The palladium‐catalyzed oxidation of glucopyranosides has been investigated using relativistic density functional theory (DFT) at ZORA‐BLYP−D3(BJ)/TZ2P. The complete Gibbs free energy profiles for ...the oxidation of secondary hydroxy groups at C2, C3, and C4 were computed for methyl β‐glucoside and methyl carba‐β‐glucoside. Both computations and oxidation experiments on carba‐glucosides demonstrate the crucial role of the ring oxygen in the C3 regioselectivity observed during the oxidation of glucosides. Analysis of the model systems for oxidized methyl β‐glucoside shows that the C3 oxidation product is intrinsically favored in the presence of the ring oxygen. Subsequent energy decomposition analysis (EDA) and Hirschfeld charge analysis reveal the role of the ring oxygen: it positively polarizes C1/C5 by inductive effects and disfavors any subsequent buildup of positive charge at neighboring carbon atoms, rendering C3 the most favored site for the β‐hydride elimination.
The physical factors behind the remarkable site‐selectivity in palladium‐catalyzed oxidation of unprotected glucosides was uncovered. The regioselectivity is traced back to the presence of the ring oxygen which steers the reactivity in order to minimize inductive charge repulsion.
•Glycosidases carry out many essential functions across all domains of life.•Activity-based probes can interrogate complex biological samples for glycosidase activity.•Glycosidase probes can ...characterize enzymes of biomedical/biotechnological interest.•Analysis of conformational itineraries may inform the design of future probes.•Activity-based probes assist high-throughput discovery of inhibitors.
As the scope of modern genomics technologies increases, so does the need for informative chemical tools to study functional biology. Activity-based probes (ABPs) provide a powerful suite of reagents to probe the biochemistry of living organisms. These probes, featuring a specificity motif, a reactive chemical group and a reporter tag, are opening-up large swathes of protein chemistry to investigation in vitro, as well as in cellular extracts, cells and living organisms in vivo. Glycoside hydrolases, by virtue of their prominent biological and applied roles, provide a broad canvas on which ABPs may illustrate their functions. Here we provide an overview of glycosidase ABP mechanisms, and review recent ABP work in the glycoside hydrolase field, encompassing their use in medical diagnosis, their application for generating chemical genetic disease models, their fine-tuning through conformational and reactivity insight, their use for high-throughput inhibitor discovery, and their deployment for enzyme discovery and dynamic characterization.
INTRODUCTION
We assessed whether co‐morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease.
METHODS
In 1090 non‐demented participants ...(65.4 ± 10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aβ) with lumbar puncture and/or positron emission tomography scan (mean follow‐up for cognitive function 3.1 ± 2.4 years).
RESULTS
Thirty‐nine percent had neither Aβ nor SVD (A–V–), 21% had SVD only (A–V+), 23% Aβ only (A+V–), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A–V– (reference), A+V– had a faster rate of cognitive decline. Co‐morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A–V+ (hazard ratio 95% confidence interval: 1.8 1.0–3.2) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups.
DISCUSSION
In non‐demented persons Aβ was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A–, but did not increase deleterious effects in A+.
Highlights
Amyloid beta (Aβ; A) was predictive for cognitive decline, dementia, and mortality.
Small vessel disease (SVD) had no additional deleterious effects in A+.
SVD modestly predicted dementia in A–.
Aβ should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment.
There is a vast genomic resource for enzymes active on carbohydrates. Lagging far behind, however, are functional chemical tools for the rapid characterization of carbohydrate‐active enzymes. ...Activity‐based probes (ABPs) offer one chemical solution to these issues with ABPs based upon cyclophellitol epoxide and aziridine covalent and irreversible inhibitors representing a potent and widespread approach. Such inhibitors for enzymes active on polysaccharides are potentially limited by the requirement for several glycosidic bonds, themselves substrates for the enzyme targets. Here, it is shown that non‐hydrolysable trisaccharide can be synthesized and applied even to enzymes with challenging subsite requirements. It was found that incorporation of carbasugar moieties, which was accomplished by cuprate‐assisted regioselective trans‐diaxial epoxide opening of carba‐mannal synthesised for this purpose, yields inactivators that act as powerful activity‐based inhibitors for α‐1,6 endo‐mannanases. 3‐D structures at 1.35–1.47 Å resolutions confirm the design rationale and binding to the enzymatic nucleophile. Carbasugar oligosaccharide cyclophellitols offer a powerful new approach for the design of robust endoglycosidase inhibitors, while the synthesis procedures presented here should allow adaptation towards activity‐based endoglycosidase probes as well as configurational isosteres targeting other endoglycosidase families.
Carba‐trisaccharide cyclophellitols are potent GH76 α‐1,6 endo‐mannanase inactivators and resistant to endoglycosidic bond cleavage.
Aim
In diagnostics of Alzheimer's disease (AD), the Mini‐Mental State Examination (MMSE) questionnaire is frequently used to test cognitive decline. The final subtest of the MMSE, in which patients ...have to copy two interlocking pentagons, tests a variety of visuomotor functions. Recent imaging studies suggest that visuomotor function could decline in early stage AD, as a result of degeneration of the brain networks involved. The goal of the present study was to compare memory and visuomotor function in AD patients, reflected by the MMSE subscores for orientation, recall and interlocking pentagons.
Methods
The MMSE subscores for orientation, recall and interlocking pentagons of 125 AD patients was extracted from their medical history. Patients were divided into three groups based on disease duration. Using related‐samples Wilcoxon signed‐rank tests, the performance between subtests using normalized subscores was compared within each group.
Results
In all three groups, the subscores of recall and interlocking pentagons were significantly lower than orientation. No differences were found between the subscores of recall and interlocking pentagons.
Conclusions
The presented data suggest that memory function and visuomotor function are equally impaired in the present study population. This could indicate that visuomotor dysfunction might be a more important clinical feature of AD than is currently assumed. This knowledge can be used to develop new tests and markers for AD reflecting deficits in visuomotor functions, such as quantification of eye and hand movements. Geriatr Gerontol Int 2014; 14: 880–885.
The Amyloid/Tau/Neurodegeneration (ATN) framework has been proposed as a means of evidencing the biological state of Alzheimer's disease (AD). Predicting ATN status in pre-dementia individuals ...therefore provides an important opportunity for targeted recruitment into AD interventional studies. We investigated the extent to which ATN-defined biomarker status can be predicted by known AD risk factors as well as vascular-related composite risk scores.
One thousand ten cognitively healthy older adults were allocated to one of five ATN-defined biomarker categories. Multinomial logistic regression tested risk factors including age, sex, education, APOE4, family history of dementia, cognitive function, vascular risk indices (high systolic blood pressure, body mass index (BMI), high cholesterol, physical inactivity, ever smoked, blood pressure medication, diabetes, prior cardiovascular disease, atrial fibrillation and white matter lesion (WML) volume), and three vascular-related composite scores, to predict five ATN subgroups; ROC curve models estimated their added value in predicting pathology.
Age, APOE4, family history, BMI, MMSE and white matter lesions (WML) volume differed between ATN biomarker groups. Prediction of Alzheimer's disease pathology (versus normal AD biomarkers) improved by 7% after adding family history, BMI, MMSE and WML to a ROC curve that included age, sex and APOE4. Risk composite scores did not add value.
ATN-defined Alzheimer's disease biomarker status prediction among cognitively healthy individuals is possible through a combination of constitutional and cardiovascular risk factors but established dementia composite risk scores do not appear to add value in this context.
Clinical research with remote monitoring technologies (RMTs) has multiple advantages over standard paper-pencil tests, but also raises several ethical concerns. While several studies have addressed ...the issue of governance of big data in clinical research from the legal or ethical perspectives, the viewpoint of local research ethics committee (REC) members is underrepresented in the current literature. The aim of this study is therefore to find which specific ethical challenges are raised by RECs in the context of a large European study on remote monitoring in all syndromic stages of Alzheimer's disease, and what gaps remain.
Documents describing the REC review process at 10 sites in 9 European countries from the project Remote Assessment of Disease and Relapse-Alzheimer's Disease (RADAR-AD) were collected and translated. Main themes emerging in the documents were identified using a qualitative analysis approach.
Four main themes emerged after analysis: data management, participant's wellbeing, methodological issues, and the issue of defining the regulatory category of RMTs. Review processes differed across sites: process duration varied from 71 to 423 days, some RECs did not raise any issues, whereas others raised up to 35 concerns, and the approval of a data protection officer was needed in half of the sites.
The differences in the ethics review process of the same study protocol across different local settings suggest that a multi-site study would benefit from a harmonization in research ethics governance processes. More specifically, some best practices could be included in ethical reviews across institutional and national contexts, such as the opinion of an institutional data protection officer, patient advisory board reviews of the protocol and plans for how ethical reflection is embedded within the study.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Noninvasive interventions to aid healthy cognitive aging are considered an important healthcare priority. Traditional approaches typically focus on cognitive training or aerobic exercise training. In ...the current study, we investigate the effect of exercises that directly combine cognitive and motor functions on visuomotor skills and general cognition in elderly with various degrees of cognitive deficits.
A total of 37 elderly, divided into four groups based on their level of cognition, completed a 16-week cognitive-motor training program. The weekly training sessions consisted of playing a videogame requiring goal-directed hand movements on a computer tablet for 30 minutes. Before and after the training program, all participants completed a test battery to establish their level of cognition and visuomotor skills.
We observed an overall change in visuomotor behavior in all groups, as participants completed the tasks faster but less accurately. More importantly, we observed a significant improvement in measures of overall cognition in the subaverage cognition group and the mild-to-moderate cognitive deficits group.
Our findings indicate that (1) cognitive-motor exercises induce improved test scores, which is most prominent in elderly with only mild cognitive deficits, and (2) cognitive-motor exercises induce altered visuomotor behavior and slight improvements in measures of general cognition.
Functional decline in Alzheimer's disease (AD) is typically measured using single-time point subjective rating scales, which rely on direct observation or (caregiver) recall. Remote monitoring ...technologies (RMTs), such as smartphone applications, wearables, and home-based sensors, can change these periodic subjective assessments to more frequent, or even continuous, objective monitoring. The aim of the RADAR-AD study is to assess the accuracy and validity of RMTs in measuring functional decline in a real-world environment across preclinical-to-moderate stages of AD compared to standard clinical rating scales.
This study includes three tiers. For the main study, we will include participants (n = 220) with preclinical AD, prodromal AD, mild-to-moderate AD, and healthy controls, classified by MMSE and CDR score, from clinical sites equally distributed over 13 European countries. Participants will undergo extensive neuropsychological testing and physical examination. The RMT assessments, performed over an 8-week period, include walk tests, financial management tasks, an augmented reality game, two activity trackers, and two smartphone applications installed on the participants' phone. In the first sub-study, fixed sensors will be installed in the homes of a representative sub-sample of 40 participants. In the second sub-study, 10 participants will stay in a smart home for 1 week. The primary outcome of this study is the difference in functional domain profiles assessed using RMTs between the four study groups. The four participant groups will be compared for each RMT outcome measure separately. Each RMT outcome will be compared to a standard clinical test which measures the same functional or cognitive domain. Finally, multivariate prediction models will be developed. Data collection and privacy are important aspects of the project, which will be managed using the RADAR-base data platform running on specifically designed biomedical research computing infrastructure.
First results are expected to be disseminated in 2022.
Our study is well placed to evaluate the clinical utility of RMT assessments. Leveraging modern-day technology may deliver new and improved methods for accurately monitoring functional decline in all stages of AD. It is greatly anticipated that these methods could lead to objective and real-life functional endpoints with increased sensitivity to pharmacological agent signal detection.
Research assessing the relationship of physical activity and dementia is usually based on studies with individuals younger than 90 years of age. The primary aim of this study was to determine ...physical activity levels of cognitively normal and cognitively impaired adults older than 90 years of age (oldest-old). Our secondary aim was to assess if physical activity is associated with risk factors for dementia and brain pathology biomarkers.
Physical activity was assessed in cognitively normal (N = 49) and cognitively impaired (N = 12) oldest-old by trunk accelerometry for a 7-day period. We tested physical performance parameters and nutritional status as dementia risk factors, and brain pathology biomarkers. Linear regression models were used to examine the associations, correcting for age, sex and years of education.
Cognitively normal oldest-old were on average active for a total duration of 45 (SD 27) minutes per day, while cognitively impaired oldest-old seemed less physically active with 33 (SD 21) minutes per day with a lower movement intensity. Higher active duration and lower sedentary duration were related to better nutritional status and better physical performance. Higher movement intensities were related to better nutritional status, better physical performance and less white matter hyperintensities. Longer maximum walking bout duration associated with more amyloid binding.
We found that cognitively impaired oldest-old are active at a lower movement intensity than cognitively normal oldest-old individuals. In the oldest-old, physical activity is related to physical parameters, nutritional status, and moderately to brain pathology biomarkers.
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