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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.

Mutations in the CHMP2B gene have been recently identified in a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). We report the frequency of CHMP2B mutations in 162 FTD patients recruited from a large population-based study of FTD carried out in The Netherlands. Our results suggest that mutations in CHMP2B are a rare cause of FTD as compared to MAPT mutations., ((c) 2006 Wiley-Liss, Inc.)

Objective: To determine the diagnostic value of CSF amyloid beta(1-42) (Abeta42), 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 Abeta42, 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 Abeta42 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 Abeta42 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 Abeta42 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 Abeta42 and CSF Ptau-181 may help in differentiating EAD from FTLD.

Hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in the tau gene shows a wide range in age at onset, several distinct clinical presentations, and a spectrum of tau pathology. Although the clinical and pathological phenotype often correlate with the location of the mutation, there also exists considerable interfamilial and intrafamilial phenotypical variation. Not all families with FTDP-17 do have mutations and deposition of hyperphosphorylated tau in the brain, but show ubiquitin-positive, tau-negative inclusions. Future research should focus on the role of other genetic and environmental factors in this form of FTDP-17, whereas the responsible gene defect(s) has still to be identified for hereditary FTD without tau mutations., (Copyright 2004 S. Karger AG, Basel)

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., (2004 S. Karger AG, Basel)

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 Pick's 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.

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.

Background: Frontotemporal dementia (FTD) is a pathologically heterogeneous group of presenile neurodegenerative disorders, with or without the deposition of hyperphosphorylated tau protein in affected brain regions. Mutations in the tau gene have been found in the familial form of FTD, linked to chromosome 17q21-22, showing a spectrum of tauopathy., Objective: To evaluate levels of total tau, phosphorylated tau 181 (Ptau-181), and amyloid-beta1-42 in the cerebrospinal fluid (CSF) of patients with FTD, with special emphasis on FTD due to tau mutations., Design: Case-control study., Setting: Outpatient neurology clinics at 2 university medical centers, in Rotterdam and Amsterdam (the Netherlands)., Patients: Twenty-six patients with FTD (9 with tau mutations 7 P301L and 2 G272V), 18 patients with Alzheimer disease (AD), and 13 nondemented controls., Methods: Total tau, Ptau-181, and amyloid-beta1-42 levels in CSF, obtained by lumbar puncture, were determined by sandwich enzyme-linked immunosorbent assay. Patients were diagnosed after clinical examination, neuropsychologic evaluation, and neuroimaging. Differences between patient groups were statistically evaluated using nonparametric tests., Results: Although CSF levels of total tau were mildly increased in FTD patients compared with nondemented controls (P =.05), median CSF total tau levels were low in the subgroup with tau mutations compared with AD patients. Furthermore, CSF levels of Ptau-181 and amyloid-beta1-42 were not different in FTD patients, including the patients with tau mutations, compared with nondemented controls., Conclusions: The tauopathy in P301L and G272V does not appear to be associated with an evident increase in CSF levels of Ptau-181 in FTD patients with these tau mutations, in contrast with findings in patients with AD.

Since 1994, a population-based study of frontotemporal dementia (FTD) in The Netherlands has aimed to ascertain all patients with FTD, and first prevalence estimates based on 74 patients were reported in 1998. Here, we present new prevalence estimates after expansion of our FTD population to 245 patients, with emphasis on the prevalence in the province Zuid-Holland where the main study centre is 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, supported by neuroimaging and neuropsychology. tau mutation analysis was performed in a subgroup of 154 patients (63%), and 40 out of 98 patients (41%) who died during follow-up were autopsied during the course of the study. The prevalence of FTD in the province Zuid-Holland was 3.6 per 100,000 at age 50-59 years, 9.4 per 100,000 at age 60-69 years and 3.8 per 100,000 at age 70-79 years. The median age at onset of the 245 patients (51% female) was 58.0 years (range 33-80 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, five L315R, four G272V, four R406W, one Delta K280 and one S320F), all with a positive family history for dementia (14% of the total population, 32% of patients with a positive family history). Pathological findings in the 40 autopsied patients consisted of dementia lacking distinctive histology in 22%, FTD with ubiquitin-positive inclusions in 33%, Pick's disease in 15% and tauopathy in the remaining 30% of patients, with tau mutations identified in more than half of the latter patients. We conclude that the prevalence of FTD in The Netherlands is higher than previously reported, confirming that FTD is more common than was previously thought. The finding of tau mutations in 32% of patients with a positive family history for dementia justifies mutation screening in FTD patients with a positive family history, while tau mutations in non-familiar cases are rare.

Purpose of Review: The identification of tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has revealed invaluable information regarding the role of the tau protein in neurodegenerative disease. Over the past year several new mutations have been identified, and experimental studies have provided further insight into the mechanism of neurodegeneration due to tau mutations and possible interactions with amyloid pathology., Recent Findings: Extensive clinical and pathological variation is seen in patients with different types of mutation, as well as in patients with the same mutation. Mutations may be found in patients with frontotemporal dementia (FTD), parkinsonism, progressive supranuclear palsy and corticobasal degeneration, justifying mutation analysis in familial cases of these disorders. Genetic heterogeneity exists in frontotemporal dementia, because a number of FTDP-17 families have neither tau mutations nor tau pathology. Genetic linkage has been found in familial FTD (chromosome 3), FTD with amyotrophic lateral sclerosis (9q21-q22), and FTD with inclusion body myopathy (9q13.3-p12). Tau deposits may consist of mainly mutated protein, or of mutated and wild-type protein in equal amounts, depending on the mutation. Recent animal studies show that amyloid-beta deposition may accelerate formation of neurofibrillary tangles., Summary: Hopefully, the identification of responsible genetic defects and associated proteins will be helpful in improving our understanding of the role of the tau protein in the common neurodegenerative process of frontotemporal degeneration.

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 Alzheimer's 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.

Objective: As metabolic and structural changes in frontotemporal-subcortical pathways have been reported in patients with obsessive-compulsive disorders, we investigated the correlation between complex compulsive behaviour (CCB) and the distribution of atrophy in a group of 90 patients with frontotemporal dementia (FTD)., Methods: CCB was defined as complex, intentional, and time consuming repetitive behaviour, which was distinguished from simple compulsive behaviour (SCB), such as verbal and motor repetitions and utilisation behaviour. Cortical atrophy on CT and/or MRI was semi-quantitatively assessed in frontal, temporal, parietal and occipital regions, and the pattern of atrophy was compared between patients with and without CCB or SCB. Linear measures were used to establish the presence of caudate atrophy (bicaudate ratio) and ventricular enlargement (bifrontal ratio)., Results: CCB was reported in 18 (21%) and SCB in 53 (61%) FTD patients. Frontotemporal atrophy was present in 64 patients (74%), and predominant temporal atrophy in 23 (26%). The pattern of atrophy was asymmetric in 25 patients (29%). Logistic regression analysis showed that temporal lobe atrophy (p < 0.005), as well as asymmetry of atrophy (p < 0.05) were independently associated with CCB, after adjusting for age at onset, gender, duration of symptoms at the time of imaging, severity of atrophy, and bicaudate and bifrontal ratio. No relationship was found between the presence of SCB and the distribution of atrophy, although patients with SCB tended to have more caudate atrophy (p < 0.1)., Conclusion: Temporal lobe atrophy appears to mediate CCB in patients with FTD, especially if asymmetry of atrophy is present. Future studies with quantitative and volumetric measurements of the cortical and subcortical structures may further clarify the aetiology of CCB in FTD.

Hereditary frontotemporal dementia (FTD) is an autosomal dominant neurodegenerative disorder that is associated with mutations in the tau gene and with the pathological accumulation of hyperphosphorylated tau protein in affected brain cells in about a quarter of cases. However, most FTD families have no demonstrable tau mutations. Here we describe the clinical and neuropathological features of a large family with hereditary FTD. Genetic analysis showed strong evidence for linkage to chromosome 17q21-22 (maximum lod score 3.46, theta = 0 for marker D17S950), but mutations in the tau gene were not found. Clinical symptoms, neuropsychological deficits and neuroimaging findings of affected family members were similar to sporadic and tau-related FTD. The mean age at onset was 61.2 years, with loss of initiative and decreased spontaneous speech as the most prominent presenting symptoms. Pathological examination of the brains of two affected family members showed non-specific neuronal degeneration with dense cytoplasmic ubiquitin-positive inclusions in neurones of the second layer of the frontotemporal cortex and dentate gyrus of the hippocampus. In a number of neurones these inclusions appeared to be located inside the nucleus, although due to the small number of these inclusions this localization could not be confirmed by electron microscopy. The inclusions were not stained by tau, alpha-synuclein or polyglutamine antibodies. Biochemical analysis of soluble tau did not reveal abnormalities in tau isoform distribution and analysis of mRNA showed the presence of both three- and four-repeat transcripts. This is the first report of ubiquitin-positive, tau-negative inclusions in an FTD family with significant linkage to chromosome 17q21-22. Further characterization of the ubiquitin-positive inclusions may clarify the neurodegenerative pathways involved in this subtype of FTD.

Hereditary frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is associated with different mutations in the microtubule-associated protein (MAP) tau gene. Pathological changes consist of accumulation of hyperphosphorylated tau protein in frontal and temporal cortex, hippocampus, and some subcortical nuclei. We describe the neuropathological findings in five patients with P301L mutation, and in two affected sibs with R406W mutation. The P301L brains all showed a pretangle-type tauopathy of the frontal and temporal cortices. One of these patients, however, also showed an Alzheimer-type tauopathy with neurofibrillary tangles (NFT), neuritic plaques, and amyloid angiopathy of the temporoparietal cortex. Three tau bands (64, 68, and 72 kDa) were seen in the frontal cortex, while the temporal cortex revealed four bands (60, 64, 68, and 72 kDa), containing all six tau isoforms. The first R406W brain showed many NFT in affected regions with only a few diffuse amyloid plaques. The second R406W brain contained a much higher density of NFT in affected regions, and an extensive amyloid deposition consisting of both diffuse and neuritic plaques with dense cores. An intriguing question is whether the FTD and Alzheimer disease changes are concomitant, or whether there is an interaction between tau and amyloid pathology. An acceleration of NFT formation due to amyloid deposition has been observed in nondemented aging and preclinical AD. The question whether this mechanism occurs in FTD with tau mutations remains to be elucidated.

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 (deltaK280, 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 deltaK280 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.