Sonia M. Rosso

Phenotypic Variation in Hereditary Frontotemporal Dementia with Tau Mutations

Several mutations in the tau gene have been found in families with hereditary frontotemporal dementia and parkinsonism linked to chromosome 17q21‐22 (FTDP‐17). This study is the first attempt to correlate genotype and phenotype in six families with FTDP‐17 with mutations in the tau gene (ΔK280, G272V, P301L, and R406W). We have investigated tau pathology in 1 P301L and 1 R406W patient. The R406W family showed a significantly higher age at onset (59.2 ± 5.5 years) and longer duration of illness (12.7 ± 1.5 years) than the families with the other mutations. The six families showed considerable variation in clinical presentation, but none of them had early parkinsonism. Mutism developed significantly later in the R406W family than in the other families. Frontotemporal atrophy on neuroimaging in the R406W family was less severe than in the P301L and ΔK280 families. The P301L brain contained many pretangles in the frontal and temporal cortex, and the dentate gyrus of hippocampus, showing three tau bands (64, 68, and 72 kd) of extracted tau from the frontal cortex. The presence of many neurofibrillary tangles, many diffuse and classic neuritic plaques in the temporal and parietal cortex, and the hippocampus of the same P301L brain correlated with the presence of four sarkosyl‐insoluble (60, 64, 68, and 72 kd) tau bands. The coexistence of characteristic P301L and Alzheimer pathology in the same brain needs further explanation. The R406W brain showed abundant neurofibrillary tangles in several brain regions, and four tau bands (60, 64, 68, and 72 kd) of extracted tau from these regions. The slower progression of the disease in the R406W family might be explained by the microtubule‐binding properties of the mutant protein.

CSF biomarkers in frontotemporal lobar degeneration with known pathology

Objective: To evaluate the diagnostic value of CSF biomarkers in patients with known pathology due to frontotemporal lobar degeneration (FTLD). Background: It is important to distinguish FTLD from other neurodegenerative diseases like Alzheimer disease (AD), but this may be difficult clinically because of atypical presentations. Methods: Patients with FTLD (n = 30) and AD (n = 19) were identified at autopsy or on the basis of genetic testing at University of Pennsylvania and Erasmus University Medical Center. CSF was obtained during a diagnostic lumbar puncture and was analyzed using assays for total tau and amyloid-beta 1-42 (Aβ42). Patients also were assessed with a brief neuropsychological battery. Results: CSF total tau level and the ratio of CSF total tau to Aβ42 (tau/Aβ42) were significantly lower in FTLD than in AD. Receiver operating characteristic curve analyses confirmed that the CSF tau/Aβ42 ratio is sensitive and specific at discriminating between FTLD and AD, and is more successful at this than CSF total tau alone. Although some neuropsychological measures are significantly different in autopsy-proven FTLD and AD, combining these neuropsychological measures with CSF biomarkers did not improve the ability to distinguish FTLD from AD. Conclusions: The ratio of CSF tau/Aβ42 is a sensitive and specific biomarker at discriminating frontotemporal lobar degeneration from Alzheimer disease in patients with known pathology.

Amyloid β(1–42) and phosphorylated tau in CSF as markers for early-onset Alzheimer disease

Objective: To determine the diagnostic value of CSF amyloid β(1–42) (Aβ42), CSF total tau, and CSF tau phosphorylated at threonine-181 (Ptau-181) in early-onset Alzheimer disease (EAD) vs frontotemporal lobar degeneration (FTLD). Methods: Levels of Aβ42, total tau, and Ptau-181 in CSF were measured using commercially available ELISA in 47 EAD patients, 28 FTLD patients, and 21 nondemented control subjects. Results: CSF Aβ42 was significantly lower and CSF total tau and CSF Ptau-181 significantly higher in EAD patients than FTLD patients and control subjects. There was an increase in diagnostic accuracy for CSF Ptau-181 vs CSF total tau (p = 0.067). Combining low CSF Aβ42 and high CSF Ptau-181 allowed EAD patients to be distinguished from FTLD patients with a sensitivity of 72% and a specificity of 93%. Logistic regression analysis with CSF Aβ42 and CSF Ptau-181 as independent continuous variables resulted in correct classification of 46 of 47 (98%) EAD patients and 23 of 28 (82%) FTLD patients. The diagnostic accuracy for EAD was independent of gender, disease duration, and disease severity. Conclusion: The combination of CSF Αβ42 and CSF Ptau-181 may help in differentiating EAD from FTLD.

Distinct genetic forms of frontotemporal dementia

Background: Frontotemporal dementia (FTD) is the second most common type of presenile dementia and can be distinguished into various clinical variants. The identification of MAPT and GRN defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes. In addition to these genetic subtypes, there exist familial forms of FTD with unknown genetic defects. Methods: We investigated the frequency, demographic, and clinical data of patients with FTD with a positive family history in our prospective cohort of 364 patients. Genetic analysis of genes associated with FTD was performed on all patients with a positive family history. Immunohistochemical studies were carried out with a panel of antibodies (tau, ubiquitin, TDP-43) in brains collected at autopsy. Results: In the total cohort of 364 patients, 27% had a positive family history suggestive for an autosomal mode of inheritance, including MAPT (11%) and GRN (6%) mutations. We identified a new Gln300X GRN mutation in a patient with a sporadic FTD. The mean age at onset in GRN patients (61.8 ± 9.9 years) was higher than MAPT patients (52.4 ± 5.9 years). In the remaining 10% of patients with suggestive autosomal dominant inheritance, the genetic defect has yet to be identified. Neuropathologically, this group can be distinguished into familial FTLD+MND and familial FTLD-U with hippocampal sclerosis. Conclusion: Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease. GLOSSARY: CA1 = cornu ammonis field 1; FTD = frontotemporal dementia; FTD-bv = behavioral variant of FTD; FTD+MND = FTD with motor neuron disease; FTLD = frontotemporal lobe degeneration; FTLD-tau = FTLD with tau-positive pathology; FTLD-U = FTLD with tau-negative, ubiquitin-positive inclusions; HS = hippocampal sclerosis; PNFA = progressive nonfluent aphasia; TDP-43 = TAR-DNA binding protein 43.

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-

Frontotemporal Dementia: Behavioral Symptoms and Caregiver Distress

Objective: To discern behavioral problems that co-occur in frontotemporal dementia (FTD) patients, and to investigate the relation between behavioral clusters and the burden for caregivers. Patients and Methods: Baseline data of 63 FTD patients and their respective caregivers were used to detect the behavioral clusters in the Neuropsychiatric Inventory (NPI) and the accompanying distress evoked in caregivers. To detect the clusters in behavior of the FTD patients, we performed multidimensional scaling (procedure: PROXSCAL). Multiple regression analysis was used to determine the association between behavior of patients and the distress experienced by caregivers. Results: This was the first study that found behavioral clusters for FTD. Two behavioral clusters were found: agitation/psychosis (comprising delusions, hallucinations, irritability and agitation) and mood (made up of anxiety and depression). The remaining NPI domains (euphoria, disinhibition, aberrant motor behavior and apathy were found to be autonomous. After controlling for relevant confounding factors, caregiver distress was strongest related to agitation/psychosis, followed by mood. Disinhibition and aberrant motor behavior were mildly related to caregiver distress. Euphoria and apathy were not significantly related to distress. Caregivers of patients living at home were more distressed by the behavioral problems of the FTD patients than caregivers of hospitalized patients. Discussion: The high prevalence of psychopathology in FTD patients and the associated caregiver distress was confirmed in this study. Clustering behavioral symptoms allows investigation of the relationship between structural or functional cerebral deficits and neuropsychiatric symptoms.

Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval.

We report the results of a genome-wide search in a four-generation pedigree with autosomal dominant early-onset dementia (mean onset age: 64.9 years, range 53–79 years). In this family we previously excluded the known Alzheimers disease genes based on linkage analysis and mutation screening of the amyloid precursor protein gene (exons 16 and 17) and the presenilin 1 and 2 genes. In addition we excluded mutations in the prion protein gene and exons 9–13 of the microtubule associated protein tau (MAPT) gene. We obtained conclusive linkage with chromosome 17q21 markers with a maximum multi-point LOD score of 5.51 at D17S951 and identified a candidate region of 4.8 cM between D17S1787 and D17S958 containing MAPT. Recent clinical and neuropathological follow-up of the family showed that the phenotype most closely resembled frontotemporal dementia (FTD) characterized by dense ubiquitin-positive neuronal inclusions that were tau negative. Extensive mutation analysis of MAPT identified 38 sequence variations in exons, introns, untranslated regions and the 5′ regulatory sequence, however none was comprised within the disease haplotype. Although our findings do not entirely exclude a mutation in a yet unanalyzed region of MAPT, the apparent absence of MAPT mutations combined with the lack of tau pathology is highly suggestive for another defective gene at 17q21 responsible for FTD in this family.

Variable Phenotypic Expression and Extensive Tau Pathology in Two Families with the Novel tau Mutation L315R

Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe two Dutch families with familial frontotemporal dementia associated with the novel missense mutation L315R in exon 11 of tau. The age at onset of disease showed a large variation within each family, ranging from 25 to 64 years. Incomplete penetrance was established in an 82‐year‐old mutation carrier with no signs of dementia and appeared probable in two additional subjects. The brains of two affected subjects were studied and showed extensive tau pathology in neurons (Pick‐like inclusions) and astroglial cells, particularly in the frontotemporal cortex and the hippocampal formation. Sarkosyl‐insoluble tau extracted from the cerebral cortex showed the presence of straight and twisted tau filaments and a pattern of pathological tau bands similar to that of Picks disease. Upon dephosphorylation, only five of the six brain tau isoforms were observed, with the shortest isoform being undetectable. All six tau isoforms were present in soluble brain tau. Recombinant tau proteins with the L315R mutation showed a reduced ability to promote microtubule assembly. Ann Neurol 2003;54:573–581

A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick's disease.

Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. In this article, we describe a novel missense mutation, S320F, in the tau gene in a family with presenile dementia. To our knowledge, it is the first mutation to be described in exon 11 of tau. The proband died at age 53 years, after a disease duration of 15 years, and autopsy revealed a neuropathological picture similar to Picks disease. Recombinant tau protein with the S320F mutation showed a greatly reduced ability to promote microtubule assembly.

Medical and environmental risk factors for sporadic frontotemporal dementia: a retrospective case–control study

A retrospective case-control study was carried out on 80 patients with sporadic frontotemporal dementia and 124 age, sex, and surrogate informant matched controls with respect to various medical and environmental risk factors. Head trauma was associated with an odds ratio of 3.3 (95% confidence interval (CI), 1.3 to 8.1). Although recall bias may play a role, the frontal lobes are known to be especially vulnerable to even mild head trauma. Thyroid disease was associated with a 2.5 times increased risk of frontotemporal dementia (95% CI, 0.9 to 7.9), which was not statistically significant (p = 0.09) owing to limited power. As altered thyroid hormone status has been observed before in frontotemporal dementia, future studies will be important to confirm this observation.