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BACKGROUND Modern technologies, including smartphone apps, have the potential to assist people with cognitive impairment with activities of daily living, allowing them to maintain their independence and reduce carer burden. However, such tools have seen a slow rate of uptake in this population, and data on the acceptability of assistive technologies in this population are limited. OBJECTIVE This pilot study included older adults with cognitive impairment and their carers, and explored the perceived needs for and acceptability of an app that was designed to be a simple assistive tool for activities of daily living. In particular, this study aimed to assess the acceptability of common app functions such as communication, reminder, navigation, and emergency tools in this population, and to compare patients’ and carers’ responses to them. METHODS A total of 24 German participants with mild cognitive impairment or dementia and their family carers separately completed two short questionnaires. The first questionnaire asked the participants with cognitive impairment and their carers to self-rate the patients’ cognitive impairment levels and affinity to technology. Following a demonstration of the app, participants rated the usability and acceptability of the app and its functions in a second questionnaire. RESULTS Participants rated themselves as much less cognitively impaired than their carers did (P=.01), and insight into the level of support they received was low. The majority of the participants (19/24, 79%) and their carers (20/24, 83%) had low affinity to technology, and even after the demonstration, 63% (15/24) of the participants had low interest in using the app. A breakdown of acceptability responses by app function revealed that participants were more amenable to the reminder function, the emergency feature, and a wearable form of the app. Features that centered around carers monitoring participants’ movements were reported to be less acceptable to participants. CONCLUSIONS This study highlights the importance of focusing on acceptability and the consumer’s perceptions in the development of assistive technology for older adults with cognitive impairment. Participants showed an aversion to functions they perceived as eroding their independence, while functions that more closely aligned with independence and autonomy were perceived as more acceptable.

Functional MRI (fMRI) studies have reported altered integrity of large-scale neurocognitive networks (NCNs) in dementing disorders. However, findings on the specificity of these alterations in patients with Alzheimer disease (AD) and behavioral-variant frontotemporal dementia (bvFTD) are still limited. Recently, NCNs have been successfully captured using PET with 18F-FDG. Methods: Network integrity was measured in 72 individuals (38 male) with mild AD or bvFTD, and in healthy controls, using a simultaneous resting-state fMRI and 18F-FDG PET. Indices of network integrity were calculated for each subject, network, and imaging modality. Results: In either modality, independent-component analysis revealed 4 major NCNs: anterior default-mode network (DMN), posterior DMN, salience network, and right central executive network (CEN). In fMRI data, the integrity of the posterior DMN was found to be significantly reduced in both patient groups relative to controls. In the AD group the anterior DMN and CEN appeared to be additionally affected. In PET data, only the integrity of the posterior DMN in patients with AD was reduced, whereas 3 remaining networks appeared to be affected only in patients with bvFTD. In a logistic regression analysis, the integrity of the anterior DMN as measured with PET alone accurately differentiated between the patient groups. A correlation between indices of 2 imaging modalities was low overall. Conclusion: FMRI and 18F-FDG PET capture partly different aspects of network integrity. A higher disease specificity for NCNs as derived from PET data supports metabolic connectivity imaging as a promising diagnostic tool.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/., Background: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. Methods: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). Results: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p, This study was funded by a Memorabel grant from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development, and Alzheimer Nederland grant number 7330598105), National Institutes of Health (Grants AG010124, AG032953, AG043503, NS088341, AG017586, AG052943, AG038490), the Wyncote Foundation, Dana Foundation, Brightfocus Foundation, Penn Institute on Aging, Pla estratègic de recerca i innovació en salut 2016-2020, Catalan Department of Health (grant number SLT002/16/00408), Italian Ministry of Health (Ricerca Corrente) and the German Federal Ministry of Education and Research (FTLDc 01GI1007A). MS was supported by the Else Kröner-Fresenius-Stiftung. CW was supported by the Vaillant Stiftung

ATENCIÓ: la correcció està també al DDD, cal relacionar??? https://ddd.uab.cat/record/226203 Altres ajuts: The following studies and consortia have contributed to this manuscript. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe): This study/publication is part of the German Research Network on Dementia (KND), the German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe), and the Health Service Research Initiative (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+; AgeQualiDe)) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, 01GY1322G). Alfredo Ramirez was partly supported by the ADAPTED consortium: Alzheimer's disease Apolipoprotein Pathology for Treatment Elucidation and Development, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. Brain compendium: This work was funded by the UK Medical Research Council (13044). P.F.C. is a Wellcome Trust principal Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.Clinical AD, Sweden: We would like to thank UCL Genomics for performing the genotyping analyses. Danish data: The studies behind the Danish long-lived cases received funding from The National Program for Research Infrastructure 2007 (grant no. 09-063256), the Danish Agency for Science Technology and Innovation, the Velux Foundation, the US National Institute of Health (P01 AG08761), the Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research (grant no. 11-107308), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the CERA Foundation (Lyon), the AXA Research Fund, Paris, and The Health Foundation (Helsefonden), Copenhagen, Denmark. The GOYA study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth Cohort which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Fundació ACE (FACE): We would like to thank patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). Agustín Ruiz has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED Grant No. 115975 and by grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- "Una manera de Hacer Europa"), by Fundación bancaria "La Caixa" and Grifols SA (GR@ACE project). Genetics of Healthy Ageing Study (GEHA - NL): The work described in this paper was funded mainly by the EU GEHA Project contract no. LSHM-CT-2004-503-270. Gothenburg Birth Cohort (GBC) Studies: We would like to thank UCL Genomics for performing the genotyping analyses. The studies were supported by The Stena Foundation, The Swedish Research Council (2015-02830, 2013-8717), The Swedish Research Council for Health, Working Life and Wellfare (2013-1202, 2005-0762, 2008-1210, 2013-2300, 2013-2496, 2013-0475), The Brain Foundation, Sahlgrenska University Hospital (ALF), The Alzheimer's Association (IIRG-03-6168), The Alzheimer's Association Zenith Award (ZEN-01-3151), Eivind och Elsa K:son Sylvans Stiftelse, The Swedish Alzheimer Foundation. International FTD-Genomics Consortium (IFGC): International FTD-Genomics Consortium (IFGC): The authors thank the IFGC for providing relevant data to support the analyses presented in this manuscript. Further acknowledgments for IFGC (https://ifgcsite.wordpress.com/), e.g. full members list and affiliations, are found in the online supplementary files. IPDGC (​The International Parkinson Disease Genomics Consortium): We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgements and funding http://pdgenetics.org/partners. Kompetenznetz Multiple Sklerose (KKNMS): This work was supported by the German Ministry for Education and Research (BMBF) as part of the "German Competence Network Multiple Sclerosis" (KKNMS) (grant nos. 01GI0916 and 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). TA was supported by the BMBF through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J). BH was supported by the EU Horizon 2020 project MultipleMS.Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. Leiden Longevity Study: This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (Grant 050-060-810), all in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and by Unilever Colworth.Maria Carolina Dalmasso: Georg Forster Research Award (Alexander von Humboldt Foundation). Mayo Clinic AD, DLB, PD, PSP: We thank the patients and their families for their participation, without whom these studies would not have been possible. Funding for this work was supported by National Institute on Aging [RF AG051504 to NET.; U01 AG046139 to NET]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET; P50 NS072187]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information and Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to OAR). The PD program at the Mayo Clinic Florida is also supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and The Sol Goldman Charitable Trust. Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP The online version of this article (10.1007/s00401-019-02026-8) contains supplementary material, which is available to authorized users.

Background: We investigated the global and age-specific association between Apolipoprotein E (APOE) genotype and Alzheimer's disease (AD) in a large multicentric case-control study, using cerebrospinal fluid (CSF) biomarkers-based diagnostic criteria for AD. Methods: In this case-control design, data on 1,599 Caucasian AD cases with abnormal values of CSF biomarkers came from 9 European memory clinics and the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. AD cases were compared to 11,724 dementia-free controls, drawn from two longitudinal cohort studies (Whitehall II and 3-City). Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were reported, overall and by 5-year age categories. Findings. 63*4% of CSF biomarker-defined AD patients and 22*6% of population controls carried at least one APOE e4 allele; respective percentages for APOE e4 homozygotes were 16*7% and 1*4%. Compared to none4 carriers, heterozygous e4 carriers had a 4*6 (95% confidence interval: 4*1 - 5*2) and e4/e4 homozygotes a 25*4 (20*5 - 31*3) higher OR of AD. This association was strongly modified by age (p for interaction < 0*001). The PAF associated with carrying at least one e4 allele was greatest in the 65-70 age group (69*7%), and weaker before 55 years (14*2%) and after 85 years (22*6%). There was some evidence of a stronger effect of APOE on AD risk in women. Interpretation: Incorporating biomarkers for diagnosis of AD led to a stronger association with APOE e4 than previously reported, perhaps due to better diagnostic accuracy. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE e4 at the population level. Funding Statement: US National Institutes of Health, Fondation Plan Alzheimer. Declaration of Interests: ASM is supported by NIH/NIA R01AG056477. IZ is supported by the Robert-Koch-Institute through funds of Federal Ministry of Health (grant no. 1369-341) and DZNE (German Center for Neurodegenerative Diseases). KB reports consulting fees from Fujirebio Europe, IBL International, Roche Diagnostics. HZ is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. MB has been a consultant for Araclon, Avid, Bayer, Elan, Grifols, Janssen/Pfizer, Lilly, Neuroptix, Nutricia, Roche, Sanofi, and Servier. All other authors declare no competing interests. Ethics Approval Statement: Ethical clearance was obtained by the institutional review boards of all participating sites (European memory centers and ADNI Study sites) and all participants provided written, informed consent.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n >= 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

The overlapping symptoms of behavioural variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (such as depressive disorder, schizophrenia spectrum, and bipolar disorder) present a challenge for the differential diagnosis of bvFTD in middle and older-aged people. Neurofilaments are cytoskeletal proteins in the neurons, and several studies have reported elevated levels of neurofilament light chain (NfL) in cerebrospinal fluid of neurodegenerative as well as psychiatric disorders. The study aims to determine the utility of serum NfL levels as a biomarker to differentiate between bvFTD and psychiatric disorder. In our study, we investigated the levels of NfL in the serum of schizophrenia (n = 11), depression (n = 28), bipolar (n = 11), bvFTD (n = 20) patients and controls (n = 27) by single molecule array (Simoa) technology. The schizophrenia, depression and bipolar patients did not show significant changes in serum NfL levels in comparison to the control group (p 0.99). The serum NfL levels were significantly elevated in bvFTD patients in comparison to the control cohort (p 0.0001), depression (p 0.0001), schizophrenia (p 0.0002) and bipolar patients (p 0.0083). We propose serum NfL as a biomarker to differentiate bvFTD from psychiatric disorders and to rule out neurodegeneration in the course of psychiatric disorders.

Objective Features of behavioral variant frontotemporal dementia (bvFTD) such as executive dysfunction, apathy, and impaired empathic abilities are also observed in major depressive disorder (MDD). This may contribute to the reason why early stage bvFTD is often misdiagnosed as MDD. New assessment tools are thus needed to improve early diagnosis of bvFTD. Although emotion processing is affected in bvFTD and MDD, growing evidence indicates that the pattern of emotion processing deficits varies between the two disorders. As such, emotion processing paradigms have substantial potentials to distinguish bvFTD from MDD. Design and Participants The current study compared 25 patients with bvFTD, 21 patients with MDD, 21 patients with Alzheimer disease (AD) dementia, and 31 healthy participants on a novel facial emotion intensity rating task. Stimuli comprised morphed faces from the Ekman and Friesen stimulus set containing faces of each sex with two different degrees of emotion intensity for each of the six basic emotions. Measurements and Results Analyses of covariance uncovered a significant dissociation between bvFTD and MDD patients in rating the intensity of negative emotions overall (i.e., bvFTD patients underrated negative emotions overall, whereas MDD patients overrated negative emotions overall compared with healthy participants). In contrast, AD dementia patients rated negative emotions similarly to healthy participants, suggesting no impact of cognitive deficits on rating facial emotions. Conclusions By strongly differentiating bvFTD and MDDpatients through negative facial emotions, this sensitive and short rating task might help improve the early diagnosis of bvFTD.

Presently, visual and quantitative approaches for image-supported diagnosis of dementing disorders rely on regional intensity rather than on connectivity measurements. Here, we test metabolic connectivity for differentiation between Alzheimer’s disease and frontotemporal lobar degeneration. Positron emission tomography with 18F-fluorodeoxyglucose was conducted in 47 patients with mild Alzheimer’s disease, 52 patients with mild frontotemporal lobar degeneration, and 45 healthy elderly subjects. Sparse inverse covariance estimation and selection were used to identify patterns of metabolic, inter-subject covariance on the basis of 60 regional values. Relative to healthy subjects, significantly more pathological within-lobe connections were found in the parietal lobe of patients with Alzheimer’s disease, and in the frontal and temporal lobes of subjects with frontotemporal lobar degeneration. Relative to the frontotemporal lobar degeneration group, more pathological connections between the parietal and temporal lobe were found in the Alzheimer’s disease group. The obtained connectivity patterns differentiated between two patients groups with an overall accuracy of 83%. Linear discriminant analysis and univariate methods provided an accuracy of 74% and 69%, respectively. There are characteristic patterns of abnormal metabolic connectivity in mild Alzheimer’s disease and frontotemporal lobar degeneration. Such patterns can be utilized for single-subject analyses and might be more accurate in the differential diagnosis of dementing disorders than traditional intensity-based analyses.

Objective The aim of the present study was to gain insight into the living and care situation in advanced behavioral variant frontotemporal dementia (bvFTD), to describe symptoms and findings in advanced bvFTD, and to evaluate somatic comorbidities and circumstances of death. Methods Standardized interviews were conducted with family caregivers of 83 patients with bvFTD. Forty-four percent of the patients were already deceased at the time of the interview. Results At the time of the interview or death, respectively, 47% of the patients lived in a nursing home. The median time between symptom onset and nursing home admission was 5.0 ± 5.5 years. In moderate and severe dementia stages almost all patients suffered from severe disabilities including impairment of language, gait, swallowing, and of the ability to care for themselves. Sixteen percent of the patients had got enteral tube feeding. Comorbid somatic diseases were diagnosed in 46% of the patients. Twenty-three percent of the deceased patients had been admitted into a hospital before death. Cardiovascular disease and respiratory disease, mostly pneumonia, were the most frequent causes of death. Conclusions Advanced bvFTD is characterized by severe cognitive impairment and physical disabilities. BvFTD leads to a premature death. Our findings stress the importance of strategies that maximize patient comfort in advanced disease stages and allow for a peaceful death. Copyright © 2016 John Wiley & Sons, Ltd.

The authors apologize for misspelling the last name of the author Ratnavalli Ellajosyula. This has now been corrected.

Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P −3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.

We evaluated the genetic contribution of the T cell-restricted intracellular antigen-1 gene (TIA1) in a European cohort of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Exonic resequencing of TIA1 in 1120 patients (693 FTD, 341 ALS, 86 FTD-ALS) and 1039 controls identified in total 5 rare heterozygous missense variants, affecting the TIA1 low-complexity domain (LCD). Only 1 missense variant, p.Met290Thr, identified in a familial FTD patient with disease onset at 64 years, was absent from controls yet received a combined annotation-dependent depletion score of 11.42. By contrast, 3 of the 4 variants also detected in unaffected controls, p.Val294Glu, p.Gln318Arg, and p.Ala381Thr, had combined annotation-dependent depletion scores greater than 20. Our findings in a large European patient-control series indicate that variants in TIA1 are not a common cause of ALS and FTD. The observation of recurring TIA1 missense variants in unaffected individuals lead us to conclude that the exact genetic contribution of TIA1 to ALS and FTD pathogenesis remains to be further elucidated. ispartof: NEUROBIOLOGY OF AGING vol:69 ispartof: location:United States status: published

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.

Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

Objective Methods To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-beta pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) epsilon 4 status was determined using generalized estimating equation models. Results Interpretation Amyloid-beta positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p

TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13-1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts. ispartof: Neurobiology of Aging vol:62 pages:245- ispartof: location:United States status: published

Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency

Den meisten psychischen Erkrankungen des Erwachsenenalters liegt eine multifaktorielle Verursachung zugrunde. Dies trifft auch fur die Demenzerkrankungen zu, wobei es jedoch seltene Erkrankungen bzw. familiare Unterformen haufiger Demenzerkrankungen gibt, die einem monogenen (mendelischen) Erbgang folgen. Die durch Mutationen in den Genen Prasenilin 1, Prasenilin 2 und Amyloid-Precursor-Protein verursachte Alzheimer-Demenz betrifft in erster Linie Patienten mit Krankheitsbeginn im jungeren Lebensalter. Bei den frontotemporalen Lobardegenerationen liegt eine autosomal-dominante Vererbung in rund 10 % der Falle vor. Die genetische Beratung bei Demenzerkrankungen, die nach den aktuellen S3-Leitlinien der S3-Leitlinien Demenz der Deutschen Gesellschaft fur Psychiatrie, Psychotherapie und Nervenheilkunde und der Deutschen Gesellschaft fur Neurologie bei Verdacht auf das Vorliegen einer monogen vererbten Demenzerkrankung angeboten werden sollte, muss den Vorgaben des Gendiagnostikgesetzes folgen.

Definitionsgemas beginnen Demenzen im jungeren Lebensalter vor dem 65. Lebensjahr. Allerdings ausert sich die Alzheimer-Demenz bei einem Drittel der jungeren Patienten atypisch. Um potenziell reversible Ursachen des demenziellen Syndroms nicht zu ubersehen, sollte eine besonders sorgfaltige Diagnostik erfolgen.

Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795GA(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125GA (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.

Dementia impairs the ability to perform everyday activities. Reduced motor capacity and executive functions as well as loss of memory function and forms of apraxia and action disorganization syndrome can be reasons for such impairments. In this study, an analysis of the hand trajectories during the sequential movements in an adapted version of the trail making task, the reciprocal trail making task (RTMT), was used to predict performance in activities of daily living (ADL) of patients suffering from mild cognitive impairment and dementia. 1 patient with dementia of the Alzheimer’s type and 15 healthy, age-matched adults were tested in the standardized ADL of tea making and document filing. The characteristics of the kinematic performance in the RTMT were assessed, and models of multiple linear regression were computed to predict the durations of the ADL. Patients showed increased trial durations (TDs) in the ADL (Cohen’s d: tea making 1.64, document filing 1.25). Parameters and explained variability differed across patients and control as well as between different activities. The models for the patient sample were stronger and particularly high for the document filing task for which kinematics explained 71% of the variance (Radjusted2: tea making 0.62, document filing 0.71; both tasks combined patients 0.55, controls 0.25). The most relevant factors for the models were the TD and a parameter characterizing movement fluency and variability (“movement harmonicity”) in the RTMT. The models of multiple linear regression suggested that the patients’ activity of daily living performance was limited by cognitive demands, namely, identifying the varying targets during sequencing and the healthy controls’ performance by their motor capacity. Such models could be used to estimate the severity of ADL impairments in patients.

Neurovascular coupling can be directly assessed by retinal vessel response to flickering light using optical imaging methods. The response is altered in a number of ocular and cardiovascular diseases. Whether it is altered in Alzheimer’s disease (AD) is investigated. Retinal vessel reaction to monochromatic flicker stimulation was examined by Dynamic Vessel Analyzer independent of the commercial software in elderly subjects: 15 patients with mild-to-moderate dementia due to AD (ADD); 24 patients with mild cognitive impairment due to AD (MCI); 15 cognitively healthy controls (HC). Retinal vessels in ADD showed a more emphasized and delayed reactive dilation as compared to HC. In MCI, these aspects still differed from those seen in ADD. Maximal arterial reaction was increased and dilation was delayed in ADD as compared to HC (p = 0.004 and p

Background:Evidence-based data on prevalence and risk factors of suicidal intentions and behavior in dementia are as scarce as the data on assisted dying. The present literature review aimed on summarizing the current knowledge and provides a critical discussion of the results.Methods:A systematic narrative literature review was performed using Medline, Cochrane Library, EMBASE, PSYNDEX, PSYCINFO, Sowiport, and Social Sciences Citation Index literature.Results:Dementia as a whole does not appear to be a risk factor for suicide completion. Nonetheless some subgroups of patients with dementia apparently have an increased risk for suicidal behavior, such as patients with psychiatric comorbidities (particularly depression) and of younger age. Furthermore, a recent diagnosis of dementia, semantic dementia, and previous suicide attempts most probably elevate the risk for suicidal intentions and behavior. The impact of other potential risk factors, such as patient's cognitive impairment profile, behavioral disturbances, social isolation, or a biomarker based presymptomatic diagnosis has not yet been investigated. Assisted dying in dementia is rare but numbers seem to increase in regions where it is legally permitted.Conclusion:Most studies that had investigated the prevalence and risk factors for suicide in dementia had significant methodological limitations. Large prospective studies need to be conducted in order to evaluate risk factors for suicide and assisted suicide in patients with dementia and persons with very early or presymptomatic diagnoses of dementia. In clinical practice, known risk factors for suicide should be assessed in a standardized way so that appropriate action can be taken when necessary.

Objective:To assess the utility of serum neurofilament for diagnosis and monitoring of primary progressive aphasia (PPA) variants.Methods:We investigated neurofilament light chain (NF-L) levels in blood of 99 patients with PPA (40 with nonfluent variant PPA [nfvPPA], 38 with semantic variant PPA [svPPA], 21 with logopenic variant PPA [lvPPA]) and compared diagnostic performance with that reached by CSF NF-L, phosphorylated neurofilament heavy chain (pNF-H), β-amyloid (Aβ1-42), tau, and phosphorylated tau. The longitudinal change of blood NF-L levels was measured and analyzed for correlation with functional decline and brain atrophy.Results:Serum NF-L is increased in PPA compared to controls and discriminates between nfvPPA/svPPA and lvPPA with 81% sensitivity and 67% specificity (cutoff 31 pg/mL). CSF NF-L, pNF-H, tau, phosphorylated tau, and Aβ1-42 achieved similar performance, and pNF-H was the only marker for discrimination of nfvPPA from svPPA/lvPPA. In most patients with nfvPPA and svPPA, but not lvPPA, serum NF-L increased within follow-up. The increase correlated with functional decline and progression of atrophy of the left frontal lobe of all patients with PPAs and the right middle frontal gyrus of patients with nfvPPA and svPPA.Conclusions:Blood level of NF-L can aid the differential diagnosis of PPA variants, especially in combination with CSF pNF-H. Because serum NF-L correlates with functional decline and atrophy in the disease course, it qualifies as an objective disease status marker. Extended follow-up studies with cases of known neuropathology are imperative.Classification of evidence:This study provides Class I evidence that in patients with PPA, blood levels of NF-L can distinguish the logopenic variant from the nonfluent/agrammatic and semantic variants.

Altres ajuts: The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The research was funded in part by the European Commission Seventh Framework Programme for research, technological development, and demonstration under grant agreement 305299 (AgedBrainSYSBIO), the Belgian Science Policy Office Interuniversity Attraction Poles program, the Alzheimer Research Foundation (SAO-FRA), the Flemish government-initiated Flanders Impulse Program on Networks for Dementia Research (VIND), the Flemish government-initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO), the VIB Technology Fund, the University of Antwerp Research Fund, Belgium; European Regional Development Fund, the Italian Ministry of Health (Ricerca Corrente and RF-2010-2319722), and the Fondazione Cassa di Risparmio di Pistoia e Pescia grant (2014.0365). Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.

Background: Primary progressive aphasia (PPA) is a rare disorder. Data on health care utilisation and care-relevant symptoms are scarce.Aims: The study aimed at finding out how patients with PPA are cared for, the extent of professional support utilised by family caregivers, and which care-relevant clinical symptoms and signs occur with advanced disease.Method & Procedures: Forty-three family caregivers of patients with PPA were interviewed with a standardised questionnaire.Outcomes & Results: A majority of caregivers cared for the patients at home without any support. More than 40% of the patients were treated with cholinesterase inhibitors or memantine. Only 9% of the patients received speech therapy. In advanced PPA, the majority of patients were unable to communicate and almost all needed 24-hr care. Other neurological symptoms appeared, and a considerable number of patients suffered from moderate or severe somatic illnesses.Conclusion: Future studies are necessary to investigate the reasons why the P...

Hereditary diffuse leukencephalopathy with spheroids (HDLS) is a rare progressive form of leukodystrophy with variable clinical presentation and little known pathophysiology. Characteristic pathological features at brain biopsy or postmortem can support the diagnosis. The genetic basis of HDLS was elusive until 2011 when mutations in the colony-stimulating factor 1 receptor (CSF1R) gene were identified as the cause. Mutations in the CSF1R gene had previously been associated with tumor development, including hematological malignancies. We report three patients with HDLS who carried missense mutations in the CSF1R gene, two of them novel (p.L582P and p.V383L). Particularly in younger patients with rapid cognitive decline and/or leukencephalopathy of unknown origin, HDLS appears to be more common than previously thought. Various compounds acting on the CSF1 receptor are available from the treatment of hemato-oncological malignancies, so novel therapeutic approaches could be developed for this devastating condition.

OBJECTIVE: Our aim was to compare the frequency of criminal conduct in patients with behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and Alzheimer disease. BACKGROUND: A few small-scale studies of antisocial and criminal behavior in patients with frontotemporal lobar degeneration have focused on the clinical subtype bvFTD. It is not yet known whether antisocial behavior affects patients with other clinical subtypes of frontotemporal lobar degeneration, like SD, and patients with other dementing disorders, like Alzheimer disease. METHODS: We used a standardized caregiver interview to assess criminal behavior in 83 outpatients: 32 with bvFTD, 18 with SD, and 33 with Alzheimer disease. RESULTS: We found criminal behavior (theft, willful damage to property, housebreaking, assault, or indecent behavior) in 54% of the patients with bvFTD and 56% of those with SD, but only 12% of those with Alzheimer disease. CONCLUSIONS: Just over half of our patients with bvFTD or SD had committed crimes. When middle-aged or older patients commit minor crimes, frontotemporal lobar degeneration should be considered as a possible cause. If an affected person faces criminal charges, the court might take incapability or diminished responsibility into account in reaching a verdict. Language: en

Frontotemporal dementia, a heterogeneous neurodegenerative disorder, is a common cause of young-onset dementia (i.e., dementia developing in midlife or earlier). The estimated point prevalence is 15–22/100,000, and incidence 2.7–4.1/100,000. Some 25% are late-life onset cases. Population studies show nearly equal distribution by gender, which contrasts with myriad clinical and neuropathology reports. FTD is frequently familial and hereditary; five genetic loci for causal mutations have been identified, all showing 100% penetrance. Non-genetic risk factors for are yet to be identified. FTD shows poor life expectancy but with survival comparable to that of Alzheimer disease. Recent progress includes the formulation of up-to-date diagnostic criteria for the behavioral and language variants, and the development of new and urgently needed instruments for monitoring and staging the illness. There is still need for descriptive populations studies, to fill gaps in our knowledge about minority groups and developing regions. More pressing, however, is the need for reliable physiologic markers for disease. There is a present imperative to develop a translational science to form the conduit for transferring neurobiological discoveries and insights from bench to bedside.

© 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.

Impairment of central auditory processing is a well-known symptom of neurodegenerative dementia; however, whilst numerous studies have examined verbal processing impairment, to date few have attempted to describe impairments of non-verbal, environmental sound recognition in patients with dementia. As these impairments may have direct implications on patient support and care, such studies are urgently necessary.The aim of the study was to determine whether the recognition of meaningful environmental sounds is impaired in patients with mild or early stage neurodegenerative dementia.We developed a test of non-verbal sound recognition consisting of 16 sound sequences from the familiar and unfamiliar environments. We included 18 patients with mild cognitive impairment and mild dementia caused by Alzheimer's disease and frontotemporal dementia, as well as 20 cognitively healthy controls.Patients and controls were given the test of recognizing 16 meaningful sounds from the familiar and unfamiliar environments. Patients with dementia performed significantly worse in comparison to cognitively healthy controls. Whilst healthy controls correctly recognized on average 12.1 ± 2.2 out of 16 sounds, cognitively impaired patients recognized 9.2 ± 2.5. Correlation analysis showed that the mini mental state examination (MMSE) scores were positively correlated with the number of correctly recognized sounds (MMSE: r = 0.556, p = 0.017).The fact that even in mild stages of Alzheimer's disease or frontotemporal dementia patients either do not recognize or misinterpret environmental sounds must be taken into consideration not only in everyday life but in particular when patients need to leave their familiar living environment, whether temporarily (e. g. hospitalization) or permanently (e. g. nursing home admission).

Copyright © International Psychogeriatric Association 2016, Background: Young Onset Dementia (YOD), defined by first symptoms of cognitive or behavioral decline occurring before the age of 65 years, is relatively rare compared to dementia of later onset, but it is associated with diagnostic difficulty and heavy burden on affected individuals and their informal carers. Existing health and social care structures rarely meet the needs of YOD patients. Internet-based interventions are a novel format of delivering health-related education, counseling, and support to this vulnerable yet underserved group. Methods: The RHAPSODY (Research to Assess Policies and Strategies for Dementia in the Young) project is a European initiative to improve care for people with YOD by providing an internet-based information and skill-building program for family carers. The e-learning program focuses on managing problem behaviors, dealing with role change, obtaining support, and looking after oneself. It will be evaluated in a pilot study in three countries using a randomized unblinded design with a wait-list control group. Participants will be informal carers of people with dementia in Alzheimer's disease or behavioral-variant Frontotemporal degeneration with an onset before the age of 65 years. The primary outcome will be caregiving self-efficacy after 6 weeks of program use. As secondary outcomes, caregivers' stress and burden, carer health-related quality of life, caring-related knowledge, patient problem behaviors, and user satisfaction will be assessed. Program utilization will be monitored and a health-economic evaluation will also be performed. Conclusions: The RHAPSODY project will add to the evidence on the potential and limitations of a conveniently accessible, user-friendly, and comprehensive internet-based intervention as an alternative for traditional forms of counseling and support in healthcare, aiming to optimize care and support for people with YOD and their informal caregivers.

Background:Frontotemporal lobar degeneration (FTLD) is a relatively rare disease compared to Alzheimer' disease (AD), but nevertheless causes higher burden and stress to caregivers. Only little is known about the problems and needs of the caregivers of patients with FTLD. Such information is crucial for the development of caregiver support interventions. The aim of the current study is to systematically review publications on (1) burden, problems, and needs of FTLD caregivers, and (2) the feasibility and efficacy of caregiver interventions in FTLD.Methods:A systematic review was conducted. Medical, psychological, and social sciences databases were searched for publications on burden, problems, needs of FTLD caregivers, and support interventions.Results:Very little published data are available on burden, problems, and needs of FTLD caregivers. Burden among FTLD caregivers is higher than among AD caregivers and correlated with neuropsychiatric symptoms. Specific problems include delayed diagnosis, young age of patients, behavioral disturbances, lack of information and suitable care facilities, caregivers' depression, social isolation, and neglect of personal needs. Hardly any literature is available on the actual needs of FTLD caregivers. Regarding interventions for caregivers, no randomized controlled trials exist. Eight publications could be identified that provide narrative reports on structured caregiver support groups or respite care in combination with caregiver support intervention or advanced practice nursing.Conclusion:More research and funding are needed to elucidate the complex construct of burden of FTLD caregivers to identify and quantify their problems and needs in order to develop helpful interventions and services.

The aim of this study was to find out how patients with frontotemporal lobar degeneration are cared for, to which extent family caregivers utilize professional support, and which medical treatment patients receive. Using a standardized interview, information was obtained from the caregivers of 124 patients with frontotemporal lobar degeneration on patient survival, sociodemographic characteristics, living arrangements, health care situation including formal and informal support, and pharmacological and nonpharmacological treatment. At the time of the interview, 72 patients were still alive, whereas 52 patients had already died before the interview. Fifty-seven percent of the patients lived at home. At the time of the interview/before death, respectively, 43% of the patients had been institutionalized into a nursing home on average 6.4 years after the onset of first symptoms. The mortality risk for patients who were admitted to a nursing home was 5 times higher than for those who were cared for at home. Fifty-one percent of the patients were treated with antidepressants, 23% with antipsychotics, and 34% with cholinesterase inhibitors or memantine. Forty percent of the patients received nonpharmacological treatment.

This work describes the characteristics of diagnosis, therapy and management of patients with presenile, early onset Alzheimer's disease on the basis of two case reports. The current state of knowledge regarding aetiological, pathophysiological and clinical characteristics is presented. The diagnostic procedures and differential diagnostic considerations are illustrated. The importance of the disclosure of the diagnosis is highlighted. Options for non-cognitive treatment, counselling and support are described.

The author listing has been updated to indicate that Timo Grimmer and Kuangyu Shi are equally contributing authors.

Die fortschreitende Hirnschadigung bei neurodegenerativen Erkrankungen wie der Alzheimer-Krankheit ist ohne Zweifel die Hauptursache der klinischen Demenzsymptome. Der Zusammenhang zwischen Hirnschadigung und Symptomatik ist jedoch nicht linear. Bestimmte interindividuelle Unterschiede wie eine gute Schulbildung oder ein groses Hirnvolumen bedingen eine hohere Widerstandsfahigkeit gegen die Hirnpathologie. Dieses Phanomen wird als kognitive Reservekapazitat (KR) bezeichnet. Menschen mit hoher KR haben ein geringeres Demenzrisiko, wobei sowohl passive als auch aktive Reservekonzepte diskutiert werden. Bei der passiven KR geht man von hirnstrukturellen Besonderheiten wie einer hoheren Neuronen- oder Synapsenzahl aus, die einen groseren Puffer gegen Verluste darstellen. Erst wenn eine bestimmte Verlustgrenze durch eine fortschreitende Hirnschadigung uberschritten wird, treten Symptome auf. Neben dem passiven Konzept werden auch aktive Mechanismen diskutiert, die unabhangig von rein strukturellen Unterschieden zur langeren Aufrechterhaltung der kognitiven Leistungsfahigkeit beitragen. Bei kognitiv gesunden Menschen fuhren diese Mechanismen zur Adaption der Hirnaktivitat bei Steigerung des Schwierigkeitsgrades einer Aufgabe; bei fortschreitender Neurodegeneration kompensieren diese Mechanismen die Schadigung. Menschen mit hoher KR zeigen dabei eine effizientere Aktivierung bei derselben Aufgabe und konnen dadurch das normale kognitive Leistungsniveau langer aufrecht erhalten.

Background: Only a small number of studies on the natural disease course in behavioral variant frontotemporal dementia (bvFTD) have been conducted. This is surprising because knowledge about the progression of symptoms is a precondition for the design of clinical drug trials.Methods: The aim of the present study was to examine the cognitive decline of 20 patients with mild bvFTD over one year using the Consortium to Establish a Registry for Alzheimer's Disease – Neuropsychological Assessment Battery (CERAD-NAB).Results: Within an average follow-up interval of 13 months, patient scores declined significantly in the Mini-mental-State-Examination (MMSE) and the CERAD-NAB subtests of naming, verbal and nonverbal memory. No significant changes were found in the CERAD-NAB subtests of category fluency, recognition, and visuoconstruction. The average annualized decline on the MMSE was 4.0 ± 4.9 points. Ceiling effects were detected in Figures Copy, Word List Recognition and Modified Boston Naming Test. Though the included patient group was rather homogeneous regarding severity of dementia, the cognitive changes were very heterogeneous.Conclusion: Given the heterogeneity of cognitive decline, the design of a test battery for clinical trials in FTD will be challenging. A cognitive battery should definitely include the MMSE, Word List Learning and Word List Delayed Recall.

In folgender Studie werden die bei Patienten mit Alzheimer-Demenz (AD) und Demenz bei frontotemporaler Lobardegeneration (FTLD) auftretenden Veranderungen im Fahrverhalten untersucht. Mittels standardisierter Interviews wurden 56 Angehorige von Patienten mit AD (n=26) und FTLD (n=30) zu potenziellen Veranderungen im Fahrverhalten befragt. Veranderungen in ihrem Fahrverhalten hatten 90% der Patienten mit FTLD und 58% der Patienten mit AD gezeigt. Bei den Patienten mit AD fielen in erster Linie zunehmende Schwierigkeiten auf, sich zu orientieren. Die Patienten mit FTLD zeigten hingegen einen aggressiven, risikofreudigen Fahrstil mit auffallig haufigen Ubertretungen der Verkehrsregeln. Signifikante Unterschiede zwischen den beiden Gruppen ergaben sich bezuglich Geschwindigkeitsubertretungen, Missachtung roter Ampeln, inadaquater Verhaltensweisen und Fahren trotz Verbot durch die Familie. 37% der Patienten mit FTLD hatten seit Beginn der Erkrankung einen Unfall verschuldet, verglichen mit 19% der Patienten mit AD (p=0,24). Wahrend die meisten der Patienten mit AD sich einsichtig hinsichtlich ihres veranderten Fahrverhaltens zeigten, sah der Grosteil der Patienten mit FTLD nicht ein, das Autofahren aufzugeben (p=0,023). Patienten mit FTLD sollten fruhestmoglich im Krankheitsverlauf das Autofahren einstellen. Bei Patienten mit leichtgradiger AD muss individuell abgewogen werden.