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Background The semantic fluency test is one of the most widely used neuropsychological tests in dementia diagnosis. Research utilizing the qualitative, psycholinguistic information embedded in its output is currently underexplored in presymptomatic and prodromal genetic FTD. Methods Presymptomatic MAPT ( n  = 20) and GRN ( n  = 43) mutation carriers, and controls ( n  = 55) underwent up to 6 years of neuropsychological assessment, including the semantic fluency test. Ten mutation carriers became symptomatic ( phenoconverters ). Total score and five qualitative fluency measures (lexical frequency, age of acquisition, number of clusters, cluster size, number of switches) were calculated. We used multilevel linear regression modeling to investigate longitudinal decline. We assessed the co-correlation of the qualitative measures at each time point with principal component analysis. We explored associations with cognitive decline and grey matter atrophy using partial correlations, and investigated classification abilities using binary logistic regression. Results The interrater reliability of the qualitative measures was good (ICC = 0.75–0.90). There was strong co-correlation between lexical frequency and age of acquisition, and between clustering and switching. At least 4 years pre-phenoconversion, GRN phenoconverters had fewer but larger clusters ( p  < 0.001), and fewer switches ( p  = 0.004), correlating with lower executive function ( r  = 0.87–0.98). Fewer switches was predictive of phenoconversion, correctly classifying 90.3%. Starting at least 4 years pre-phenoconversion, MAPT phenoconverters demonstrated an increase in lexical frequency ( p  = 0.009) and a decline in age of acquisition ( p  = 0.034), correlating with lower semantic processing ( r  = 0.90). Smaller cluster size was predictive of phenoconversion, correctly classifying 89.3%. Increase in lexical frequency and decline in age of acquisition were associated with grey matter volume loss of predominantly temporal areas, while decline in the number of clusters, cluster size, and switches correlated with grey matter volume loss of predominantly frontal areas. Conclusions Qualitative aspects of semantic fluency could give insight into the underlying mechanisms as to why the “traditional” total score declines in the different FTD mutations. However, the qualitative measures currently demonstrate more fluctuation than the total score, the measure that seems to most reliably deteriorate with time. Replication in a larger sample of FTD phenoconverters is warranted to identify if qualitative measures could be sensitive cognitive biomarkers to identify and track mutation carriers converting to the symptomatic stage of FTD.

Background Onset-predictive biomarker tests (OPBT) in genetic frontotemporal dementia (FTD) may be used to recruit mutation carriers into preventive clinical trials before symptoms manifest. This would require disclosure of OPBT results to potential participants. This study investigates the perspectives of Dutch presymptomatic mutation carriers and individuals at 50% risk of genetic FTD on disclosure of OPBT results. It focuses on their willingness to receive OPBT results, what impacts they foresee from disclosure, and their preferences for the process of disclosure. Methods Semi-structured interviews were conducted with presymptomatic mutation carriers and individuals at 50% risk of developing genetic FTD ( n  = 25), who had received genetic counselling or participate in a longitudinal cohort study. The interview transcripts were analysed using thematic inductive analysis. Results Main themes were: willingness to undergo biomarker testing, foreseen impact of test results, preferences regarding biomarker test features, and understanding of biomarker testing. Most participants would be willing to receive OPBT results in the context of clinical trial recruitment. Participants would also be willing to receive OPBT results without access to clinical trial participation, as they perceived utility from these results. They would use positive OPBT results to prepare for the future, e.g. by planning for care, drawing up advance care directives, retiring early, and spending final healthy years well. At the same time, they thought positive OPBT results might also have negative psychological impacts on self-image or social dynamics with others. Implications of positive OPBT results for self-image as healthy or ill differed between participants. Negative OPBT results would provide relief and not lead to life changes. Conclusions Dutch presymptomatic mutation carriers and individuals at 50% risk of developing genetic FTD tend to be willing to receive OPBT results. The results would allow for participation in a clinical trial and preparation for onset through personal life planning. At the same time, disclosure of OPBT results might have negative psychological consequences. This study provides valuable input for developing ethical guidance and an appropriate counselling process to ensure responsible disclosure of OPBT results with clinical trial recruitment.

Neuroimaging MRI data in scientific research is increasingly pooled, but the reliability of such studies may be hampered by the use of different hardware elements. This might introduce bias, for example when cross-sectional studies pool data acquired with different head coils, or when longitudinal clinical studies change head coils halfway. In the present study, we aimed to estimate this possible bias introduced by using different head coils to create awareness and to avoid misinterpretation of results. We acquired, with both an 8 channel and 32 channel head coil, T1-weighted, diffusion tensor imaging and resting state fMRI images at 3T MRI (Philips Achieva) with stable acquisition parameters in a large group of cognitively healthy participants ( = 77). Standard analysis methods, i.e., voxel-based morphometry, tract-based spatial statistics and resting state functional network analyses, were used in a within-subject design to compare 8 and 32 channel head coil data. Signal-to-noise ratios (SNR) for both head coils showed similar ranges, although the 32 channel SNR profile was more homogeneous. Our data demonstrates specific patterns of gray and white matter volume differences between head coils (relative volume change of 6 to 9%), related to altered image contrast and therefore, altered tissue segmentation. White matter connectivity (fractional anisotropy and diffusivity measures) showed hemispherical dependent differences between head coils (relative connectivity change of 4 to 6%), and functional connectivity in resting state networks was higher using the 32 channel head coil in posterior cortical areas (relative change up to 27.5%). This study shows that, even when acquisition protocols are harmonized, the results of standardized analysis models can be severely affected by the use of different head coils. Researchers should be aware of this when combining multiple neuroimaging MRI datasets, to prevent coil-related bias and avoid misinterpretation of their findings.

INTRODUCTION We aimed to assess the knowledge of social norms in patients with behavioral variant frontotemporal dementia (bvFTD) with the Dutch version of the Social Norms Questionnaire (SNQ‐NL). METHODS The SNQ‐NL was administered in 34 patients with bvFTD, 20 prodromal mutation carriers, 76 presymptomatic mutation carriers, and 56 controls. Group differences and correlations with other neuropsychological tests and gray matter volume were examined. RESULTS Patients with bvFTD had lower total SNQ‐NL scores and more over‐adherence errors than presymptomatic mutation carriers and controls (P < 0.001). SNQ‐NL performance correlated with tests for executive functioning and social cognition, and with gray matter volume in bilateral frontal and unilateral temporal regions. DISCUSSION The SNQ‐NL can identify impairments in knowledge of social norms in bvFTD, highlighting its significance in clinical diagnosis and upcoming clinical trials. The SNQ‐NL currently fails to differentiate presymptomatic mutation carriers from controls; to this end, larger sample sizes from larger cohorts and longitudinal follow‐up are warranted. Highlights The Dutch version of the Social Norms Questionnaire (SNQ‐NL) is able to detect impairment in social cognition in symptomatic bvFTD patients. A trend towards a lower performance in prodromal mutation carriers was found. Performance on the SNQ‐NL is related to other measures of social cognition, executive functioning, and language. Lower SNQ‐NL performance is related to gray matter volume loss in bilateral frontal and temporal regions. The SNQ‐NL provides insight into the underlying cause of deficits in social cognition in bvFTD.

Background: Impairment in navigation abilities and object location memory are often seen in early-stage Alzheimer’s Disease (AD), yet these constructs are not included in standard neuropsychological assessment. We investigated the differential ability of a short digital spatial memory test in mild AD dementia and mild cognitive impairment (MCI). Methods: 21 patients with AD dementia (66.9 ± 6.9; 47% female), 22 patients with MCI (69.6 ± 8.3; 46% female) and 21 patients with subjective cognitive decline (SCD) (62.2 ± 8.9; 48% female) from the Amsterdam Dementia Cohort performed the Object Location Memory Test (OLMT), consisting of a visual perception and memory trial, and the Virtual Tübingen (VT) test, consisting of a scene recognition, route continuation, route ordering and distance comparison task. The correlations with other cognitive domains were examined. Results: Patients with mild AD dementia (Z: −2.51 ± 1.15) and MCI (Z: −1.81 ± 0.92) performed worse than participants with SCD (Z: 0.0 ± 1.0) on the OLMT. Scene recognition and route continuation were equally impaired in patients with AD dementia (Z: −1.14 ± 0.73; Z: −1.44 ± 1.13) and MCI (Z: −1.37 ± 1.25; Z: −1.21 ± 1.07). Route ordering was only impaired in patients with MCI (Z: −0.82 ± 0.78). Weak to moderate correlations were found between route continuation and memory (r(64) = 0.40, p < 0.01), and between route ordering and attention (r(64) = 0.33, p < 0.01), but not for the OLMT. Conclusion: A short digital spatial memory test battery was able to detect object location memory and navigation impairment in patients with mild AD dementia and MCI, highlighting the value of incorporating such a test battery in standard neuropsychological assessment.

Objective Methylation of plasma cell‐free DNA (cfDNA) has potential as a marker of brain damage in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, we study methylation of cfDNA in presymptomatic and symptomatic carriers of genetic FTD pathogenic variants, next to healthy controls. Methods cfDNA was isolated from cross‐sectional plasma of 10 presymptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), 10 symptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), and 9 healthy controls. Genome‐wide methylation of cfDNA was determined using a high‐resolution sequencing technique (MeD‐seq). Cumulative scores based on the identified differentially methylated regions (DMRs) were estimated for presymptomatic carriers (vs. controls and symptomatic carriers), and reevaluated in a validation cohort (8 presymptomatic: 3 C9orf72, 3 GRN, and 2 MAPT; 26 symptomatic: 7 C9orf72, 6 GRN, 12 MAPT, and 1 TARDBP; 13 noncarriers from genetic FTD families). Results Presymptomatic carriers showed a distinctive methylation profile compared to healthy controls and symptomatic carriers. Cumulative DMR scores in presymptomatic carriers enabled to significantly differentiate presymptomatic carriers from healthy controls (p < 0.001) and symptomatic carriers (p < 0.001). In the validation cohort, these scores differentiated presymptomatic carriers from symptomatic carriers (p ≤ 0.007) only. Transcription‐start‐site methylation in presymptomatic carriers, generally associated with gene downregulation, was enriched for genes involved in ubiquitin‐dependent processes, while gene body methylation, generally associated with gene upregulation, was enriched for genes involved in neuronal cell processes. Interpretation A distinctive methylation profile of cfDNA characterizes the presymptomatic stage of genetic FTD, and could reflect neuronal death in this stage.

BackgroundThe emotion recognition task (ERT) was developed to overcome shortcomings of static emotion recognition paradigms, by identifying more subtle deficits in emotion recognition across different intensity levels. In this study, we used the ERT to investigate emotion recognition deficits across the frontotemporal (FTD) and Alzheimer’s Dementia (AD) spectrum.MethodsWith the ERT, we assessed the recognition of facial emotional expressions (anger-disgust-fear-happiness-sadness-surprise) across four intensities (40–60–80–100%) in patients with behavioural variant FTD (bvFTD; n = 32), and AD (n = 32), presymptomatic FTD mutation carriers (n = 47) and controls (n = 49). We examined group differences using multilevel linear regression with age, sex and education level as covariates, and performed post hoc analyses on presymptomatic (MAPT, GRN and C9orf72) mutation carriers. Classification abilities were investigated by means of logistic regression.ResultsLowest ERT total scores were found in patients with bvFTD and AD, whereas equal highest performance was found in presymptomatic mutation carriers and controls. For all emotions, significantly lower subscores were found in patients with bvFTD than in presymptomatic mutation carriers and in controls (highest p value = 0.025). Patients with bvFTD performed lower than patients with AD on anger (p = 0.005) and a trend towards significance was found for a lower performance on happiness (p = 0.065). Task performance increased with higher emotional intensity, and classification was better at the lowest than at the highest intensity. C9orf72 mutation carriers performed worse on recognizing anger at the lowest intensity than GRN mutation carriers (p = 0.047) and controls (p = 0.038). The ERT differentiated between patients with bvFTD and controls, and between patients with AD and controls (both p < 0.001).DiscussionOur results demonstrate emotion recognition deficits in both bvFTD and AD, and suggest the presence of subtle emotion recognition changes in presymptomatic C9orf72-FTD. This highlights the importance of incorporating emotion recognition paradigms into standard neuropsychological assessment for early differential diagnosis, and as clinical endpoints in upcoming therapeutic trials.

Objectives: A meta-analysis of the extent, nature and pattern of memory performance in behavioral variant frontotemporal dementia (bvFTD). Multiple observational studies have challenged the relative sparing of memory in bvFTD as stated in the current diagnostic criteria. Methods: We performed a meta-analytic review covering the period 1967 to February 2017 of case-control studies on episodic memory in bvFTD versus control participants (16 studies, 383 patients, 603 control participants), and patients with bvFTD versus those with Alzheimer’s disease (AD) (20 studies, 452 bvFTD, 874 AD). Differences between both verbal and non-verbal working memory, episodic memory learning and recall, and recognition memory were examined. Data were extracted from the papers and combined into a common metric measure of effect, Hedges’ d. Results: Patients with bvFTD show large deficits in memory performance compared to controls (Hedges’ d –1.10; 95% confidence interval [CI] [–1.23, –0.95]), but perform significantly better than patients with AD (Hedges’ d 0.85; 95% CI [0.69, 1.03]). Learning and recall tests differentiate best between patients with bvFTD and AD (p<.01). There is 37–62% overlap in test scores between the two groups. Conclusions: This study points to memory disorders in patients with bvFTD, with performance at an intermediate level between controls and patients with AD. This indicates that, instead of being an exclusion criterion for bvFTD diagnosis, memory deficits should be regarded as a potential integral part of the clinical spectrum. (JINS, 2018, 24, 593–605)

Most neuropsychiatric symptoms (NPS) common in frontotemporal dementia (FTD) are currently not part of the Neuropsychiatric Inventory (NPI). We piloted an FTD Module that included eight extra items to be used in conjunction with the NPI. Caregivers of patients with behavioural variant FTD ( n  = 49), primary progressive aphasia (PPA; n  = 52), Alzheimer’s dementia (AD; n  = 41), psychiatric disorders ( n  = 18), presymptomatic mutation carriers ( n  = 58) and controls ( n  = 58) completed the NPI and FTD Module. We investigated (concurrent and construct) validity, factor structure and internal consistency of the NPI and FTD Module. We performed group comparisons on item prevalence, mean item and total NPI and NPI with FTD Module scores, and multinomial logistic regression to determine its classification abilities. We extracted four components, together explaining 64.1% of the total variance, of which the largest indicated the underlying dimension ‘frontal-behavioural symptoms’. Whilst apathy (original NPI) occurred most frequently in AD, logopenic and non-fluent variant PPA, the most common NPS in behavioural variant FTD and semantic variant PPA were loss of sympathy/empathy and poor response to social/emotional cues (part of FTD Module). Patients with primary psychiatric disorders and behavioural variant FTD showed the most severe behavioural problems on both the NPI as well as the NPI with FTD Module. The NPI with FTD Module correctly classified more FTD patients than the NPI alone. By quantifying common NPS in FTD the NPI with FTD Module has large diagnostic potential. Future studies should investigate whether it can also prove a useful addition to the NPI in therapeutic trials.