What is frontotemporal neurocognitive disorder?

What is Frontotemporal Neurocognitive Disorder

Frontotemporal neurocognitive disorder (frontotemporal dementia, FTD) is a progressive neurodegenerative disease characterized by selective degeneration of the frontal and temporal lobes, presenting primarily with behavioral changes, personality alterations, and/or language deficits, typically beginning between ages 40-70 years. 1, 2

Core Clinical Features

FTD represents one of the most common forms of early-onset dementia in patients under 65 years of age. 1, 3 The disorder encompasses three main clinical variants:

Behavioral Variant FTD (bvFTD)

This is the most common presentation, characterized by six core behavioral features: 1, 2

• Disinhibition - socially inappropriate behaviors, impulsivity, loss of social boundaries 2
• Apathy/inertia - loss of motivation, reduced initiative 2
• Loss of sympathy/empathy - reduced emotional responsiveness to others' feelings 2
• Perseverative/compulsive behaviors - repetitive actions, ritualistic behaviors 2
• Hyperorality - dietary changes, binge eating, oral exploration of objects 2
• Dysexecutive profile - impaired planning, organization, and problem-solving 2

At least three of these six features must be present for diagnosis. 2

Language Variants

• Semantic dementia (SD) - progressive loss of knowledge about words and objects with prominent anomia and asymmetrical anterior temporal lobe atrophy 3
• Progressive nonfluent aphasia (PNFA) - effortful speech output, loss of grammar, and motor speech deficits with left perisylvian atrophy 3, 4

Cognitive Profile

Contrary to common belief, executive dysfunction is not always the most prominent deficit in early-stage FTD and may not appear on formal neuropsychological testing. 1 Key cognitive features include:

• Social cognition deficits are the hallmark, including impaired emotion recognition, theory of mind deficits, reduced empathy, and impaired moral reasoning 1
• Action naming is more affected than object naming (the reverse pattern of Alzheimer's disease) 1
• 10% of pathologically-confirmed cases show marked episodic memory deficits at presentation, contrary to diagnostic criteria 1
• Qualitative behavioral observations during testing (stereotypies of speech, impulsivity, rigidity, obsessionality, clock watching) are often more informative than test scores 1

Distinguishing Features from Psychiatric Disorders

This distinction is critical because approximately 50% of FTD patients receive an initial psychiatric misdiagnosis, with diagnostic delays averaging 5-6 years. 1 Key differentiating features include:

• Insidious onset with gradual, progressive deterioration (not episodic or fluctuating) 1, 2
• Age of onset typically 40-70 years for new-onset behavioral changes 2
• Impaired insight into behavioral changes 2
• Progressive course despite psychiatric treatment 1

Associated Neurological Features

FTD frequently overlaps with other neurological conditions: 3, 5

• Motor neuron disease/amyotrophic lateral sclerosis (FTD-ALS) 3
• Parkinsonism 2
• Progressive supranuclear palsy features (falls, vertical gaze palsy) 2
• Corticobasal syndrome 3

Genetic Considerations

Approximately 20-40% of cases have a family history, with autosomal dominant inheritance in one-third to one-half of familial cases. 3 The three most common genetic mutations are:

• C9orf72 hexanucleotide repeat expansion - can present with heterogeneous neuropsychiatric phenotypes including late-onset psychosis or mania, sometimes years before typical FTD features 1
• Progranulin (GRN) mutations 3
• Microtubule-associated protein tau (MAPT) mutations 3

Genetic testing for C9orf72 should be performed in all possible/probable FTD cases or suspected cases with strong psychiatric features. 1

Neuropathological Classification

FTD is classified based on predominant protein accumulation: 3

• FTLD-TAU (tau protein)
• FTLD-TDP (TAR DNA-binding protein-43)
• FTLD-FUS (fused in sarcoma protein)

Neuroimaging Patterns

Structural MRI shows frontal and anterior temporal lobe atrophy, though sensitivity is only 70% in early stages. 1, 2 FDG-PET demonstrates hypometabolism in these regions but has limited specificity (68%) due to overlap with psychiatric disorders. 1

Critical Diagnostic Pitfalls

Three major pitfalls lead to missed or delayed diagnosis: 2

1. Dismissing FTD diagnosis due to positive psychiatric history - psychiatric symptoms can be the initial presentation of FTD
2. Relying on patient self-report - impaired insight is characteristic of FTD
3. Missing diagnosis due to family psychiatric history - genetic FTD can present with psychiatric phenotypes

Prognosis and Management

FTD is a progressive, fatal neurodegenerative disease with no FDA-approved disease-modifying treatments. 3, 6 Current management focuses on symptomatic treatment with SSRIs for behavioral symptoms, though evidence is limited. 6, 5 The distinction from psychiatric disorders is crucial because of drastically different prognosis, management approaches, family counseling needs, and eligibility for future clinical trials. 1