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Summary Table

Category	Detail
Risk Factors	Age < 65 (second most common dementia in this group), positive family history (~40%), known genetic mutations (MAPT, GRN, C9orf72)
Etiology	Selective neurodegeneration of frontal and temporal lobes due to abnormal accumulation of tau, TDP-43, or FUS proteins
Patient Presentation	Gradual personality change, socially inappropriate behavior, apathy, loss of empathy, compulsive behaviors, or progressive language difficulty; brought in by family rather than patient
Classic Physical Exam	Disinhibition, poor hygiene, hyperorality, utilization behavior, executive dysfunction on bedside testing, primitive reflexes (grasp, snout); memory and visuospatial function relatively preserved early
Key Diagnostic Results	MRI showing frontal and/or anterior temporal atrophy (often asymmetric, "knife-edge" pattern); FDG-PET showing frontal/temporal hypometabolism; neuropsychological testing revealing executive dysfunction with preserved memory
Management	SSRIs (first-line for behavioral symptoms); trazodone for agitation; supportive and caregiver-focused care; avoid cholinesterase inhibitors
Keywords	"Personality change before age 65," "socially inappropriate," "loss of empathy," "compulsive eating," "disinhibition with preserved memory," "frontal atrophy," "Pick bodies"

1. Pathophysiology

Frontotemporal dementia is a neurodegenerative disorder characterized by progressive atrophy of the frontal and anterior temporal lobes. Unlike Alzheimer disease, which primarily targets the hippocampus and parietal cortex early, FTD selectively destroys the regions responsible for personality, social conduct, judgment, and language. This anatomical distinction is the single most important concept for differentiating FTD from other dementias on an exam.

The underlying molecular pathology involves abnormal intracellular accumulation of misfolded proteins. Roughly half of FTD cases involve tau protein aggregates, and the other half involve TDP-43 or, more rarely, FUS protein. Pick disease is the classic histological subtype, defined by the presence of Pick bodies (round, silver-staining, tau-positive cytoplasmic inclusions composed of 3-repeat tau) and Pick cells (ballooned, achromatic neurons). However, Pick disease represents only one pathological form within the broader FTD umbrella.

The frontal lobe damage explains the hallmark behavioral features. The orbitofrontal cortex governs social awareness and impulse control, so its destruction leads to disinhibition, impulsivity, and loss of social decorum. The dorsolateral prefrontal cortex mediates executive function, so its involvement produces poor planning, inflexibility, and impaired judgment. The medial frontal cortex regulates motivation, and its degeneration results in apathy and emotional blunting, which can be mistaken for depression.

The temporal lobe damage explains the language variants. The left anterior temporal lobe stores semantic knowledge (the meaning of words and objects), so its destruction causes semantic dementia, where the patient speaks fluently but uses empty, meaningless language and cannot name common objects. The left inferior frontal region (Broca area and surrounding cortex) supports speech production and grammar, so its damage causes the nonfluent/agrammatic variant, where speech becomes effortful, halting, and grammatically broken.

Approximately 40% of FTD cases have a positive family history, making it the most heritable form of dementia. Three genes account for the majority of familial cases: MAPT (codes for tau), GRN (codes for progranulin), and C9orf72 (a hexanucleotide repeat expansion that is also the most common genetic cause of familial ALS). The C9orf72 expansion is of particular importance because it links FTD and ALS on a shared pathological spectrum, explaining why some patients develop both behavioral/cognitive decline and motor neuron disease.

2. Classification and Clinical Manifestation

Variant	Predominant Lobe	Core Features	Speech/Language	Memory	Distinguishing Detail
Behavioral variant FTD (bvFTD)	Frontal (bilateral or right-dominant)	Disinhibition, apathy, loss of empathy, compulsive/ritualistic behavior, hyperorality, executive dysfunction	Relatively preserved early	Relatively preserved early	Most common variant (~60%); personality change is the presenting complaint
Semantic variant PPA (svPPA)	Left anterior temporal	Loss of word and object meaning, surface dyslexia, prosopagnosia (if right-sided)	Fluent but empty; cannot name objects or comprehend single words	Preserved early	Asks "what is a ___?" for common objects; speech is fluent but devoid of content
Nonfluent/agrammatic variant PPA (nfvPPA)	Left posterior frontal / insular	Effortful, halting speech; grammatical errors; speech apraxia	Nonfluent, agrammatic, labored	Preserved early	Comprehension of single words preserved, but complex sentences difficult
FTD-ALS (FTD-MND)	Frontal + motor cortex/spinal cord	Behavioral or language changes combined with upper and lower motor neuron signs	Variable	Variable	Look for fasciculations, muscle wasting, or bulbar signs in a patient with behavioral changes; linked to C9orf72
Progressive supranuclear palsy (PSP)	Midbrain, basal ganglia, frontal	Vertical gaze palsy (especially downward), early postural instability and falls, axial rigidity, frontal cognitive decline	Dysarthria common	Subcortical pattern	Falls backward early; cannot look down; does not respond to levodopa
Corticobasal degeneration (CBD)	Asymmetric frontoparietal cortex, basal ganglia	Asymmetric limb rigidity, dystonia, myoclonus, "alien limb" phenomenon, cortical sensory loss	Nonfluent aphasia possible	Variable	One hand "acts on its own"; markedly asymmetric presentation

3. Diagnostic Workup

Test	Role	Expected Finding
Clinical assessment and neuropsychological testing	Best initial approach	Executive dysfunction (poor Trails B, clock drawing, verbal fluency) with relatively preserved episodic memory early on
MRI brain	Best initial imaging	Frontal and/or anterior temporal atrophy, often asymmetric; may show "knife-edge" gyral thinning; hippocampal volume relatively spared early
FDG-PET	Confirmatory / supportive imaging	Frontal and/or temporal hypometabolism; helps distinguish from Alzheimer (which shows temporoparietal hypometabolism)
Amyloid PET or CSF amyloid/tau	Rule out Alzheimer disease	Negative amyloid supports FTD over Alzheimer; FTD is a non-amyloid tauopathy or TDP-43 proteinopathy
Genetic testing	When family history is positive	C9orf72 expansion, MAPT mutation, GRN mutation
Neuropathological exam (autopsy)	Gold standard / most accurate	Pick bodies (3R tau), TDP-43 inclusions, or FUS inclusions confirm pathological subtype

The diagnosis of FTD is fundamentally clinical, built on a pattern of progressive behavioral or language deterioration that does not fit Alzheimer disease. The first and most important step is a thorough neuropsychological evaluation. Patients with the behavioral variant will show impaired executive function (poor performance on set-shifting tasks, category fluency, Wisconsin Card Sorting) but will perform relatively well on episodic memory tasks (word list recall, story recall). This dissociation between poor executive function and preserved memory is the cardinal testing pattern that separates FTD from early Alzheimer disease, where memory loss is the dominant early deficit.

MRI of the brain is the best initial imaging study. Classic findings include disproportionate atrophy of the frontal lobes, the anterior temporal lobes, or both. In advanced cases, the cortex may appear paper-thin with widened sulci, described as "knife-edge" atrophy. Atrophy is often asymmetric, and the pattern of asymmetry correlates with the clinical variant: left temporal predominance suggests the semantic variant, left frontal/insular predominance suggests the nonfluent variant, and bilateral or right frontal predominance suggests the behavioral variant.

FDG-PET is the most useful confirmatory imaging study when the MRI is equivocal or when the clinical picture overlaps with Alzheimer disease. In FTD, PET reveals frontal and/or anterior temporal hypometabolism. In Alzheimer disease, by contrast, hypometabolism is seen in the temporoparietal regions and posterior cingulate cortex. This geographic difference in metabolic deficit is highly testable.

Amyloid PET or CSF biomarkers (amyloid-beta 42, phosphorylated tau) are used primarily to exclude Alzheimer disease. A negative amyloid PET in a patient with progressive dementia strongly favors FTD over Alzheimer disease. This is an increasingly tested concept: amyloid biomarkers do not confirm FTD, but their absence in a demented patient redirects the diagnosis away from Alzheimer.

Definitive diagnosis requires neuropathological examination at autopsy. This is the most accurate test but is not used clinically to guide management. It is included in vignettes to test whether you understand the distinction between clinical and pathological diagnosis.

4. Management and Treatment

Setting	Intervention	Notes
Behavioral symptoms (disinhibition, compulsions, irritability)	SSRIs (e.g., sertraline 50-200 mg daily, citalopram 10-20 mg daily, or fluvoxamine)	First-line pharmacotherapy; target serotonergic deficits in frontal circuits
Agitation / aggression	Trazodone (50-300 mg daily in divided doses)	Second-line; useful for sleep disturbance and daytime agitation
Apathy	No consistently effective pharmacotherapy	Structured activity programs; avoid misdiagnosing as depression
Language variants (PPA)	Speech-language therapy	Focus on compensatory strategies; augmentative communication devices as disease progresses
Motor neuron disease overlap (FTD-ALS)	Riluzole (if ALS component present); multidisciplinary ALS care	Does not alter FTD course but addresses the motor neuron component
Caregiver support	Education, behavioral management strategies, respite care, safety planning	Often more impactful than pharmacotherapy; high caregiver burnout
Medications to AVOID	Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and memantine	Not effective in FTD; cholinesterase inhibitors may worsen behavioral symptoms (agitation, disinhibition)

There is no disease-modifying therapy for FTD. This is a critical point that distinguishes it from Alzheimer disease management on an exam. The treatment is entirely symptomatic and supportive.

SSRIs are the first-line agents for managing the behavioral symptoms of FTD, including disinhibition, repetitive/compulsive behaviors, irritability, and eating disturbances. The rationale is that frontal lobe degeneration in FTD causes serotonergic deficits in frontostriatal circuits. Sertraline is commonly started at 50 mg daily and titrated up to 200 mg. Citalopram (10-20 mg daily, noting the QTc ceiling at higher doses) and fluvoxamine are alternatives. The effect is modest but represents the best-studied pharmacological approach.

Trazodone (a serotonin antagonist and reuptake inhibitor) is used as a second-line agent, particularly for agitation, sleep-wake disturbances, and irritability, typically at doses of 50 to 300 mg daily in divided doses.

Atypical antipsychotics (e.g., quetiapine at low doses) are reserved for severe aggression or psychosis that does not respond to SSRIs or trazodone. They carry the standard risk of adverse effects in elderly patients and should be used cautiously and for the shortest duration possible.

The single most testable management pearl is this: do not prescribe cholinesterase inhibitors (donepezil, rivastigmine, galantamine) or memantine for FTD. These drugs target the cholinergic and glutamatergic deficits of Alzheimer disease. In FTD, the cholinergic system is relatively preserved, and giving cholinesterase inhibitors can paradoxically increase agitation, disinhibition, and behavioral disturbance. If an exam vignette presents a patient with early-onset dementia, prominent personality change, and preserved memory, and then offers donepezil as a management option, it is a trap.

For the primary progressive aphasia variants, speech-language therapy focusing on compensatory strategies is the mainstay. As the disease progresses, patients may benefit from augmentative and alternative communication devices.

Caregiver education and support is arguably the most impactful intervention. Families must understand that the patient's inappropriate behavior is neurological, not volitional. Safety planning (driving restrictions, financial safeguards, wandering prevention) is essential. Referral to support groups and respite care services reduces caregiver burnout.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Alzheimer disease	Both cause progressive dementia; can overlap in age range	Alzheimer presents with early memory loss (hippocampal), not personality change; visuospatial deficits and temporoparietal atrophy on imaging; positive amyloid PET; responds to cholinesterase inhibitors
Late-onset psychiatric disorder (bipolar mania, schizophrenia, depression)	Personality change, disinhibition, and apathy can mimic psychiatric illness	FTD shows progressive worsening, structural atrophy on MRI, and executive dysfunction on formal testing; psychiatric disease typically has episodic course and no cortical atrophy
Lewy body dementia	Both are non-Alzheimer dementias with behavioral features	Lewy body dementia has visual hallucinations, fluctuating cognition, REM sleep behavior disorder, and parkinsonism; FTD does not have prominent hallucinations or fluctuating awareness
Vascular dementia	Stepwise cognitive decline in a patient with cardiovascular risk factors	Vascular dementia shows white matter lesions and lacunar infarcts on MRI; stepwise or fluctuating course tied to vascular events, not insidious personality change
Normal pressure hydrocephalus (NPH)	Cognitive decline in an older adult	NPH has the classic triad of gait apraxia (magnetic gait), urinary incontinence, and dementia; MRI shows ventriculomegaly out of proportion to sulcal atrophy; treatable with VP shunt
Creutzfeldt-Jakob disease (CJD)	Rapidly progressive dementia	CJD progresses over weeks to months (not years); shows myoclonus, periodic sharp wave complexes on EEG, and cortical ribboning on DWI-MRI; 14-3-3 protein and RT-QuIC positive in CSF
Huntington disease	Personality change, behavioral disturbance, and cognitive decline	Look for chorea, positive family history with autosomal dominant inheritance, and caudate atrophy on imaging; CAG trinucleotide repeat expansion on genetic testing

6. Traps and High-Yield Pearls

The most common way students get FTD questions wrong is by defaulting to Alzheimer disease whenever they see the word "dementia." The exam is testing whether you can recognize that a patient under 65 with prominent personality change, social misconduct, or progressive language breakdown, but with relatively preserved memory, does not have Alzheimer disease. If the vignette describes a 58-year-old who was previously well-mannered and is now making inappropriate comments at work, eating excessively, and showing no concern for others, but can still remember recent events and navigate familiar places, the answer is FTD, not Alzheimer.

The second major trap is the management question that offers donepezil or another cholinesterase inhibitor as an answer choice. Students who correctly identify the diagnosis as FTD may still reflexively pick a cholinesterase inhibitor because they associate "dementia" with "donepezil." In FTD, this class of medication is not only ineffective but potentially harmful. The correct pharmacological answer for behavioral symptoms is an SSRI.

A third trap involves confusing FTD with a primary psychiatric disorder. The vignette may describe a middle-aged patient brought in by family for "acting strangely," and the answer choices may include bipolar disorder or major depression. The key discriminator is progressive, relentless worsening (not episodic), combined with structural brain atrophy on imaging and executive dysfunction on cognitive testing. Psychiatric disorders do not produce focal cortical atrophy.

Finally, be alert for the FTD-ALS overlap. If a vignette pairs behavioral/personality change with fasciculations, muscle wasting, or difficulty swallowing, the diagnosis is FTD with motor neuron disease, and the genetic association being tested is the C9orf72 hexanucleotide repeat expansion.

The core competency being tested across all FTD questions is pattern recognition: distinguishing FTD from Alzheimer by the type of early deficit (behavior/language vs. memory), the age of onset (younger), the imaging pattern (frontal/temporal vs. temporoparietal), and the treatment approach (SSRIs, not cholinesterase inhibitors).

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