Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics

Objective: To identify novel CSF biomarkers in GRN-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). Methods: Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high-resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers. Results: Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptortype tyrosine-protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin-A (CHGA), and V-set and transmembrane domain-containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers. Interpretation: We identified and validated five novel CSF biomarkers in GRN-associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers

Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study

Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-secti

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of l

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10 -10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10 -7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD

Occupational therapy at home for older individuals with mild to moderate cognitive impairments and their primary caregivers: A pilot study

The objective of this pilot study was to explore the effects of occupational therapy on the performance of daily activities by older individuals with cognitive impairments and on the sense of competence of their primary caregivers. The design was a single group design. Older individuals with cognitive impairments and their primary caregivers were assessed prior to the first occupational therapy visit in hospital and after 5 weeks of occupational therapy at home. Participants were older individuals with mild to moderate cognitive impairments living at home (n = 12) and their primary caregivers (n = 12). These older clients with cognitive impairments and their primary caregivers received an occupational therapy intervention in hospital and at home after discharge in accordance with an occupational therapy guideline. This guideline is client-centered and makes use of collaborative, psychosocial, and environmental approaches. The main outcome measures were older clients' motor and process skills, initiative, need for assistance, self-perception in occupational performance, and satisfaction with this performance in daily activities and primary caregivers' sense of competence. The results of this study indicated that older clients' motor and process skills and self-perception in occupational performance improved and that they needed less help. The sense of competence of their primary caregivers also improved. This study provides preliminary evidence for the effectiveness of occupational therapy in older individuals with cognitive impairments and their primary caregivers, which should be tested in a randomized, controlled trial

Effects of community occupational therapy on quality of life, mood, and health status in dementia patients and their caregivers: A randomized controlled trial

Background. Cure of dementia is not possible, but quality of life of patients and caregivers can be improved. Our aim is to investigate effects of community occupational therapy on dementia patients' and caregivers' quality of life, mood, and health status and caregivers' sense of control over life. Methods. Community-dwelling patients aged 65 years or older, with mild-to-moderate dementia, and their informal caregivers (n = 135 couples of patients with their caregivers) were randomly assigned to 10 sessions of occupational therapy over 5 weeks or no intervention. Cognitive and behavioral interventions were used to train patients in the use of aids to compensate for cognitive decline and caregivers in coping behaviors and supervision. Outcomes, measured at baseline, 6 weeks, and 12 weeks, were patients' and caregivers' quality of life (Dementia Quality of Life Instrument, Dqol), patients' mood (Cornell Scale for Depression, CSD), caregivers' mood (Center for Epidemiologic Studies Depression Scale, CES-D), patients' and caregivers' health status (General Health Questionnaire, GHQ-12), and caregivers' sense of control over life (Mastery Scale). Results. Improvement on patients' Dqol overall (0.8; 95% confidence interval [CI], 0.6-.1, effect size 1.3) and caregivers' Dqol overall (0.7; 95% CI, 0.5-.9, effect size 1.2) was significantly better in the intervention group as compared to controls. Scores on other outcome measures also improved significantly. This improvement was still significant at 12 weeks. Conclusion. Community occupational therapy should be advocated both for dementia patients and their caregivers, because it improves their mood, quality of life, and health status and caregivers' sense of control over life. Effects were still present at follow-up

How can occupational therapy improve the daily performance and communication of an older patient with dementia and his primary caregiver?:A case study

Objective: To enhance insight into the process of occupational therapy (OT) and the changes after OT, in an older patient with mild dementia and his primary caregiver. Design and setting: Case study: content analysis of an OT patient record. Intervention: System-based OT at home using a guideline focusing on both patient's performance in daily activities and caregiver's cognition on patient behaviour and caregiver role and focusing on adaptation of the physical environment. Measures: Triangulation of results of qualitative content analysis and quantitative description using the following measures: Brief Cognitive Rating Scale (BCRS), Assessment of Motor and Process Skills (AMPS), Interview of Deterioration in Daily Activities in Dementia (IDDD), Canadian Occupational Performance Measurement (COPM), Dementia Quality of Life Instrument (DQOL), Sense of Competence Scale (SCQ) and the Mastery Scale. Results: The global categories derived from content analysis were: daily performance and communication. The specific categories were the patient with dementia, his or her caregiver and the occupational therapist. Important themes derived from content analysis were: patient's capacity for pleasure, autonomy and appreciation in performing daily activities and caregiver's competence. Patient's changes reported after OT: more initiative, autonomy and pleasure in performing daily activities, increase of quality of life; caregiver's changes reported after OT: improved communication and supervision skills, changed cognition on patient behaviour and caregiver role, improved sense of competence. The quantitative results showed an improved daily performance (e.g. initiative, motor and process skills, need for assistance) and quality of life of the patient and improved sense of competence, quality of life and mastery of the situation of the caregiver after OT intervention. Thus the results of the qualitative content analysis were supported by the quantitative results. Additionally, based on the results of the content analysis an exploratory and system-based model has been developed connecting OT diagnosis and OT treatment at home for patients with dementia and their primary caregivers. Conclusion: This case study provides information on how occupational therapy can improve the daily performance, communication, sense of competence and quality of life of an older patient with dementia and his or her primary caregiver. A combination of education, setting feasible goals, using adaptations in physical environment, training compensatory skills, training supervision skills, and changing dysfunctional cognitions on patient behaviour and caregiver role seemed to be successful. A randomized controlled trial must provide information on the effects of OT at home for older patients with dementia and their primary caregivers