White matter hyperintensities and working memory: an explorative study

Contains fulltext : 73317.pdf (publisher's version ) (Closed access)White matter hyperintensities (WMH) are commonly observed in elderly people and may have the most profound effect on executive functions, including working memory. Surprisingly, the Digit Span backward, a frequently employed working memory task, reveals no association with WMH. In the present study, it was investigated whether more detailed analyses of WMH variables and study sample selection are important when establishing a possible relationship between the Digit Span backward and WMH. To accomplish this, the Digit Span backward and additional working memory tests, WMH subscores, and cardiovascular risk factors were examined. The results revealed that performance on the Digit Span backward test is unrelated to WMH, whereas a relationship between other working memory tests and WMH was confirmed. Furthermore, a division between several white matter regions seems important; hyperintensities in the frontal deep white matter regions were the strongest predictor of working memory performance.16 p

Effect of D222G Mutation in the Hemagglutinin Protein on Receptor Binding, Pathogenesis and Transmissibility of the 2009 Pandemic H1N1 Influenza Virus

Influenza viruses isolated during the 2009 H1N1 pandemic generally lack known molecular determinants of virulence associated with previous pandemic and highly pathogenic avian influenza viruses. The frequency of the amino acid substitution D222G in the hemagglutinin (HA) of 2009 H1N1 viruses isolated from severe but not mild human cases represents the first molecular marker associated with enhanced disease. To assess the relative contribution of this substitution in virus pathogenesis, transmission, and tropism, we introduced D222G by reverse genetics in the wild-type HA of the 2009 H1N1 virus, A/California/04/09 (CA/04). A dose-dependent glycan array analysis with the D222G virus showed a modest reduction in the binding avidity to human-like (α2-6 sialylated glycan) receptors and an increase in the binding to avian-like (α2-3 sialylated glycan) receptors in comparison with wild-type virus. In the ferret pathogenesis model, the D222G mutant virus was found to be similar to wild-type CA/04 virus with respect to lethargy, weight loss and replication efficiency in the upper and lower respiratory tract. Moreover, based on viral detection, the respiratory droplet transmission properties of these two viruses were found to be similar. The D222G virus failed to productively infect mice inoculated by the ocular route, but exhibited greater viral replication and weight loss than wild-type CA/04 virus in mice inoculated by the intranasal route. In a more relevant human cell model, D222G virus replicated with delayed kinetics compared with wild-type virus but to higher titer in human bronchial epithelial cells. These findings suggest that although the D222G mutation does not influence virus transmission, it may be considered a molecular marker for enhanced replication in certain cell types.Centers for Disease Control and Prevention (U.S.)United States. National Institutes of Health (merit award R37 GM057073-13)Singapore-MIT Alliance for Research and Technolog

Neurosci Lett

Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimer's disease (AD). Moreover, the risk allele increased amyloid-beta (A beta) levels in conditioned media from cultured cells. Therefore, we hypothesized that CALHM1 P86L may modulate A beta or tau levels in cerebrospinal fluid (CSF). Nearly 200 individuals with AD or other cognitive disorders were included for CSF analysis and CALHM1 genotyping. No significant differences in CSF levels of A beta 42, tau or phospho-tau were found across the various CALHM1 genotypes. In conclusion, we found no evidence that CALHM1 P86L is associated with altered CSF levels of the investigated AD biomarkers

Apolipoprotein E genotypes and longevity across dementia disorders

INTRODUCTION: The ε4 allele of the apolipoprotein E (APOE) gene is a prominent risk factor for Alzheimer's disease (AD), but its implication in other dementias is less well studied. METHODS: We used a data set on 2858 subjects (1098 AD, 260 vascular dementia [VaD], 145 mixed AD and VaD, 90 other dementia diagnoses, and 1265 controls) to examine the association of APOE polymorphisms with clinical dementia diagnoses, biomarker profiles, and longevity. RESULTS: The ε4 allele was associated with reduced longevity as ε4 versus ε3 homozygotes lived on average 2.6 years shorter (P = .006). In AD, ε4 carriers lived 1.0 years shorter than noncarriers (P = .028). The ε4 allele was more prevalent in AD, mixed AD and VaD, and VaD patients compared to controls, but not in other dementia disorders. DISCUSSION: The APOE ε4 allele is influential in AD but might also be of importance in VaD and in mixed AD and VaD, diseases in which concomitant AD pathology is common

Improved Differential Diagnosis of Alzheimer’s Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers

BACKGROUND: Alzheimer’s disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ₄₂, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD. OBJECTIVE: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects. METHODS: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4–9 years and 21 of these converted to AD, whereas 53 remained stable. RESULTS: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively. CONCLUSIONS: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects

Depression, anxiety, stress, social interaction and health-related quality of life in men and women with unexplained chest pain

<p>Abstract</p> <p>Background</p> <p>Unexplained chest pain (UCP) is a common reason for emergency hospital admission and generates considerable health-care costs for society. Even though prior research indicates that psychological problems and impaired quality of life are common among UCP patients, there is lack of knowledge comparing UCP patients with a reference group from the general population. The aim of this study was to analyse differences between men and women with UCP and a reference group in terms of psychosocial factors as depression, anxiety, stress, social interaction and health-related quality of life (HRQOL).</p> <p>Methods</p> <p>A self-administered questionnaire about psychosocial factors was completed by 127 men and 104 women with acute UCP admitted consecutively to the Emergency Department (ED) or as in-patients on a medical ward. A reference group from the general population, 490 men and 579 women, participants in the INTERGENE study and free of clinical heart disease, were selected.</p> <p>Results</p> <p>The UCP patients were more likely to be immigrants, have a sedentary lifestyle, report stress at work and have symptoms of depression and trait-anxiety compared with the reference group. After adjustment for differences in age, smoking, hypertension and diabetes, these factors were still significantly more common among patients with UCP. In a stepwise multivariate model with mutual adjustment for psychosocial factors, being an immigrant was associated with a more than twofold risk in both sexes. Stress at work was associated with an almost fourfold increase in risk among men, whereas there was no independent impact for women. In contrast, depression only emerged as an independent risk factor in women. Trait-anxiety and a low level of social interaction were not independently associated with risk in either men or women. Patients with UCP were two to five times more likely to have low scores for HRQOL.</p> <p>Conclusion</p> <p>Both men and women with UCP had higher depression scores than referents, but an independent association was only found in women. Among men, perceived stress at work emerged as the only psychosocial variable significantly associated with UCP.</p

Serum selenium levels do not differ in type 2 diabetic subjects with and without coronary artery disease

<p>Abstract</p> <p>Background</p> <p>The aim of the present study was to investigate whether selenium levels differ between type 2 diabetic subjects with and without coronary artery disease (CAD).</p> <p>Methods</p> <p>A total of 200 subjects with type 2 diabetes (100 with CAD and 100 without CAD), consecutively selected from the diabetes outpatient clinic of our hospital were enrolled into the study. A detailed medical history and a physical examination were obtained by all the participants.</p> <p>Results</p> <p>Serum selenium levels did not differ between diabetic subjects with and without CAD (102.40 ± 31.10 vs. 108.86 ± 33.88 microg/L, p = 0.16). In diabetic subjects with CAD multivariate linear regression analysis demonstrated significant independent associations between selenium and sex (beta = 0.21, p = 0.03) and glucose levels (beta = 0.25, p = 0.008). In diabetic subjects without CAD multivariate linear regression analysis demonstrated significant independent associations between selenium and peripheral artery disease (beta = 0.16, p = 0.05) and glucose levels (beta = -0.09, p = 0.05).</p> <p>Conclusion</p> <p>Serum selenium levels did not differ between diabetic subjects with and without CAD. In diabetic subjects with CAD, the only determinants of serum selenium levels were sex and glucose levels. In diabetic subjects without CAD the only determinants of serum selenium levels were peripheral artery disease and glucose levels.</p

Immune cells lacking Y chromosome show dysregulation of autosomal gene expression

Abstract: Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease

The rationale and design of the antihypertensives and vascular, endothelial, and cognitive function (AVEC) trial in elderly hypertensives with early cognitive impairment: Role of the renin angiotensin system inhibition

<p>Abstract</p> <p>Background</p> <p>Prior evidence suggests that the renin angiotensin system and antihypertensives that inhibit this system play a role in cognitive, central vascular, and endothelial function. Our objective is to conduct a double-blind randomized controlled clinical trial, the antihypertensives and vascular, endothelial, and cognitive function (AVEC), to compare 1 year treatment of 3 antihypertensives (lisinopril, candesartan, or hydrochlorothiazide) in their effect on memory and executive function, cerebral blood flow, and central endothelial function of seniors with hypertension and early objective evidence of executive or memory impairments.</p> <p>Methods/Design</p> <p>The overall experimental design of the AVEC trial is a 3-arm double blind randomized controlled clinical trial. A total of 100 community eligible individuals (60 years or older) with hypertension and early cognitive impairment are being recruited from the greater Boston area and randomized to lisinopril, candesartan, or hydrochlorothiazide ("active control") for 12 months. The goal of the intervention is to achieve blood pressure control defined as SBP < 140 mm Hg and DBP < 90 mm Hg. Additional antihypertensives are added to achieve this goal if needed. Eligible participants are those with hypertension, defined as a blood pressure 140/90 mm Hg or greater, early cognitive impairment without dementia defined (10 or less out of 15 on the executive clock draw test or 1 standard deviation below the mean on the immediate memory subtest of the repeatable battery for the assessment of neuropsychological status and Mini-Mental-Status-exam >20 and without clinical diagnosis of dementia or Alzheimer's disease). Individuals who are currently receiving antihypertensives are eligible to participate if the participants and the primary care providers are willing to taper their antihypertensives. Participants undergo cognitive assessment, measurements of cerebral blood flow using Transcranial Doppler, and central endothelial function by measuring changes in cerebral blood flow in response to changes in end tidal carbon dioxide at baseline (off antihypertensives), 6, and 12 months. Our outcomes are change in cognitive function score (executive and memory), cerebral blood flow, and carbon dioxide cerebral vasoreactivity.</p> <p>Discussion</p> <p>The AVEC trial is the first study to explore impact of antihypertensives in those who are showing early evidence of cognitive difficulties that did not reach the threshold of dementia. Success of this trial will offer new therapeutic application of antihypertensives that inhibit the renin angiotensin system and new insights in the role of this system in aging.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov NCT00605072</p