Most studies investigating the genetics of dementia have focused on Alzheimer disease, but little is known about the genetics of vascular dementia. The aim of our study was to identify new loci ...associated with vascular dementia.
We performed a genome-wide association study in the Rotterdam Study, a large prospective population-based cohort study in the Netherlands. We sought to replicate genome-wide significant loci in 2 independent replication samples.
In the discovery analysis of 5700 dementia-free individuals, 67 patients developed incident vascular dementia over a mean follow-up time of 9.3 ± 3.2 years. We showed genome-wide significance for rs12007229, which is located on the X chromosome near the androgen receptor gene (OR, 3.7; 95% CI, 2.3-5.8, per copy of the minor allele; P=1.3 × 10(-8)). This association was further confirmed in 2 independent populations (probability value of combined replication samples=0.024).
Our study shows a novel genetic locus for vascular dementia on the X chromosome. Further replication of this finding is required.
A swell memory: Samples of adamantyl‐modified cross‐linked hydrophilic polymers were swollen in water or aqueous cyclodextrin solution. The cyclodextrin dramatically enhanced the swelling (see ...picture). If the materials were twisted after heating above their glass‐transition temperature and swollen in aqueous cyclodextrin solution, a shape‐memory effect was observed.
Inferior frontal sulcal hyperintensities (IFSHs) on fluid-attenuated inversion recovery (FLAIR) sequences have been proposed to be indicative of glymphatic dysfunction. Replication studies in large ...and diverse samples are nonetheless needed to confirm them as an imaging biomarker. We investigated whether IFSHs were tied to Alzheimer's disease (AD) pathology and cognitive performance. We used data from 361 participants along the AD continuum, who were enrolled in the multicentre DELCODE study. The IFSHs were rated visually based on FLAIR magnetic resonance imaging. We performed ordinal regression to examine the relationship between the IFSHs and cerebrospinal fluid-derived amyloid positivity and tau positivity (Aβ42/40 ratio ≤ 0.08; pTau181 ≥ 73.65 pg/mL) and linear regression to examine the relationship between cognitive performance (i.e., Mini-Mental State Examination and global cognitive and domain-specific performance) and the IFSHs. We controlled the models for age, sex, years of education, and history of hypertension. The IFSH scores were higher in those participants with amyloid positivity (OR: 1.95, 95% CI: 1.05-3.59) but not tau positivity (OR: 1.12, 95% CI: 0.57-2.18). The IFSH scores were higher in older participants (OR: 1.05, 95% CI: 1.00-1.10) and lower in males compared to females (OR: 0.44, 95% CI: 0.26-0.76). We did not find sufficient evidence linking the IFSH scores with cognitive performance after correcting for demographics and AD biomarker positivity. IFSHs may reflect the aberrant accumulation of amyloid β beyond age.
NMR-based metabolomics investigations of human biofluids offer great potential to uncover new biomarkers. In contrast to protocols for sample collection and biobanking, procedures for sample ...preparation prior to NMR measurements are still heterogeneous, thus compromising the comparability of the resulting data. Herein, we present results of an investigation of the handling of cerebrospinal fluid (CSF) samples for NMR metabolomics research. Origins of commonly observed problems when conducting NMR experiments on this type of sample are addressed, and suitable experimental conditions in terms of sample preparation and pH control are discussed. Sample stability was assessed by monitoring the degradation of CSF samples by NMR, hereby identifying metabolite candidates, which are potentially affected by sample storage. A protocol was devised yielding consistent spectroscopic data as well as achieving overall sample stability for robust analysis. We present easy to adopt standard operating procedures with the aim to establish a shared sample handling strategy that facilitates and promotes inter-laboratory comparison, and the analysis of sample degradation provides new insights into sample stability.
Impaired long-term memory is a defining feature of mild cognitive impairment (MCI). We tested whether this impairment is item specific, limited to some memoranda, whereas some remain consistently ...memorable.
We conducted item-based analyses of long-term visual recognition memory. Three hundred ninety-four participants (healthy controls, subjective cognitive decline SCD, and MCI) in the multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were tested with images from a pool of 835 photographs.
We observed consistent memorability for images in healthy controls, SCD, and MCI, predictable by a neural network trained on another healthy sample. Looking at memorability differences between groups, we identified images that could successfully categorize group membership with higher success and a substantial image reduction than the original image set.
Individuals with SCD and MCI show consistent memorability for specific items, while other items show significant diagnosticity. Certain stimulus features could optimize diagnostic assessment, while others could support memory.
Alzheimer's disease (AD) may affect all cell types in the central nervous system. Astrocytes have rarely been investigated in the aged brain and the role of astrocytes in AD is poorly understood. In ...this study, we used acute brain slices from an amyloid-beta overexpressing double transgenic mouse line where astrocytes express the enhanced green fluorescent protein under the control of the glial fibrillary acidic protein promoter. Using the patch-clamp technique, we analyzed cell coupling and glutamate reactivity, two main features of astrocytes, in the living tissue of aged mice in an AD mouse model. We found large astrocytic networks in the aged (20 to 27 months) transgenic animals in the neocortex, but not in the hippocampus. In contrast, coupling was low in all brain regions of aged control mice. We furthermore noticed significant changes in the responses of astrocytes to glutamate. The expression of functional glutamate transporters and AMPA/kainate-type glutamate receptors increases in the amyloid-beta protein precursor overexpressing mice. Thus, exposure to amyloid-beta leads to altered astrocyte properties and this change might be beneficial to maintain synaptic function.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
After years of failed attempts to develop a disease-modifying therapy for Alzheimer's disease, consistent evidence in support of clinical efficacy was finally presented for a monoclonal antibody ...targeting the amyloid-β protofibrils. In addition to meeting the primary outcome of slowing clinical disease progression over 18 months, secondary clinical outcomes and amyloid-β lowering on PET also underpin the positive results of the trial. In this opinion piece, we highlight the key characteristics of the previous unsuccessful trials and analyse the potential reasons why those attempts to develop a treatment for early Alzheimer's disease failed. We compare the safety profiles of the different antibodies and highlight cautionary measures for their routine clinical use. Last, we discuss the role of blood-based biomarkers in transforming the clinical care pathway to facilitate the uptake of antibody treatments, proposing an integrated case-finding and treatment model crossing the different healthcare sectors. Taken together, a real breakthrough may have been achieved by proving that amyloid-β reduction results in clinical benefits, rather than just biomarker changes. At the same time, routine use of the new generation of drugs will show if statistical efficacy translates into clinically meaningful change. This may just be the beginning of a new era of Alzheimer's disease drug development.
The role of genetic risk markers for Alzheimer's disease (AD) in mediating the neurocognitive endophenotypes (NEs) of subjects with mild cognitive impairment (MCI) has rarely been studied. The aim of ...the present study was to investigate the relationship between well-known AD-associated single-nucleotide polymorphisms (SNPs) and individual NEs routinely evaluated during diagnosis of MCI, AD, and other dementias. The Fundació ACE (ACE) dataset, comprising information from 1245 patients with MCI, was analyzed, including the total sample, amnestic MCI (aMCI) (
= 811), and non-amnestic MCI (naMCI) (
= 434). As probable-MCI (Pr-MCI) patients with memory impairment have a higher risk of AD, which could influence the statistical power to detect genetic associations, the MCI phenotype was also stratified into four related conditions: Pr-aMCI (
= 262), Pr-naMCI (
= 76), possible (Pss)-aMCI (
= 549), and Pss-naMCI (
= 358). Validation analyses were performed using data from the German study on Aging, Cognition, and Dementia in primary care patients (AgeCoDe), and the German Dementia Competence Network (DCN). SNP associations with NEs were calculated in PLINK using multivariate linear regression analysis adjusted for age, gender, and education. In the total MCI sample,
-ε4 was significantly associated with the memory function NEs "delayed recall (DR)" (β = -0.76,
= 4.1 × 10
), "learning" (β = -1.35,
= 2.91 × 10
), and "recognition memory" (β = -0.58,
= 9.67 × 10
); and with "DR" in the aMCI group (β = -0.36,
= 2.96 × 10
). These results were confirmed by validation in the AgeCoDe (
= 503) and DCN (
= 583) datasets.
-ε4 was also significantly associated with the NE "learning" in individuals classified as having Pss-aMCI (β = -1.37,
= 5.82 × 10
). Moreover, there was a near study-wide significant association between the
locus (rs6448799) and the "backward digits" working memory NE (β = 0.52,
= 7.57 × 10
) among individuals with Pr-aMCI, while the
locus (rs10751667) was significantly associated with the language NE "repetition" (β = -0.19,
= 5.34 × 10
). Overall, our findings support specific associations of established AD-associated SNPs with MCI NEs.
Clinical trials have demonstrated a significant effectiveness of Ginkgo biloba therapy versus placebo in patients with dementia.
The present study aims to analyze the impact of Ginkgo biloba drug ...prescriptions on dementia incidence in patients with mild cognitive impairment (MCI) in a real-world setting.
This retrospective study was based on the IQVIA Disease Analyzer database and included patients aged 65 or older with a first diagnosis of MCI from January 2000 to December 2019. Each patient was followed for up to 20 years after MCI diagnosis until February 2021. Date of the first diagnosis of dementia or loss to follow-up, whichever occurred first, was noted. To estimate the association between Ginkgo biloba prescriptions during the follow-up and dementia incidence, a multivariable Cox regression analysis was performed, adjusted for age, sex, health insurance, documented co-diagnoses, and prescription of cholinesterase inhibitors.
Overall, 24,483 MCI patients (mean age: 77.0 years, 56.3% women) were included. It was found that > 2 prescriptions of Ginkgo biloba were significantly associated with a reduced dementia incidence (HR: 0.71 (95% CI: 0.55-0.91), p = 0.007), as compared with no Ginkgo biloba prescription. The effect of receiving > 3 Ginkgo biloba prescriptions was even stronger, with an HR of 0.64 (95% CI: 0.48-0.86), p = 0.003), while for > 4 prescriptions the HR was 0.58 (95% CI: 0.41-0.82) (p = 0.002).
All-cause dementia incidence decreased with higher numbers of Ginkgo biloba prescriptions in MCI patients.
Abstract
While the 2030 agenda addresses the United Nation member states primarily at their national levels, municipalities play a crucial role in implementing all of the 17 SDGs and many of the 169 ...targets. These processes must be monitored and evaluated. However, the UN indicators are not sufficiently applicable to the local context. Therefore, a multi-stakeholder working group was formed in Germany to develop a comprehensive set of Sustainable Development Goal (SDG) indicators for municipalities, together with additional instruments to support local SDG monitoring such as an SDG data portal. The first catalogue which included 47 core SDG indicators was published in 2018. According to consecutive evaluations and practical tests, the indicator set was substantially expanded and revised to a final number of 120 SDG indicators. About half of the 120 indicators are provided with local-level data and the other half must be assessed individually for comprehensive local SDG monitoring. Likewise, accompanying tools were relaunched with additional functionalities. Although this new and unique set of indicators now covers a majority of the municipally relevant targets, there are still some decisive monitoring gaps for various reasons. The strengths and weaknesses of our methodological approach, as well as implications for future research and practical developments, are discussed.
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