bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive performance among participants with Alzheimer’s disease and cerebral amyloid angiopathy
Authors: Teylan Merilee , Schwabe‐Fry Kristen , Hughes Timothy M. , Besser Lilah M , Brenowitz Willa D. , Keene C. Dirk , Gauthreaux Kathryn , Culhane Jessica E. , Miller Zachary , Chen Yen‐Chi , Chan Kwun Chuen Gary , Mock Charles , Kukull Walter A. 
Published: December 2020

AbstractBackgroundBeta‐amyloid found in Alzheimer’s disease (AD) plaques can also be present in the brain’s blood vessels as cerebral amyloid angiopathy (CAA). Co‐occurrence of AD and CAA is common. We examined the relationship between AD and CAA, and cognitive performance.MethodData were obtained from the National Alzheimer’s Coordinating Center. The sample was restricted to those with an autopsy ≤2 years of their last clinic visit and non‐missing data on Braak neurofibrillary tangle stage, neuritic plaque score, and CAA at autopsy. We excluded participants who had autopsy evidence of rare neuropathological diseases. Linear regression models with generalized estimating equations were run comparing CDR® Dementia Staging Instrument sum of boxes (CDR‐SB) and cognitive domain z‐scores across four groups (AD+/CAA+, AD+/CAA‐, AD‐/CAA+, AD‐/CAA‐). AD+ included those with Braak III‐VI and moderate/frequent neuritic plaques. Overall neocortical amyloid angiopathy was assessed for presence of CAA. Models accounted for clustering by center and adjusted for covariates. We also examined the mean differences in CDR‐SB by CAA severity (absent, mild, moderate, severe), stratifying by AD+/‐ and APOE ε4+/‐.ResultWe identified 1723 AD+/CAA+, 547 AD+/CAA‐, 443 AD‐/CAA+, and 741 AD‐/CAA‐ participants. All groups were more likely to be APOE ε4 carriers compared to AD‐/CAA‐. CAA+ participants, regardless if they had AD, were more likely to have arteriolosclerosis. After adjusting for covariates, AD+/CAA+ and AD+/CAA‐ participants had worse CDR‐SB scores compared to AD‐/CAA‐. There was no significant difference in CDR‐SB scores among AD‐ participants with or without CAA. Similar results were seen when examining differences in cognitive domain z‐scores, where AD+ participants performed worse regardless of the presences of CAA when compared to AD‐/CAA‐ participants. We did not observe significant differences in CDR‐SB scores by CAA severity after adjusting for covariates.ConclusionThese results demonstrate that the presence of AD neuropathologic features appears to be driving the cognitive performance irrespective of the presence or severity of CAA. Our observation that arteriolosclerosis was more likely to be present among those with CAA even in the absence of AD is of note and something to investigate further. Future work should also examine if these differences hold true when examining longitudinal cognitive performance.
Automatic annotation of head movement among elderly people susceptible to Alzheimer's disease
Authors: Helmi Garraoui 
Published: December 2020

AbstractBackgroundSeveral researchers have revealed that sensory and motor changes can predate the cognitive symptoms of Alzheimer's disease (AD) by many years and may signify increased risk of developing AD. Therefore, studying the non‐verbal communication among the elderly susceptible to AD can contribute to a better understanding of their daily needs. Among these non‐verbal communications, we can mention head gestures, hand gestures, etc. This research discusses a new system model of nonverbal language annotation associated to hand gestures among elderly people susceptible to AD.MethodThe proposed approach aims at establishing a longitudinal study based on the use of recurrent neural network as a deep learning technique. We propose an interdisciplinary approach for automatic annotation of hand phases (rest position, preparation, hold, retraction), defined in many existing research works. To perform the classification, we rely on a ground truth, initiated by experts, known as CorpAGEst corpus. The latter is a collect of spontaneous conversations between interviewers and elderly people, which is used to train and test our modelResultExperimentations show promising results, where the proposed approach succeeded in classifying the hand gesture phases with an 87.5% of precision and recall.ConclusionThe proposed process focused on the automatic annotation of hand phases, reducing the cost of manual annotations and establishing a back and forth dialog between computer science communities and researchers in AD. The principal impact of this work is to contribute in establishing stronger gesture recognition techniques adapted to the aging population, giving the community of researchers tools to explore specificities in an automated fashion.
Serum cholesterol levels and APOEε4 status potentiate metabolic decline in non‐demented individuals
Authors: Souza João Pedro Ferrari , Pascoal Tharick A. , Povala Guilherme , Brum Wagner Scheeren , De Bastiani Marco Antônio , Benedet Andréa Lessa , Therriault Joseph , das Ros Lucas U. , Bellaver Bruna , Rosa‐Neto Pedro , Zimmer Eduardo R. 
Published: December 2020

AbstractBackgroundEpidemiological investigations have shown that midlife elevated total serum cholesterol levels increase the risk of Alzheimer’s disease (AD). However, observational studies in late‐life subjects suggested that high cholesterol levels reduce the risk of dementia. Since hypometabolism is a pivotal marker of AD progression, understanding the impact of peripheral cholesterol levels over the brain’s metabolic state in older adults has become crucial to clarify these seemingly conflicting findings. Therefore, whether high serum cholesterol levels accelerate brain metabolic decline in older subjects remains a key question to be answered. Here, we investigated whether total serum cholesterol levels are associated with cerebral metabolic decline. We hypothesized that elevated total serum cholesterol levels accelerate metabolic decline in AD‐related brain regions.MethodWe evaluated 499 cognitively unimpaired and mild cognitive impaired elderly subjects (age>55 years) from Alzheimer's Disease Neuroimaging Initiative (ADNI) with available total serum cholesterol measurements at baseline and longitudinal [18F]FDG‐PET scans. Voxel‐wise general linear modelling was used to assess the baseline association between total serum cholesterol levels and cerebral metabolic rate for glucose (CMRglc), as well as cholesterol’s impact over the 2‐year’s rate of metabolic decline. Age, gender, BMI, cholesterol treatment and diagnostic group were set as covariates for adjustment. APOEε4 genotype was used as both, a covariate or an interaction factor.ResultNo significant associations were observed at baseline. We found a negative correlation between cholesterol levels and the 2‐year CMRglc variation rates in brain regions affected in early stages of AD, which was driven by the interaction with APOEε4 status (Figure 1). Regions affected include the right precuneus (peak t(491) = ‐3.93, p<0.0001) and the right posterior cingulate gyrus (peak t(491) = ‐4.12, p<0.0001). Associations were greater in the right hemisphere.ConclusionOur results support the concept that the interaction of higher serum cholesterol levels with APOEε4 genotype accelerate metabolic decline in AD‐related brain regions. These findings complement cross‐sectional studies postulating that, even among older adults, serum cholesterol levels, in association with the APOEε4 status, might be related to brain functional changes similar to those observed in the development of AD.
Preserved cholinergic forebrain structure reduces the impact of strategic lesions to the connectome in mild cognitive impairment
Authors: Berlot Rok , Koritnik Blaž , Pirtošek Zvezdan , Ray Nicola 
Published: December 2020

AbstractBackgroundUndetected neurodegeneration is present in many patients with stroke. Clinical consequences of stroke might be partly determined by pre‐existing changes in brain structure. Cortical acetylcholine allows favourable adaptation to pathological changes within the limbic system. However, it remains unclear if it acts more broadly, affecting the configuration of the structural connectome. To test this, we aimed to assess the relationship between nucleus basalis of Meynert (NBM) structure and vulnerability of the connectome to simulated strategic lesions in patients with mild cognitive impairment (MCI).MethodTwenty patients with MCI and 20 healthy elderly controls underwent 3T structural and diffusion‐weighted MRI. Whole‐brain tractograms were represented as network graphs. Lesions of individual nodes were simulated by removing a node and its connections from the graph. The impact of simulated lesions was measured as the proportional change in global efficiency of the connectome. Relationships between NBM volume, global efficiency of intact connectomes and impacts of individual simulated lesions of network nodes were assessed, controlling for demographic variables and atrophy of individual nodes.ResultArtificial removal of the thalamus and the hippocampus from the connectome had a lower impact on global efficiency in MCI compared to controls. In MCI, NBM volume was correlated with global efficiency of intact connectomes. Higher NBM volumes were associated with reduced impact of thalamic lesions and lesions of the entorhinal and posterior cingulate cortices. These relationships were not present in other cortical or subcortical nodes or in controls.ConclusionReduced vulnerability to damage of the hippocampus and thalamus in MCI suggests that connections essential for efficient network structure “shift” away from these areas. In MCI, preserved NBM is associated with efficient network topology and has a protective effect against the global impact of simulated strategic lesions. By influencing the configuration of the connectome in MCI, the cholinergic system might have a protective effect against the impact of targeted damage. Structural connectome alterations in response to early neurodegeneration represent a potential mechanism for synergy between neurodegeneration and vascular lesions in post‐stroke cognitive impairment and mixed dementia.
The late‐onset Alzheimer's disease genetic risk factor CD2AP impacts synapses via actin dynamics
Authors: Mirfakhar Farzaneh S. , Almeida Claudia G. 
Published: December 2020

AbstractBackgroundIn late‐onset Alzheimer’s disease (LOAD) the causal mechanisms of synaptic dysfunction that underlie the memory deficits that lead to dementia are not established. The search for genetic risk factors in LOAD led to the identification of more than 20 genes and three main mechanisms: endocytic trafficking, lipid metabolism and immune response. Here we aim to establish causality between a mutation in CD2AP, one of the endocytic trafficking risk factors, and synaptic dysfunction. Since CD2AP is a regulator of the actin cytoskeleton dynamics which is essential for spine morphology, we hypothesize that a LOAD mutation CD2AP may impact spines by deregulating actin.MethodWe have analyzed synapses and spines density as well as spinal actin in cortical mouse primary neurons either transiently overexpressing wild‐type and mutant CD2AP‐GFP as well as GFP as control or infected with lentivirus expressing GFP and shCD2AP or non‐targeting shRNA as control. Moreover, we investigated CD2AP synaptic localization by immunofluorescence microscopy. We used quantitative single‐cell analysis using ICY and Imaris software.ResultWe discovered that a pool of CD2AP is present in spines; and that both CD2AP wild‐type and mutant are significantly enriched in spines. Spines length decreased with larger spine heads, by CD2AP wild‐type and more pronouncedly by mutant CD2AP overexpression. Indicating that CD2AP might function at synapses, by regulating spine morphology. Indeed, synapses density was reduced by CD2AP knockdown. Mechanistically, we found that spinal F‐actin increased by CD2AP wild‐type and more pronouncedly by mutant CD2AP overexpression compared to control neurons. We are currently investigating whether spinal F‐actin is altered by CD2AP knockdown.ConclusionThese results indicate that CD2AP regulates spine morphology and thus synapses. A LOAD mutant CD2AP may interfere with its function by dysregulating actin dynamics at spines. Overall CD2AP variants may contribute to LOAD development by directly interfering with synapses. References: (1) Ubelmann, Florent, et al. “Bin1 and CD2AP polarise the endocytic generation of beta‐amyloid.” EMBO reports 18.1 (2017): 102‐122. (2) Hollingworth, Paul, et al. “Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.” Nature genetics 43.5 (2011): 429.
A qualitative analysis of study participant and study partner experiences with the consent process: Assessments guiding the development of an electronic consent (ECONSENT)
Authors: Chin Erin , Croes Kenneth , Dykema Jennifer , Suver Christine , Hamann Jennifer , Truong Amy , Doerr Megan , Lah James J , Goldstein Felicia C , Blazel Hanna , Manzanares Cecelia , Edwards Dorothy Farrar 
Published: December 2020

AbstractBackgroundThe informed consent process educates potential participants about a research study and guides them to make a decision about participation. Most important, the consent document should meet the needs of the participant so they can make an educated decision. Studies have shown consent documents can be lengthy, redundant and ineffective at enhancing comprehension. We examined the traditional consent process from the perspective of research participants, including people commonly underrepresented in research, and from study partners from the University of Wisconsin‐Madison and Emory University Alzheimer’s Disease Research Centers.MethodPrivate interviews were conducted with 15 participants and 8 participant/study partner dyads. The interviews were voluntary and the interviewer was not the same person who consented the participants to avoid any bias or influence over the participant’s response. Each person was asked a series of questions about their overall experience with the informed consent process. In order to evoke prior observations, respondents were encouraged to review the consent form throughout the interview. Responses were recorded, transcribed and coded.ResultAnalysis of the interviews revealed participants were overall satisfied with the consent process. Well‐trained study coordinators made a notable difference in the consent experience. Reported shortcomings highlighted by study partners include the length of the consent form and complex language. Some people felt that both the length and complexity were excessive based on the risks and benefits of participation. Others felt a better explanation was needed to explain more complex procedures and concepts, with one pointing out, “The DNA might pose a little problem for people…depending on how far along the person is with their understanding of medical stuff.” Some recommended using videos or online chats to make it easier for people to understand.ConclusionWhen designing an update for a process as vital as the consent it is imperative to capture the perspective and needs of those it directly affects. Participants and study partners offered recommendations, providing a starting point in the development of an eConsent version. In exploring an electronic approach, we hope to improve comprehension by allowing participants to have control over the order and level of detail of information presented to them.
The Critical Path for Alzheimer’s Disease (CPAD): Pre‐competitive data sharing and generation of innovative high‐impact quantitative tools to support Alzheimer’s disease drug development
Authors: Sivakumaran Sudhir , Romero Klaus , Hanan Nathan J , Sinha Vikram , Haeberlein Samantha Budd , Gold Michael 
Published: December 2020

AbstractBackgroundThe Critical Path for Alzheimer’s Disease (CPAD) consortium’s primary objective is to promote, support, and manage pre‐competitive data sharing from Alzheimer disease (AD) clinical trials to allow quantification of Alzheimer’s Disease progression across the AD continuum. A quantitative understanding of disease dynamics will drive scientific discovery provided by aggregated and standardized primary clinical trial data. This will provide solutions to optimize the design of clinical trials of AD drugs intended for regulatory review in support of marketing approval. CPAD is a nonprofit, pre‐competitive consortium (https://c‐path.org/programs/cpad/) of the Critical Path Institute (C‐Path) and convenes diverse stakeholders from academia, advocacy groups, industry, and regulators.MethodAs of January 2020, CPAD’s database (www.codr.c‐path.org) contains data contains 38 studies, representing 14,853 individual records and more than 420,000 data points, standardized to the AD CDISC (Clinical Data Interchange Standards Consortium) standards. CPAD’s objective is to collaborate with industry and regulators to leverage their wealth of drug development knowledge by enabling pre‐competitive data sharing from clinical trials in AD. Analysis of datasets (at meta‐data and patient levels) enables generation of tools involving comprehensive disease progression models across the AD continuum, to support successful drug development.ResultCPAD continues ongoing efforts towards expansion of the CPAD database with contemporary datasets containing patient‐level data from both control and active arms of clinical trials in AD. By aggregating such datasets into our rich clinical trial repository, CPAD will fill existing gaps in our models and generate of quantitative solutions for drug development in AD, in collaboration with the Quantitative Medicine team. Key focus of CPAD in 2020 includes completion of the pre‐dementia model (which has received a Letter of Support from the EMA) and generation of the comprehensive disease progression model. This effort will be based on an evolving workflow initiating with dataset exploration at the level of meta‐data and patient level data and determination of model specifications, resulting in model validation, simulations and regulatory submissions.ConclusionPre‐competitive sharing of contemporary clinical trial data will allow us to develop a comprehensive understanding of the disease continuum in AD, enable a fully informed trial design and advance effective drug development in AD.
The role of intermittent fasting in brain health
Authors: Francis Nikita 
Published: December 2020

AbstractBackgroundDespite the continuous efforts to combat dementias, researchers still have not found a pharmaceutical intervention that reliably reverses degeneration or improves cognitive functions. Therefore, lifestyle factors that could potentially aid in healthy brain aging and prevent or delay neurodegenerative diseases are of considerable interest. In particular, the ancient practice of fasting has been the subject of study for potential beneficial effects on longevity, obesity and diabetes, cancers, heart diseases as well as for neurodegenerative diseases. This review examines the health benefits of intermittent fasting (IF) in regard to brain health.MethodA search employing relevant search terms was conducted in PubMed and Google scholar to produce a comprehensive accounting of the pertinent literature.ResultThe current review specifically focused on the role of IF in neuroinflammation, insulin resistance and autophagy, as they apply to brain health. Studies showed positive effects of IF in reducing neuroinflammation, decreasing insulin resistance and increasing autophagy. Much of the research on the above‐mentioned benefits utilized an alternate day fasting regimen. The current literature indicates that these benefits are more associated with the metabolic switch that occurs during the fasting state than restriction of calories alone. As glucose levels deplete during a fast, insulin levels stay low and ketone bodies are released for cellular fuel. The release of ketone bodies is associated with activating anti‐inflammatory mechanisms as well as activating cellular pathways that induce autophagy.ConclusionIF appears to be promising for its potential to protect the brain from the effects of aging and disease. Nevertheless, the mechanisms for these benefits are poorly understood. Additionally, the potential benefits of IF combined with other positive lifestyle factors such as exercise should also be further investigated. Moreover, the effects of long‐term IF and the differences in different IF regiments need to be assessed in animal models as well as clinically.
Astrocyte changes in MRI‐guided immunohistochemistry of white matter hyperintensities in advanced aging
Authors: Roese Natalie E. , Woltjer Randy , Lahna David , Schwartz Daniel L. , Krajbich Victoria , Boespflug Erin L. , Silbert Lisa C. 
Published: December 2020

AbstractBackgroundMagnetic Resonance Imaging (MRI) white matter hyperintensities (WMH), a hallmark of subcortical cerebrovascular disease (CVD), are commonly associated with cognitive impairment in older individuals. Glial abnormalities have been reported in subjects with high WMH burden, suggesting a role of astrocyte changes in vascular cognitive impairment. This study aims to use post‐mortem (PM) 7T MRI to specifically target WMH lesions for histopathologic evaluation of markers of astrocytic dysfunction.MethodBrain tissue from six older Oregon Alzheimer’s Disease Center subjects were included (Table 1). Left brain hemispheres were formalin fixed, sliced into 6mm coronal sections, and scanned using 7 Tesla MRI. Five cassettes (Table 2) were targeted for immunohistochemistry (IHC) from the sliced MR images (Figure 1) and stained with hematoxylin & eosin‐luxol fast blue (HELFB), aquaporin‐1 (AQP1), glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule‐1 (IBA1), and vimentin. Slides were scanned and registered to the corresponding MRI slice. 25 2x2 mm WMH and normal appearing white matter (NAWM) regions of interest were selected on MRI and cropped from corresponding IHC images (Figure 3). Resulting images were assessed semi‐quantitatively by a neuropathologist using a 0‐3 point scale, and quantitatively using mean pixel saturation or thresholded area coverage. Blue pixels were segmented from LFB images and area coverage was quantified. Semi‐quantitative ratings were analyzed using a Wilcoxon signed‐rank test. Quantitative data was analyzed using a pairwise T‐test. Bonferroni correction was conducted within assessment.ResultLFB area coverage was lower in WMH compared to NAWM (p=0.0003), confirming demyelination as a feature of the WMHs identified. Quantitative assessment of mean pixel saturation values showed decreased AQP1 (p=0.0075) and increased vimentin (p=0.0008) in WMH compared to NAWM. In semi‐quantitative assessments, WMH displayed increased myelin pallor, increased vimentin expression, and decreased GFAP expression (p=0.0038, 0.0004, 0.0452).ConclusionPM MRI‐targeted IHC sectioning allows for the comparison of WMH and adjacent NAWM to investigate the nature of astrocyte changes in WM disease and may relate these to myelin and oligodendroglial alterations in age‐associated CVD.