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Mutations in the gene for valosin containing protein (VCP) cause autosomal dominant inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD). To investigate the role of this novel gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 27 single nucleotide polymorphisms covering the entire VCP genomic region in 198 patients with sporadic FTD and 184 matched controls from Germany. No significant association could be demonstrated. There is no evidence, that common variants in VCP confer a strong risk to the development of sporadic FTD.

A hyperphosphorylated, ubiquitinated form of TDP-43, known as pathologic TDP-43, was shown to be a central component of ubiquitin-positive, tau-negative and alpha-synuclein-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amytrophic lateral sclerosis (ALS). To investigate the role of the TDP-43 gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 10 single nucleotide polymorphisms covering the entire TDP-43 genomic region, including the MASP2 gene in 173 patients with sporadic FTD (including 7 patients that were diagnosed with FTD and ALS) and 184 matched controls from Germany. Although we could observe a weak trend towards a potential disease association in a few FTD/ALS patients, no significant association with sporadic FTD could be demonstrated. There is no evidence, that common variants in TDP-43 confer a strong risk to the development of sporadic FTD.

Mutations of the chromatin modifying protein 2B gene (CHMP2B) were identified, in a Danish pedigree, to cause familial frontotemporal dementia (FTD). To explore the possible genetic contribution of common CHMP2B variants in sporadic FTD, we analyzed 14 single nucleotide polymorphisms covering the entire genomic region of CHMP2B. After adjustment for multiple testing single marker and haplotype analysis revealed no significant association with sporadic FTD. Thus, we conclude that CHMP2B can be excluded as a susceptibility gene conferring risk to sporadic forms of FTD.

Objective: The microtubule-associated protein tau gene (MAPT) contains two extended haplotypes, H1 and H2, which have been linked with sporadic tauopathies. However, there is little evidence as to how these haplotypes may influence the clinical features of the disease. The aim of this study was to investigate the MAPT haplotypes in relation to risk for, and functional alterations of glucose metabolism in, patients with frontotemporal dementia (FTD)., Method: The authors investigated MAPT haplotypes in 142 individuals with FTD and 292 comparison subjects. Additionally, in a subset of 41 individuals with FTD and 16 comparison subjects, the authors undertook functional [ (18)F]fluorodeoxyglucose positron emission tomography (PET) imaging., Results: MAPT haplotype distribution did not differ significantly between individuals with FTD and comparison subjects. However, the H2 haplotype was clinically associated with an earlier age at onset of FTD, which presented in a dose-dependent manner. Correspondingly, PET analysis revealed functional differences in glucose utilization patterns between MAPT haplotypes, with H2 carriers having a more pronounced hypometabolism in frontal brain areas than H1 carriers, which could not be accounted for by differences in duration of illness., Conclusions: While the extended MAPT H1 and H2 haplotypes do not appear to confer risk for disease development, the H2 haplotype appears to modify age at onset and functionally shows a more severe decline of glucose utilization in frontal brain areas.

Objective: To describe differences in cerebral glucose metabolism between frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD)., Methods: 14 patients with FTLD (7 f/7 m, mean age 60.1 years) and 14 patients with AD (7 f/7 m, mean age 59.5 years) were examined. [18F]FDG positron emission tomography (PET) scans were analysed with statistical nonparametric mapping (SnPM) and statistical parametric mapping (SPM99)., Results: Significant decreases in glucose metabolism in FTLD compared to AD were detected in the left insula/left inferior frontal gyrus (Brodman area [BA]13, 45 and 47) and in the medial frontal gyrus bilaterally (BA10). A significant decrease in AD compared to FTLD was identified in the right middle temporal gyrus (BA39)., Conclusion: Cerebral PET could be a promising tool to discriminate FTLD from AD.

Objective: [corrected] To evaluate tau-associated genetic polymorphisms in patients with sporadic frontotemporal dementia (FTD) and healthy control subjects., Method: Tau-gene sequence of 30 patients with FTD and 30 healthy controls was analysed by polymerase-chain-reaction (PCR). Subsequent sequencing was performed to identify exonic and intronic differences between both groups., Results: The following polypmorphisms, which are localized closely to each exon-intron-border, have been identified: In 37 % (n = 11) of the control subjects three different intronic polymorphisms occur simultaneously (Intron 2, 263, C --> Y; Intron 3, 590, A --> R; Intron 11, 150, G --> A). In the FTD group, this coexistance has been observed only in 17 % (n = 5)., Conclusions: In how far there exists a significant correlation between the newly identified triple polymorphism in the Tau gene and an alternated risk for FTD must be evaluated in a lager population. The proximity of these polymorphisms to the exon-intron border would facilitate functional influences on gene expression patterns. These preliminary results described, above potentially point to further pathogenetic factors in the genesis of FTD.

Caregiver counselling is an indispensable feature of current concepts for dementia treatment. Self-support groups and psychoeducative programms for caregivers of patients with Alzheimer's disease may reduce the burden of nursing and psychological strain. Specific caregiver needs from patients with frontotemporal lobar dementia (FTLD [frontotemporal dementia, semantic dementia, progressive aphasia, corticobasal degeneration]) are only partially taken into account. We conducted a German wide epidemiologic study which revealed that specific counselling for supporting relatives and caregivers of patients with FTLD is only fragmentary in hospital services for old age psychiatry. In most cases, they are referred to the local Alzheimer's disease Associations (89 %). Besides that, the existence of large hospital care units has significant negative repercussions on psychosocial supply for caregivers of patients with FTLD. To establish decentralized support units by these hospitals would lead to a significant improvement of medical and social care in this field.

Test results (raw scores) are composed of an unknown true score and an error term. The error term can be estimated by means of test reliability which is defined by the ratio of true variance and obtained variance. Different estimates of reliability either based on single measurements (e.g. Cronbach's coefficient, split half reliability, Kuder Richardson method) or two measurements (test/retest, inter- or intrarater reliability) are available. Parallel test reliability depends on the correlation of two different tests obtained in one session. Canonical correlation methods allow an extension of the parallel test situation and split half technique. Two or more tests are performed in a sample of subjects. Randomized subsets are correlated using canonical correlation technique. The objective of this study is to estimate the homogeneity of test batteries. 94 patients (64 f, 30 m; age: 54-89 ys.) supposed to have dementia were tested using the clocktest (CT, scores: 1-5), MMSE (mini mental state examination) and SKT (Syndrom Kurztest). Four (i, j: 1-4) subsets of 20 patients each were determined by random and the following characteristics were calculated: Empiric correlation coefficient for n = 94 (R), canonical correlation coefficient (Rcan), eigenvalues (EV) and redundancy (Rnd) of corresponding variable sets. The results of canonical analysis showed canonical correlation coefficients in order of 0.8 to 0.9 (p-values < 0.001). This high internal consistency can be interpreted as a measure of reliability of the test batteries. In conclusion, canonical correlation based on parallel tests splitted in subsets gives information on consistency, i.e. reliability, of test batteries in addition to conventional correlation methods.

The concept of frontotemporal lobar degeneration comprises a heterogenous group of cortical dementias, including frontotemporal dementia, as the major clinical variant. Because of their highly variable clinical presentation, to establish the diagnosis of frontotemporal dementia could be a diagnostic challenge for the clinician. Here we report a 53 years old caucasian male patient who was admitted for hospitalization due to acute severe schizophrenia-like symptoms. The leading symptomatology comprised acoustic and bizarre optical hallucinations with euphoria and self-overestimation. Remission of the psychotic symptoms demasked the clinical picture of a rapidly progressive frontotemporal dementia with marked apathy, indifference, emotional blunting, loss of insight, change of personality and typical cognitive impairment. The diagnosis was supported by the results of cerebral MRI and FDG-18 PET. This first clinical manifestation of a schizophrenia-like syndrome in the 6th life decade implicates frontotemporal dementia as an important differential diagnosis of schizophrenic disorders in late life. In addition of basically thinking about frontotemporal dementia, a detailed medical history, cognitive testing, neuroimaging and eventually the evaluation of the further disease course are necessary to establish a diagnosis of frontotemporal dementia.

BackgroundThe etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach.MethodsFUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold.ResultsWe identified 73 significant gene-tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed.ConclusionsWe identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

BackgroundFrontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.MethodsWe did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p

Abstract: We prospectively evaluated the diagnostic accuracy of cerebrospinal fluid (CSF)-β-amyloid1–42 (Aβ42), -total-tau (tau) and -phosphorylated-tau181 (p-tau181) as measured by sandwich ELISAs in the clinical routine of a community state hospital to discriminate between patients with Alzheimer''s disease (AD), healthy controls (HC), non-AD-dementias, a group composed of various psychiatric disorders (non-AD-dementias, mental diseases) and an age-matched random sample (RS) (total N =219). By comparing patients with AD to HC as reference, tau revealed sensitivity (sens)/specificity (spec) of 88%/80%, p-tau181 88%/80%, tau/Aβ42-ratio 81%/85% and phospho-tau181/Aβ42-ratio 81%/78%. Discriminative power between HC and all dementias under investigation was estimated lower for tau (78%/77%) and p-tau181 (73%/79%). Relative to patients with AD, ROC analysis for the RS revealed highest sens/spec for p-tau181 (79%/77%) and p-tau181/Aβ42 ratio (78%/75%). Differentiation between AD versus a group made of patients with various psychiatric disorders was optimised by using CSF-p-tau181 (80%/77%). Under clinical routine conditions current CSF-biomarkers show a substantial capacity to discriminate between AD and HC as reference and to mark off AD patients from RS and heterogeneous diagnostic groups composed of non-AD dementias and other psychiatric conditions. Despite a residual substantial overlap between the groups, we conclude that current CSF markers are well suited to support AD-related diagnostic procedures in every-day clinics. [Copyright &y& Elsevier]

Abstract: Emotional stimuli can have beneficial effects on memory in healthy aged subjects and partly on patients with dementia. So far, no experimental study has explored the effects of memory for emotional stimuli in patients with mild cognitive impairment (MCI), a concept that describes a transitional state between normal aging and dementia. The present fMRI study explored working memory for emotional stimuli in 16 patients with amnestic MCI (aMCI) and 16 healthy aged participants. Subjects performed an n-back task (2-back) with neutral, positive, and negative emotional pictures. The analysis focused on target processing. Results showed that groups did not differ in working memory performance. In healthy aged participants emotional targets had no significant impact on working memory. In patients with aMCI a negativity bias was observed, indicating that negative targets were better remembered compared to neutral and positive targets. Regarding fMRI results, both groups showed an increase in functional activity in prefrontal and lateral parietal brain regions associated with target processing. As a key result, we observed significant group by emotion interaction effects in the precuneus. Healthy aged participants showed a signal decrease in the left precuneus for positive compared to neutral targets. The precuneus deactivation in healthy aged participants may indicate a disengagement of self-referential processes towards task-related processes. Patients with aMCI revealed a signal increase in the right precuneus for negative compared to neutral targets. This increase in precuneus activity, combined with a behavioural facilitation effect, may indicate a mechanism to compensate disease related processes in aMCI. [Copyright &y& Elsevier]