Major or mild frontotemporal NCD is a common cause of early-onset NCD in individuals younger than 65 years. Population prevalence estimates are in the range of 2—10 per 100,000. Approximately 20%—25% of cases of frontotemporal NCD occur in individuals older than 65 years. Frontotemporal NCD accounts for about 5% of all cases of dementia in unselected autopsy series. Prevalence estimates of behavioral variant and semantic lan- guage variant are higher among males, and prevalence estimates of nonﬂuent language variant are higher among females.
Individuals with major or mild frontotemporal NCD commonly present in the sixth de- cade of life, although the age at onset varies from the third to the ninth decades. The dis- ease is gradually progressive, with median survival being 6-11 years after symptom onset and 3—4 years after diagnosis. Survival is shorter and decline is faster in major or mild fron- totemporal NCD than in typical Alzheimer’s disease.
Genetic and physiological. Approximately 40% of individuals with major or mild fron- totemporal NCD have a family history of early-onset NCD, and approximately 10% show an autosomal dominant inheritance pattern. A number of genetic factors have been identified, such as mutations in the gene encoding the microtubule associated protein tau (MAPT), the granulin gene (GRN), and the C9ORF72 gene. A number of families with causative muta- tions have been identified (see the section ”Diagnostic Markers” for this disorder), but many individuals with known familial transmission do not have a known mutation. The presence of motor neuron disease is associated with a more rapid deterioration.
distinct patterns of atrophy. In behavioral-variant major or mild frontotemporal NCD, both frontal lobes (especially the medial frontal lobes) and the anterior temporal lobes are atrophic. In semantic language—variant major or mild frontotemporal NCD, the middle, inferior, and anterior temporal lobes are atrophic bilaterally but asymmetrically, with the left side usually being more affected. Nonﬂuent language—variant major or mild fronto- temporal NCD is associated with predominantly left posterior frontal-insular atrophy.
The logopenic variant of major or mild frontotemporal NCD is associated with predomi- nantly left posterior perisylvian or parietal atrophy. Functional imaging demonstrates hy- poperfusion and/ or cortical hypometabolism in the corresponding brain regions, which may be present in the early stages in the absence of structural abnormality. Emerging bio— markers for Alzheimer’s disease (e.g., cerebrospinal ﬂuid amyloid-beta and tau levels, and amyloid imaging) may help in the differential diagnosis, but the distinction from Alzhei- mer’s disease can remain difficult (the logopenic variant is in fact often a manifestation of
Alzheimer’s disease).
In familial cases of frontotemporal NCD, the identification of genetic mutations may help confirm the diagnosis. Mutations associated with frontotemporal NCD include the genes encoding microtubule-associated protein tau (MAPT) and granulin (GRN),
C9ORF72, transactive response DNA-binding protein of 43 kDa (TDP—43, or TARDBP), valosin-containing protein (VCP), chromatin modifying protein ZB (CHMPZB), and fused in sarcoma protein (FUS).
Functional Consequences of Major or Mild