bluuebunny/crossref_metadata_2025_split huggingface dataset:
Astrocyte activation and neurovascular function in a diet‐based model of vascular contributions to cognitive impairment and dementia (VCID)
Authors: Sompol Pradoldej , Edelmann Stephanie E. , Lin Ruei‐Lung , Gant Christopher C. , Kraner Susan D. , Weiss Blaine E. , Farr N. Drew , Gollihue Jenna L. , Thibault Olivier , Wilcock Donna M. , Norris Christopher M. 
Published: December 2020

AbstractBackgroundVascular contributions to cognitive impairment and dementia (VCID) are highly comorbid with Alzheimer’s disease (AD) pathology and may accelerate the progression of dementia and/or reduce the clinical efficacy of anti‐AD treatments. Neurotoxic astrocyte activation linked to aberrant calcineurin/NFAT signaling is a shared mechanism between VCID and AD. Recently, hyperhomocysteinemia, a major risk factor for VCID and a variety of other vascular‐related diseases, was linked to astrocyte dysfunction and calcineurin/NFAT hyperactivation. However, causal relationships between astrocytes and neurovascular dysfunction under hyperhomocysteine conditions has yet to be determined. Here, we investigate the hypothesis that diet‐induced hyperhomocysteinemia disrupts cerebrovascular function, in part, through an astrocyte‐based calcineurin/NFAT mechanism.MethodWild type mice (2‐3 months‐of‐age) received intracortical injections of adeno associated virus (AAV) equipped with an astrocyte‐specific promoter to target astrocytes with EGFP (control) or VIVIT‐EGFP, to inhibit the calcineruin/NFAT pathway. A chronic, glass cranial window was then installed for longitudinal multiphoton imaging of astrocytes and cerebrovascular parameters in barrel cortex. Three weeks post‐surgery, mice were fed with control or hyperhomocysteinemia‐inducing diet (low levels of folate, vitamins B6 and B12 and enriched with methionine) for 12 weeks. Astrocytic EGFP volume, microvessel leakage, and functional hyperemia (during whisker stimulation) were measured in the same brain region before and after 12 weeks of diet treatment.ResultUpregulation of astrocytic EGFP volume developed during hyperhomocysteinemia consistent with astrocyte activation. This change was attenuated by CN/NFAT inhibition with VIVIT, similar to previous observations in amyloidogenic mice. Hyperemic capillary responses to whisker stimulation in barrel cortex were also reduced with the development of hyperhomocysteinemia, suggesting an impairment of cerebrovascular function. Microvessel integrity (leakage) and the role of astrocytic NFATs are currently under investigation.ConclusionThe results indicate that hyperhomocysteinemia, a major risk factor for VCID, may trigger a neurotoxic activated astrocyte phenotype leading to neurovascular injury, and ultimately cognitive decline.
Relationship between state‐level administrative school quality data, years of education, cognitive decline and dementia risk
Authors: Avila Justina F , Murchland Audrey R , Glymour M Maria , Manly Jennifer J 
Published: December 2020

AbstractBackgroundWe examined indicators of state‐level administrative school quality as predictors of cognitive decline and dementia risk in later life across racial/ethnic by sex/gender groups.MethodParticipants included 2,446 men and women enrolled in the Washington Heights/Inwood Columbia Aging Project (WHICAP) who attended elementary school in the U.S., including 858 non‐Hispanic Whites (NHWs) and 1,588 non‐Hispanic Blacks (Blacks) followed up to 21 years. Cognitive outcomes were memory and language trajectories. A school quality indicator was created using U.S. census microsample data to combine historical measures of state compulsory schooling (mandatory enrollment age, minimum drop out age, and minimum work permit age) and school quality (term length, student‐teacher ratio, and percent attendance) on a scale corresponding to years of education via regression. The school quality indicator values were linked to WHICAP individual data via birth state, birth year, sex/gender, and race/ethnicity (black or NHW). Multiple‐group growth curve modeling and multiple‐group Cox regressions analyses were used to examine associations between school quality, cognitive decline, and dementia risk across racial/ethnic by sex/gender groups.ResultAfter adjusting for age, childhood SES, and state of childhood residence, higher quality of early‐life education was associated with level and change in language performance across groups, level of memory performance in Black women, and change in memory for NHWs and Black women. Higher quality of education was associated with lower risk of dementia for NHW women, Black men and women. Quality of education was not associated with dementia risk for NHW men after accounting for covariates. When years of education was included in the models, the influence of school quality on dementia risk and level and change in memory and language performance was fully attenuated for Black men and partially attenuated for NHWs and Black women.ConclusionQuality of early‐life education positively impacts cognitive outcomes and dementia risk later in life. Our results suggest an indirect relationship of school quality to late‐life cognitive outcomes through enabling additional years of educational attainment. Associations also varied across racial/ethnic by sex/gender groups. These findings provide evidence that later life brain health is influenced by early‐life state educational policies.
The legal capacity of patients with Alzheimer's disease
Authors: Mroczko Piotr 
Published: December 2020

AbstractBackgroundAs human life extends, problems affecting people over the age of 60 are becoming an important challenge for scientists. One of the biggest threats to these people is the risk of Alzheimer's disease. This is not only a medical, but also a sociological, psychological and legal problem. One of the most important problems in legal sciences is the issue of legal capacity. It defines when a particular person has the ability to acquire rights and incur obligations under civil law. Usually a person achieves legal capacity at the age of majority. Another factor that affects having legal capacity is the occurrence of a mental illness. The progressive symptoms of Alzheimer's disease, such as memory loss or lack of awareness about one's life situation, significantly limit patient competence to knowingly acquire rights and incur obligations.MethodsThe research was carried out using the method of analyzing scientific literature in the field of medicine, medical law and civil law.ResultsThere is no doubt that in the first phase of Alzheimer's disease the patient has legal capacity. The patient's situation in the third phase, i.e. dementia due to Alzheimer's disease, is also clear ‐ he no longer has legal capacity. The second phase, i.e. Mild cognitive impairment, is problematic from a legal point of view. It is difficult to unequivocally assess the patient's competence to consciously acquire rights and incur obligations. Each time in such a situation, a court that assesses a person's legal capacity should seek the opinion of expert neurologists and psychiatrists to determine the person's state of consciousness.ConclusionsAlzheimer's disease affects a person's legal capacity. The assessment of whether a person is able to consciously acquire rights and incur obligations should always belong to the doctors and lawyers cooperating with each other.
Plasma soluble TREM2 and inflammatory markers in Alzheimer’s disease
Authors: Weber Grace E. , Khrestian Maria , Shao Yvonne , Tuason Elizabeth D. , Rao Stephen M. , Pillai Jagan A. , Leverenz James B. , Bekris Lynn M. 
Published: December 2020

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) activation is involved in several cellular functions such as cell survival, phagocytosis and cytokine production. TREM2 genetic variants have been shown to increase risk for AD and other neurodegenerative disorders. Leukocyte TREM2 mRNA has been described as elevated in AD. However, the cleaved, soluble protein (sTREM2) is not elevated in AD plasma suggesting that plasma sTREM2 is less likely to play a significant a role in AD. As TREM2 mRNA is elevated in AD, it is also possible that membrane bound TREM2 plays a more important role in AD, by inhibiting certain cytokine or chemokines. We therefore hypothesized that plasma sTREM2 positively correlates with certain plasma cytokines and chemokines in cognitively normal controls, but not in AD.MethodWe investigated this hypothesis in a study of adults with AD, mild cognitive impairment (MCI), and age‐matched cognitively normal controls (HC). A panel of 38 immune factors and sTREM2 were measured in plasma utilizing the Luminex platform. Hierarchical clustering and correlation analyses were used to demonstrate differing relationships between sTREM2, cytokines and chemokines in AD or MCI, compared to HC.ResultWe observed a relationship between plasma sTREM2 and cytokines in our cohort that varied by disease status.ConclusionsOur results suggest that plasma sTREM2 is related to an aberrant peripheral inflammatory profile in AD. Increased levels of sTREM2 correlated positively with anti‐inflammatory, regulatory, and pro‐inflammatory cytokines in plasma. This study provides a basis for future studies investigating peripheral sTREM2 and the development of AD.
What am I measuring? Disentangling cognitive status from sensory impairment
Authors: Nichols Emma , Swenor Bonnielin K , Deal Jennifer A , Abraham Alison , Carlson Michelle C , Ramulu Pradeep , Resnick Susan M , Gross Alden L 
Published: December 2020

AbstractBackgroundSensory impairment in hearing or vision affects 55% of older adults aged 60+. Some studies have shown sensory impairment is associated with impaired cognitive test performance, however tests rely to varying degrees on hearing, vision, or both. We hypothesized that scores for cognitive tests whose administration or instructions depend on vision (e.g., Trail Making) or hearing (e.g., word‐list learning) are biased among those with vision or hearing impairment, respectively, after controlling for underlying cognitive performance.MethodWe leveraged cross‐sectional data from a comprehensive neuropsychological battery on N=658 men and women from the Baltimore Longitudinal Study of Aging (BLSA) and N=1,008 participants from the Atherosclerosis Risk in Communities study (EyeDOC ancillary study), all of whom had objective diagnostic hearing and vision assessed. We used item response theory methods to test for differential item functioning (DIF) by hearing (PTA>25 db in 4 speech frequencies) and visual acuity (20/40) impairment.ResultThe BLSA sample was 55.7% female and 66.3% white. The EyeDoc sample had a higher proportion of women (63.4%) but fewer white participants (54.3%). Overall, we found more evidence of DIF in the EyeDoc study, a sample with lower cognitive performance and a higher number of comorbidities, as compared to the BLSA. No DIF by visual impairment was observed in BLSA, but in EyeDoc we observed DIF by visual impairment for the Delayed Word Recall Task such that the task was harder for those with visual impairment. A larger number of tests showed DIF by hearing impairment in both BLSA and EyeDoc, including the Delayed Word Recall Task in EyeDoc and the Digit Symbol Substitution Task in BLSA.ConclusionWe identified DIF by hearing impairment for tests that do not rely on hearing and DIF by vision impairment for tests that do not rely on vision. Based on these findings, if bias is found in cognitive tests independent of characteristics of the test administration or instructions, cognitive load may be playing a larger role than previously acknowledged. Future investigation is warranted to determine how sensory impairment impacts completion of cognitive testing, as this study was limited to participants who successfully completed cognitive testing.
Safety monitoring in the U.S. study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (US POINTER)
Authors: Williams Benjamin J , Felton Deborah M , Nichols John E , Espeland Mark A , Baker Laura D 
Published: December 2020

AbstractBackgroundUS POINTER is a multisite randomized clinical trial funded by the Alzheimer's Association. It is designed to evaluate whether different lifestyle interventions (exercise, nutrition, and cognitive and social stimulation) protect cognitive function over a 2‐year period in approximately 2000 older adults.MethodWe have designed a web‐based safety tracking system (STS) that meets the complexity of this trial that involves oversight of participants as they carry out the interventions by community partners at 5 trial sites.ResultIn US POINTER, participants interact with community interventionists as well as research clinic staff and clinicians. All personnel are charged with documenting potential safety events. We designed the STS to allow timely and accurate collection of safety data by study personnel regardless of their role in the study or the location of their contact with the participant. This ensures that safety data are complete. Health events entered by interventionists and clinical trial staff are reviewed by local site clinicians to determine if the event meets criteria for an adverse event (AE). If so, the clinician then determines the expectedness, relatedness, and risk of harm of the AE. These determinations are captured on the STS. Safety reporting is then reviewed and adjudicated by the central Safety Manager and the trial Safety Officer and, if needed, by the Safety Committee. The STS facilitates these processes and ensures the accuracy and consistency of safety data reporting throughout the trial. Importantly, the trial design requires that study personnel, Safety Manager, Safety Officer, and the Data Coordinating Center remain masked or unmasked as to study interventions and outcomes. The STS was designed so that access to the STS is restricted by study role in order to maintain the intervention assignment mask. These attributes of the STS help to maintain the rigor and integrity of the trial.ConclusionThe innovation of the POINTER STS is that it allows for reporting of AEs obtained during any point of contact between the participant, community partners and study personnel, and allows for a multi‐level review of safety events in a centralized, efficient and timely manner thus ensuring participant’s ongoing safety throughout the trial.
Infocaregiver: Co‐conception of an information campaign on assistive technology solutions to support informal caregivers of older adults with neurocognitive disorders in priority areas of needs
Authors: Pino Maribel , Laabar Amal , Rigaud Anne‐Sophie , Damnee Souad , Cantegreil‐Kallen Inge , Benveniste Samuel 
Published: December 2020

AbstractBackgroundInformal caregivers of older adults with neurocognitive disorders participate in essential tasks in the life of their loved one, ranging from household chores to following complex medical treatments or coordinating home care and services. Caregivers report a strong lack of support regarding this role which can lead to high levels of stress and depression, musculoskeletal disorders and general exhaustion. The access to information on assistive technology (AT) resources, could help caregivers improve quality of life and care. Particularly, since AT could provide them with an affordable and effective daily support. However, in France, many caregivers lack of information regarding AT. A consequence of this situation is the limited AT use.MethodThe objective of the InfoCaregiver project is to create and distribute 6 information packs (animation videos and flyers) for informal caregivers regarding the use of AT to support caregiving tasks. The conception process of this information campaign includes: a literature review, a need’s assessment study regarding AT use among caregivers using a questionnaire, interviews and focus groups, and an iterative process involving caregivers and professionals for the definition of the scripts and video scenarios and their production. A particular attention will be paid to the provision of neutral and accessible information. These packs will be then freely distributed (Creative Commons license).ResultSix main priority themes have been identified for the AT information campaign : 1) The caregiver role and the general benefits for caregivers of using AT, 2) the use of AT for improving security at home, 3) the use of AT for promoting social life and communication, 4) the use of AT for the coordination of home care services, 5) the use of AT for leisure activities, and 6) the use of AT for providing psychosocial support to caregivers. Video and print material is currently under developmentConclusionInvolving caregivers in the design process allows the creation of useful, acceptable and ethical AT information. Caregivers reached by our AT information campaign will gain a better knowledge of AT possibilities. It is expected that this action will lead to an increased use of AT in France.
Genetics, diet, and sex interact to modulate cognitive decline in Alzheimer’s disease
Authors: Dunn Amy R. , O'Connell Kristen M.S. , Kaczorowski Catherine C. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) etiology is complex, with disease risk and progression mediated by individual genetic and environmental factors. Additionally, there are significant sex differences in aging, brain metabolism, and AD risk. This complexity adds challenges to understanding disease mechanisms and developing treatment strategies that will be effective across the AD population; human studies have been limited in understanding these interacting effects due to human genome complexity and difficulty controlling environmental factors, such as diet.MethodWe recently developed a population of genetically diverse mice carrying the 5XFAD transgene (AD‐BXDs; Neuner, et al. 2019). Because they model human genetic heterogeneity, AD‐BXDs are ideally suited to investigate translationally‐relevant gene‐environment and sex interactions. Here, we used AD‐BXDs to determine how genetics, diet, and sex interact to modify AD‐related symptoms. We fed a chronic 45% high fat diet (HFD) starting at ∼2.5mo of age to 39 strains of AD‐BXDs and nontransgenic littermates (Ntg‐BXD). We monitored hippocampus‐dependent cognitive function using y‐maze (working memory) and contextual fear conditioning (short‐ and long‐term memory) across their lifespan.ResultGene‐by‐diet interactions accounted for a significant proportion of variance in cognitive phenotypes across the population of AD‐BXDs and Ntg‐BXDs, and the effect of HFD differed depending on sex. We saw a protective effect of HFD in female AD mice on working memory through middle age that was not seen in male mice. By 14mo, female Ntg – but not AD – mice on HFD experienced significantly worse cognitive decline than those on chow—an effect that again was not seen in males.ConclusionOur results suggest that diet affects AD risk and progression differentially based on sex and genetic background: intriguingly, HFD may be protective in female AD mice while being detrimental to cognitive function in “normal” aging. These findings in the AD‐BXDs demonstrate individual variation in how diet affects AD risk and cognitive aging, and that the mechanisms underlying this variation are ripe for discovery. Future analyses will build upon these data to identify genetic and molecular targets contributing to AD pathogenesis sensitized by sex and HFD that may be exploited to delay, prevent or treat AD.
Do senescent cells play a role in Alzheimer’s disease?
Authors: Walker Lauren , Jacobs Eleanor , McAleese Kirsty E. , Johnson Mary , Attems Johannes 
Published: December 2020

AbstractBackgroundCellular senescence, the irreversible arrest of the cell cycle, is a common occurrence in ageing. Astrocytes have been shown to demonstrate a senescent phenotype, which is increased in ageing, and in Alzheimer’s disease (AD) (as evidenced by p16INK4a expression). Recently, a causal link was established between p16INK4a expression and hyperphosphorylated tau (HPT) pathology in the MAPTP301SPS19 mouse model of tauopathy, where treatment with a senolytic agent removed senescent p16INK4a positive astrocytes, prevented aggregation of HPT, and preserved cognitive function, suggesting senescent astrocytes may play a role in HPT deposition observed in AD. However, data in human post‐mortem tissue from AD cases (inclusive of Aβ pathology) is lacking.MethodFrontal cortex (BA9) from 10 AD and 10 control cases were double immunolabelled for GFAP and p16INK4a. A mean number of p16INK4a positive astrocytes (identified by the presence of co‐localisations) was determined at 6 regions of interest across each section. HPT and Aβ were quantified by percentage area of immunopositivity in the same region.ResultAD cases had significantly more p16INK4a positive astrocytes compared to controls (p<0.05). We observed a positive association between number of p16INK4a positive astrocytes and HPT load in AD cases (p<0.05). No association was observed between the mean number of p16INK4a positive astrocytes and Aβ load.ConclusionWe found a positive association was found between p16INK4a positive astrocytes and HPT. This area of research warrants further investigation to determine whether the development of senolytic therapies are a viable option for the treatment of AD and other tauopathies.
Disease progression modeling‐based prediction of cognitive decline
Authors: Ghazi Mostafa Mehdipour , Sørensen Lauge , Pai Akshay , Cardoso Jorge , Modat Marc , Ourselin Sebastien , Nielsen Mads 
Published: December 2020

AbstractBackgroundThe objective of this study is to investigate decline prediction of cognitive test scores in stable and converting mild cognitive impairment (MCI) subjects using both nonparametric and parametric Alzheimer’s disease (AD) progression modeling methods trained on data including cognitive tests, CSF measures, and neuroimaging biomarkers.MethodThe study dataset consisted of yearly visits (2005‐2017) for 782 Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects with normal cognition, MCI, or AD, including FreeSurfer‐based T1‐weighted brain MRI volumes (ventricles, hippocampus, whole brain, fusiform, and entorhinal cortex, all normalized with intracranial volume), cognitive tests (MMSE, CDR‐SB, ADAS‐Cog‐13, FAQ, and RAVLT‐immediate‐recall), CSF measures (Amyloid‐beta and p‐tau), and FDG‐PET. Two state‐of‐the‐art disease progression modeling methods, a nonparametric using LSTMs (Ghazi, M. M., et al., Medical Image Analysis 53, 39‐46, 2019) and a parametric using regression (Jedynak, B. M., et al., Neurobiology of Aging 36, 178‐184, 2015), were trained on 632 subjects and subsequently applied to predict month 24 to 96 MMSE scores for 150 independent test subjects using only their baseline and month 12 data.ResultThe predictive power and prognostic capability of the AD progression modeling methods were assessed using the per‐visit mean absolute error (MAE) and area under the ROC curve (AUC) of predicted MMSE scores for stable MCI (sMCI) and converting MCI (cMCI) test subjects. The average MAE results for month 24 to 96 MMSE scores were as follows: nonparametric 1.39 to 1.04 (sMCI), 2.41 to 3.62 (cMCI); parametric 1.46 to 4.00 (sMCI), 2.42 to 2.53 (cMCI). The average AUC results for month 24 to 96 obtained based on the predicted MMSE scores were as follows (two‐sample t‐test, p < 0.001 in all cases): nonparametric 0.79 to 0.73; parametric 0.83 to 0.69.ConclusionIn almost all cases, the nonparametric method outperforms the parametric model in predicting MMSE scores. Moreover, predictions from both nonparametric and parametric methods can significantly discriminate between sMCI and cMCI groups. Though, the discrimination capability of the nonparametric method is superior in long‐term prediction of cognitive decline.