bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does the presence of type II Diabetes affect cognitive decline in Alzheimer’s Disease Dementia?
Authors: Davidson Skylar , Allenback Gayle , Decourt Boris , Sabbagh Marwan N. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is sometimes referred to as Type 3 diabetes. While it is very likely that insulin dysregulation and resistance participate in the etiology of AD pathologies, little is known about the possible correlation between diabetes and the progression of cognitive decline in AD patients. Previous studies have shown an increased risk of developing AD in patients with type 2 diabetes mellitus (T2DM). The specific aim of our study was to determine whether differences exist in cognitive decline experienced by AD subjects with and without T2DM co‐morbidity.MethodAll cognitive performance data and the presence or absence of T2DM co‐morbidity in AD patients used in the present report were derived from the Uniform Data Set (UDS) of the database maintained by the National Alzheimer’s Coordinating Center (NACC), USA. The scanning of the UDS database identified 3055 participants with AD who had more than one epoch completed. The dataset culled clinically‐diagnosed AD patients who were assessed for diabetes type in form A5 or D2 during at least one visit. These patients were divided into two groups dependent upon the presence of a diagnosis of T2DM. The data from these groups was then analyzed for differences in cognitive decline based upon Neuropsychological Battery Scores and a Clinician Dementia Rating (CDR) using a general linear model.ResultCognitive function tests looked at language, cognitive executive function, and verbal and nonverbal memory. Comparison of the mean scores in 16 selected tests from the Neuropsychological Battery test showed no significant differences in baseline scores and scores at subsequent visits between the T2DM and non‐diabetic groups.ConclusionUsing the NACC database, which receives longitudinal data from Alzheimer’s Disease research Centers (ADRCs), it was found that there were no differences in cognitive decline metrics over the course of 5 visits in either group. This supports the position that the presence of T2DM does not appear to increase the magnitude of cognitive decline in AD patients
Proteomic profiling of human brain coupled to functional assays for the identification of neurotoxic proteins
Authors: Hsieh Yi‐Chen , Negri Joseph , He Amy , II Richard V Pearse , Liu Lei , Duong Duc M. , Chibnik Lori B. , Bennett David A , Seyfried Nicholas T. , Young‐Pearse Tracy 
Published: December 2022

AbstractBackgroundAlzheimer’s Disease (AD) affects millions globally, but therapy development is lagging. The dearth of new therapies requires a reconsideration of pre‐clinical models of AD to facilitate the discovery of efficacious treatments. Ideally, such models would allow for monitoring the functional behavior of neurons in conditions approximating the AD brain.MethodsTowards the goal of developing more representative, pre‐clinical AD models, we employ multiple‐electrode arrays (MEAs) and live‐cell imaging for assessing neuronal firing and neurite integrity (NI), respectively. We use this system to examine changes in neuronal activity and neurite integrity following treatment with TBS‐soluble human brain extract from a panel of 43 individuals comprised of AD patients, unaffected persons not exhibiting AD pathology nor cognitively impaired, and individuals not cognitively impaired but exhibited AD‐related postmortem pathology. To determine the molecular etiology of these functional changes in an unbiased manner, we perform label‐free proteomic analyses on the panel of 43 brain extracts.ResultsAmyloid‐β (Aβ) and tau accumulate in the AD brain, and specific forms of each of these proteins have shown neurotoxic properties. We observe associations between spontaneous activity and Aβ42:40 levels, and between neurite integrity and oligomeric Aβ or tau containing N inserts. Additionally, the proteomic analyses reveal several candidates whose expression correlated with changes in neuronal structure and activity. Proteins associated with neurotoxic activities in MEA and NI assays are enriched in proteins implicated in lysosomal storage disorders, while proteins associated with neuroprotective properties are enriched in proteins of the WAVE regulatory complex that are involved in the regulation of actin polymerization. We further show that elevated GM2A in the AD brain and AD CSF is associated with reductions in both neurite integrity and MEA activity. Applying cell derived GM2A in the absence of brain extract is sufficient to induce a subtle but significant loss of neurite integrity.ConclusionThe techniques and data herein introduce a system for modeling neuronal vulnerability in response to factors present in the aged human brain and provide insights into proteins potentially contributing to AD pathogenesis.
Cardiovascular Risk and Ethnic Disparities in Cognition among Mexican Americans and Non‐Hispanic Whites: The Health and Aging Brain Study
Authors: Jiang Xiaqing , Peltz Carrie , Johnson Leigh , O'Bryant Sid E. , Yaffe Kristine 
Published: December 2022

AbstractBackgroundMexican Americans (MAs) may have increased risk for cognitive impairment and greater cardiovascular risk (CVR) compared to non‐Hispanic whites (NHWs). This disproportionate burden of CVR in MAs may be an important driver for ethnic differences in cognitive aging, although population‐based evidence is lacking. As part of the Health and Aging Brain Study, we investigated the contribution of CVR burden to ethnic differences in cognition.MethodsWe studied 1,320 MA and NHW participants without dementia (63% women, 57% MAs) aged 50‐74 years (2017‐2021, mean age 63.7±6.7 years) who underwent a cognitive battery of five tests: Trail Making Test Part A (attention) and B (executive function), Digit Symbol Substitution (processing speed), FAS and Animal Naming (verbal fluency), and Spanish English Verbal Learning Test 30‐minute delay (verbal memory). CVR burden was assessed using the Framingham Risk Score (FRS, range ‐2 to 25 in woman, ‐2 to 19 in men). We used linear regression to assess the association of CVR (intermediate/high: FRS ≥10 vs. low: FRS <10) with cognitive function (z‐standardized) and its contribution to ethnic differences in cognition.ResultsMAs were on average four years younger but have higher FRS (1.8 points; 95% CI 1.5 to 2.2) compared to NHWs. In unadjusted models, intermediate/high CVR was associated with lower cognition in all domains. After adjusting for ethnicity, age, sex, education, and APOE ε4, intermediate/high CVR remained associated with lower cognition in two domains: processing speed (‐0.13, 95% Cl ‐0.23 to ‐0.03) and verbal memory (‐0.13, 95% Cl ‐0.23 to ‐0.03). The strength of the association in MAs was similar to NHW (p >0.05 for interactions by ethnicity). In unadjusted models, intermediate/high CVR explained 4‐6% of ethnic differences in cognition in all domains. Results in multivariable‐adjusted models were similar, although FRS explained a greater portion of the ethnic differences in some domains: 10% in processing speed and 15% in verbal memory.ConclusionCompared to NHWs, MAs had greater CVR burden, which explained some of the ethnic differences in cognition. Efforts to lessen ethnic disparities in cognitive outcomes may benefit from a better understanding, prevention, and management of CVR in a population with growing number of ethnic minorities.
Higher Household Air Pollution Levels Correlate with Poorer Cognitive Function in the Longitudinal Aging Study in India (LASI)
Authors: Adar Sara , D'Souza Jennifer , Shaddick Gavin , Langa Kenneth M , Gross Alden L , Angrisani Marco , Khobragade Pranali , Banerjee Joyita , Chattopadhyay Aparajita , Dey A. B. , Sekher T.V. , Bloom David , Lee Jinkook 
Published: December 2022

AbstractBackgroundIndians have some of the highest fine particulate matter (PM2.5) exposures in the world, not only due to high ambient air levels but also because of household combustion of biomass fuel. To understand the burdens of these exposures for older adults, we evaluated associations of indoor PM2.5 with cognitive function in India.MethodWe used data from the 2017‐2019 baseline survey of the nationally‐representative Longitudinal Aging Study in India (LASI) to derive a general cognition score for each participant. For indoor PM2.5 levels, we used an India‐specific prediction model informed by participant cooking and housing characteristics. We estimated associations between indoor PM2.5 with cognitive function using linear mixed‐effects models after adjustment for age, sex, individual and community‐level socioeconomic variables, region, clustering by village, and sample weights.ResultWe observed a population of 61,708 participants aged 45 and over. Many of these individuals (48%) used highly polluting fuel, resulting in average indoor PM2.5 concentrations of 205± 110 µg/m3. After adjustment for individual and area‐level confounders, we found that indoor PM2.5 was associated with poorer cognitive function. For each 100 µg/m3 of indoor PM2.5, we observed ‐0.027 (95% CI: ‐0.033, ‐0.02) lower cognition scores. These associations were strongest among women as well as among adults less than age 65 years. When scaling these associations to the observed interquartile range (150 µg/m3), household exposures resulted in cognitive differences comparable to those observed between people 2 years apart.ConclusionAmong older adults living in India, household PM2.5 is associated with poorer cognition at older ages even after adjustment for individual sociodemographic characteristics and regional trends.
The Effect of COVID‐19 Lockdown on Dementia Caregivers in the U.S.
Authors: Bullard Breanna M , Merrilees Jennifer , Wang Gene , Levenson Robert W 
Published: December 2022

AbstractBackgroundIn response to the COVID‐19 pandemic, mandated state lockdowns in the U.S. profoundly changed day‐to‐day life for many individuals providing informal care for a person with dementia or mild cognitive impairment. The present study explored changes in caregiver burden, depression, and anxiety associated with lockdown.MethodWe used questionnaire data collected as part of a randomized controlled trial conducted between February 2019 ‐ June 2021. Participants (N = 260 familial caregivers for people with dementia or mild cognitive impairment living in the US) completed a baseline survey at the start of the study and follow‐up surveys every three months for six‐nine months. Questionnaires included the Zarit Burden Index, the Beck Anxiety Inventory, and the Center for Epidemiological Studies Depression scale. We determined the date of lockdown based on the first lockdown order issued in the participant’s state of residence. For each survey score, we also determined the number of days before or after the lockdown date.ResultThe mean age of caregivers in the sample was 63.93 years and 68% were female. A regression predicting caregiver burden from the days before/after lockdown revealed that burden decreased over time, (β = ‐0.008, p = .051). Consistent with this, comparing the average of all scores obtained after lockdown with those obtained before lockdown indicated that burden decreased during lockdown, (t(172) = ‐2.52, p = .013). Levels of caregiver anxiety and depression were not associated with days before/after lockdown and did not change from before lockdown to after lockdown (p’s >.05).ConclusionSurprisingly, caregivers in our sample experienced a decrease in burden associated with COVID lockdown. We believe this may result from lockdown providing relief from caregivers’ other responsibilities (e.g., being able to work from home, reduced social obligations). The lack of changes in anxiety and depression may reflect this as well, with these areas of relief offsetting some of the stresses that would normally result in worsening mood for caregivers. In future research we hope to further explore these complex relationships among lockdown, burden, depression, and anxiety.
A molecular approach in DRUG DEVELOPMENT for the management of cognitive dysfunction in Alzheimer’s Disease.
Authors: Silakari Pragati , Piplani Poonam 
Published: December 2022

AbstractBackgroundCognitive decline is budding as one of the greatest health threats in the current scenario as it results in conditions like impaired attention, learning, memory, and problem solving incapability in the patient of Alzheimer’s disease. Neuroinflammation, neurodegradation and oxidative stress can lead to cognitive decline and neuronal loss. Currently, only four AChE inhibitors (tacrine, rivastigmine, donepezil and galantamine) have been approved by the FDA for the symptomatic treatment of AD. However, these acetylcholinesterase inhibitors are not devoid of side effects and have lesser CNS permeability. This instigated further development in the fields of AChEIs and antioxidants for cognitive decline as investigations in these fields seems promising and encouraging. A series of novel polyamino‐substituted‐1,4‐benzoquinone molecules were designed and synthesized against the target AChE and evaluated for their in vitro, in vivo, and ex vivo AChE inhibitory activity and antioxidant potential for the development of novel potent molecules for the management of cognitive decline.MethodSeries of novel amino‐substituted‐1,4‐benzoquinone derivatives have been designed and docked with the binding pocket of the enzyme AChE. These molecules were synthesized and evaluated for their selective in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential, and for antioxidant potential using DPPH and hydrogen peroxide radical scavenging protocols. Further these compounds have been evaluated against behavioral alterations using step down passive avoidance and escape learning protocol with reference to the standard donepezil. Subsequently, compounds were further subjected for their ex vivo AChE inhibition using mice brain homogenate as the source of enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione and catalase) has also been carried out to determine the role of the synthesized molecules on the scopolamine induced oxidative damage.ResultOur outcomes depicted that the anti‐amnesic effect of the synthesized conjugates on scopolamine‐induced memory impairment may be related to the mediation of cholinergic system and their effective antioxidant activity.ConclusionThe results obtained from pharmacological studies were found to be appreciable and provided promising leads which can be further explored structurally and pharmacologically, presenting a favorable scenario for the development of selective AChE inhibitors for the management of cognitive decline.
Evidence of hospital‐based HIT infrastructure and reduced Medicare payment and racial and ethnic disparities among ADRD patients
Authors: Chen Jie , Spencer Merianne , Buchongo Portia , Wang Minqi 
Published: December 2022

AbstractBackgroundUnderstanding the potential cost‐saving or cost‐enhancing of HIT adoptions can help policymakers understand the capacity of HIT investment for population health and racial and ethnic groups. The objective of the study is to examine access to the hospital‐based HIT infrastructure and its association with Medicare payments by Alzheimer’s disease and related dementia (ADRD) patients’ racial and ethnic groups. ADRD is one of the most expensive health conditions in the Unites States and substantial racial and ethnic disparities are observed.MethodWe used 2017 Medicare Beneficiary Summary File, inpatient claims, and the American Hospital Annual survey. Generalized linear models were used for the payment regressions.ResultsThe adjusted total Medicare payment and acute inpatient Medicare payment per person per year were higher for ADRD beneficiaries treated in hospitals with telehealth‐post discharge functions (e.g., an incremental increase of $542 in total payment). However, it relates to a significant reduction of Medicare payments to Black ADRD patients (approximately a reduction of $1,104). The finding suggested that telehealth‐post discharge might be cost‐enhancing at the population level; however it is cost‐saving to Black patients with ADRD. The cost‐saving of Black patients exceeded the incremental cost of the adoption of HIT‐post discharge. Similar findings were found for the telehealth‐treatment, which was associated with a significant reduction of payments among Black and Hispanic ADRD patients.ConclusionsResults suggested that personalized HIT utilization and provisions (telehealth‐post‐discharge for Black and telehealth‐treatment for Black and Hispanic ADRD patients) are critical components of receiving high‐quality ADRD treatment for minority patients.
APOE4 mice rely more on the plasma DHA than APOE3 mice, especially in glia morphology and cognitive performance.
Authors: Plourde Melanie 
Published: December 2022

AbstractBackgroundThe metabolism of docosahexaenoic acid (DHA), an omega‐3 fatty acid, is different in APOE4 carriers. Brain relies on the plasma DHA pool for its need but the plasma‐liver‐brain axis in relation to cognition remains obscure. We hypothesized that this relation is compromised in APOE4 mice considering the differences in fatty acid metabolism between APOE3 and APOE4 mice.MethodMale and female APOE3 and APOE4 mice were fed either a diet enriched with DHA (0.7 g DHA/100 g diet) or a control diet for 8 months. Barnes maze and object recognition tests were performed in mice. Immunofluorescence was eprformed on parafin embeded brain slides with GFAP and IBA‐1 and multiplex cytokines were measured in hippocampus protein extracts.ResultIn the cortex, a genotype effect was found where APOE4 mice had higher concentration of DHA than APOE3 mice fed the control diet. APOE4 mice had 20‐30% lower plasma DHA and arachidonic acid (AA) concentrations, adipose tissue AA concentrations than APOE3 mice, independent of diet. In APOE4 mice, there was a significant correlation between plasma DHA and scores on the Barnes maze and with better recognition index. In addition, APOE4 mice fed the DHA diet had lower hippocampal concentrations of interleukin‐7, lipopolysaccharide‐induced CXC chemokine and monocyte chemoattractant protein 1, and higher concentration of interferon‐gamma compared to APOE4 mice fed the control diet. We also found that a diet rich in DHA enhances reactive astrogliosis and ramified microglia morphology in APOE4 mice.ConclusionAltogether, our data support that APOE4 mice rely more on the plasma DHA than APOE3 mice, especially in cognitive performance and astrocytes and microglia morphology. Any disturbance in plasma DHA metabolism might have a greater impact on cognition in APOE4 carriers.
Lymphatic drainage at the meningeal‐brain interface in aging and Alzheimer’s disease
Authors: Da Mesquita Sandro 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent form of dementia. We have recently shown that proper meningeal lymphatic drainage is important for brain fluid flow, learning and memory in aging and for brain amyloid beta (Aβ) clearance in mouse models of AD. Interestingly, genetic factors that increased the risk for AD are also linked to altered meningeal lymphatic function.MethodMeningeal lymphatic function was evaluated in mouse models of AD at different ages by RNA sequencing of sorted meningeal lymphatic endothelial cells (LECs) and by assessing of lymphatic vessel morphology and drainage capacity. Meningeal lymphatic dysfunction was induced by photoablation, whereas enhancement of meningeal lymphatic drainage was achieved by increasing the levels of VEGF‐C. The transcriptional signatures of brain blood endothelial cells and microglia were determined by single‐cell RNA sequencing upon manipulation of meningeal lymphatic drainage. Changes in Aβ plaque clearance by monoclonal antibodies were assessed upon prolonged manipulation of meningeal lymphatic drainage. Integrated analysis was performed using murine and human cell RNA‐seq data, as well as AD summary statistics.ResultWe show that a progressive deposition of meningeal Aβ with aging leads to gene expression changes in meningeal lymphatic endothelial cells and an accelerated reduction in meningeal lymphatic vessel coverage in the 5xFAD mouse model. Interestingly, modulating meningeal lymphatic function in AD transgenic mice affects the clearance of Aβ by monoclonal antibodies, a feature that is closely associated with the activation signatures in brain blood endothelial cells and microglia. Furthermore, genes that are highly expressed in lymphatic vasculature are associated with increased risk for AD and altered levels of Aβ in the CSF of AD patients. Integrated analysis of murine and human microglia transcriptomes revealed an association between the signatures of activated microglia from mice with defective meningeal lymphatic function and activated microglia isolated from the AD brain. We are now turning our attention to the interaction between the main genetic risk factor for AD, expression of the apolipoprotein E4, and changes in brain drainage by the meningeal lymphatic vascular system.ConclusionCollectively, our data underline the notion that a dysfunctional meningeal lymphatic vasculature may impact on AD pathophysiology and therapeutic outcome.
Impacts of Aerobic Capacity, Liver Function, and Metabolism on Brain Health
Authors: Lysaker Colton R , Troutwine Benjamin R , Strope Taylor A. , Franczak Edziu M , Allen Julie A , Chauhan Munish , Harris Janna L , Thyfault John P , Wilkins Heather M 
Published: December 2022

AbstractBackgroundAerobic capacity (VO2 max) strongly influences biological functions including both liver and brain function. Low aerobic capacity has far reaching impacts with both increased risk of non‐alcoholic fatty liver disease (NAFLD) and Alzheimer’s disease (AD). Previous work has shown that poor liver function was associated with decreased cognitive function and increased risk of AD. In addition, diet and lipid metabolism play a critical role in brain health, however, the full relationship between these factors and AD risk needs to be elucidated.MethodWe assessed brain mitochondrial function and AD pathology in rats selectively bred for aerobic capacity (low‐capacity runners or high capacity runners, bred over 43 generations). Mitochondrial function was assessed using Seahorse XF technology and spectrophotometric Vmax assays. Phosphorylated tau and Aβ levels were analyzed using western blotting and ELISAs. We assessed outcomes at 12, 18, 24, and 28 months. A separate cohort of rats were fed a low‐fat diet (LFD), high fat diet (HFD), or high fat diet with bile acid sequestrant (HFD+BA) and followed from age 6 to 12 months. Barnes and Y‐maze were performed to measure cognitive outcomes. MRI/MRS was completed to measure hippocampal volume and neurochemical profiles.ResultMitochondrial function parameters were different between groups and with different diets in both brain and liver. Overall LCR animals had reduced brain mitochondrial function and reduced resilience with long term HFD. LCR rats had increased phosphorylated tau levels. Female rats with a low intrinsic aerobic capacity (LCR) have significantly higher levels of Aβ42 when compared to rats with a high intrinsic aerobic capacity (HCR). LCR rats performed worse on the Y‐maze beginning at 10 months of age irrespective of diet.ConclusionAerobic capacity and diet affect brain health during aging. Liver function appears to play a large role in brain health outcomes. We continue to analyze MRI/MRS and cognitive data in correlation with liver function.