bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep health and subjective cognitive decline in the Vanderbilt Memory and Aging Project
Authors: Full Kelsie M , Gogniat Marissa A. , Pechman Kimberly R. , Hohman Timothy J. , Jefferson Angela L. , Gifford Katherine A. 
Published: December 2023

AbstractBackgroundIdentifying modifiable risk factors for Alzheimer’s disease (AD) and related dementias (ADRD) may reveal critical evidence for early prevention. It is commonly believed that poor sleep is an early symptom of neurodegeneration and ADRD. However, distinct neurobiological processes occur during sleep, and dysfunction of these processes may also contribute to AD pathogenesis. Less is known about poor sleep and associations with subjective cognitive decline (SCD), a clinical symptom occurring before overt cognitive impairment due to early pathological AD. This study investigated associations between objective and self‐reported measures of sleep health and SCD in a community‐based cohort of older adults.MethodParticipants from the Vanderbilt Memory and Aging Project (n = 220; 74±7 years; 34% female) completed 7‐days of wrist actigraphy and self‐report measures for SCD [Everyday Cognition Scale (ECog)] and sleep quality [Pittsburgh Sleep Quality Index (PSQI)]. Actigraphy data was processed to estimate average nightly sleep duration, sleep efficiency, and wake after sleep onset. Linear regressions related objective and self‐report sleep health measures with total ECog score adjusting for age, sex, race/ethnicity, education, body mass index, depressive symptoms, Framingham cardiovascular risk score, and apolipoprotein E‐e4 carrier status.ResultIn main effect models, longer sleep duration was associated with greater SCD (b = 0.05, p<0.01). In models adjusted for age, sex, race/ethnicity, and education, higher PSQI (indicative of poorer sleep quality) was associated with greater SCD (b = 1.06, p = 0.01); however, the association was no longer statistically significant in the fully adjusted model. No associations were observed between sleep efficiency or wake after sleep onset and SCD.ConclusionIn this community cohort of older adults, longer nightly sleep duration and self‐reported poor sleep quality were linked with higher SCD. Findings could suggest that abnormal sleep duration and poor sleep quality increase the earliest clinical symptoms of AD. Further investigations are needed to evaluate the potential pathways connecting sleep health to ADRD development.
Mini‐Cog acceptance and conversion rate in Medicare beneficiaries in the primary care
Authors: Saxena Saket , Factora Ronan , Hashmi Ardeshir , Wang Mary , Jones Robert 
Published: December 2023

AbstractBackgroundAssessing patients for cognitive impairment is a required element of Medicare’s Annual Wellness Visit (AWV). Variability exist in the type of cognitive assessment methods used to assess patients for cognitive impairment during such visits. Paper and pencil tests such as the Mini‐Cog are commonly used in such visits, as they are easy to administer and interpret. Our study aims to assess acceptance of Mini‐Cog use in primary care and conversion of Mini‐Cog from normal to abnormal in the older adults visiting primary care for repeat AWV.MethodsCleveland Clinic implanted Mini‐Cog as a cognitive screening tool in Primary Care Institute in 2019. Inclusion criteria were Age 65+, AWV, no preexisting diagnosis of dementia, normal Mini‐Cog in previous year. Since this process was established, primary care providers were educated about use of Mini‐Cog by internal continuous quality improvement (CQI) platform. Use of Mini‐Cog in AWV within the Primary Care Institute was registered during the study period from January 2021 ‐ December 2022. The number of repeated tests, the rates of conversion of normal (3‐5) to abnormal (0‐2) and the total proportion of abnormal scores overall were recorded.ResultsTotal number of Mini‐Cog during the study period was 46094 out of which 2843 (6.2%) were abnormal.16644 were repeat tests and out of these 507 were abnormal suggesting a 3% conversion rate when testing was repeated on previously normal subjects. An upward trend and 1.7 fold increase was observed in the total number of tests on year to year basis (2021 vs 2022). (Figure 1)ConclusionCurrently, variability exists in the type of cognitive assessments methods used during the AWV in primary care. Consistent use of Mini‐Cog combined with CQI over the period of two years have shown to increase usability and acceptance within Primary Care community. As the repeat assessment have increase over period of time; now we have the opportunity to identify a narrow subset of converted patient (3%) who could benefit from urgent comprehensive cognitive assessment to confirm a diagnosis of dementia and can subsequently close examination of the risk factors that could have contributed to measurable cognitive decline.
GM‐CSF reduces amylin amyloid, inhibits pancreatic apoptosis, and sustains lowered blood glucose levels in the hIAPP mouse model of Type 2 diabetes mellitus, a known risk factor for Alzheimer’s disease
Authors: Wang Athena Ching‐Jung , Boyd Timothy D. , Adame Vanesa , Potter Huntington 
Published: December 2023

AbstractBackgroundPeople with Type II diabetes mellitus (T2D) are at higher risk for developing Alzheimer’s disease (AD). T2D is characterized histopathologically by accumulation of pancreatic amyloid deposits comprised primarily of self‐aggregating amylin/human islet amyloid polypeptide (hIAPP). Amylin is implicated in both T2D and AD pathogenesis, and in T2D patients, pancreatic amyloid deposition occurs before and induces islet β‐cell apoptosis.Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) has demonstrated anti‐apoptotic, neuroprotective, neurotrophic, immunomodulatory, and regenerative effects in several neuronal injury models. We discovered that GM‐CSF treatment rapidly reduced cerebral amyloidosis and reversed cognitive impairment in transgenic AD models (Boyd et al, 2010), which led to the initiation and successful completion of a Phase 2 clinical trial (NCT01409915) using sargramostim (rhuGM‐CSF) in mild‐to‐moderate AD participants (Potter et al., 2021). Thus, we hypothesized the GM‐CSF might also reduce amyloid, prevent pancreatic apoptosis, and thereby reduce blood glucose in the hIAPP mouse model of T2D.MethodWe investigated GM‐CSF treatment effects in hIAPP mice (Jackson strain Tg(Ins2‐IAPP)RHFSoel), which accumulate amylin amyloid in pancreatic islets. Hemizygous mice received daily subcutaneous injections (5 days/week for 23 total injections) of either recombinant murine GM‐CSF (5 µg/day or ∼167 µg/kg) or sterile saline, and were then euthanized, perfused according to CU Anschutz OLAR regulations, and pancreatic tissues obtained and processed for histopathology. Contrastingly, homozygous mice received 15 total injections and were monitored for 45 days post‐treatment, before euthanizing and perfusion procedures. In homozygous mice, blood glucose levels were measured 3 days/week (weeks 2‐4) and at 45 days post‐treatment. Unpaired t‐tests were used to determine significant differences (p<0.05) between treatment groups.ResultIn pancreas of male GM‐CSF‐treated hemizygous mice (n = 9), Thioflavin‐S staining revealed significantly less pancreatic amyloid (p = 0.0140) and Caspase‐3 immunohistochemistry showed significantly less apoptosis (p = 0.0057), compared to the saline‐treated group (n = 7). In homozygous mice, GM‐CSF‐treated male (n = 5) and female (n = 3) mice showed significantly reduced blood glucose from baseline levels, which treatment effects were sustained 45 days post‐treatment (p<0.001 female, p = 0.0002 combined M/F), whereas saline treatments (n = 5 male; n = 3 female) had no effect.ConclusionThese preliminary data suggest therapeutic potential for GM‐CSF to prevent or treat T2D, and thereby reduce AD risk.
The Asian Cohort for Alzheimer’s Disease pilot study at University of California San Francisco: A focus on recruitment of Chinese American older adults
Authors: Qian James , Tee Boon Lead , Tzuang Marian , Lieu Kevin , Mei Diana , Rosen Howard J. , Lanata Serggio , Wang Li‐San , Chow Tiffany W , Jun Gyungah R , Park Van Ta , Consortium ACAD 
Published: December 2023

AbstractBackgroundAsian American and Canadian (ASAC) populations have long been under‐represented in Alzheimer’s disease (AD) research. The Asian Cohort for Alzheimer’s Disease (ACAD) is the first large US and Canada cohort to study genetic and non‐genetic AD risk factors specifically for older ASAC persons. The University of California San Francisco (UCSF) is one of ACAD’s largest recruitment sites for Chinese American participants.MethodThe UCSF ACAD team has adopted a collaborative multifaceted approach to outreach, recruitment, and data collection including a) recruitment from community partners, social media platforms, clinic referrals, CARE (a research recruitment registry for Asian Americans, Native Hawaiians, and Pacific Islanders), and other ongoing studies (e.g., UCSF’s Alzheimer’s Disease Research Center); b) coordination of multilingual and culturally appropriate outreach events with multiple San Francisco Bay Area community organizations that serve the Chinese American community; c) pilot of ACAD’s data collection packet and procedures in two testing modes (in‐person, on‐line) and three spoken languages (Cantonese, English, Mandarin).ResultAs of January 2023, UCSF has enrolled 121 participants, 116 (95.87%) of whom have completed their visits since we began enrollment in July 2021. Out of the 116 participants, 80 (68.97%) were co‐enrolled with other ongoing studies, 21 (18.10%) were recruited from outreach events in the community, and 15 (12.93%) participated in ACAD through CARE registry, clinic referrals, or social media platforms. The age of our cohort ranges from 60‐90 years (m = 70.45 years). Most of the participants were females (72.4%) and had a college or graduate level education (68.97%). Approximately 50% of the participants completed the study in Mandarin, 32.76% in English, and 17.24% in Cantonese. Nearly two‐thirds of the participants completed their visits virtually. Consensus diagnoses were fully reviewed on 106 participants, including 61 cognitively normal controls, 16 with subjective cognitive complaints, 23 with mild cognitive impairments, and 6 with AD diagnosis.ConclusionACAD aims to enhance the representation of ASAC communities in AD research. The use of culturally and linguistically tailored approaches has and will continue to assist us in outreach, recruitment, and data collection efforts as we aim to expand our sample size and collect longitudinal data.
A multi‐site study of Alzheimer’s disease neuroimaging and cognitive biomarkers in 2819 cognitively normal individuals
Authors: Xie Long , Das Sandhitsu R. , Wisse Laura EM , Lyu Xueying , McGrew Emily , de Flores Robin , Gibson Eli , Yushkevich Paul A. , Wolk David A. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundDeveloping effective Alzheimer’s disease (AD) biomarkers in cognitively normal (CN) individuals is crucial. Prior studies have identified neuroimaging and cognitive measures that are sensitive to preclinical AD. However, the generalizability of these biomarkers in large, multi‐site cohorts and their power to predict disease progression remain unclear. Structural MRI, tau PET and standardized cognitive tests of 2819 CN adults were pooled from three studies to investigate the power of these measures in discriminating β‐amyloid positivity (A+/‐) and predicting disease progression.MethodsT1‐weighted MRI and cognitive data of 2819 CN (A‐/A+: 1180/1540, Table 2) individuals from ADNI, HABS and A4 were included. Baseline medial temporal lobe structural measures were extracted from MRI (complete list in Table 1). For participants with prospective longitudinal MRI or cognitive measures (4.5 years), annualized change rate of each measurement was estimated. ANCOVA and receiver operating characteristic analyses were used to test biomarker differences between A+/A‐. In 563 CN with cross‐sectional tau PET available, stepwise linear mixed effect modeling was performed to identify the subset of baseline cross‐sectional biomarkers (tau, MRI and cognition) that yields the optimal model (smallest Akaike information criterion) in predicting longitudinal atrophy and cognitive decline. The area under the curve (AUC) of each model in discriminating the first (fast) and last (slow progressors) tertiles of each longitudinal measurement was reported.ResultsSignificant differences between A+/A‐ (Table 2) were observed in cross‐sectional tau (most significant), cross‐sectional and longitudinal cognitive, as well as longitudinal structural MRI measures. When predicting disease progression with baseline measures (Figure 1‐a), tau (selected in all the models) and cognitive biomarkers were included in the most predictive models while MRI biomarkers did not provide additional information. The selected biomarkers can identify fast versus slow progressors with AUCs ranging from 0.63‐0.78 (Figure 1‐b).ConclusionsThe results demonstrated that both cross‐sectional (tau PET and cognition) and longitudinal biomarkers (MRI and cognition) are sensitive to amyloid status in CN. In addition, baseline tau PET and cognitive measures provide complementary information in predicting disease progression regardless of amyloid status. This indicates that these biomarkers may have important utility in preclinical AD clinical trials and normal aging studies.
Investigation of IL1RAP in vascular endothelial and microglia interactions
Authors: Fisher Elizabeth S , Tubbesing Kate , Bertucci Taylor , Stevens Katherine , TCW Julia , Goate Alison , Temple Sally 
Published: December 2023

AbstractBackgroundApproximately 84% of Alzheimer’s Disease (AD) patients have cerebrovascular pathology. It remains unclear if vascular damage is causative or a result of disease progression. Blood‐brain barrier breakdown can be induced by inflammation, which is increased in aging and AD. IL1β is a cytokine upregulated in patients with AD and in mouse models of the disease. Released IL1β interacts with IL1R1, which relies on its obligate co‐receptor, IL1RAP, for signaling. A genome wide association study identified a SNP in IL1RAP with increased incidence of AD and higher rates of amyloid accumulation. This IL1RAP variant exerts independent, additive effects with APOE44. These findings suggest IL1RAP could play an important role in AD and vascular damage.MethodHuman induced pluripotent stem cells (iPSCs) isogenic for the APOE33 or APOE44 allele were differentiated into vascular endothelial cells (ECs) or microglia. Differentiated cells were treated with inflammatory factors then subjected to several assays relevant to AD‐pathological changes. For ECs, barrier properties were assessed via trans‐endothelial resistance measurements and by immunohistochemistry for junctional proteins. For microglia, the ability to phagocytose Aβ was assessed. Both ECs and microglia were examined for inflammatory factor gene expression and protein secretion via ELISA. IL1RAP was overexpressed and knocked down in both APOE33 and APOE44 ECs, and changes were assessed by select assays described above.ResultsAPOE44 iPSC‐ECs exhibited disrupted barrier properties compared to ECs derived from APOE33 cells. Different inflammatory stimuli have differential effects on the EC response, including the level of upregulation of the EC‐specific inflammatory gene E‐selectin. On‐going experiments will determine if there is a modifying effect of overexpression or KD of IL1RAP in ECs and microglia in these assays, and notably, if there is a different response depending on APOE allele.ConclusionAPOE alleles alter the functional properties of human iPSC‐ECs and microglia and their responses to inflammatory challenges. In the future, we will determine if interactions between microglia and ECs are altered by APOE genotype and how altering IL1RAP levels modifies the observed changes. These experiments will help establish the role of microglia‐EC interactions in inflammatory reactions, and how these may contribute to the development or progression of AD.
Astrocyte Ca2+ dysregulation and neurovascular coupling deficits in a diet‐based mouse model of small cerebral vessel disease
Authors: Weiss Blaine E. , Sompol Pradoldej M , Gant John C , Lin Ruei‐Lung , Nelson Peter T , Thibault Olivier , Wilcock Donna M. , Norris Christopher M. 
Published: December 2023

AbstractBackgroundMice exposed to a diet deficient in B6/B12 vitamins and enriched in methionine exhibit hyperhomocysteinemia (HHcy) concomitant with many pathologic features of vascular cognitive impairment and dementia: a very common Alzheimer’s disease related dementia. Here, we evaluated the impact of astrocyte Ca2+ dysregulation and astrocytic Ca2+ signaling pathways in the context of functional hyperemia in fully awake mice exposed to HHcy diet.MethodAdult C57/BL6 mice were fed for 15 weeks with control chow, or chow deficient in vitamins B6/B12 and enriched in methionine (HHcy diet). Spontaneous and evoked (via air puff whisker stimulation) Ca2+ transients in astrocytes of fully awake mice were investigated in barrel cortex using the Ca2+ sensor GCaMP6f (expressed specifically in astrocytes using AAV) and two‐photon imaging. In other experiments, mice were treated with AAV‐Gfa2‐VIVIT to inhibit the Ca2+‐sensitive calcineurin/NFAT pathway in astrocytes, which regulates reactive astrocyte phenotypes. Two‐photon imaging was then used to assess diet and VIVIT effects on functional hyperemia in barrel cortex of fully awake mice.ResultCa2+ transients in individual barrel cortex astrocytes were significantly augmented (greater in amplitude, with faster rise/decay kinetics) in mice treated with HHcy diet. However, the functional connectivity in astrocyte networks of HHcy mice was significantly impaired, particularly during engagement of brain activity with whisker stimulation. Compared to control diet mice, HHcy mice also showed impaired functional hyperemia during whisker stimulation characterized by impaired arteriole dilations and reduced red blood cell velocity in nearby capillaries. Inhibition of reactive astrocyte signaling in HHcy diet mice with VIVIT significantly ameliorated these neurovascular coupling deficits.ConclusionThe results show that astrocyte Ca2+ dysregulation is a major feature of HHcy and contributes to cerebrovascular dysfunction through hyperactivation of the astrocytic CN/NFAT pathway.
Using subject‐specific disease progression as an estimation of the disease time to model longitudinal neurodegeneration in AD
Authors: Shafiee Neda , Collins D Louis 
Published: December 2023

AbstractBackgroundWhen patients with clinically probable‐AD get their diagnosis, it is difficult to determine exactly when the disease started. Moreover, not all subjects progress in the same manner and rate. However, clinical measurements such as cognitive scores can help give an estimation of where in the disease trajectory each patient stands. To address the issue of estimating the time of disease onset, we investigated a new technique that leverages cognitive test scores to estimate a latent timeline that models the subject‐specific disease progression.MethodWe used the work of Kühnel et al. (2021) to model the progression of AD using cognitive scores (ADAS13 and MMSE). This method aligns patients along a continuous latent timeline based on their predicted disease progression. Data included the MRI scans of 677 amyloid‐positive subjects from ADNI. Scan resolution was increased to 0.5mm isotropic voxel‐size by super‐sampling (Manjón et al. 2010) before non‐linear registration to an ADNI‐based unbiased template. The resulting deformation fields were used to compute the Jacobian determinant map for each subject and find mean atrophy for different ROIs. we were then able to plot the changes in different regions of the brain across the estimated disease progression timeline and compare slopes for the two methods.ResultAssuming a zero time‐shift for normal subjects, the average time‐shift for the eMCI, lMCI, and AD group was 36.8, 87.5, and 128.8 months respectively. Using the latent time‐shift variable to offset the individual baseline scans, we were able to plot the changes in different regions of the brain across the disease timeline. The results for Hippocampus are shown in figure 1, comparing the estimated timeline to the age as the time‐related axes. We saw much sharper slopes (‐0.01 vol/estimated_time vs ‐0.0025 vol/age) when using the individualized time offset.ConclusionCalendar time is perhaps not a good measure for disease progression. The new method offers an estimation of a latent timeline that models the subject‐specific disease progression and may better model the longitudinal changes in different brain regions, and in turn, would enable us to better compare the magnitude and speed of degeneration across brain regions.
Factor Analyses and Age Effects in the CCAB At‐Home Computerized Cognitive Test Battery
Authors: Herron Timothy J , Chok Jas M. , Lwi Sandy J. , Schendel Krista , Curran Brian , Geraci Kristin , Blank Michael , Williams Garrett , Hall Kathleen , Woods David L. , Baldo Juliana 
Published: December 2023

AbstractBackgroundThe California Cognitive Assessment Battery (CCAB; ccabstudy.com) is a remotely monitored, at‐home, computerized behavioral test and questionnaire suite. Here we evaluate the interpretation of 25 tests within the US English version of the CCAB using both an exploratory factor analysis (EFA) of 155 healthy adults and a confirmatory factor analysis (CFA) of 312 healthy older adults participating in a longitudinal study. We also estimated cross‐sectional age gradients for best fitting latent factors [1].MethodFirst, one set of “classic” latent factors (from 1 factor to 8 factors) was extracted from the literature [2][3][4] for assignment of CCAB tests into traditional categories. Second, 155 adult participants (age 22‐86 y.o., mn 54, 57% male, education 8‐20 yrs., md 14) participated in a prefinal version of the CCAB. EFA was performed on their primary CCAB results using the ‘psych’ (v. 1.9.12.31‐1) toolbox in R (v. 3.6.3) with 11 different rotations to extract a second set of CFA latent factors. Third, above two sets of latent factors were used in the ‘lavaan’ CFA toolbox (v. 0.6.5‐1) in R and applied to the first timepoint (enrollment and session 1) of CCAB longitudinal data from an older adult group (age 56‐89 y.o., mn 71, 58% male, education 0‐20 yrs., mn 14).ResultThe EFA and CFA model fit characteristics (Fig 1) show moderately good fits for the EFA and best fitting CFA models. The EFA produced reasonable models from 2 factors to 6 factors. The best fitting “classic” CFA along with its latent factor age regressions is shown in Figure 2. The best fitting EFA‐derived CFA along with its latent factor age regressions is shown in Figure 3.ConclusionThe best‐fit classic CFA results showed moderately good fit, and visual tests of both speed and memory showed steeper cross‐sectional age gradients than did respective verbal response tests. The EFA‐derived latent factors were better fitting than were the classic factors as they were derived from the CCAB itself. In both cases, however, CCAB test speed measures showed steeper cross‐sectional age gradients than did memory measures. Ongoing work will characterize longitudinal latent factor age gradients.