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Objectives To investigate electronic care notes to better understand reporting and management of neuropsychiatric symptoms (NPS) by residential aged care (RAC) staff. Methods We examined semi-structured care notes from electronic healthcare notes of 77 residents (67% female; aged 67-101; 79% with formal dementia diagnosis) across three RAC facilities. As part of standard clinical practice, staff documented the NPS presentation and subsequent management amongst residents. Using a mixed-method approach, we analyzed the type of NPS reported and explored care staff responses to NPS using inductive thematic analysis. Results 465 electronic care notes were recorded during the 18-month period. Agitation-related behaviors were most frequently reported across residents (48.1%), while psychosis (15.6%), affective symptoms (14.3%), and apathy (1.3%) were less often reported. Only 27.5% of the notes contained information on potential causes underlying NPS. When faced with NPS, care staff responded by either providing emotional support, meeting resident's needs, removing identified triggers, or distracting. Conclusion Results suggest that RAC staff primarily detected and responded to those NPS they perceived as distressing. Findings highlight a potential under-recognition of specific NPS types, and lack of routine examination of NPS causes or systematic assessment and management of NPS. These observations are needed to inform the development and implementation of non-pharmacological interventions and care programs targeting NPS in RAC. Supplemental data for this article is available online at https://doi.org/10.1080/13607863.2022.2032597 .

Background and ObjectivesIt is important to identify at what age brain atrophy rates in genetic frontotemporal dementia (FTD) start to accelerate and deviate from normal aging effects to find the optimal starting point for treatment. We investigated longitudinal brain atrophy rates in the presymptomatic stage of genetic FTD using normative brain volumetry software.MethodsPresymptomaticGRN,MAPT, andC9orf72pathogenic variant carriers underwent longitudinal volumetric T1-weighted magnetic resonance imaging of the brain as part of a prospective cohort study. Images were automatically analyzed with Quantib® ND, which consisted of volume measurements (CSF and sum of gray and white matter) of lobes, cerebellum, and hippocampus. All volumes were compared with reference centile curves based on a large population-derived sample of nondemented individuals (n = 4,951). Mixed-effects models were fitted to analyze atrophy rates of the different gene groups as a function of age.ResultsThirty-fourGRN, 8MAPT, and 14C9orf72pathogenic variant carriers were included (mean age = 52.1, standard deviation = 7.2; 66% female). The mean follow-up duration of the study was 64 ± 33 months (median = 52; range 13–108).GRNpathogenic variant carriers showed a faster decline than the reference centile curves for all brain areas, though relative volumes remained between the 5th and 75th percentiles between the ages of 45 and 70 years. InMAPTpathogenic variant carriers, frontal lobe volume was already at the 5th percentile at age 45 years and showed a further decline between the ages 50 and 60 years. Temporal lobe volume started in the 50th percentile at age 45 years but showed fastest decline over time compared with other brain structures. Frontal, temporal, parietal, and cerebellar volume already started below the 5th percentile compared with the reference centile curves at age 45 years forC9orf72pathogenic variant carriers, but there was minimal decline over time until the age of 60 years.DiscussionWe provide evidence for longitudinal brain atrophy in the presymptomatic stage of genetic FTD. The affected brain areas and the age after which atrophy rates start to accelerate and diverge from normal aging slopes differed between gene groups. These results highlight the value of normative volumetry software for disease tracking and staging biomarkers in genetic FTD. These techniques could help in identifying the optimal time window for starting treatment and monitoring treatment response.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.

Contains fulltext : 232053.pdf (Publisher’s version ) (Open Access) The Social Norms Questionnaire-Dutch version (SNQ-NL) measures the ability to understand and identify social boundaries. We examined the psychometric characteristics of the SNQ-NL and its ability to differentiate between patients with behavioral variant frontotemporal dementia (bvFTD; n = 23), Alzheimer's dementia (AD; n = 26), chronic psychiatric disorders (n = 27), and control participants (n = 92). Between-group differences in the Total score, Break errors, and Overadhere errors were examined and associations with demographic variables and other cognitive functions were explored. Results showed that the SNQ-NL Total Score and Break errors differed between patients with AD and bvFTD, but not between patients with bvFTD and psychiatric disorders. Modest correlations with age, sex, and education were observed. The SNQ-NL Total score and Break errors correlated significantly with emotion recognition and verbal fluency but not with processing speed or mental flexibility. In conclusion, the SNQ-NL has sufficient construct validity and can be used to investigate knowledge of social norms in clinical populations. 12 p.

Objective: Neuropsychological assessment of culturally diverse populations is hindered by barriers in language, culture, education, and a lack of suitable tests. Furthermore, individuals from diverse backgrounds are often unfamiliar with being cognitively tested. The aim of this study was to develop a new neuropsychological test battery and study its feasibility in multicultural memory clinics. Method: Composition of the TULIPA battery (Towards a Universal Language: Intervention and Psychodiagnostic Assessment) entailed a literature review and consultation with experts and individuals from diverse backgrounds. Feasibility was investigated by examining administration and completion rates and the frequency of factors complicating neuropsychological assessment in 345 patients from 37 countries visiting four multicultural memory clinics in the Netherlands. Results: The test battery included existing tests such as the Cross-Cultural Dementia screening (CCD), Rowland Universal Dementia Assessment Scale (RUDAS), tests from the European Cross-Cultural Neuropsychological Test Battery, and newly developed tests. Completion rates for the test battery were generally high (82%–100%), except for CCD Dots subtest B (58%). Although tests of the “core” TULIPA battery were administered often (median: 6 of 7, IQR: 5–7), supplementary tests were administered less frequently (median: 1 of 9; IQR: 0–3). The number of administered tests correlated with disease severity (RUDAS, ρ=.33, adjusted p

Background: While neuropsychiatric symptoms (NPS) are common in early Alzheimer’s disease (AD), they are currently underdiagnosed and undertreated in the memory clinic. Therefore, we evaluated the effectiveness of the Describe, Investigate, Create, Evaluate (DICE™) approach to structure and standardize the care for NPS in AD in the memory clinic. Method: A total of 60 community-dwelling patients with MCI, AD dementia, or AD/VaD dementia were enrolled with their caregivers in two waves (Table-1). The first wave (n = 36) received care as usual and served as a control group, while the second wave of patients (n = 24, of which n = 20 have currently completed the study) underwent the DICE method. We applied the DICE method during two visits in which NPS were assessed, underlying causes were examined, and patients and caregivers were instructed on management strategies to deal with NPS, which were evaluated after one month. Outcomes were assessed after three and six months. Primary outcomes were quality of life of patients (QoL-AD) and caregivers (Carerqol-7D). Secondary outcomes included caregiver burden (Perseverance time), NPS prevalence and severity (NPI-Q & BEHAVE-AD), NPS-related distress (NPI-Q), competence managing NPS (additional NPI-Q item), and psychotropic drug use. We used linear mixed models to examine differences in outcomes at group-level and reliable change index to examine which participants in the intervention group showed reliable improvement in the primary outcomes. Result: We found no significant differences between the two groups in change in quality of life or any of the secondary outcomes (all p>0.05, Table-2). A proportion of the intervention group showed reliable improvement in quality of life of patients (n = 6/20) and caregivers (n = 7/20). At baseline, these patients tended to show higher NPS burden and their caregivers reported more NPS-related distress and lower feelings of competence while managing NPS compared to participants that did no show reliable improvement. Conclusion: This Stage 2 efficacy study shows no benefits of the DICE method on in early AD at group-level, but suggest that particular participants might benefit from this approach. Data will be re-analyzed when all intervention group participants have completed the study and will be extended with qualitative data investigating NPS-related knowledge and management styles of participants.

Introduction: Although qualitative studies have highlighted substantial barriers to dementia diagnosis and care in culturally diverse populations in Europe, quantitative studies examining the level of caregiver burden in these populations have been lacking thus far and are urgently needed. Methods: We compared the caregiver burden levels on the Caregiver Strain Index (CSI)-Expanded of 63 culturally diverse patient-caregiver dyads from a multicultural memory clinic with 30 native Dutch patient-caregiver dyads and examined the association between caregiver burden and determinants of burden. Results: Informal caregivers in the multicultural memory clinic cohort experienced a high level of caregiver burden (mean CSI-score multicultural cohort: 6.1 [SD: 3.3]; mean CSI-score native Dutch cohort: 4.8 [SD: 3.2]). Burden was significantly associated with impairment on proxy-rated and objective measures of cognitive functioning, such as the Informant Questionnaire on Cognitive Decline and the Rowland Universal Dementia Assessment Scale, and with instrumental activities of daily living. Burden was the highest in spousal caregivers. The positive subscale of the CSI-Expanded provided limited additional information. Conclusion: Caregivers of culturally diverse patients experience a high level of caregiver burden, in particular at more advanced disease stages. This study highlights the need to screen culturally diverse caregivers in European memory clinics on caregiver burden to identify those in need of caregiver support.

ObjectiveThe clinical phenotype of the rare behavioural variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.MethodsFor the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a ‘typical’ memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).ResultsIndividual regional W-scores ≥1.96 (corresponding to p0.05).ConclusionsBoth in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

ObjectiveTo assess the [18F]flortaucipir binding distribution across MAPT mutations in presymptomatic and symptomatic carriers.MethodsWe compared regional [18F]flortaucipir binding potential (BPND) derived from a 130-minute dynamic [18F]flortaucipir PET scan in 9 (pre)symptomatic MAPT mutation carriers (4 with P301L [1 symptomatic], 2 with R406W [1 symptomatic], 1 presymptomatic L315R, 1 presymptomatic S320F, and 1 symptomatic G272V carrier) with 30 cognitively normal controls and 52 patients with Alzheimer disease.Results[18F]Flortaucipir BPND images showed overall highest binding in the symptomatic carriers. This was most pronounced in the symptomatic R406W carrier in whom tau binding exceeded the normal control range in the anterior cingulate cortex, insula, amygdala, temporal, parietal, and frontal lobe. Elevated medial temporal lobe BPND was observed in a presymptomatic R406W carrier. The single symptomatic carrier and 1 of the 3 presymptomatic P301L carriers showed elevated [18F]flortaucipir BPND in the insula, parietal, and frontal lobe compared to controls. The symptomatic G272V carrier exhibited a widespread elevated cortical BPND, with at neuropathologic examination a combination of 3R pathology and encephalitis. The L315R presymptomatic mutation carrier showed higher frontal BPND compared to controls. The BPND values of the S320F presymptomatic mutation carrier fell within the range of controls.ConclusionPresymptomatic MAPT mutation carriers already showed subtle elevated tau binding, whereas symptomatic MAPT mutation carriers showed a more marked increase in [18F]flortaucipir BPND. Tau deposition was most pronounced in R406W MAPT (pre)symptomatic mutation carriers, which is associated with both 3R and 4R tau accumulation. Thus, [18F]flortaucipir may serve as an early biomarker for MAPT mutation carriers in mutations that cause 3R/4R tauopathies.

Objectives: This study investigates the stability of neuropsychiatric symptoms (NPS) assessed biweekly using the Neuropsychiatric Inventory (NPI) in a memory clinic population during a 6 week period. Methods: Twenty-three spousal caregivers (mean [SD] age = 69.7 [8.8], 82.6% female) of 23 patients (43.5% had dementia) completed all assessments. The NPI was assessed four times during 6 weeks. We examined whether NPI domains were present during all four assessments, studied within-person variation for each NPI domain, and calculated Spearman's correlations between subsequent time-points. Furthermore, we associated repeated NPI assessments with repeated measures of caregiver burden to examine the clinical impact of changes in NPI scores over time. Results: The course of NPS was highly irregular according to the NPI, with only 35.8% of the NPI domains that were present at baseline persisted during all 6 weeks. We observed large within-person variation in the presence of individual NPI domains (61.3%, range 37.5%–83.9%) and inconsistent correlations between NPI assessments (e.g., range r s = 0.20–0.57 for agitation, range r s = 0.29–0.59 for anxiety). Higher NPI total scores were related to higher caregiver burden (r s = 0.60, p s = 0.16, p = 0.20). Conclusions: We observed strong fluctuations in NPI scores within very short time windows raising the question whether this represents erratic symptoms and/or scores. Further studies are needed to investigate the origins of these fluctuations.

Contains fulltext : 283195.pdf (Publisher’s version ) (Open Access) BACKGROUND: Young-onset dementia (YOD) has many underlying etiologies, leading to a large heterogeneity in first symptoms. This makes it difficult for general practitioners (GPs) to recognize YOD. OBJECTIVE: Identify early symptoms that are more common in the pre-diagnostic phase of YOD. METHODS: We performed a case-control study nested in a primary-care registry on 89 cases and 162 matched controls, where we compared symptoms of people with YOD up to 5 years before diagnosis to their matched control group without YOD. The variables included in this study were International Classification of Primary Care codes and symptoms extracted from written GP notes and categorized in groups. We used Generalized Equation Estimation to analyze symptom's time-trajectories and logistic regression and ROC-curves to analyze differences in number of symptom categories reported. RESULTS: Cognitive symptoms were more common in people with YOD 5 years before diagnosis, affective symptoms 4 years before diagnosis, social symptoms 3 years, behavioral symptoms 2 years, and daily functioning disturbances 1 year before diagnosis. The ROC-curve suggested that reporting two or more symptom categories at the GP gave the best trade-off between sensitivity (85%) and specificity (77%), for the highest percentage of correctly diagnosed persons. CONCLUSION: This study showed people with YOD present differently than people without YOD. However, it may still be difficult for GPs to use these symptom categories to distinguish people with YOD, since the symptoms also occur in people with other diseases. A combination of reported symptom categories increases the probability of an underlying cause of YOD.

Objective To investigate the differential ability of the “Test Relaties Abstracte Concepten” (TRACE), a Dutch test for abstract semantic knowledge, in frontotemporal dementia (FTD). Methods The TRACE was administered in patients with behavioral variant FTD (bvFTD; n = 16), nonfluent variant (nfvPPA; n = 10), logopenic variant (lvPPA; n = 10), and semantic variant primary progressive aphasia (svPPA; n = 9), and controls (n = 59). We examined group differences, performed correlational analyses with other neuropsychological tests and investigated discriminative ability. We compared the TRACE with a semantic association test for concrete stimuli (SAT). Results All patient groups, except nfvPPA, performed worse on the TRACE than controls (p 0.6), whereas in svPPA the concrete task correlated (ρ ≥ 0.75) with language tests. Patients with bvFTD, nfvPPA and lvPPA performed lower on the TRACE than the SAT (p Discussion We demonstrated impaired abstract semantic knowledge in patients with bvFTD, lvPPA, and svPPA, but not nfvPPA, with svPPA patients performing worse than the other subtypes. The TRACE was a good classifier between each patient group versus controls and between svPPA versus other patient groups. This highlights the value of incorporating semantic tests with abstract stimuli into standard neuropsychological assessment for early differential diagnosis of FTD subtypes.

Since the heterogeneity of the growing group of older outpatients with cognitive decline, it is challenging to evaluate survival rates in clinical shared decision making. The primary outcome was to determine whether the Multidimensional Prognostic Index (MPI) predicts mortality, whilst assessing the MPI distribution was considered secondary. This retrospective chart review included 311 outpatients aged ≥65 years and diagnosed with dementia or mild cognitive impairment (MCI). The MPI includes several domains of the comprehensive geriatric assessment (CGA). All characteristics and data to calculate the risk score and mortality data were extracted from administrative information in the database of the Alzheimer’s Center and medical records. The study population (mean age 76.8 years, men = 51.4%) was divided as follows: 34.1% belonged to MPI category 1, 52.1% to MPI category 2 and 13.8% to MPI category 3. Patients with dementia have a higher mean MPI risk score than patients with MCI (0.47 vs. 0.32; p < 0.001). The HRs and corresponding 95% CIs for mortality in patients in MPI categories 2 and 3 were 1.67 (0.81–3.45) and 3.80 (1.56–9.24) compared with MPI category 1, respectively. This study shows that the MPI predicts mortality in outpatients with cognitive decline.

Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers’ clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson’s disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Introduction Trials to test disease-modifying treatments for frontotemporal dementia are eagerly awaited and sensitive instruments to assess potential treatment effects are increasingly urgent, yet lacking thus far. We aimed to identify gene-specific instruments assessing clinical onset and disease progression by comparing cognitive functioning between bvFTD patients across genetic mutations. Methods We examined differences in 7 cognitive domains between bvFTD patients with GRN (n = 20), MAPT (n = 29) or C9orf72 (n = 31) mutations, and non-carriers (n = 24), and described longitudinal (M = 22.6 months, SD = 16.6) data in a subsample (n = 27). Results Patients showed overall cognitive impairment, except memory recall, working memory and visuoconstruction. GRN patients performed lower on executive function (mean difference − 2.1; 95%CI − 4.1 to − 0.5) compared to MAPT and lower on attention compared to MAPT (mean difference − 2.5; 95%CI − 4.7 to − 0.3) and C9orf72 (mean difference − 2.4; 95%CI − 4.5 to − 0.3). Only MAPT patients were impaired on delayed recall (mean difference − 1.4; 95%CI − 2.1 to − 0.7). GRN patients declined rapidly on attention and memory, MAPT declined in confrontation naming, whereas C9orf72 patients were globally impaired but remained relatively stable over time on all cognitive domains. Discussion This study shows gene-specific cognitive profiles in bvFTD, which underlines the value of neuropsychological tests as outcome measures in upcoming trials for genetic bvFTD.

© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)., A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease.

The behavioral variant of Alzheimer's disease is characterized by early predominant behavioral changes, mimicking the behavioral variant of frontotemporal dementia, which is characterized by social cognition deficits and altered biometric responses to socioemotional cues. These functions remain understudied in the behavioral variant of Alzheimer's disease. We investigated multiple social cognition components(i.e., emotion recognition, empathy, social norms and moral reasoning), using the Ekman-60-faces-test, Interpersonal-Reactivity-Index, empathy eliciting videos, Social-Norms-Questionnaire and moral dilemmas, while measuring eye-movements and galvanic skin response. We compared 12 patients with the behavioral variant of Alzheimer's disease with patients with the behavioral variant of frontotemporal dementia(n = 14), typical Alzheimer's disease(n = 13) and individuals with subjective cognitive decline(n = 13), using ANCOVAs and age and sex adjusted post hoc testing. Patients with the behavioral variant of Alzheimer's disease(40.1 ± 8.6) showed lower scores on the Ekman-60-faces-test compared to individuals with subjective cognitive decline(49.7 ± 5.0, p 0.001), and patients with typical Alzheimer's disease(46.2 ± 5.3, p = 0.05) and higher scores compared to patients with behavioral variant of frontotemporal dementia(32.4 ± 7.3, p = 0.002). Eye-tracking during the Ekman-60-faces-test revealed no differences in dwell time on the eyes(all p 0.05), but patients with the behavioral variant of Alzheimer's disease(18.7 ± 9.5%) and frontotemporal dementia(19.4 ± 14.3%) spent significantly less dwell time on the mouth than individuals with subjective cognitive decline(30.7 ± 11.6%, p 0.01) and patients with typical Alzheimer's disease(32.7 ± 12.1%, p 0.01). Patients with the behavioral variant of Alzheimer's disease(11.3 ± 4.6) exhibited lower scores on the Interpersonal-Reactivity-Index compared with individuals with subjective cognitive decline(15.6 ± 3.1, p = 0.05) and similar scores to patients with the behavioral variant of frontotemporal dementia(8.7 ± 5.6, p = 0.19) and typical Alzheimer's disease(13.0 ± 3.2, p = 0.43). The galvanic skin response to empathy eliciting videos did not differ between groups(all p 0.05). Patients with the behavioral variant of Alzheimer's disease(16.0 ± 1.6) and frontotemporal dementia(15.2 ± 2.2) showed lower scores on the Social-Norms-Questionnaire than patients with typical Alzheimer's disease(17.8 ± 2.1, p 0.05) and individuals with subjective cognitive decline(18.3 ± 1.4, p 0.05). No group differences were observed in scores on moral dilemmas(all p 0.05), while only patients with the behavioral variant of frontotemporal dementia(0.9 ± 1.1) showed a lower galvanic skin response during personal dilemmas compared with subjective cognitive decline(3.4 ± 3.3 peaks per minute, p = 0.01). Concluding, patients with the behavioral variant of Alzheimer's disease showed a similar though milder social cognition profile and a similar eye-tracking signature to patients with the behavioral variant of frontotemporal dementia and greater social cognition impairments and divergent eye-movement patterns compared with patients with typical Alzheimer's disease. Our results suggest reduced attention to salient facial features in these phenotypes, potentially contributing to their emotion recognition deficits.

The behavioral variant of Alzheimer’s disease (bvAD) is characterized by early and predominant behavioral changes, resembling the clinical profile of the behavioral variant of frontotemporal dementia (bvFTD). Social cognition deficits form hallmark features in bvFTD and altered biometric responses to socioemotional cues have been observed in bvFTD. However, little is known about social cognition and its biometric signature in bvAD. In this explorative study, we investigated all levels of social cognition (i.e., level-1: perception, level-2: interpretation and level-3: reasoning), using the Ekman 60 faces test (level-1), Interpersonal Reactivity Index (IRI) and empathy eliciting videos (level-2), the Social Norms Questionnaire (SNQ) and moral dilemmas (level-3), while measuring eyemovements and galvanic skin response (GSR). We compared 12 patients with bvAD with patients with bvFTD (n=14), typical AD (tAD, n=13) and controls (n=15), using ANCOVAs and post hoc testing, adjusting for age and sex. Regardingperception, bvAD (40.1±8.6) showed lower scores on the Ekman test compared to controls (50.1±4.6, p0.05), but bvAD (18.7±9.5%) and bvFTD (19.4±14.3%) spent significantly less dwell time on the mouth when viewing the faces than controls (30.4±10.6%, pempathy, bvAD (11.3±4.6) exhibited lower scores on the IRIPerspective Takingsubscale compared with controls (15±3.4, p=0.02) and similar scores to bvFTD (8.7±5.6, p=0.19) and tAD (13.0±3.2, p=0.43). The GSR to empathy eliciting videos did not differ between groups (all p>0.05). Regardingknowledge of social norms, bvAD (16.0±1.6) and bvFTD (15.2±2.2) showed lower scores on the SNQ than tAD (17.8±2.1, both pmoral reasoning, no differences among the groups were observed in responses to moral dilemmas (all p>0.05), while only bvFTD (0.9±1.1) showed a lower GSR during the personal condition compared with controls (3.2±3.3 peaks per minute, p=0.02). In conclusion, bvAD showed a similar though milder social cognition profile and a similar eyetracking signature compared with bvFTD and greater social cognition impairments and divergent eyemovement patterns compared with tAD. Our results suggest that bvAD and bvFTD show reduced attention to salient features during facial expression perception, potentially contributing to their emotion recognition deficits. These social cognition and biometric measures provide important insights into the basis of behavioral changes in bvAD, and might be valuable for its clinical diagnosis.

INTRODUCTION: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study.METHODS: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses.RESULTS: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains.DISCUSSION: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment.HIGHLIGHTS: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary Information: Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; Additional file 2 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; both files are available online at https://doi.org/10.1186/s13024-021-00499-4 Copyright © The Author(s) 2021. Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD. This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.

BACKGROUND: Populations living in European countries are becoming increasingly diverse. As performance on traditional neuropsychological tests is heavily influenced by culture, language, (level and quality of) education, literacy, and other factors, neuropsychological assessment practices need to be adapted to account for this diversity. METHOD: The European Consortium for Cross-Cultural Neuropsychology (ECCroN) aims to improve assessment of culturally, educationally, and linguistically diverse individuals across Europe by 1) collaborating on the validation and implementation of cross-cultural neuropsychological tests and 2) working on initiatives geared at improving interpreter use and training programs for neuropsychologists. RESULT: The consortium was founded in late 2019 and currently consists of 16 experts based in 9 countries - some of whom work in multinational contexts. The first meetings of the network stressed several points. First, ECCroN aims to develop and/or validate cross-culturally applicable tests, as opposed to race-based norms for existing tests; for example, current projects aim to validate measures of social cognition and language (naming) in patients with migration backgrounds. Second, ECCroN emphasizes the importance of taking into account diversity across the entire spectrum, both in populations traditionally considered to be 'majority' and 'minority' groups, e.g. best practices should be developed for those with little education regardless of native-born or migrant status. Third, ECCroN aims to identify and share suitable instruments to measure factors potentially influencing the assessment, such as bilingualism, acculturation and educational quality. CONCLUSION: Joint efforts should be undertaken to develop, validate, publish, and implement cross-cultural tests across European countries to reduce misdiagnoses in diverse patient populations.

BackgroundThe neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer’s disease (bvAD) remain unclear. A selective loss of Von Economo Neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD.MethodsVENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n=9) and compared to typical AD (tAD, n=6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n=18) and controls (n=13) using ANCOVAs adjusted for age and Bonferroni correceted. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss.ResultsThe number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0±15.3, GABRQ-ir pyramidal: 260.44±87.13) and tAD (VENs: 32.0±18.1,p=1.00, GABRQ-ir pyramidal: 349.83±109.64,p=0.38) and controls (VENs: 33.5±20.3,p=1.00, GABRQ-ir pyramidal: 339.38±95.88,p=0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.39±82.58,p=0.01) and no significant differences in number of VENs (bvFTD: 10.9±13.8,p=0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5.DiscussionVENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.

Background and ObjectivesTo investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of β-amyloid–positive (A+) individuals across the Alzheimer disease (AD) clinical spectrum.MethodsIn this single-center observational study, we included all individuals who visited the Alzheimer Center Amsterdam and had a clinical diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia and were A+. We measured NPS with the Neuropsychiatric Inventory (NPI), examining total scores and the presence of specific NPI domains. Cognition was assessed across 5 cognitive domains and with the Mini-Mental State Examination (MMSE). We examined trajectories including model-based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time points (subsample n = 520, mean 1.8 [SD 0.7] years follow-up).ResultsWe included 1,524 A+ individuals from the Amsterdam Dementia Cohort with A+ SCD (n = 113), A+ MCI (n = 321), or A+ AD dementia (n = 1,090). NPS were prevalent across all clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia; ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia). Cognitive functioning showed a uniform gradual decline; while in contrast, large intraindividual heterogeneity of NPS was observed over time across all AD groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β = −0.18 to −0.11, false discovery rate [FDR]–adjustedp< 0.05), while there were no cross-sectional relationships in SCD and MCI (range β = −0.32 to 0.36, all FDR-adjustedp> 0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (range β = −0.13 to 0.44, all FDR-adjustedp> 0.05).DiscussionNPS and cognitive symptoms are both prevalent across the AD clinical spectrum, but show a different evolution during the course of the disease.

ImportanceThe behavioral variant of Alzheimer’s disease (bvAD) is characterized by early and predominant behavioral deficits caused by AD pathology. This AD phenotype is insufficiently understood and lacks standardized clinical criteria, limiting reliability and reproducibility of diagnosis and scientific reporting.ObjectiveTo perform a systematic review and meta-analysis of the bvAD literature, and use the outcomes to propose provisional research criteria for this syndrome.Data sourcesA systematic literature search in PubMed/Medline and Web-of-Science databases (from inception through April 7th, 2021, performed in duplicate) led to the assessment of 83 studies, including 13 suitable for meta-analysis.Study selectionStudies reporting on behavioral, neuropsychological or neuroimaging features in bvAD, and, when available, providing comparisons with “typical” amnestic-predominant AD (tAD) or behavorial variant frontotemporal dementia (bvFTD).Data extraction and synthesisWe performed random-effects meta-analyses on group-level study results of clinical data, and systematically reviewed the neuroimaging literature.Main outcome and measuresBehavioral symptoms (neuropsychiatric symptoms and bvFTD core clinical criteria), cognitive function (global cognition, episodic memory and executive functioning) and neuroimaging features (structural MRI, [18F]FDG-PET, perfusion SPECT, amyloid-PET and tau-PET).ResultsData were collected for 591 patients with bvAD. There was moderate-to-substantial heterogeneity and moderate risk of bias across studies. bvAD showed more severe behavioral symptoms compared to tAD (standardized mean difference [SMD, 95% confidence interval]: 1.16[0.74–1.59], pConclusions and relevanceOur data indicate that bvAD is clinically most similar to bvFTD, while it shares most pathophysiological features with tAD. Based on these insights, we propose provisional research criteria for bvAD aimed at improving the consistency and reliability of future research and aiding the clinical assessment of this AD phenotype.KEY POINTSQuestionHow does the behavioral variant of Alzheimer’s disease (bvAD) relate to typical AD (tAD) and to behavioral variant frontotemporal dementia (bvFTD) in terms of clinical presentation and neuroimaging signatures?FindingsIn this systematic review and meta-analysis, we found that, at time of diagnosis, bvAD showed more severe neuropsychiatric symptoms and other behavioral deficits compared to tAD. Two distinct neuroimaging phenotypes were observed across reported bvAD cases: an “AD-like” posterior-predominant pattern and a “bvFTD-like” anterior-predominant pattern, with the posterior-predominant neuroimaging phenotype being the most prevalent across reported bvAD cases.MeaningbvAD is clinically most reminiscent of bvFTD, while it shares most pathophysiological features with tAD. The provisional research criteria are aimed at improving the consistency and reliability of future research, and potentially aid in the clinical assessment of bvAD.