bluuebunny/crossref_metadata_2025_split huggingface dataset:
Implementation outcomes of the ACT Trial in older adults with amnestic Mild Cognitive Impairment
Authors: Cervantes Hector , Verhoef Nicholas , Spafford Russell , Han SeungYong , Salisbury Dereck , Lin Feng Vankee , Yu Fang 
Published: December 2023

AbstractBackgroundPreventing Alzheimer’s disease is a public health priority to address its substantial social and healthcare impacts. Exercise and cognitive training interventions are promising but show mixed effects on cognition in older adults with and without mild cognitive impairment (MCI), which is at least partially attributable to varied quality in trial implementation. The purpose of this study was to evaluate the implementation outcomes of the 3‐site Aerobic exercise and Cognitive training (ACT) trial that tests the cognitive effects and underlying mechanisms.MethodThe ACT Trial enrolled 146 older adults with amnestic MCI (aMCI). Participants were randomized equally to ACT, aerobic exercise only, cognitive training only, or attention control ed for six months and followed for another 12 months. Participants completed a 3‐step screening process that included a 30‐minute phone screen (step 1), a 120‐minute in‐person screening (step 2), medical clearance (step 3), and a 60‐minute graded exercise test and MRI (steps 4a & 4b). The implementation outcomes included durations between each screening step, from phone screen to enrollment, from enrollment to the first intervention section. Implementation outcomes were compared across sites using ANOVA.ResultThe mean age was 73.57±5.49 years, with 47.95% female, 91.78% white, 91.09% had a college degree or higher, and a mean Montreal Cognitive Assessment (MoCA) score of 23.38±2.16. The duration from step 1 to step 2 was 20.23±31.21 days, step 2 to step 3 was 24.42±41.27 days, step 3 to step 4a was 36.84±76.86 days, step 4a to step 4b was 25.84±60.75 days, and the duration from step 4b to enrollment was 25.60±60.17 days. The duration from step 1 to enrollment is 121.16±109.16 days. ANOVA results indicate no significant differences in implementation outcomes across the three sites.ConclusionThe screening took longer than projected regarding completing a participant’s in‐person screening (step 2) and obtaining medical clearance from the participant’s provider (step 3). The major contributors to longer screen duration were delays in receiving faxed documentation from medical providers. Future trials need to build in adequate screening duration to ensure screening success.
Predictive Modeling Leveraging Electronic Health Records Identifies Early Predictors of Alzheimer’s Disease
Authors: Tang Alice S , Rankin Katherine P , Cerano Gabriel , Miramontes Silvia , Mills Hunter , Oskotsky Tomiko , Zeng Billy , Nelson Charlotte , Soman Karthik , Woldemariam Sarah , Li Yaqiao , Lee Albert M , Miller Zachary , Allen Isabel Elaine , Sanders Stephan , Baranzini Sergio , Sirota Marina 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is a neurodegenerative disorder of aging that is difficult to diagnose. Electronic health records (EHR) are a valuable source of longitudinal data for disease phenotyping and prediction. Knowledge graphs, such as SPOKE (Scalable Precision Medicine Open Knowledge Engine), help derive biological meaning from phenotypic data. Here we utilize machine learning on EHR to predict and better understand AD.MethodAD patients and controls were identified from the UCSF EHR. The index time was identified as the first dementia diagnosis or drug record among the AD patients, and 1 year before the last visit among controls. Controls matched on demographics and visit‐related factors were identified at five time points relative to the index time (‐7years, ‐5years, ‐3years, ‐1year, and ‐1day) at a 1:8 ratio. Random forest (RF) classification models for AD were trained utilizing clinical data (conditions, drugs, abnormal measurements) and evaluated with bootstrapped AUROCs on a 30% held‐out set. Top features mapped to phecodes were ranked based on average impurity decrease. Networks were created from SPOKE knowledge graph by identifying shortest paths between top 25 model features and AD, and associations were validated with genetic colocalization analysis on shared variants in the UK Biobank.ResultFrom the UCSF EHR, 749 AD patients and 250,545 Controls were identified with clinical concepts 7 years prior to each individual’s index time. RF trained on AD and matched control individuals’ data performed with AUROC of 0.58 (‐7years) to 0.77 (‐1day). Top phecode features from models include those that are important earlier (osteoarthritis, allergic rhinitis), progress in importance closer to index time (dizziness, vitamin D deficiency, memory loss), and persist in importance throughout time (hyperlipidemia) (Figure 1). Knowledge networks highlight shared biological relationships between top features (e.g., hyperlipidemia, osteoporosis), including identification of relevant genes (e.g., APOE, PSEN 1/2, INS, AKT1, HFE) (Figure 2). Colocalization analysis of LDL cholesterol and AD confirms a commonly associated SNP in APOE.ConclusionEHR together with knowledge networks provide an opportunity to identify early clinical predictors of AD diagnosis, with utility for early intervention, hypothesis generation and biological insight.
Aberrant DJ‐1 expression underlies L‐type calcium channel hypoactivity in dendrites in Alzheimer’s disease (AD) and tuberous sclerosis complex (TSC)
Authors: Niere Farr 
Published: December 2023

AbstractBackgroundL‐type voltage‐dependent Ca2+ channels (L‐VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown if molecular mechanisms leading to disrupted L‐VGCC across neurodegenerative disorders is conserved. Importantly, L‐VGCC integrate synaptic signals to facilitate a plethora of cellular mechanisms; however, mechanisms that regulate L‐VGCC channel density and subcellular compartmentalization are understudied.MethodThe following methods were used: bioinformatics; RNA immunoprecipitation; Surface Sensing of Translation–Proximity Ligation Assay (SUnSET‐PLA); calcium imaging, immunocytochemistry; Western blots, dissociated hippocampal neurons and acute hippocampal slices from APP/PS1 mouse mode of AD and Tsc1 conditionally knockout mice; Postmortem human prefrontal cortex tissue.ResultHerein, we report that in disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), deficits in dendritic L‐VGCC activity are associated with increased expression of the RNA‐binding protein (RBP) DJ‐1. DJ‐1 binds the mRNA coding for the alpha and auxiliary Ca2+ channel subunits CaV1.2 and alpha2delta2 (α2δ2), and represses their mRNA translation, only in the disease states, specifically preclinical models of Alzheimer’s disease (AD) and tuberous sclerosis complex (TSC). In agreement, DJ‐1 mediated repression of CaV1.2/α2δ2 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L‐VGCC calcium activity. These preclinical findings are recapitulated in the synaptic and dendritic regions of prefrontal cortices of humans diagnosed with AD.ConclusionDiscovery of DJ‐1 regulated L‐VGCC activity in dendrites in TSC and AD provides a new signaling pathway that can be targeted in clinical mTORopathies.
Racial and ethnic differences in lifetime Medicare expenditures for dementia patients
Authors: Olchanski Natalia , Zhu Yingying , Liang Lichen , Cohen Joshua T , Neumann Peter J , Faul Jessica D , Fillit Howard M , Freund Karen M , Lin Pei‐Jung 
Published: December 2023

AbstractBackgroundResearch on racial and ethnic disparities in lifetime dementia costs is sparse. We analyzed lifetime Medicare expenditures for dementia patients to identify when during the course of care costs are the highest, and whether these costs differ by race and ethnicity.MethodWe analyzed data from the 2000‐2016 Health and Retirement Survey (HRS) linked with corresponding Medicare claims to estimate total Medicare expenditures for four “phases”: 1) the year before dementia diagnosis; 2) the first year following a dementia diagnosis; 3) ongoing care for dementia after the first year; and 4) the last year of life. We then estimated each patient’s phase‐specific and lifetime Medicare expenditures by using a race‐specific survival model and monthly expenditures adjusted for demographics, socio‐economic status, year of dementia diagnosis, nursing home status, functional limitations, cognitive impairment, comorbidities, and Medicaid eligibility status.ResultAdjusted mean lifetime Medicare expenditures for non‐Hispanic Blacks ($166,548) and Hispanics with dementia ($163,425) exceeded corresponding expenditures for non‐Hispanic whites ($135,648) (Figure). In the year preceding and immediately following an initial dementia diagnosis, mean Medicare expenditures for non‐Hispanic Blacks ($26,384 and $20,824) exceeded expenditures for Hispanics and non‐Hispanic whites (ranging $21,340‐23,379 and 17,382‐18,085). Ongoing care costs for non‐Hispanic Blacks with dementia (mean $1,734/month) exceeded costs for Hispanics ($1,538/month) and non‐Hispanic whites ($1,424/month). Of the four phases, the last year of life was responsible for the greatest cost contribution: $52,003 for non‐Hispanic Blacks, $48,377 for Hispanics, and $39,648 for non‐Hispanic whites.ConclusionsTotal mean Medicare expenditures for non‐Hispanic Black and Hispanic beneficiaries with dementia exceeded corresponding expenditures for non‐Hispanic whites. Expenditures were highest for non‐Hispanic Blacks with dementia in every phase of care. Compared to non‐Hispanic whites, Hispanics had lower expenditures in the first year following dementia diagnosis and similar monthly ongoing care expenditures but much higher expenditures during their last year of life. Research should identify factors contributing to the disparities identified here so that policy makers can address problems adversely affecting disadvantaged populations.
Figure: Estimated mean lifetime Medicare expenditures for beneficiaries newly diagnosed with dementia, by phase of care and by race and ethnicity (adjusted)
Preserved Autophagy in Cognitive Intact Non‐Demented Individuals with Alzheimer’s Neuropathology
Authors: Fracassi Anna , Tumurbaatar Batbayar , Scaduto Pietro , Guptarak Jutatip , Jupiter Daniel , Taglialatela Giulio 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a terminal neurodegenerative disease and the most common cause of dementia. Notably, some individuals, here referred to as Non‐Demented individuals with Alzheimer’s Neuropathology (NDAN) are cognitively intact despite the presence of neuropathology consistent with fully symptomatic AD and have decreased Tau oligomers at synapses. Growing evidence supports that dysfunctional autophagy, the primary cell mechanism responsible for removing protein aggregates and a route of clearance for Tau in healthy neurons, is a major finding in demented AD patients. However, the association of autophagy with maintenance of cognitive integrity in resilient individuals has not been evaluated. Thus, the understanding of the neuroprotective mechanisms to evade cognitive decline to preserve synaptic functional integrity is important for the development of therapeutic approaches to prevent dementia.MethodHere we evaluated autophagy as a key protective mechanism for maintenance of cognitive integrity in NDAN subjects by efficient removal of tau oligomers. Using postmortem hippocampal samples from age‐matched healthy controls (n = 6), AD (n = 7) and NDAN (n = 7) we performed immunofluorescence and comparative western blot analyses for regulatory molecules and ATGs (autophagy‐related genes) involved in autophagy. Tauopathy was accessed by the expression and phosphorylation levels at Ser202/Thr205 (AT8), Thr231 (AT180) and Ser396 (PHF13.6) of Tau oligomers.ResultWe found that NDAN subjects have significantly increased regulatory Beclin‐1, and Atg16L, Atg12, Atg3, Atg5, Atg7, LC3AB, and proteasomal PSMA5 but not lysosomal LAMP1 as compared to AD. Expression levels were comparable with healthy controls. Autophagic proteins, except p62, were negatively correlated to Tau oligomer (>65 kDa), but not to total Tau (>45 kDa), indicating autophagy being specific to tau oligomer clearance. Tau oligomer expression and levels of phosphorylation at Ser202/Thr205, Thr231, and Ser396 were significantly reduced in hippocampal tissue in NDAN as compared to AD, also confirmed by immunofluorescence analyses of Tau tangles.ConclusionOur results indicate, for the first time, intact autophagy and associated reduced tauopathy as one of protective mechanism in cognitive intact NDAN. This novel observation supports the potential of autophagy‐induced strategies in AD therapeutics
Evaluation of quantitative measurements of tau pathology with semi‐quantitative ratings and age
Authors: Denning Amanda E , Ittyerah Ranjit , Sadeghpour Niyousha , Chung Eunice , Ravikumar Sadhana , Sadaghiani Shokufeh , Capp Noah , Teunissen‐Bermeo Eric , Arezoumandan Sanaz , Ohm Daniel T , Schuck Theresa , Robinson John L. , Grossman Murray , Lee Eddie B , Trojanowski John Q , Wisse Laura EM , Das Sandhitsu R. , Wolk David A. , Irwin David J. , Yushkevich Paul A. 
Published: December 2023

AbstractBackgroundIt is assumed quantitative digital neuropathology methods will provide more information than semi‐quantitative ratings, but this presumption lacks formal assessment. Here, we compare quantitative, whole‐slide measurements of phosphorylated tau tangles and threads with semi‐quantitative tau pathology ratings. We evaluate whether quantitative measurements provide additional prediction beyond Braak stage for variables associated with tau pathology, examining the association of quantitative tau measurements in high Braak stages with age at death and measures of severity of TDP‐43 and alpha‐synuclein co‐pathologies. We hypothesized that even within the same high Braak stage, quantitative tau measurements would decrease with age at death, as younger patients often require more tau pathology for disease severity comparable to older patients, and increase with higher co‐pathology ratings, since prior work suggests co‐pathologies increase with disease severity.MethodWe scanned 6µm tissue sections stained with phosphorylated tau PHF1 in 14 brain regions from 215 patients with Alzheimer’s Disease continuum neuropathological diagnoses (53% male, age = 74.37 ± 11.51). A machine learning method (Figure 1) generated summary measures of tangle and thread pathology for each slide (Yushkevich et al., 2021, Sadaghiani et al., 2022). Semi‐quantitative tau ratings (0‐3) were also available in nine regions and compared to quantitative measurements in matching regions. In 150 patients with high Braak stages (V/VI), correlation analyses were performed using summary scores averaging semi‐quantitative ratings of TDP‐43 in medial temporal lobe regions (“TDP‐43 severity”), and alpha‐synuclein in commonly affected regions (“alpha‐synuclein severity”).ResultFigure 2 shows high overall agreement between quantitative tau measures and corresponding semi‐quantitative ratings. When evaluating quantitative tau measurements in high Braak stage patients, after Bonferroni correction we found significant negative associations between age and tangles in middle frontal cortex, orbital frontal cortex (OFC), and thalamus, and between age and threads in OFC. We found significant positive association between TDP‐43 severity and tangles in substantia nigra, but no associations with alpha‐synuclein severity (Figure 3).ConclusionQuantitative tau measurements largely agree with established semi‐quantitative ratings. Significant associations of quantitative tau measurements with TDP43 pathology and age were found within high Braak stage patients, suggesting quantitative pathology measurements can offer additional information beyond stage alone in these patients.
Autonomic Function and Cognitive Function in the U.S. POINTER Neurovascular Ancillary Study
Authors: Shaltout Hossam A , Garcia Katelyn R , Leng Xiaoyan , Baker Laura D , Snyder Heather M , Bailey Margie J , Brinkley Tina E 
Published: December 2023

AbstractBackgroundAutonomic regulation plays a major role in maintaining stable blood supply to the brain. Impaired autonomic function, as evidenced by high blood pressure variability (BPV) and/or low heart rate variability (HRV), is common in older adults and is associated with reduced perfusion, which can ultimately lead to impaired cognitive function. The U.S. POINTER Neurovascular (POINTER‐NV) ancillary study is an ongoing study designed to evaluate autonomic function in participants from the U.S. POINTER trial. Here we describe the baseline characteristics of the POINTER‐NV participants, focusing on autonomic measures and their relationship to cognitive function.MethodContinuous blood pressure and ECG recordings were used to assess BPV, HRV, and sympathovagal balance. Autonomic variables were compared according to cognitive status using the baseline Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) score. Linear regression was used to assess cross‐sectional associations between sympathovagal balance and BPV variables and composite scores for global cognition, executive function, memory, and processing speed, with and without adjustment for age, sex, and race/ethnicity.ResultAutonomic measures were available for 212 POINTER‐NV participants (mean age: 67.9 ± 5.4 years, 67% female, 33% people of color). There were no significant differences in BPV or HRV measures between participants with normal cognition (CDR‐SB score = 0) and those with possible cognitive impairment (CDR‐SB score = 0.5–1.0). Higher sympathovagal balance was significantly associated with higher scores of global cognition, executive function, and processing speed; however, this association became statistically insignificant after adjustment for age, sex, and race/ethnicity. Higher BPV measured as standard deviation of mean arterial pressure (SDMAP) was associated with lower scores for episodic memory after adjustment for age, sex, and race/ethnicity (p = 0.03). There was some suggestion that lower HRV might be associated with worse cognition, however, these associations were inconsistent across cognitive domains and did not remain after covariate adjustment.ConclusionAge‐related changes in autonomic function can promote cognitive decline and dementia. Our data are consistent with prior evidence suggesting a role for sympathovagal balance and blood pressure variability in modulating cognitive function
Overexpression of astrocytic glutamate transporters alleviates hyperexcitability in mouse model of Alzheimer’s Disease
Authors: Gollihue Jenna L , Gant Christopher C , Kraner Susan D. , Norris Christopher M. 
Published: December 2023

AbstractBackgroundAstrocytes are the main cells responsible for clearing glutamate from the synapse; their glutamate transporters quickly and efficiently clear glutamate within the synaptic cleft, preventing neuronal excitotoxicity. In mouse models and human cases of Alzheimer’s Disease (AD), the astrocyte‐specific glutamate transporter (Glt1 in rodents and EAAT2 in humans) is decreased. Our goal is to study the effects of decreased glutamate transporters on synaptic measures of function and plasticity.MethodUsing a 5XFAD mouse model of amyloid pathology, we utilized an adeno‐associated virus (AAV) to over‐express Glt1 in the hippocampus. Electrophysiological field recordings examined the role of astrocyte‐specific glutamate transporters in synaptic plasticity and hyperexcitability. Animals received injections of AAV‐Luciferase (control) in one hippocampus, and AAV‐Glt1a in the contralateral hippocampus. Field recordings were performed to assess excitatory postsynaptic potentials in the hippocampal CA1 stratum radiatum elicited by stimulation of CA3 axons.ResultCompared to control (AAV‐Luciferase), AAV‐Glt1 significantly increased the expression of glutamate transporters in hippocampal tissue. We then compared measures of neuronal hyperexcitability, synaptic strength, and long‐term synaptic potentiation. Results indicate that there is more hyperexcitability in control tissues compared to AAV‐Glt injections, as evident by decreased population spike thresholds.ConclusionOthers have reported hippocampal hyperexcitability may lead to memory impairment; in human cases of AD it is thought to encourage epileptic episodes. By using our AAV‐directed technique to increase glutamate transporters, and thus reduce network hyperexcitability, we will be able to examine how reactive astrocytes and their loss of glutamate transporters contribute to memory or cognition loss. Ongoing studies will do exactly this‐ use a mouse model of AD with and without AAV Glt1 overexpression to determine changes in behavioral cognitive outcome measures that may be attributed to hyperexcitability in neuronal networks.
The Puipui Malu Manatu study to assess Alzheimer’s Disease and Related Dementias (ADRD) prevalence in American Samoa
Authors: Tofaeono Vaatausili , Galvin James E , Park Van Ta , Pagano Ian , McCutchan Jueta , Thompson Lemala , Atuatasi Casuallen , Faaiuaso Siumukuka , Vaofanua Tulimalefoi 
Published: December 2023

AbstractBackgroundAmerican Samoa is the only U.S. territory located south of the equator. The U.S. Census recorded 46,466 residents, with 11,025 (23.8%) of the population age 50 and over. Healthcare access is extremely limited and the lack of culturally‐sensitive screening tests characterizing the earliest signs of impairment, correspondence to Alzheimer’s Disease and Related Dementias (ADRD) biomarkers, and potential benefits versus harms from screening are barriers for the detection of ADRD. The inability to detect mild cognitive impairment (MCI) and ADRD may affect eligibility determination for acre and services, impeded case ascertainment, and limit ADRD research. Furthermore, social determinants of health, genetic risks, and lifestyle factors may plan an important role in relative vulnerability or resilience of the American Samoa population to develop MCI and ADRD.MethodUsing our prior work, partnerships, and nascent research infrastructure, we submitted a R01 application creating the Puipui Malu Manatu, or Protecting Memories, study to conduct important phenotypic and genotypic characterization of ADRD in a probability sample of 981 Samoans age 50 and above. Our hypotheses are: 1) ADRD knowledge and research readiness is low, 2) culturally‐adapted instructions will detect MCI and ADRD; and 3) unique patterns of plasma and genetic biomarkers define ADRD in American Samoa older adults.ResultWe were funded by the National Institutes of Aging (RF1AG075904) for the project to complete the following specific aims: 1) Test ADRD knowledge, health literacy, research readiness and determine ADRD resilience and vulnerability factors, and cognitive status using culturally adapted instruments, 2) Conduct Gold Standard evaluations using the Uniform Data Set (UDSv3.0) from the NIA Alzheimer’s disease research Center program to determine a population‐based prevalence of MCI and ADRD for harmonization, data sharing, and comparison to other groups, 3) Cross‐validate Gold Standard dementia evaluations with genetic and plasma Amyloid‐Tau‐Neuronal Injury/Neurodegeneration framework biomarkers in our probability sample and compare to information available for other racial/ethnic groups.ConclusionStrong collaborations are needed to conduct novel ADRD research studies in American Samoa that is resource poor, yet culturally rich. Our approach allows to weave Westernized and Indigenous approaches to increase knowledge in this field for our population.