortex, useful in semantic variant primary progressive aphasia rather than in dysexecutive presentations.
Copying a drawing of two intersecting pentagons — a visuospatial construction task that localizes to parietal cortex.
Pantomiming the use of a toothbrush on verbal command — a hand-movement task that resembles the keyed sequence, but it probes ideomotor praxis, which localizes chiefly to the dominant parietal lobe, rather than the sequencing, inhibition, and planning that are failing in this frontal presentation.
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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
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) or 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
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