What causes Frontotemporal dementia (FTD)?

Causes of Frontotemporal Dementia

Frontotemporal dementia (FTD) is primarily caused by genetic mutations in approximately 20% of cases and abnormal protein accumulation in the brain, including tau, TDP-43, and FUS proteins, which lead to progressive degeneration of the frontal and temporal lobes. 1

Genetic Causes

Genetic factors play a significant role in FTD development:

• Familial cases (20% of FTD): Show autosomal-dominant inheritance patterns 1

• Major genetic mutations:

  • C9orf72 repeat expansions: Most common genetic cause, with repeats varying from 430 to several thousands in FTD patients (compared to 2-20 copies in healthy controls) 2
  • MAPT (Microtubule Associated Protein Tau): Second most common mutation 1, 3
  • GRN (Progranulin): Third most common mutation 1, 3
  • Less common mutations: CHMP2B, VCP, TBK1, TIA1, OPTN, TARDBP, CCNF, and CHCHD10 2

• Sporadic cases: Genetic causes found in 1-10% of apparently sporadic FTD cases 2

Pathological Protein Accumulations

FTD is characterized by abnormal processing and accumulation of specific proteins:

• FTLD-tau: Cases with tau-positive inclusions 3

  • Associated with MAPT mutations
  • Includes Pick's disease, Progressive Supranuclear Palsy (PSP), and Corticobasal Degeneration (CBD)

• FTLD-TDP: Cases with TDP-43 (TAR DNA-binding protein of 43 kDa) positive inclusions 3

  • Often associated with GRN mutations and C9orf72 expansions
  • Represents a significant percentage of FTD cases

• FTLD-FUS: Cases with FUS (Fused in Sarcoma) protein inclusions 4

  • Represents approximately 10% of FTD cases
  • Associated with atypical FTLD with ubiquitinated inclusions (aFTLD-U)
  • Typically sporadic cases with early-onset and severe behavioral changes

Clinical-Pathological Correlations

Different clinical presentations correlate with specific pathologies:

• Behavioral variant FTD (bvFTD):

  • Frequently caused by FTLD-tau or FTLD-TDP43 2
  • C9orf72 mutations often present with psychiatric symptoms including delusions and hallucinations 2

• Progressive Aphasic Syndrome:

  • Logopenic variant: Usually due to Alzheimer's disease pathology
  • Semantic variant: Usually due to FTLD-TDP43, rarely FTLD-tau
  • Non-fluent variant: Usually due to FTLD-tau, sometimes FTLD-TDP43 2

Risk Factors and Disease Mechanisms

• Age: Typically presents between 40-70 years, making it a common cause of early-onset dementia 5

• Neurodegeneration pattern: Progressive nerve cell loss in frontal and anterior temporal lobes 6

• Pathophysiological mechanisms:

  • Abnormal protein folding and aggregation
  • Disruption of cellular processes
  • Neuroinflammation
  • Synaptic dysfunction

Diagnostic Considerations

• Neuroimaging: Shows frontal and/or anterior temporal lobe atrophy on MRI, hypometabolism in these regions on FDG-PET 1

• Biomarkers: CSF and serum neurofilament light chain (NfL) are discriminative biomarkers between FTD and psychiatric disorders 2

• Misdiagnosis: Approximately 50% of FTD patients initially receive psychiatric diagnoses 1

Important Distinctions

• FTD differs from Alzheimer's disease in age of onset, clinical presentation, and underlying pathology

• Unlike Alzheimer's disease, FTD is rare after age 75 2

• C9orf72 repeat expansions can cause very slowly progressive FTD with disease duration up to 22 years 2

Understanding the complex genetic and pathological basis of FTD is crucial for developing targeted therapies, as current research focuses on addressing specific mutations or protein abnormalities rather than symptomatic treatment alone 7.