Protein disulfide isomerases as CSF biomarkers for the neuronal response to tau pathology

Introduction: Cerebrospinal fluid (CSF) biomarkers for specific cellular disease processes are lacking for tauopathies. In this translational study we aimed to identify CSF biomarkers reflecting early tau pathology-associated unfolded protein response (UPR) activation. Methods: We employed mass spectrometry proteomics and targeted immunoanalysis in a combination of biomarker discovery in primary mouse neurons in vitro and validation in patient CSF from two independent large multicentre cohorts (EMIF-AD MBD, n = 310; PRIDE, n = 771). Results: First, we identify members of the protein disulfide isomerase (PDI) family in the neuronal UPR-activated secretome and validate secretion upon tau aggregation in vitro. Next, we demonstrate that PDIA1 and PDIA3 levels correlate with total- and phosphorylated-tau levels in CSF. PDIA1 levels are increased in CSF from AD patients compared to controls and patients with tau-unrelated frontotemporal and Lewy body dementia (LBD). Highlights: Neuronal unfolded protein response (UPR) activation induces the secretion of protein disulfide isomerases (PDIs) in vitro. PDIA1 is secreted upon tau aggregation in neurons in vitro. PDIA1 and PDIA3 levels correlate with total and phosphorylated tau levels in CSF. PDIA1 levels are increased in CSF from Alzheimer's disease (AD) patients compared to controls. PDIA1 levels are not increased in CSF from tau-unrelated frontotemporal dementia (FTD) and Lewy body dementia (LBD) patients

Foot pain and foot health in an educated population of adults: results from the Glasgow Caledonian University Alumni Foot Health Survey

Abstract Background Foot pain is common amongst the general population and impacts negatively on physical function and quality of life. Associations between personal health characteristics, lifestyle/behaviour factors and foot pain have been studied; however, the role of wider determinants of health on foot pain have received relatively little attention. Objectives of this study are i) to describe foot pain and foot health characteristics in an educated population of adults; ii) to explore associations between moderate-to-severe foot pain and a variety of factors including gender, age, medical conditions/co-morbidity/multi-morbidity, key indicators of general health, foot pathologies, and social determinants of health; and iii) to evaluate associations between moderate-to-severe foot pain and foot function, foot health and health-related quality-of-life. Methods Between February and March 2018, Glasgow Caledonian University Alumni with a working email address were invited to participate in the cross-sectional electronic survey (anonymously) by email via the Glasgow Caledonian University Alumni Office. The survey was constructed using the REDCap secure web online survey application and sought information on presence/absence of moderate-to-severe foot pain, patient characteristics (age, body mass index, socioeconomic status, occupation class, comorbidities, and foot pathologies). Prevalence data were expressed as absolute frequencies and percentages. Multivariate logistic and linear regressions were undertaken to identify associations 1) between independent variables and moderate-to-severe foot pain, and 2) between moderate-to-severe foot pain and foot function, foot health and health-related quality of life. Results Of 50,228 invitations distributed, there were 7707 unique views and 593 valid completions (median age [inter-quartile range] 42 [31–52], 67.3% female) of the survey (7.7% response rate). The sample was comprised predominantly of white Scottish/British (89.4%) working age adults (95%), the majority of whom were overweight or obese (57.9%), and in either full-time or part-time employment (82.5%) as professionals (72.5%). Over two-thirds (68.5%) of the sample were classified in the highest 6 deciles (most affluent) of social deprivation. Moderate-to-severe foot pain affected 236/593 respondents (39.8%). High body mass index, presence of bunions, back pain, rheumatoid arthritis, hip pain and lower occupation class were included in the final multivariate model and all were significantly and independently associated with moderate-to-severe foot pain (p < 0.05), except for rheumatoid arthritis (p = 0.057). Moderate-to-severe foot pain was significantly and independently associated lower foot function, foot health and health-related quality of life scores following adjustment for age, gender and body mass index (p < 0.05). Conclusions Moderate-to-severe foot pain was highly prevalent in a university-educated population and was independently associated with female gender, high body mass index, bunions, back pain, hip pain and lower occupational class. Presence of moderate-to-severe foot pain was associated with worse scores for foot function, foot health and health-related quality-of-life. Education attainment does not appear to be protective against moderate-to-severe foot pain

Limited Value of Staging Squamous Cell Carcinoma of the Anal Margin and Canal Using the Sentinel Lymph Node Procedure: A Prospective Study with Long-Term Follow-Up

Background. Selection of patients with anal cancer for groin irradiation is based on tumor size, palpation, ultrasound, and fine needle cytology. Current staging of anal cancer may result in undertreatment in small tumors and overtreatment of large tumors. This study reports the feasibility of the sentinel lymph node biopsy (SLNB) in patients with anal cancer and whether this improves the selection for inguinal radiotherapy. Methods. A total of 50 patients with squamous anal cancer were evaluated prospectively. Patients without a SLNB (n = 29) received irradiation of the inguinal lymph nodes based on lymph node status, tumor size, and location of the primary tumor. Inguinal irradiation treatment in patients with a SLNB was based on the presence of metastases in the SLN. Results. SLNs were found in all 21 patients who underwent a SLNB. There were 5 patients (24%) who had complications after SLNB and 7 patients (33%) who had a positive SLN and received inguinal irradiation. However, 2 patients with a tumor-free SLN and no inguinal irradiation developed lymph node metastases after 12 and 24 months, respectively. Conclusions. We conclude that SLNB in anal cancer is technically feasible. SLNB can identify those patients who would benefit from refrain of inguinal irradiation treatment and thereby reducing the incidence of unnecessary inguinal radiotherapy. However, because of the occurrence of inguinal lymph node metastases after a tumor-negative SLNB, introduction of this procedure as standard of care in all patients with anal carcinoma should be done with caution to avoid undertreatment of patient who otherwise would benefit from inguinal radiotherapy

Neighbourhood Socioeconomics Status Predicts Non-Cardiovascular Mortality in Cardiac Patients with Access to Universal Health Care

BACKGROUND: Although the Canadian health care system provides essential services to all residents, evidence suggests that socioeconomic gradients in disease outcomes still persist. The main objective of our study was to investigate whether mortality, from cardiovascular disease or other causes, varies by neighbourhood socioeconomic gradients in patients accessing the healthcare system for cardiovascular disease management. METHODS AND FINDINGS: A cohort of 485 patients with angiographic evidence of coronary artery disease (CAD) and neighbourhood socioeconomic status information was followed for 13.3 years. Survival analyses were completed with adjustment for potentially confounding risk factors. There were 64 cases of cardiovascular mortality and 66 deaths from non-cardiovascular chronic diseases. No socioeconomic differentials in cardiovascular mortality were observed. However, lower neighbourhood employment, education, and median family income did predict an increased risk of mortality from non-cardiovascular chronic diseases. For each quintile decrease in neighbourhood socioeconomic status, non-cardiovascular mortality risk rose by 21-30%. Covariate-adjusted hazard ratios (95% confidence interval) for non-cardiovascular mortality were 1.21 (1.02-1.42), 1.21 (1.01-1.46), and 1.30 (1.06-1.60), for each quintile decrease in neighbourhood education, employment, and income, respectively. These patterns were primarily attributable to mortality from cancer. Estimated risks for mortality from cancer rose by 42% and 62% for each one quintile decrease in neighbourhood median income and employment rate, respectively. Although only baseline clinical information was collected and patient-level socioeconomic data were not available, our results suggest that environmental socioeconomic factors have a significant impact on CAD patient survival. CONCLUSIONS: Despite public health care access, CAD patients who reside in lower-socioeconomic neighbourhoods show increased vulnerability to non-cardiovascular chronic disease mortality, particularly in the domain of cancer. These findings prompt further research exploring mechanisms of neighbourhood effects on health, and ways they may be ameliorated

Team players against headache: multidisciplinary treatment of primary headaches and medication overuse headache

Multidisciplinary approaches are gaining acceptance in headache treatment. However, there is a lack of scientific data about the efficacy of various strategies and their combinations offered by physiotherapists, physicians, psychologists and headache nurses. Therefore, an international platform for more intense collaboration between these professions and between headache centers is needed. Our aims were to establish closer collaboration and an interchange of knowledge between headache care providers and different disciplines. A scientific session focusing on multidisciplinary headache management was organised at The European Headache and Migraine Trust International Congress (EHMTIC) 2010 in Nice. A summary of the contributions and the discussion is presented. It was concluded that effective multidisciplinary headache treatment can reduce headache frequency and burden of disease, as well as the risk for medication overuse headache. The significant value of physiotherapy, education in headache schools, and implementation of strategies of cognitive behavioural therapy was highlighted and the way paved for future studies and international collaboration

A comprehensive screening of copy number variability in dementia with Lewy bodies

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.info:eu-repo/semantics/publishedVersio

Heritability and genetic variance of dementia with Lewy bodies

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia withLewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that asubstantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. Toovercome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability)in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. Thisshows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%).We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from eitherParkinson’s disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amountof variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed geneticcorrelation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positivecorrelation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic riskfactors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition