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Frontotemporal Dementia

Chapter 443 | Harrison's 22e · Part 13 – Neurologic Disorders · Chapter 443

Key Clinical Points

  1. Frontotemporal dementia (FTD) is a group of clinical syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology.
  2. FTD is characterized by abnormal protein aggregation, primarily involving tau, transactive response DNA-binding protein of 43 kDa (TDP-43), or FUS (Fused in Sarcoma).
  3. Clinical presentation typically begins in the fifth to seventh decades of life and is nearly as prevalent as Alzheimer's disease (AD) in this age group.
  4. Three primary clinical phenotypes are defined by distinct neuroanatomical patterns: behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent/agrammatic variant primary progressive aphasia (nfvPPA).
  5. Differential diagnosis includes psychiatric disorders (e.g., schizophrenia, pseudodementia), psychogenic conditions (e.g., fugue states), drug-induced states, and rare genetic disorders.
  6. Schizophrenia is typically distinguished by an earlier age of onset (second/third decades) and less complex delusions compared to dementia.
  7. Pseudodementia (depression or anxiety) can mimic FTD but often presents with vegetative symptoms and responds to treatment of the underlying condition.
  8. Psychogenic conditions are identified by 'wrong' answers to questions (understanding the question but providing incorrect info) rather than a lack of understanding.
  9. Genetic disorders such as MLD, Adrenoleukodystrophy, and CADASIL can present with frontotemporal symptoms and have specific diagnostic markers (e.g., arylsulfatase A, very-long-chain fatty acids, Notch 3).
  10. The ALS/parkinsonian/dementia complex of Guam is a rare degenerative disease involving tau and TDP-43 pathology.

DEFINITION & CLASSIFICATION

• Frontotemporal Dementia (FTD): Group of clinical syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology. • Pathological Basis: Considered a disease of abnormal protein aggregation. • Primary Proteins Involved: 1. Tau 2. TDP-43 (transactive response DNA-binding protein of 43 kDa) 3. FUS (Fused in Sarcoma)

EPIDEMIOLOGY

• Age of Onset: Typically begins in the fifth to seventh decades of life. • Prevalence: Nearly as prevalent as Alzheimer’s disease (AD) in this age group.

ETIOLOGY & PATHOPHYSIOLOGY

• Molecular Basis: FTD is linked to the accumulation of specific proteins. • Tauopathies: Associated with tau protein aggregation. • TDP-43 Proteinopathies: Associated with transactive response DNA-binding protein of 43 kDa. • Other Pathologies: FUS (Fused in Sarcoma) and other variants like FTLD-J. • Environmental/Infectious Factors: The ALS/parkinsonian/dementia complex of Guam suggests potential environmental causes, such as exposure to neurotoxins (e.g., seed of the false palm tree) or an infectious agent with a long latency period.

CLINICAL FEATURES

• Primary Clinical Syndromes: Three major syndromes are identified by distinct neuroanatomical patterns of atrophy. 1. Behavioral variant FTD (bvFTD): - Features anterior cingulate and frontoinsular atrophy. - Spreads to orbital and dorsolateral prefrontal cortex. 2. Semantic variant PPA (svPPA): - Shows prominent temporopolar atrophy. - More often occurs on the left side. 3. Nonfluent/agrammatic variant PPA (nfvPPA): - Associated with dominant frontal opercular and dorsal insula degeneration.

DIFFERENTIAL DIAGNOSIS

• Psychiatric Disorders: 1. Schizophrenia: - Distinction: Typically has a much earlier age of onset (second/third decades) and intact memory. - Delusions/hallucinations in schizophrenia are usually more complex, bizarre, and threatening than those of dementia. 2. Pseudodementia: - Caused by severe depression or anxiety. - Presentation: Patients appear demented but memory/language are intact when carefully tested; often accompanied by vegetative symptoms (insomnia, lack of energy, poor appetite).

• Psychogenic Conditions: 1. Psychogenic Amnesia: - May result from deliberate avoidance, malingering, or unconscious repression. - Event-specific amnesia: Often follows trauma (e.g., homicide, sexual abuse). 2. Fugue States: - Sudden loss of personal identity; patient may wander far from home. - Distinction: Memory for other recent events and the ability to learn/use new information are preserved. 3. Distinguishing Feature: - Patients with psychogenic conditions often give "wrong" answers (understanding the question but providing incorrect info), whereas dementia patients lack understanding of the question.

• Drug-Induced Conditions: 1. Causes: Sedatives, tranquilizers, and analgesics used for insomnia, pain, anxiety, or agitation. 2. Presentation: Confusion, memory loss, and lethargy, especially in the elderly. 3. Resolution: Discontinuation of offending medication often improves mentation.

• Genetic & Rare Disorders: 1. ALS/parkinsonian/dementia complex of Guam: - Features parkinsonian features, dementia, and MND; involves tau and TDP-43 pathology. 2. Metachromatic leukodystrophy (MLD): - Progressively severe psychiatric or dementia syndrome with extensive, confluent frontal white matter abnormality. - Diagnosis: Reduced arylsulfatase A enzyme activity in peripheral white blood cells. 3. Adrenoleukodystrophy: - Reported in female carriers; features spinal cord and posterior white matter involvement. - Diagnosis: Increased levels of plasma very-long-chain fatty acids. 4. CADASIL: - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. - Presentation: Frontally and temporally predominant. - Diagnosis: Skin biopsy (osmophilic granules in arterioles) or genetic testing for mutations in Notch 3. 5. Neuronal ceroid lipofusicoses: - Genetically heterogeneous group; associated with myoclonus, seizures, vision loss, and progressive dementia. - Diagnosis: Eosinophilic curvilinear inclusions within white blood cells or neuronal tissue.

MANAGEMENT & TREATMENT

• Psychiatric Management: 1. Patients with pseudodementia (depression/anxiety) respond to treatment of the underlying psychiatric condition.