Epidemiology and genetics of frontotemporal dementia/Pick's disease

Epidemiology Frontotemporal dementia (FTD) is believed to be much less common than Alzheimer’s disease (AD), but data on prevalence and incidence of FTD are very sparse. The lack of data is in large part the result of the lack of methodology for diagnosing and enumerating cases of FTD. With an incidence rate of AD of approximately 1 case per 100 patients, or a prevalence of 6% or higher among individuals over age 70, traditional methods of case ascertainment yield stable and reliable estimates for AD. Because of challenges it presents in clinical diagnosis, incidence or prevalence of FTD could not be estimated by the traditional methods of case identification. What we currently know about the descriptive epidemiology of FTD comes largely from autopsy series. Because the neuropathological diagnosis of FTD was in flux until very recently, there has been a wide divergence of estimates of the incidence of FTD. One major reason for this variation derived from confusion over the relationships between Pick body–positive dementia (ie, “true” Pick’s disease to North American neuropathologists, or Pick’s type A), dementia with swollen chromatolytic neurons (Pick cell dementia, corticobasal degeneration, or Pick’s type B), and dementia lacking distinctive histology (nonspecific degeneration, or Pick’s type C). Pathologists sometimes included only one or two of these variants in their “Pick’s disease” category. In addition, clinical-pathological series could have selection biases that might exclude individuals with the FTD phenotype. Some series report very few FTD cases. Knopman and colleagues reviewed the experience of a brain bank in Minneapolis–St. Paul, Minnesota. Although FTD was infrequent overall (approximately 6%), it represented 17% of dementia patients who were under age 70 years at death. More recently, a neuropathological review of 382 cases from the State of Florida Brain Bank showed that FTD constituted 5% of the total but 8% of those cases under the age 70 years. Two groups have attempted to determine the clinical prevalence of FTD. These studies used novel methods for case identification. In the study from the United Kingdom, record review in the specialty clinics and hospitals in several communities in Cambridge was used to identify dementia cases. Seventeen FTD patients were detected. The mean age at onset was 52.8 ( 8.7) years. Men predominated (14:3). The prevalence of FTD was estimated at 15 cases per 100,000 persons in the 45to 64-year-old age range. The prevalence of AD was identical, so the proportion of FTD to AD was 1.6/1. The other study of FTD prevalence comes from The Netherlands. A total of 245 cases of FTD was reported, with emphasis on the prevalence in the province of Zuid-Holland, where the main study center was located. All neurologists and physicians in nursing homes received a yearly postal enquiry about suspected FTD cases. FTD was diagnosed in 245 patients according to the Lund–Manchester criteria, and the diagnosis was supported by neuroimaging and neuropsychology. Tau mutation analysis and apolipoprotein E (ApoE) genotyping was performed in a large subgroup of patients, and 40 of 98 patients who died during the follow-up came to autopsy during the course of the study. The prevalence of FTD in the province ZuidHolland was 3.6 cases per 100,000 persons at ages 50 to 59 years, 9.4 per 100,000 at ages 60 to 69, and 3.8 per 100,000 at ages 70 to 79. The average age at onset of the 245 patients (51% female) was 57.6 9.0 years. Dementia in one or more first-degree family members was found in 43% of patients, and mutation analysis of the tau gene showed mutations in 34 patients (19, P301L; 5, L315R; 4, G272V; 4, R406W; 1, K280; 1, S320F), all with a positive family history (14% of the total population, and 32% of patients with a positive family history). Neither the ApoE2 nor the ApoE4 allele was overrepresented compared with previously published results from a control group in The Netherlands. Pathological findings in the 40 autopsied patients consisted of dementia lacking distinc-