bluuebunny/crossref_metadata_2025_split huggingface dataset:
Donepezil prevents cognitive impairment and gut epithelial disruption in doxorubicin‐treated rats
Authors: Suparan Kanokphong , Ongnok Benjamin , Khuanjing Thawatchai , Thonusin Chanisa , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: December 2022

AbstractBackgroundDonepezil (DPZ) is an acetylcholinesterase inhibitor used to improve cognitive function. We reported that it prevented doxorubicin (Dox)‐induced chemobrain. Gut epithelial disruption, gut dysbiosis and impaired essential microbial metabolites, such as short chain fatty acids (SCFAs), have found following Dox therapy. However, the impact of DPZ to prevent gut epithelial disruption and gut dysbiosis as well as disturbance of circulating SCFAs due to Dox‐induced chemobrain have been never investigated.MethodTwenty‐four rats were divided into sham rats, vehicle‐treated Dox rats, and DPZ‐treated Dox rats. Modified Novel Object Location and Recognition tests were used to evaluate cognitive function. At the end of the study, ileums were removed to investigate occludin protein expression, and PCR of ileal luminal contents were used to calculate Firmicutes to Bacteroidetes (F/B) ratio. Serum butyric acid, a representative of SCFAs, was assessed by Gas chromatography‐mass spectrometry.ResultDox‐rats developed cognitive impairment with gut epithelial disruption, gut dysbiosis and reduced essential microbial metabolites (serum butyric acid). DPZ significantly prevented cognitive decline in Dox‐rats (Fig 1A‐C). Furthermore, DPZ restored the expression of occludin in gut tissue, suggesting that DZP improved gut epithelial integrity in Dox‐rats (Fig 1D). DZP improved gut dysbiosis in Dox‐rats as indicated by attenuated F/B ratio (Fig 1E), but level of serum butyric acid between DZP‐treated Dox rats and vehicle‐treated Dox rats was not different (Fig 1F).ConclusionDPZ co‐treatment with Dox prevented Dox‐induced cognitive impairment. Although DZP protected gut epithelial disruption, and improved gut dysbiosis, however it could not help to increase circulating SCFAs. These findings suggest that DPZ, itself, cannot completely prevent the gut disturbance in rats with Dox‐induced chemobrain. Therefore, the probiotic supplement with DZP might be the other approach to prevent gut problem following chemotherapy.
Efficacy and Safety of Adding Kami Guibi‐tang to Acetylcholinesterase Inhibitor for Cognitive Function in Mild Alzheimer’s Disease: A Pilot, Randomized, Double‐blind, Placebo‐controlled Trial
Authors: Yim Tae‐Bin , Kim Ha‐Ri , Shin Hee‐Yeon , Heo Hye‐Min , Jahng Geon‐Ho , Cho Seung‐Yeon , Park Seong‐Uk , Ko Chang‐Nam , Park Jung‐Mi 
Published: December 2022

AbstractBackgroundThe main treatments for mild AD have been acetylcholinesterase inhibitors(AChEI). However, no current drugs can fundamentally treat AD or reverse advanced cognitive decline. This clinical study was conducted to explore the efficacy and safety of adding Kami Guibi‐tang(KGT) to AChEI for cognitive function in elderly patients with mild AD.MethodThis study was designed as the pilot for a larger randomized, double‐blind, placebo‐controlled study. Elderly participants aged 55 to 90 years diagnosed with mild AD. Subjects were randomized to receive either KGT or placebo for 24 weeks, in addition to their regular AChEI. The primary study outcome was treatment efficacy as assessed by the relative amount of change over the study period in total scores on the Dementia version of the Seoul Neuropsychologic Screening Battery(SNSB‐D). Changes in SNSB sub‐scores such as the Korean Mini‐Mental State Exam(K‐MMSE) and in scores on the Korean version of Quality of Life‐Alzheimer’s Disease(KQoL‐AD), and the Caregiver‐Administered Neuropsychiatric Inventory(CGA‐NPI) were assessed as secondary outcomes. We also monitored patient safety parameters including adverse events and abnormalities in blood tests, electrocardiogram, and brain magnetic resonance imaging tests.Result7 participants in the KGT group and 7 participants in the placebo group completed the 24‐week trial. There were no significant changes in SNSB‐D total/subindex scores, KQoL‐AD or CGA‐NPI scores for either group, and no significant differences were observed between the two groups. K‐MMSE scores were decreased significantly within each group, but were not significantly different between groups. No adverse events related to KGT were reported. In addition, we compared / analyzed the results of a previous pilot study conducted on amnestic mild cognitive impairment(aMCI) with the same protocol as this study. The aMCI group showed a significant improvement in the total SNSB‐D score(especially in the memory domain) and K‐MMSE and Korean Instrumental Activities of Daily Living scores compared with the mild AD group.ConclusionAdding KGT to AChEI did not significantly improve cognitive function in SNSB compared to placebo. Although KGT did not show cognitive improvement in the patients with mild AD in this study, we suggest that KGT would have a positive effect on the patients with early stages of cognitive impairment such as aMCI.
Is the U.S. clinical trial infrastructure optimized to meet the current and growing enrollment needs?
Authors: Scholler Emily , Beck Erin , Eimerbrink Micah 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) clinical development continues to expand with 28 drugs in Phase 3, 74 in Phase 2, and 24 in Phase 1 in 2021. This study seeks to investigate how the U.S. clinical trial infrastructure is prepared to meet the current and growing enrollment needs. We aim to evaluate the overlap between regional density of persons with dementia (PWD) and trial site service areas with attention to how coverage gaps impact the ability to enroll study participants representative of the national population diagnosed with AD.MethodPrevalence of AD by race, gender, socioeconomic status and language was collected using the 2019 US Census Bureau. Data on trial site location was gathered using ClinicalTrials.gov and a third party service. The SiteRx Provider Network, a network of over 1,200 treating neurologists and primary care physicians that refer patients to research across 28 US states, was gathered using ZIP codes from a proprietary database. AD prevalence by ZIP code was compared against ZIP codes of current clinical trials sites that conduct Phase 1‐3 CNS trials across the U.S and SiteRx Provider Network using a radius of approximately 60 miles.ResultThere are gaps between PWD and trial sites locations, which are significantly worse for minority patients. Heat maps were created using Excel and Tableau to visualize data, which indicated key areas of infrastructure misalignment given existing patient populations. Additional analysis was performed to explore how PWD and site location incompatibility impacted potential enrollment based on key demographic domains.ConclusionThe current AD clinical trial site infrastructure is not well equipped to meet the growing need for clinical trial recruitment. SiteRx is positioned to strengthen trial infrastructure through their ability to bridge community‐based care with nearby research sites to optimize enrollment at current sites and identity geographies in need of trial sites given the existing AD patient population.
Higher CSF Ab38 levels protect against cognitive decline in high‐functioning individuals
Authors: Bruno Davide , Reichert Chelsea , Zetterberg Henrik , Blennow Kaj , Pomara Nunzio 
Published: December 2022

AbstractBackgroundThe amyloid cascade hypothesis proposes that Alzheimer’s disease (AD) pathology starts with accumulation of b‐amyloid (Ab) peptides, leading to plaque deposition. In this context, the spotlight has been pointed firmly onto Ab42, but evidence suggests that shorter isoforms may also play an important role in modulating AD pathophysiology. A recent report with individuals with mild cognitive impairment or subjective cognitive decline (Cullen et al., 2021) has shown that higher cerebrospinal fluid (CSF) levels of Ab38 were associated with less decline on the mini‐mental state exam (MMSE) score and reduced risk of conversion to AD. The aim of this study was to test whether CSF Ab38 levels also predicted change in MMSE scores in cognitively intact individuals.MethodData were obtained from 40 individuals (age = 67.3, 6.3), who had taken part in a study on late‐life major depressive disorder at the Nathan Kline Institute and New York University. Data were available for baseline examination as well as three‐year follow up. Twenty‐three individuals were depressed at baseline, and 17 were controls; all had an MMSE score of 28 or higher at baseline. To test our hypothesis, we carried out a Bayesian linear regression analysis with change in MMSE score from baseline to follow‐up as outcome; CSF Ab38, CSF Ab42, and CSF phosphorylated (p) tau as predictors; and controlling for age, sex, APOE e4‐status and depression diagnosis (null model).ResultThe results showed that the model combining CSF Ab38 and CSF p tau was the strongest, with moderate evidence (BFm = 4), carrying nearly double the odds of the model with all predictors (BF10 = 0.539), and 4.6 times the odds of the null model (BF10 = 0.219): higher baseline levels of CSF Ab38 were associated with less decline in MMSE score, while higher p tau levels were linked to more decline. When isolating depressed individuals, the pattern of results was unchanged, while the null model was strongest with controls.ConclusionThese findings confirm the importance of examining shorter Ab isoforms also in individuals with no cognitive impairment or subjective cognitive decline.
Projected costs of dementia and quality adjusted life years lost between 2020‐2050: a population‐based microsimulation study
Authors: Brück Chiara C. 
Published: December 2022

AbstractBackgroundThe total cost of dementia has passed the $1 trillion mark in 2018 and dementia was the sixth most burdensome disease in 2016, causing an immense loss of quality adjusted life years (QALYs). Due to population ageing, costs and burden will further increase. We have quantified the expected future increase in costs and QALYs lost due to dementia.MethodWe used the microsimulation model MISCAN‐Dementia to simulate the life history and development of dementia of 10 million individuals. MISCAN‐Dementia synthesizes population‐based Rotterdam Study data with changes in demographics between birth cohorts from the early 1900s onwards. We assumed cost (from a societal perspective) and disutility values for patients and caregivers by dementia severity stage (MCI, mild, moderate, severe) and setting (home, institution). We determined costs and QALYs lost from 2020‐2050 for three different dementia risk trend scenarios: 1) stable age‐specific incidence, 2) linear decline by 13% per decade, 3) nonlinear declines averaging 13% per decade.ResultWe estimated total costs of dementia in 2020 at 13 billion euros and QALYs lost at 90,000 years for the general Dutch population, irrespective of the trend scenario. Assuming a stable age‐specific incidence resulted in costs of 29 billion euros and 207,000 QALYs lost in the year 2050, corresponding to a 124% increase compared to 2020. In contrast, the linearly declining trend resulted in 19 billion euros (95%CI: 15‐24) and 135,000 QALYs lost (95%CI: 106,000‐169,000) in 2050, translating into a 53% increase compared to 2020. Over the time horizon, costs and QALYs lost are roughly similar between dementia stages, although people spend more time with less severe disease (50% mild, 30% moderate, and 20% severe dementia). Similarly, costs of institutionalized care (30% of life years spent with dementia) are roughly equal to the costs while living at home (70% of life years spent with dementia).ConclusionBy 2050, the annual costs of dementia will increase to 19‐29 billion euros and dementia will cause 135,000‐207,000 QALYs lost per year. These projections highlight the need for policymakers and health care systems to prepare for an increase in the burden of dementia.
Subjective Cognitive Decline symptom burden is associated with self‐perceived risk for AD
Authors: Jacova Claudia , Robertson Frank , Smith Samantha 
Published: December 2022

AbstractBackgroundSubjective Cognitive Decline (SCD) refers to a self‐experienced decline in cognitive capacity despite normal performance on objective tests. Research has consistently linked SCD to incident Alzheimer’s disease (AD). The role of perceptions around aging and AD risk in the SCD experience has not been clearly delineated. Here we aimed to determine the association between chronological age, self‐perceived risk for AD, and SCD symptom burden.MethodCommunity‐dwelling participants aged ≥50 years (n = 483), located within the United States were recruited via the crowdsourcing website Amazon Mechanical Turk. They completed a survey consisting of demographic questions and the Subjective Cognitive Decline Questionnaire (SCD‐Q MyCog). The survey also included items about self‐perceived risk for AD (“Do you believe that you are at higher risk of AD than your peers”; endorsed = 1, not endorsed = 0) and an AD family history (endorsed = 1; not endorsed = 0). Linear regression was used to predict SCD total score from combinations of these measures, adjusted for gender.ResultThe sample’s descriptive data were: age M = 64±5.5, range 50–79, SCD total M = 4.7±5.8, range 0–24, 66.5% female. There were 17% (n = 82) who perceived themselves at heightened risk for AD, and 27% (n = 132) with a positive family history. When entered together, high perceived risk predicted higher SCD total whereas family history and age were not predictive: B = 4.9, p<.001, B = ‐.004, p = .99, B = ‐.024, p = .59, respectively, R‐squared = .11. SCD total was M = 8.8±6.6 for the high‐risk, 3.9±5.2 for low‐risk group. Adding age squared did not improve the model: B = ‐.001, p = .88. Interaction analyses revealed a trend for perceived AD risk but not family history to be conditional on age, B = ‐.260, p = .067, B = .060, p = .603..Johnson‐Neyman regions‐of‐significance indicated that beyond age 70, the coefficient for self‐perceived AD risk approached zero and was non‐significant:ConclusionOur findings highlight the importance of self‐perceptions of AD risk for SCD in the youngest old adults (age<70). These individuals appear to evaluate their cognitive capacity in relation to their perceived susceptibility to AD. Interestingly, objective risk (older age, AD family history) does not contribute to this evaluation.
Higher Dietary Inflammatory Index scores are not associated with cognitive decline in the Framingham Heart Study
Authors: van Lent Debora Melo , Gokingco Hannah , Beiser Alexa S , Yuan Changzheng , Jacques Paul F , Vasan Ramachandran S , Seshadri Sudha , Jacob Mini Elizabeth , Himali Jayandra J 
Published: December 2022

AbstractBackgroundNutritional factors can abet or protect against systemic chronic inflammation, which plays an important role in the development and progression of dementia. We evaluated whether higher (i.e. pro‐inflammatory) Dietary Inflammatory Index(DII) scores were associated with accelerated cognitive decline in the community‐based Offspring Framingham Heart Study(FHS).Method889 older adults (mean age 59 years [standard deviation (SD)], 8;58.3% women]) completed validated 126‐item Food Frequency Questionnaires(FFQ), administered at FHS examination cycle 7 (1998‐2001) and examination cycle 5 (1991‐1995) and/or 6 (1995‐1998). We created a DII score (based on the published method by Shivappa et al. 2014); a cumulative DII score was calculated by averaging across a maximum of three FFQs. Cognitive testing was completed at examination cycles 7, 8 (2005‐2008) and 9 (2011‐2014). Exam 7 was considered as study baseline and participants were followed over a mean time of 13.4 years (SD 1.3). We excluded participants with prevalent dementia or stroke at baseline and those with no cognitive testing follow‐up data. We examined associations between the cumulative DII score and cognitive test scores over time using linear mixed models adjusting for age, age‐squared, sex, education, time from exam 7 to neuropsychological exam 7, and time (model1) and additionally for apolipoprotein e4, body mass index, total energy intake, total cholesterol: high‐density lipoprotein ratio, physical activity, smoking and anti‐cholesterol medication (model2).ResultHigher DII scores were significantly associated with accelerated decline in performance on the Trail Making Test B minus A(TMT‐B minus A) (processing speed and executive function), following adjustment for model 1 covariates (β±SE, ‐0.001± 0.0004,p = 0.03). but the association failed to reach significance in Model 2 (‐0.001±0.0003,p = 0.08). We observed no relationship between higher DII scores and other cognitive domains. Stratified analyses showed that higher DII scores were associated with accelerated decline in TMT‐B minus A scores among apolipoprotein e4 carriers (Model 2:‐0.002±0.001,p = 0.047) but not among non‐carriers (Model 2:‐0.0004±0.0004,p = 0.33).ConclusionHigher DII scores were not associated with cognitive decline. To date, such studies have been very limited, most studies that found a relationship, were cross‐sectional and have used less sensitive testing. Future studies are encouraged to examine whether our findings can be replicated.
A brain atlas of astrocyte transcriptomics unveils complex states and responses to Alzheimer’s disease neuropathology
Authors: Serrano‐Pozo Alberto , Li Zhaozhi , Woodbury Maya E. , Wachter Astrid , Bryant Annie G , Noori Ayush , Welikovitch Lindsay A. , Jackson Rosemary J , Lin Gen , Kwon Taekyung , Bennett Rachel E , Talanian Robert V. , Biber Knut , Karran Eric H , Hyman Bradley T. , Das Sudeshna 
Published: December 2022

AbstractBackgroundAmyloid‐β plaques and neurofibrillary tangles in the Alzheimer’s disease (AD) brain are accompanied by prominent morphological and functional changes in astrocytes, collectively termed reactive astrogliosis. Single‐nuclei RNA‐sequencing (snRNA‐seq) has begun to unveil the molecular underpinnings of AD reactive astrocytes but technical challenges, including low numbers of nuclei and/or sequencing depth, and the lack of comparisons across brain regions have limited the full picture. Here we present the largest snRNA‐seq study of astrocytes to date across five brain regions.MethodNuclei were isolated from five brain areas of n = 32 donors with increasing AD neuropathology (total n = 160 samples). The five brain areas were chosen based on their hierarchical accumulation of tau pathology: entorhinal cortex (EC)> inferior temporal gyrus (BA20) > dorsolateral prefrontal cortex (BA46) > secondary visual cortex (V2 or BA18/19) > primary visual cortex (V1 or BA17). To enrich in astrocytic nuclei, NEUN+ and OLIG2+ nuclei were separated via FACS, whereas NEUN‐/OLIG2‐ nuclei (including astrocytes) were subjected to snRNA‐seq resulting in a transcriptomic dataset of 629,755 astrocyte nuclei, which were subsequently examined for common and region‐specific AD related changes.ResultClustering within each brain region identified likely homeostatic and reactive subclusters, as well as six other clusters which we describe as “intermediate” subclusters. Homeostatic and reactive astrocytes were most abundant in V1 (59%) and EC (21%), respectively, and their transcriptomic profiles were anticorrelated. Reactive astrocytes were enriched in cytoskeleton (GFAP MAP2, MAP7, MAPB1, MAPT), extracellular matrix (CD44, LAMA1, TNC, VCAN), chaperones (CRYAB, HSPB1, HSPB8), and oxidative stress/antioxidant (MAOB, MT1X, MT2A, SOD2) genes, whereas homeostatic subclusters in trophic factor (EGFR, PTN) and glutamate metabolism (GLUL, GRIA2, GRM3, SLC1A2) genes. The proportion of intermediate astrocyte subclusters was lowest in EC (25%) and highest in BA46 (41%), and their transcriptome correlated weakly with that of homeostatic and reactive astrocytes, representing an apparent gradient between homeostatic and reactive. Notably, these intermediate subclusters demonstrated the most heterogeneity among brain regions.ConclusionOur astrocyte snRNA‐seq dataset encompassing five regions of control and AD brains revealed homeostatic, reactive, and previously uncharacterized intermediate astrocytic states with distinct transcriptomic profiles for each brain region, suggesting complex, region‐specific responses to AD pathology.
Racial disparities in Alzheimer’s Disease (AD): Correlating a novel neuropsychological screening test to established AD fluid and imaging biomarkers in African Americans and Caucasians
Authors: Liu Andy , Rose Deborah K 
Published: December 2022

AbstractBackgroundThe Montreal Cognitive Assessment (MoCA) is a commonly used screening tool for the diagnosis of neurocognitive disorders such as mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). The current cut‐off threshold for detection of MCI on the MoCA increases risk for false positives, particularly in ethnic minorities and those of lower educational attainment. African Americans (AA) have experienced inaccurate detection of MCI and AD, leading to a delay in diagnosis and a decreased enrollment in AD‐related clinical trials. This underscores the importance of clarified cut‐offs for AD plasma biomarkers in AA and a standardized cognitive screening test independent of language and cultural norms. The Visual‐based Cognitive Assessment Test (VCAT) is a newly developed language‐neutral cognitive screening test that has good sensitivity (85.6%) and specificity (81.1%) in diagnosing MCI and mild AD. Our study will correlate VCAT scores to MRI brain findings and established AD plasma biomarkers in AA and Caucasians with and without cardiovascular diseases (i.e. prior myocardial infarction, stroke, and chronic kidney disease).MethodsAA and Caucasians diagnosed with MCI, AD, and normal cognition have been recruited (n=50) over a period of one year (recruitment remains ongoing). Plasma samples were collected, MRI brain imaging and Neuroquant data were obtained (for volumetric analyses), and the VCAT along with the MoCA were completed. Phosphorylated‐tau 181 (p‐tau 181) and phosphorylated‐tau 217 (p‐tau 217) will be measured in the samples using the Quanterix HDX device.ResultsPreliminary results reveal that levels of p‐tau 181 are elevated (from a normative cut‐off value of 1.81 pg/mL per the Youden index) in all groups, and highest in the group of patients with both CSF findings consistent with AD and a medical history of cardiovascular diseases (MI, CKD, and/or stroke).ConclusionEstablished cut‐off values for p‐tau 181 and p‐tau 217 in the literature likely underestimate these results in AA patients. In addition to elucidating the cut‐off normative values for established plasma AD biomarkers in a diverse cohort, our goal is to validate the VCAT, a cultural and language‐neutral screening assessment. This will allow for application to multilingual populations without the need for translation of its test contents.