bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying and triangulating all available evidence on the effect of blood lipids and statins on dementia outcomes
Authors: McGuinness Luke A , Higgins Julian PT , Ben‐Shlomo Yoav
Published: December 2021

Background

Much published literature exists on the effect of blood lipid levels, and lipid‐regulating agents (LRA) such as statins, on the risk of dementia and related outcomes. Several approaches, including observational studies, randomised controlled trials (RCTs) and Mendelian randomisation (MR) studies (which uses genetic variants as proxies for the risk factor of interest) have been used to try and address this question, each with distinct assumptions and limitations. However, no previous review has sought to systematically identify and integrate these distinct study designs as part of a single synthesis exercise. This comprehensive systematic review and qualitative triangulation of the evidence aims to address this.

Method

Following standard systematic review methods, 16109 potentially eligible records were identified by a systematic search and screened as part of the review. Of these, 127 records reporting 105 primary studies were included, the majority of which (n=92; ∼88%) were observational studies. Data were extracted using a piloted form, and the risk of bias in included studies was assessed using the appropriate domain‐based tool (e.g. ROBINS‐I for non‐randomised studies of interventions).

Result

Distinct study designs were only available for some exposure (lipids/statins) and outcome (all‐cause dementia, Alzheimer’s disease, vascular dementia) pairs. A common theme across study designs was the absence of vascular dementia outcomes.

A key example of the triangulation approach if the results for the effect of statins on all‐cause dementia. Evidence from the meta‐analysis of observational studies found a protective effect (HR: 0.78, 95%CI: 0.69‐0.89), in contrast to both the RCT (OR:1, 95%CI: 0.60‐1.65) and MR (RR:0.9, 95%CI: 0.29‐2.83) approaches. This discrepancy could potentially be explained by immortal time bias, which typically increases the observed protective effect of the intervention, as several observational studies were found to suffer from this bias.

Conclusion

Evidence on the effect of blood lipid levels, and lipid modifying agents, is available from study with distinct methodological designs. By identifying and integrating this evidence as part of a single synthesis exercise, the strength of the conclusions can be increased. Future research should specifically focus on vascular dementia as an outcome, as there is a lack of evidence on this condition.
Mindfulness is associated with amyloid, tau and cognition in preclinical AD
Authors: Strikwerda‐Brown Cherie , Ozlen Hazal , Binette Alexa Pichet , Chapleau Marianne , Villeneuve Sylvia ,   PREVENT‐AD Research Group
Published: December 2021

Background

Mindfulness refers to the ability to engage in non‐judgmental awareness of the present moment. This psychological trait is gaining increased attention in both scientific and general public settings, given its association with an array of health benefits. While psychological traits such as depression, anxiety, and neuroticism have been associated with increased risk for Alzheimer’s disease (AD), the potential protective benefit of ‘positive’ psychological factors, such as mindfulness, remains to be explored. Here, we examined the relationship between mindfulness and AD markers in the preclinical phase of the disease.

Method

Two hundred and sixty cognitively normal older adults, including 124 with amyloid and tau‐PET scans, were included from the PREVENT‐AD cohort. All participants completed the Five Facet Mindfulness Questionnaire and a comprehensive neuropsychological battery. Multivariate partial least squares (PLS) analyses were used to examine the relationships between different facets of mindfulness (Observing, Describing, Acting with Awareness, Nonjudgment, and Nonreactivity), AD pathology, and cognition.

Result

Higher levels of mindful nonjudgment and nonreactivity were associated with less amyloid deposition in bilateral temporoparietal and frontal cortices (p = .003; Figure 1A). Higher levels of mindful acting with awareness, nonjudgment, nonreactivity, and describing were also related to less tau deposition in bilateral medial and lateral temporal regions (p < .006; Figure 1B). Finally, higher levels of mindful nonjudgment and describing were associated with better performance on measures of global cognition, immediate and delayed memory, and attention (p = .002; Figure 2). These relationships remained significant when additional psychological (depression, anxiety, stress, perseverative thinking and personality traits) and demographic (age, sex, education and APOE status) variables were included in analyses.

Conclusion

Higher trait mindfulness was associated with less amyloid and tau pathology and better cognition in the preclinical phase of AD, with distinct combinations of mindfulness facets differentially related to each of the AD markers. These findings suggest that, in addition to its other established health benefits, mindfulness may also represent an independent psychological protective factor for AD. Moreover, this study provides empirical support for the potential utility of mindfulness interventions in early AD, which represents an area of significant ongoing international research interest.
Examining the impact of sleep apnea on the ability to participate in cognitive testing among older adults
Authors: O'Leary Kimberly , Kiselica Andrew M
Published: December 2021

Background

Although neuropsychological evaluations are indicated for older adults with suspected cognitive impairments, some patients cannot participate meaningfully in testing due to significant cognitive impairments or impacts from health conditions. One condition that may affect the ability to participate in testing is sleep apnea. Sleep apnea is a risk factor for cognitive problems. It can cause deficits in motivation, attention, and arousal, which may hinder the ability to participate meaningfully in an evaluation.

Method

We assessed whether individuals with self‐reported sleep apnea were more likely than individuals without sleep apnea to demonstrate inability to meaningfully provide test results (i.e., a futile testing profile). The sample included 9,263 older adults from the National Alzheimer’s Coordinating Center Uniform Data Set (1608 with self‐reported sleep apnea and 7393 without). Individuals were considered to demonstrate a futile testing profile if ≥75% of cognitive tests met at least one of the following criteria: 1. Unable to be completed due to a cognitive/behavioral problem; 2. A score at the floor of the range of possible scores (score of 0 for most tests); 3. Performance below the second percentile based on demographically adjusted norms, corresponding to an extremely low score.

Results

Individuals with sleep apnea (6.60%) were no more likely than individuals without sleep apnea (7.7%) to demonstrate a futile testing profile, X
2(1) = 2.404. This finding held, even when evaluating the rate of futile testing profiles by cognitive severity status.

Conclusions

Results suggest that those with sleep apnea are not more likely than those without to demonstrate a futile testing profile. Although sleep apnea is a significant predictor and complicator of cognitive impairment, individuals with sleep apnea still appear to be able to complete cognitive testing and deliver meaningful findings.
Utilizing study and site performance metrics to improve efficiency of clinical trials: An initiative of the Alzheimer’s Clinical Trials Consortium (ACTC)
Authors: Walter Sarah , Craft Suzanne , Geldmacher David S. , Menard William , Sano Mary , Obisesan Thomas O , Combs Martha , Gessert Devon , Shaffer‐Bacareza Elizabeth , Miller Garrett , Donohue Michael C , Rafii Michael S , Aisen Paul S ,   Alzheimer's Clinical Trials Consortium (ACTC)
Published: December 2021

Background

The Alzheimer's Clinical Trials Consortium (ACTC) aims to provide an optimal infrastructure, utilizing centralized resources and shared expertise, to accelerate the development of effective interventions for Alzheimer’s disease and related disorders (ADRD). Metrics help clinical research sites understand where they stand relative to other sites and share best practices. For ACTC and study leaders, metrics aid in tracking the progress towards established goals, assessing performance of the sites and of the coordinating center in supporting site efforts, and may identify areas where additional development is needed.

Method

This initiative is led by an ACTC committee, comprised of member site PIs, research staff, and ACTC’s coordinating center. Proposed metrics were approved by the ACTC Steering Committee, and include those typically used to assess performance of a clinical trial (i.e., screening and randomization totals) as well as information not typically quantified (e.g. PI oversight and responsiveness). Reports are generated by extracting data from the ACTC data system, which ensures accuracy and minimizes site burden. A key element of this initiative is feedback from sites, obtained ad hoc and semiannually. Surveys were also used to understand the impact of COVID‐19 pandemic and other barriers to study startup. Interactive reports are distributed quarterly, facilitating both high level and detailed review. Site‐specific anonymized reports allow sites to see how they are performing relative to other sites.

Result

5 surveys were distributed with response rates between 50% and 82%. Quarterly reports, including summaries of site activation and screening performance, were distributed to 75 sites. Results obtained will be in our presentation.

Conclusion

We established procedures to collect, report and disseminate metrics, providing the foundation for a strong connection between sites and study teams. Our next steps are to develop additional summaries, maximize survey responses, improve the efficiency of report dissemination, as well as to explore the utility of metrics in measuring efficiency of trial conduct. This initiative will inform the development and implementation of additional ACTC trials, as well as tracking ACTC progress in building a consortium responsive to a changing landscape of clinical trials.
Task switching challenge to reveal abnormal brain‐heart signatures in cognitively healthy individuals with abnormal CSF amyloid/tau
Authors: Arechavala Rebecca Johnson , Liu Anqi , Rochart Roger , Kloner Robert , Fonteh Alfred N. , Kleinman Michael T. , Harrington Michael G. , Arakaki Xianghong
Published: December 2021

Background

Alpha oscillations during task switching reveals general attention (low alpha) and higher executive attentional control (high alpha). Alpha oscillations have been related to heart rate variability (HRV), both change in Alzheimer’s disease (AD). We aim to explore if task switching challenge with quantitative electroencephalography (qEEG) can reveal abnormal alpha power and HRV in individuals with high risk of AD, and we predict HRV improves qEEG’s detection of high AD risk.

Method

We compared alpha power during task switching testing between two groups of cognitively healthy participants (52‐91 years) based on different cerebrospinal fluid (CSF) amyloid/tau ratio: normal (CH‐NAT, n=19) or pathological amyloid/tau ratio (CH‐PAT, n=27). Participants were required to name the color or word of a colored word for each stimulus, with two sequential stimuli per trial. Alpha event‐related desynchronization (ERD) was analyzed during low load, repeat trials (color‐color or word‐word) and high load, switch trials (color‐word or word‐color). HRV was assessed from 5‐minute ECG recording during rest or task, including: standard deviation of RR‐intervals (SDNN), root mean squared of successive differences (RMSSD) in the time domain, as well as high (HF) and low frequency (LF) in the frequency domain. We trained a binary classifier to predict the CH‐PATs using a 30 random split of training (80%) and testing (20%) data and two‐layer, fully connected neural network after identifying significant qEEG and HRV features.

Result

We found that low alpha power was less negative in CH‐PATs than CH‐NATs (Central: ‐0.18±0.66 vs. ‐0.72±0.72, p=0.011, Cohen’s d=0.79; Parietal: ‐0.25±0.75 vs. ‐0.83±0.92, p=0.024, Cohen’s d=0.70) (Fig. 1). Furthermore, we observed significant HR and LF changes from resting to task state only in CH‐PATs, but not in CH‐NATs (Fig. 2). After identifying brain features and heart features, we explored the HRV effect on brain features’ test accuracy.

Conclusion

These results suggest: 1) low alpha power during task switching challenge differs between CH‐PATs and CH‐NATs; 2) HRV suggests hyperactive autonomic regulations from resting to task in CH‐PATs, but not CH‐NATs. qEEG reveals interaction of brain and heart features in early AD pathology that may help early diagnosis and monitoring of novel therapies.
Harmonisation of assessments in Australian Memory Clinics: Challenges and opportunities
Authors: Mehrani Inga , Kochan Nicole A. , Crawford John D. , Naismith Sharon L , Sachdev Perminder S. ,   Australian Dementia Network (ADNeT) Collaboration
Published: December 2021

Background

Since the late 1980’s, Memory Clinics have been an integral part of Australia’s dementia assessment and care services. Despite their continuous growth over the past 30 years, little benchmarking data is available and no best practice standards have been established. The Australian Dementia Network‐Memory Clinics initiative (ADNeT‐MC) is committed to initiate change and facilitate the harmonisation of assessment process and national collaboration. The main objective is to provide a state‐of‐the‐art diagnostic assessment to all individuals with cognitive disorders.

Method

A survey of Australian Memory Clinics was conducted to evaluate the current situation and determine the most commonly used clinical test instruments. Further a Delphi process to develop national Memory Clinic guidelines will be completed in 2021. Informed by the survey results and national and international dementia care and assessment guidelines, a set of best practice recommendations are being developed. A group of national experts, including researchers, clinicians, patients and careers, rates and assesses each recommendation to arrive at consensual final guidelines.

Result

The ADNeT‐MC national Memory Clinics survey showed a vast heterogeneity in clinical (e.g., assessment protocols used) and structural aspects (e.g., staffing, funding). We identified more than 100 different cognitive assessment instruments currently in use, but with agreement on the screening tool (MMSE) and subset of neuropsychological tests (see Table 1). Geriatricians were the most commonly involved specialists. Few clinics reported allied health professionals or social workers, which likely affects post‐diagnostic care delivery. Indeed, the provision of post‐diagnostic care is often limited to short‐term support, whereas more extensive support (e.g., cognitive intervention) is often not funded. First results of the Delphi process as well as recommendations for a consensus assessment protocol will be presented at this session.

Conclusion

ADNeT‐MC will outline one possible pathway to achieve national harmonisation across Memory Clinics. The development of standards that can be met by all Australian Memory Clinics, independent of their location and funding constraints, has the potential to enhance the quality of diagnostic assessments of all neurocognitive disorders and make post‐diagnostic care an integral part of the service delivery.
Clinic‐based data serving Population Neuroscience: NACC example
Authors: Kukull Walter A. , Ganguli Mary
Published: December 2021

Background

Memory clinics have historically driven case‐definition, clinical diagnostic criteria, and treatment trials in Alzheimer’s disease and related disorders (ADRD) and investigated neuroimaging and molecular factors leading to the development of ADRD biomarkers. The Uniform Data Set (UDS) of the National Alzheimer’s Coordinating Center (NACC)1 provides one such repository of clinic‐based and neuropathologic data2. (https://naccdata.org) With standardized characterization, long followup with low attrition, and post‐mortem neuropathology, memory clinic studies have high internal validity. However, they are rightly faulted for low external validity (generalizability) of results, with samples not representative of definable segments of the general population3. NACC has advanced several research directions proposed by the emerging field of Population Neuroscience.4

Method

Approximately 35 U.S. Alzheimer’s Disease Research Centers (ADRCs) enroll ADRD participants. Standardized (e.g., UDS) data collection and clinico‐pathologic correlations contribute to expanding phenotypic detail and support molecular biomarker, genomics, and soon, metabolomic analyses. NACC data support behavioral intervention trials and are now being used to characterize inadequately studied groups. NACC collaborates with ADRC consortia to facilitate studies of genomics, metabolomics, biomarkers, behavioral and environmental factors. Consortia datasets are interoperable with NACC1 offering opportunities to link UDS with GWAS and genome sequencing data (through NIAGADS), and soon with prospectively collected, standardized imaging biomarker data (through the SCAN project) with other collaborators.

Result

By December 2020, NACC had data from 43,517 participants including 15,440 with normal cognition, 9453 MCI, and 18,627 dementia; 30,019 have at least two longitudinal visits. 6,416 deceased participants have provided standardized neuropathology data. This NACC “case series” has generated >500 publications; NACC data are freely available to researchers worldwide.

Conclusion

Clinic‐based studies function as laboratories observing potential data patterns and associations as a first step towards validation in more representative populations. NACC continues to make its data more “findable, interoperable, accessible and reusable” for the broader scientific community. Reference: 4. Ganguli M, Albanese E, Seshadri S, et al. Population Neuroscience: Dementia Epidemiology Serving Precision Medicine and Population Health. Alzheimer Dis Assoc Disord. Jan‐Mar 2018;32(1):1‐9.
How lifestyle shapes the brain: Associations between physical activity, sleep, beta‐amyloid and cognitive function in older adults
Authors: Sewell Kelsey R , Rainey‐Smith Stephanie R , Villemagne Victor LL , Peiffer Jeremiah J , Sohrabi Hamid R , Taddei Kevin , Ames David , Maruff Paul T , Laws Simon M , Masters Colin L , Rowe Christopher C , Martins Ralph N , Erickson Kirk I. , Brown Belinda M
Published: December 2021

Background

Lifestyle factors such as sleep and physical activity influence risk of cognitive decline and dementia. Higher habitual physical activity and optimal sleep are associated with better cognitive function and lower levels of Alzheimer’s disease biomarkers, including beta‐amyloid (Aß). There is currently a poor understanding of how physical activity may influence the relationship between sleep and cognition, and whether exercise and sleep interact to influence cognition and Aß. Developing this understanding is crucial for creating effective lifestyle interventions for dementia prevention.

Method

Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised to determine whether self‐reported physical activity moderates the cross‐sectional relationship between self‐reported sleep parameters (duration, efficiency, latency, disturbance, quality), cognitive function (episodic memory, attention and processing speed, executive function), and brain Aß (quantified by amyloid positron emission tomography, using the Centiloid scale). Analyses were adjusted for age, sex, APOE ε4 carriage, mood, premorbid intelligence, and collection point. Participants were 404 community‐dwelling cognitively normal older adults aged 60 and above (75.3 5.7 years). Data from a subset of participants (n = 220, aged 75.2 5.6 years) were used for analyses with AB as the outcome.

Result

Physical activity moderated the relationship between sleep duration and episodic memory (ß = ‐.09, SE = .03, p = .005), and sleep efficiency and episodic memory (ß = ‐.08, SE = .03, p = .016). Physical activity moderated the relationship between sleep duration and A® (ß = ‐.12, SE = .06, p = .036), and sleep quality and Aß (ß = .12, SE = .06, p = .029).

Conclusion

Physical activity may play an important role in the relationship between sleep and cognitive function, and sleep and brain Aß. Future longitudinal and intervention studies in this area are crucial for informing interventions for dementia prevention.
Characterizing extracellular vesicles from cerebrospinal fluid by a novel size exclusion chromatography method
Authors: Hirschberg Yael , Schildermans Karin , van Dam Annemieke , Sterck Karen , Boonen Kurt , Nelissen Inge , Vermeiren Yannick , Mertens Inge
Published: December 2021

Background

Extracellular vesicles (EVs) have recently been considered as a potential biomarker source for a variety of diseases, including neurodegenerative disorders. EVs are important mediators of intercellular communication due to their capacity to transfer genetic material, lipids and proteins. By means of their communication role, interesting biomarkers are often enriched in EVs compared to total biofluid. In order to isolate EVs from a biofluid, like cerebrospinal fluid (CSF), a variety of isolation methods are available of which each methods shows different results, and, to date, there is no golden standard. Our study evaluates the use of size exclusion chromatography (SEC) by the SmartSEC HT kit for EV isolation from CSF.

Method

EVs were obtained from 500µL CSF samples, isolated by SmartSEC HT. SmartSEC traps contaminants, like bulk proteins, into the resin beads and subsequently elutes EVs. To evaluate this isolation method, various characterisation analyses were run. To detect cargo or surface proteïns, analyses on the ExoView R100, Surface Plasmon Resonance imaging (SPRi) and LC‐MS based proteomics analysis were performed. Concentration, and size of the vesicles were evaluated by use of transmission electron microscopy (TEM), and fluorescence nanotracking analysis (Zetaview).

Result

By means of the ExoView, tetraspanins such as CD81 and CD9 were measured on the surface of the EVs. Other EV‐specific proteins, e.g. lactadherin, flotillin‐1, and HSP70, were detected by SPRI. Untargeted protein analysis revealed the cargo proteins. TEM images visualized the presence of EVs. Particle size and concentration was calculated by nanotracking analysis, and more specifically the particles with a lipid membrane, like EVs, with fluorescence nanotracking analysis.

Conclusion

As EVs hold a lot of promise in the biomarker field, a standard high‐performance isolation method ‐ regarding purity and yield – is essential. From our data, SmartSEC HT is suggested to be an efficient size exclusion chromatography EV isolation method for low volume CSF samples, especially for high throughput, since samples are loaded on a 96‐well plate.
Associations among clinical characteristics of sleep quality, cognitive performance, and brain architecture in Thai dementia spectrum disorders
Authors: Senanarong Vorapun , Piyaamornpan Nattaporn , Chotinaiwattarakul Wattanachai , Cheiwvit Pipat , Rattanabannakit Chatchawan , Wongkom Natthamon , Dujada Pathitta , Vichianin Yudthaphon
Published: December 2021

Background

Sleep disorders are increased with advancing age. Poor sleep quality is a risk factor for cognitive decline and dementia. We aimed 1) to explore the relationship between sleep quality, sleep architecture and cognition; 2) to investigate the association between brain volume and sleep parameters.

Method

A total of 95 participants (70 female, mean age 67.18 ± 10 years) were included in this study. Thirty were those with major cognitive disorder patients, twenty‐five individuals had mild cognitive impairment (MCI), and forty were normal controls. Sleep parameters were measured using wrist actigraphy and subjective sleep questioners. The participants were evaluated with high‐resolution MRI. Three Dimensional sequences on Free‐Surfer morphometric procedure was used as the automated segmentation method to obtain brain volume. Demographic data, medical history, sleep characteristics, neuropsychological and mood evaluation were collected from participants.

Result

MCI patients had significantly lower sleep efficiency than cognitive healthy persons, 81.30 + 7 .39 % vs. 85.12 + 5.09 %, p=0.04. 66 % of the participants had poor sleep quality. Prevalence of probable REM sleep behavior disorder (RBD) and restless leg syndrome was high in dementia group. Longer sleep latency was associated with worse performance on global cognition. Total sleep time was associated with entorhinal corex volume and hippocampal volume. Sleep latency was associated with hippocampal volume

Conclusion

Sleep disorders were common in both cognitively healthy persons and dementia spectrum disorders. Lower sleep quality and disturbance of sleep maintenance were associated with the development of cognitive impairment. The causes and the consequences of poor sleep quality in patients with dementia spectrum disorders needed to be explored.
Neurogranin: A novel biomarker of Alzheimer’s disease
Authors: Dulewicz Maciej , Kulczynska‐Przybik Agnieszka , Klimkowicz‐Mrowiec Aleksandra , Pera Joanna , Borawska Renata , Slowik Agnieszka , Mroczko Barbara
Published: December 2021

Background

Alzheimer’s disease (AD) is a progressive, incurable and fatal neurodegenerative disorder characterized by continuing cognitive decline. Early deficits of memory and other cognitive functions has closely related to synaptic loss in AD. Neurogranin (Ng) is a small protein located in postsynaptic neurons, dendrites and spines in brain structures like the hippocampus. Ng plays an crucial role in synaptic plasticity and long‐term potentiation mediated by calcium and calmodulin signalling pathway, which is essential to memory and learning functions. Considering the above mentioned facts, it seems that Ng can be novel biomarker of synaptic injury. The purposes of our investigation were the quantitive assessment of Ng levels in the CSF of AD patients and comparison with classical biomarkers of AD.

Method

The cerebrospinal fluid (CSF) levels of neurogranin and classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, hTau and pTau181 were assessed by immunoenzyme assays. The study included 15 patients with AD and 15 non‐demented controls.

Result

The significantly higher concentration of Ng in cerebrospinal fluid of AD patients compared to non‐demented controls was observed. The CSF level of neurogranin was positively correlated with hTau and pTau181 and negatively with Aβ‐42/Aβ‐40 ratio.

Conclusion

The Ng is a crucial indicator of synaptopathy in the AD.Our results suggest that Ng is a promising biomarker for AD, however, further studies on larger group patients are needed. Acknowledgement: The study was conducted with the use of equipment purchased by the Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20001/15‐00 dated 26 and project № POWR.03.02.00‐00‐I051/16 from European Union funds, POWER 2014‐2020, grant № 04/IMSD/G/2019
Low‐dose acetylsalicylic use shows protective association with Alzheimer’s disease incidence: Results from two large prospective cohort studies
Authors: Nguyen Thi Ngoc Mai , Schöttker Ben
Published: December 2021

Background

Acetylsalicylic acid (ASA), through multiple mechanisms, has been assigned a potential protective effect on dementia development. However, observational studies and randomized trials have yielded conflicting results so far.

Method

Cox regression models, adjusted for a propensity score to model the underlying cardiovascular risk, were used to assess the longitudinal associations of low‐dose ASA use with all‐cause dementia, Alzheimer’s disease (AD) and vascular dementia (VD) incidence in two population‐based cohorts: the ESTHER cohort from Germany with 6,049 participants, and the UK Biobank cohort with a total of 501,392 participants.

Result

Over a median of 14.3 years of follow‐up, 481 all‐cause dementia cases, including 158 AD and 183 VD cases were diagnosed in ESTHER. In the UK Biobank, 5,177 were diagnosed with dementia, including 1,885 AD cases and 1,281 VD cases during a follow‐up time of 8.9 years. In the ESTHER study, participants who used low‐dose ASA had a reduced risk of 21% for all‐cause dementia (hazard ratio‐HR [95% confidence interval‐CI]: 0.79 [0.62‐1.02]), of 46% for AD (HR [95%CI]: 0.57 [0.35‐0.92]) but there was no association with VD. Results pointed towards the same direction in UK Biobank cohort, with a reduced risk of 11% (HR [95%CI]: 0.89 [0.82‐0.96]) for all‐cause dementia and 14% (HR [95%CI]: 0.86 [0.76‐0.99]) for AD, while there was a null result for VD.

Conclusion

Individuals who used low‐dose ASA had a reduced the risk of total dementia and AD incidence in two independent cohort studies. In patients with pre‐existing cardiovascular conditions, who have an indication for low‐dose ASA use anyway, it should be taken care that they get low‐dose ASA prescribed and are compliant. Moreover, other individuals with known high AD risk (e.g., because of APOE ε4/ε4 positive status or family history of early onset AD) should consider to start low‐dose ASA use already in middle adulthood (at age 40‐50 years) as a preventive measure against AD development at older age.
The Cambridge Behavioural Inventory (revised) detects early behavioural and functional impairment in genetic frontotemporal dementia within the GENFI cohort
Authors: Nelson Annabel , Russell Lucy L , Peakman Georgia , Greaves Caroline V , Convery Rhian S , Rohrer Jonathan D ,   GENFI Consortium
Published: December 2021

Background

Behavioural dysfunction is a key feature of genetic frontotemporal dementia (FTD) but validated clinical scales measuring behaviour are lacking at present.

Method

We assessed behaviour using the revised version of the Cambridge Behavioural Inventory (CBI‐R) in 733 participants from the Genetic FTD Initiative study: 466 mutation carriers (195 C9orf72, 76 MAPT, 195 GRN) and 267 non‐mutation carriers (healthy controls). All mutation carriers were stratified according to their CDR® plus NACC FTLD into three groups: asymptomatic (CDR=0), mildly symptomatic (CDR=0.5) and fully symptomatic (CDR=1+). CBI‐R total scores were compared between mutation carrier groups using a mixed effects model that adjusted for age, education, sex and family clustering, with 95% bootstrapped confidence intervals with 2000 repetitions to adjust for non‐normally distributed data. We used the same mixed effects model to run a within‐group analysis between the 10 CBI‐R domains in CDR 1+ groups. Spearman rank correlations were run to assess the relationship of the CDR® plus NACC FTLD SOB and FRS scale with the CBI‐R total in CDR 1+ mutation carrier groups.

Result

CBI‐R total scores were significantly higher in all CDR 1+ mutation carrier groups compared to controls (C9orf72 mean 70.5 (standard deviation 27.8), GRN 56.2 (33.5), MAPT 62.1 (36.9)), as well as their respective CDR 0.5 groups (C9orf72 13.5 (14.4), GRN 13.3 (13.5), MAPT 9.4 (10.4)) and CDR 0 groups (C9orf72 6.0 (7.9), GRN 3.6 (6.0), MAPT 8.5 (13.3)). Both C9orf72 and GRN 0.5 groups scored significantly higher than controls and their respective CDR 0 groups. Motivation and Memory were the highest scoring domains in both C9orf72 and GRN CDR 1+ groups, and in the MAPT group it was Stereotypic Behaviour and Memory. There was a positive correlation between the CBI‐R scores and the CDR® plus NACC FTLD SOB scores in all mutation carrier groups (C9orf72: rho= 0.8, p<0.001, GRN: rho= 0.8, p<0.001, MAPT: rho= 0.6, p<0.001), and a negative correlation between CBI‐R scores and FTD Rating Scale (FRS) scores (C9orf72; rho= ‐0.9, p<0.001, GRN; rho= ‐0.9, p<0.001, MAPT; rho= ‐0.9, p<0.001).

Conclusion

The CBI‐R detects early behavioural change in genetic FTD, particularly in those with C9orf72 and GRN mutations.
Midlife subclinical atherosclerosis and cardiovascular risk factors linked to hypometabolism in Alzheimer’s disease relevant regions
Authors: Cortes‐Canteli Marta , Gispert Juan Domingo , Salvadó Gemma , Toribio‐Fernández Raquel , Tristao‐Pereira Catarina , Sanchez‐Gonzalez Javier , Ibañez Borja , Molinuevo Jose Luis , Fuster Valentin ,   The Progression of Early Subclinical Atherosclerosis study
Published: December 2021

Background

Atherosclerosis has been linked to cognitive decline in late life; however, the impact of cardiovascular risk factors (CVRFs) and subclinical atherosclerosis on brain metabolism at earlier stages remains unexplored.

Method

This study, aimed at determining the association between brain metabolism, subclinical atherosclerosis and CVRFs in midlife, included 547 asymptomatic middle‐aged participants (50±4 years, 82% men) from the Progression of Early Subclinical Atherosclerosis study with evidence of subclinical atherosclerosis. Participants underwent 18F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET). Global brain FDG uptake and voxel‐wise analyses were used to evaluate the associations of cerebral metabolism with CVRFs and atherosclerotic plaque burden in carotids and femorals assessed by 3D‐vascular ultrasound.

Result

Global FDG uptake showed an inverse correlation with 30‐year Framingham Risk Score (30y‐FRS) (β=‐0.15, p<0.001). This association was mainly driven by the presence of hypertension (d=0.36, p<0.001). Carotid plaque burden was inversely associated with global brain FDG uptake (β=‐0.16, p<0.001), even after adjusting for 30y‐FRS. Voxel‐wise approaches revealed that the brain areas most strongly affected by hypometabolism in association with 30y‐FRS, hypertension, and carotid plaque burden were parietotemporal regions (angular, supramarginal, and inferior/middle temporal gyri) and the cingulate gyrus.

Conclusion

In asymptomatic middle‐aged individuals, cardiovascular risk is associated with brain hypometabolism, with hypertension being the modifiable CVRF showing the strongest association. Subclinical carotid plaque burden is also linked to reduced brain metabolism independently of CVRFs. Cerebral areas showing hypometabolism include mainly those known to be affected in Alzheimer´s disease. These results suggest that the interplay between cardiovascular disease and altered brain metabolism starts early in life, many years before the clinical manifestation. Understanding the extent to which cardiovascular risk factors influence brain´s vulnerability early in the course of atherosclerosis may help to refine preventive strategies and reduce the incidence of dementia in late life.
From Plan to Impact IV, progress towards the WHO global action plan on dementia
Authors: Lynch Chris
Published: December 2021

Background

At the World Health Assembly 2017, the World Health Organization launched the Global action plan on the public health response to dementia 2017‐2025. Alzheimer's Disease International (ADI) monitors progress towards the action areas and targets of the Global plan and in May 20201 will publish "From plan to impact IV", which is especially poignant in the context of Covid‐19.

Method

ADI continuously gathers information and updates relating to the 7 action areas of the Global action plan through our network of over 100 member associations and federations globally, as well as our contacts and partners in research, science, health and care, people living with dementia and carers. A specific analysis of progress towards the key goal of developing national dementia plans or strategies is a focal point of the research. In addition there will be a focus on the impact and implications of Covid‐19, including disruption to services, diagnosis and research.

Result

There was some encouraging policy developments in 2020 despite the challenges of Covid‐19, with the governments of China, Dominican Republic, Germany and Iceland developing national dementia plans. However, there are still only 35 national plans in existence, increasing urgency, and a need for a new focus and mobilisation to reach the central goal of the Global action plan, of 146 Member States developing a plan by 2025. This equates to the need for over 25 new plans every year.

Conclusion

Progress is being made across all 7 action areas of the Global action plan on dementia, with hope in the form of potential breakthroughs in disease modifying treatments and diagnostics, but this too is reflected in the need for much better healthcare preparedness. ADI, working with WHO and our partners, will continue to focus attention on governments across the world to take action, to develop robust and well‐funded national plans and to monitor their progress and to fulfil their commitments in adopting the Global action plan on dementia.
CSF apolipoprotein B is associated with early tau pathology and selective activation of a cytokine cascade in cognitively unaffected subjects with a parental history of Alzheimer’s disease
Authors: Labonte Anne , Picard Cynthia , Nilsson Nathalie I.V. , Rosa‐Neto Pedro , Breitner John , Villeneuve Sylvia , Poirier Judes ,   Prevent‐AD Research Group
Published: December 2021

Background

We examine the role of CSF apolipoprotein B (apoB) as a putative indicator of early tau pathology in pre‐symptomatic Alzheimer’s disease (AD).

Method

Among 129 cognitively unimpaired elderly at increased risk of AD (PREVENT‐AD cohort), we assessed blood and cerebrospinal fluid apoB, apoC3 and apoE protein levels using the the Milliplex APOMAG‐62k human apolipoprotein cardiovascular disease multiplex kit (EMD‐Millipore, MA, USA) with those of amyloid β42, total tau and phosphorylated tau (the Innotest enzyme‐linked immunosorbent assay kit (Fujirebio, Ghent, Belgium). We contrasted results with alterations in several inflammation biomarkers using Luminex’s Milliplex HCYTMAG60PMX29BK xMap technology ((EMD‐Millipore, USA).

Result

Among cognitively unimpaired participants, we observed significant correlations between baseline CSF, but not blood, apoB levels and both CSF t‐tau (R2 = 0.23, P < 0.0001) and P‐tau (R2 = 0.28, P < 0.0001). No association was detected between CSF apoB and CSF Aβ42 levels. Using multiple brain blood barrier permeability assays, we found that the contribution from peripheral apoB to be negligible. Concomitant analyses of several key cytokines and chemokines in the CSF failed to show any association following FDR correction, except for IL‐15 (R2: 0.38, p < 0.001). IL‐15, a potent inducer of reactive gliosis in both astrocytes and microglia, is normally synthesized by compromised neurons in the CNS.

Conclusion

CSF apoB, which is normally produced by microglia, markedly associates with early tau dysregulation and the activation of select cytokines in asymptomatic subjects, years before the onset of symptoms.
Analysis of brain structural connectivity networks and white matter integrity in patients with mild cognitive impairment
Authors: Bergamino Maurizio , Walsh Ryan R. , Stokes Ashley M.
Published: December 2021

Background

Mild cognitive impairment (MCI) is considered a prodromal phase of Alzheimer’s disease (AD) and patients with MCI convert to AD at a rate of about 10–15% per year. Because of this high conversion rate to AD, studies of MCI may yield insight into early pathological changes in AD. Here, we used a novel approach to analyze structural connectivity and white matter (WM) integrity using fractional anisotropy (FA), intra‐cellular (IC), extra‐cellular (EC), and isotropic (ISO) maps between patients with MCI and healthy controls (HC).

Method

Thirty‐two HC (age mean ± S.D. = 69 ± 6 years; 22 females) and 20 MCI (71 ± 9 years; 7 females) were included in this study. All subjects completed the Mini‐Mental State Exam (MMSE) and the Montreal Cognitive Assessment (MoCA). Multi‐shell DTI were download from ADNI (http://adni.loni.usc.edu/). Pre‐processing was performed by Mrtrix3, FSL, and ANTs. Tractography was performed with 5 million seeds using the iFOD2 algorithm. Connectome was generated from the Desikan‐Killiany parcellation file and was subsequently filtered using the COMMIT2 algorithm. A three‐compartment Stick‐Zeppelin‐Ball model was used to create the IC, the EC, and the ISO compartments, respectively. Statistical analyses (ANCOVA) were performed by connectomestats (Mrtrix3), randomise (FLS), and by an in‐house Matlab script for Spearman’s correlations.

Result

The two groups did differ in MMSE and MoCA (Mann–Whitney U test: Z=2.031; p=0.021; Z=1.683; p=0.046, respectively). Differences between HC and MCI were found principally in the fornix for FA and in several WM areas for IC and ISO (Figure 1, Table 1). Connectometry analysis found differences between groups in two distinct tracts: Tract#1 between the left‐lateraloccipital and the left‐insula (t=4.25, p=0.023) and Tract#2 between the left‐middletemporal and the left‐parsopercularis (t=3.34, p=0.013) (Figure 2). Figure 3 and Table 2 show the results for the correlations between DTI metrics and the neurological scores.

Conclusion

In this study, by using a multi‐shell diffusion MRI acquisition and robust processing of DTI data, we detected alterations in WM integrity and structural connectivity in MCI subjects. Our results demonstrate the potential of these advanced diffusion MRI methods as biomarkers to distinguish MCI and HC.
EEG biomarkers differentiate Lewy body dementia from Alzheimer’s disease
Authors: Meghdadi Amir H. , Karic Marija Stevanovic , Richard Christian , Waninger Shani , Mcconnell Marissa , Poole Jared , Rupp Greg , Hamilton Joanne M. , Boeve Bradley F. , St. Louis Erik K. , Berka Chris
Published: December 2021

Background

Resting state electroencephalography (rsEEG) is a neurophysiologic Alzheimer disease (AD) and alpha‐synucleinopathy (dementia with Lewy body (DLB) and Parkinson disease (PDD)) biomarker [1]–[5]. Background slowing (increased low frequency power, dominant rhythm (DR) slowing) is frequent in AD and DLB, more so in DLB. We sought to identify distinguishing rsEEG signatures between DLB and AD.

Method

Participants included dementia patients [AD (n=26), DLB (n=12), PD (PDD; n=5)] and controls (HC; n=56). 20‐channel rsEEG was collected in eyes‐closed/eyes‐open conditions (5‐min each). Power spectral densities and coherences were measured using established methods [6]. Individual rsEEG power (delta, 1‐3 Hz; theta, 3‐7 Hz; alpha, 8‐13 Hz), theta/alpha ratio (TAR), dominant rhythm (DR), and DR frequency domain prominence were measured and averaged across groups, and effect sizes were determined and compared using Hedges g.

Result

AD, DLB, and PDD groups exhibited increased low frequency (delta‐theta, 1‐5 Hz) power and TAR compared to controls (p<4x10‐4), with higher effect sizes in the DLB and PDD groups compared to AD. DR frequency was also decreased in all patient groups (DLB>PDD>AD) compared to controls (p=3x10‐9, p=3x10‐5, p=4x10‐4).

AD alpha power and DR frequency domain prominence were reduced compared to controls and PDD/DLB groups (p<0.003). Both AD patients and controls had comparable posterior power distribution predominance of DR, while DLB power of DR was more anteriorly distributed. Compared to controls, delta coherence was higher in AD, but lower in DLB. Delta power was positively correlated with cognitive fluctuation (CAF) in DLB (r(8)=+0.67, p=0.03), while negatively correlated with MMSE in AD (r(24)=‐0.64, p=10‐5).

Conclusion

DLB and AD had both common and distinct rsEEG signatures. Both had DR slowing and background slowing that was more severe in DLB than AD. Distinctive DLB findings included reduced posterior DR spatial dominance and decreased delta coherence. Conversely, distinct AD features were increased delta coherence, decreased alpha power, and decreased DR frequency prominence. Finally, the DLB and PDD groups had a similar magnitude of DR slowing, consistent with posteriorly dominant functional impairment in synucleinopathy reflected by corresponding regional rsEEG slowing, although future longitudinal prospective sequential rsEEG analyses are necessary to confirm these findings.
Genome‐wide association study of mild cognitive impairment in diverse Hispanic/Latinos identifies novel loci and reveals heterogeneous associations across genetic backgrounds
Authors: Yang Yunju , Sofer Tamar , Tarraf Wassim , DeCarli Charles S , Gonzalez Hector M , Fornage Myriam
Published: December 2021

Background

Mild cognitive impairment (MCI) is considered a prodromal phase to Alzheimer’s disease and related dementias (ADRD) that appear to disproportionally affect Hispanics/Latinos, the largest ethnic minority in the US. The genetic architecture of MCI is poorly understood especially among Hispanics/Latinos. We performed a genome‐wide association analyses in Hispanincs/Latinos to identify genetic loci associated with MCI with consideration of genetic background.

Method

Genome‐wide association studies of MCI were performed in 4,981 participants in the Hispanic Community Health Study/Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA), distributed among six genetic background groups (backgrounds; Central American, Cuban, Dominican, Mexican, Puerto Rican and South American). MCI was defined according to the National Institute on Aging‐Alzheimer’s Association (NIA‐AA) criteria. Participants with severe CI were also included (n=68). Genetic associations were estimated using mixed effects models adjusted for age, sex, recruitment center, sampling weight, top 5 principal components, and background as fixed effects, and for kinship, household, and block group as random effects. A subgroup analysis in subjects aged 60 and above was also performed. To account for heterogeneity among Latino backgrounds, stratified analyses by background were performed and results were combined using fixed‐ and a random‐effect based methods.

Result

We identified a novel genome‐wide significant association for MCI at rs141694916 in SLC25A21 (p=2.17x10‐8). In analyses excluding cases with severe CI, its association was less significant (p=1.22x10‐6) but two novel loci were identified: rs75090804 in DAB1 (p=1.10x10‐9) and rs112528434 in APOC1 (p=3.66x10‐8). In the aged group, we identified an association for MCI in CADM2 (rs148903011, p=1.41x10‐9). Fixed‐effect meta‐analysis of background‐stratified GWAS identified two additional loci, rs144595178 near GCNT3 (p=1.37x10‐8) and rs16974577 near KC6 (p=3.51x10‐8), while random effect meta‐analysis identified 8 additional loci showing evidence of heterogeneity (heterogeneity p<0.05) by background. These included rs543428512 in STARD13 (p=5.07x10
‐9) and rs962088 near CDH10 (p=4.14x10‐8). The identified loci showed gene expression enrichment in the hippocampus and amygdala and were enriched in gene sets implicated in the regulation of plasma amyloid beta levels.

Conclusion

GWAS of MCI in diverse Hispanics/Latinos identified several novel loci with functional relevance to ADRD. Examining heterogeneity by background allowed us to detect additional loci.