bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of an Online Training Program for Savvy Caregiver Program Leaders
Authors: Hepburn Kenneth , Sherman Carey Wexler , Hobday John V , Char Adarsh 
Published: December 2022

AbstractBackgroundThe Savvy Caregiver® program (SCP) is widely disseminated evidence‐based in‐person psychoeducation program that enhances family caregivers’ knowledge, skills, and mastery for effectively performing the caregiver role. SCP is led by one or two trainers who have been trained in the role by one of the SCP developers, usually in in‐person group sessions. To ensure the fidelity of train‐the‐trainer workshops, facilitate SCP dissemination, and relieve the need for in‐person training, our educational design team, with support from NIH (RO1AG061971), produced a fully online, text and video SCP train‐the‐trainer program. The program contains four modules with sections, the first describing SC purpose, core principles, mechanism of action and role of the trainer; the remaining three cover the content and dynamic of each of the six weekly SCP sessions. Seven assessment exercises, scored by the authors, determined trainees’ ability to move forward in training. Following course revisions based on prototype testing, the training program was offered to agencies in six U.S. states. Additional online events allowed debriefing interaction between learners and course developers. A post‐course evaluation was sent to learners.MethodThe evaluation sought Likert‐type assessments (5 highest; 1 lowest) of the overall course, individual elements within it (e.g., on SCP principles, trainer role, and individual sessions), course materials (videos and slides), and assessments. We sought open‐ended comments throughout. Analysis was based on quantitative and qualitative evaluations.ResultForty‐five trainees completed the SCP training course, and 29 completed course evaluations. The course received a score of 4.21 (high/very high) on learners’ assessment of overall preparedness to lead SCP. The average score across all 8 individual segment evaluations was 4.425 and that across evaluation of 4 categories of video materials was 4.54. Comments reflected overall satisfaction with the program and its elements and provided suggestions for improvement (e.g., more illustration of how SCP segments are lead; how to adapt to COVID‐driven online SCP program delivery). The interactive debriefing sessions were deemed helpful for clarifying training questions.ConclusionEarly results indicate this new online SCP train‐the‐trainer program can successfully prepare individuals to lead SCP programs, affirming the potential of virtual training for intervention practitioners.
User‐led Design of a Self‐administered Smartphone‐based Learning and Memory Assessment
Authors: Edgar Chris J. , Simic Veronika , Stephens David , Murray Erica , Maruff Paul 
Published: December 2022

AbstractBackgroundThe International Shopping List test (ISLT) is a verbal word list learning assessment set within a realistic shopping list context, supporting ease of cultural adaptation, and addressing content validity and patient relevance. Improvements to and the wide adoption of natural language processing (NLP) software has enabled the possibility for self‐administered tests of verbal learning. A beta version of a self‐administered, smartphone‐application (app) was developed, using the virtual assistant and NLP: the “List Learning and Memory Assessment (LilaTM)”.MethodTo ensure usability of the app, a user led design process was followed. A beta version was created via several rounds of focus group development in older adults. 12 older adults were then recruited for interviews (8 healthy and 4 with Mild Cognitive Impairment). Participants were pseudo‐randomly assigned to participate in interviews during test performance, using either iPhone or Nokia devices. Each participant completed the test and provided concept elicitation feedback. Qualitative analysis of the interview results was performed using thematic coding.ResultKey positive themes included the ease with which the app could be navigated, and the clarity of visual display and instructions, whilst an important negative theme was the length of time between different components of the test.ConclusionQualitative analysis of concept elicitation interviews has suggested several areas of improvement to the beta‐app, including improvements to performance that shorten processing and wait times between test components. The clarity of the visual display and test instructions were well supported.
Conformation‐specific anti‐tau antibodies distinguish human tauopathies
Authors: Hitt Brian D , Yang Ting , Beaver Joshua D. , Shang Ping , Joachimiak Lukasz A , White Charles , Diamond Marc 
Published: December 2022

AbstractBackgroundNeurodegenerative tauopathies are defined by progressive brain accumulation of tau aggregates, and include Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease (PiD). Tau is an intrinsically disordered protein, yet it adopts diverse, highly ordered amyloid assemblies in disease states. These may amplify within cells by acting as “seeds,” or templates for their own replication. Evidence suggests that tau assemblies transfer between cells of the brain, which has inspired the development of immunotherapies that are in clinical trials. Analyses by cryo‐EM of insoluble tau filaments from tauopathies have revealed distinct fibril core structures, but these are not readily distinguished by immunohistochemistry. The tau repeat domain (RD) consists of three or four repeated segments and contains the amino acids comprising each tau filament core. The RD is required for tau assembly and has a different conformation in seed‐competent tau than in inert tau. Antibodies specific for distinct RD conformations have promise as diagnostic and therapeutic agents.MethodWe generated novel anti‐tau monoclonal antibodies against structurally defined synthetic linear peptide epitopes predicted to be exposed in seed‐competent tau. We employed a screening protocol using biosensor cell‐based seeding assays to select antibodies for sensitivity and specificity in binding soluble tau seeds from AD and non‐AD tauopathies.ResultTwo antibodies, MD2.2 and MD3.1, preferentially bind soluble tau seeds versus inert tau monomer, and distinguish seeds in AD and PSP from those of CBD and PiD. They stain tauopathy brain tissue with a pattern distinct from that of AT8.ConclusionWe have generated novel anti‐tauRD antibodies with specificity for seed‐competent conformations and which distinguish tauopathies. These may be valuable for biochemical and neuropathological investigation of tauopathies and may also improve development of immunotherapy for AD and PSP.
APOE Genotype Moderates the Relationship Between Plasma Phosphorylated‐tau181 and Pattern Separation Performance in Non‐demented Adults
Authors: Diaz Valentina E , Memel Molly B , Gaynor Leslie S , Gontrum Eva Q. , Chan Brandon , Lago Argentina Lario , Yassa Michael A. , Rojas Julio C. , Casaletto Kaitlin B , Kramer Joel H. , Saloner Rowan 
Published: December 2022

AbstractBackgroundThe apolioprotein e (APOE) e4 allele enhances risk for Alzheimer’s disease (AD), particularly an amnestic AD phenotype with medial temporal lobe tau pathology. Pattern separation, the ability to discern novel yet similar information from previously learned information, is a cognitive marker of hippocampal function. APOE e4 carriers often exhibit pattern separation deficits prior to conversion to AD dementia, however the impact of APOE on tau‐related pattern separation performance is unknown. We examined the relationship between plasma P‐tau181 and pattern separation performance in non‐demented adults, and tested whether this association was dependent on APOE e4 genotype.MethodsPlasma P‐tau181 levels were measured (Quanterix Simoa) in 171 non‐demented adults (139 cognitively unimpaired, 32 mild cognitive impairment; 29% APOE e4+, 54% female, aged 52‐92) who completed a validated behavioral task of visual pattern separation recognition. The lure discrimination index (LDI), reflecting ability to discriminate similar ‘lure’ items from old items, was modeled as the primary outcome. Linear regression examined LDI scores as a function of plasma P‐tau181, APOE4 genotype, and their interaction, controlling for age, sex, and education.ResultAPOE e4+ had higher plasma P‐tau181 than e4‐ (Cohen’s d=0.64, p<0.001), but APOE4 groups did not differ on LDI scores (Cohen’s d=0.27, p=0.124). In the full sample, higher plasma P‐tau181 significantly related to lower (worse) LDI scores (β=‐0.17, p=0.028). APOE4 status significantly moderated the relationship between plasma P‐tau181 and LDI scores (β=‐0.29, p=0.030) such that higher P‐tau181 related to lower LDI scores in e4+ (β=‐0.38, p=0.004) but not in e4‐ individuals (β=‐0.02, p=0.824).ConclusionsAPOE e4+ individuals had elevated plasma P‐tau181, which in turn related to worse pattern separation performance only within e4+ individuals. These data suggest that APOE4‐related elevations in plasma P‐tau181 may be particularly sensitive to hippocampal functioning outcomes prior to frank dementia, which could reflect underlying hippocampal hyperexcitability due to e4‐mediated GABAergic interneuron loss. Future work incorporating imaging markers of brain structure and function may help elucidate whether P‐tau181‐related alterations in pattern separation among e4+ individuals are mediated by hippocampal‐specific mechanisms.
Non‐invasive quantification and SUVR validation of [18F]‐florbetaben with total‐body EXPLORER PET
Authors: Holy Emily Nicole , Fan Audrey P. , Alfaro Evelyn Rebekha , Fletcher Evan , Spencer Benjamin A. , Cherry Simon R. , DeCarli Charles S. 
Published: December 2022

AbstractBackgroundKinetic modeling of brain amyloid deposition with [18F]‐florbetaben more accurately quantifies the binding density to amyloid plaques compared to standardized uptake ratios (SUVR) (Becker, JNM2013). The total‐body EXPLORER PET scanner with an axial field of view of 194cm supports the acquisition of a full human body in one scan and permits noninvasive Image‐Derived Input Functions (IDIFs) as an alternative to arterial blood sampling (Badawi, JNM 2019). Our aim is to quantify amyloid buildup with kinetic models that leverage dynamics in aorta IDIFs and the brain utilizing [18F]‐Florbetaben and validate with SUVR in an elderly cohort.MethodTwelve adults aged 66‐86 underwent dynamic total‐body 18F‐florbetaben PET for 110min, spatial resolution = 2.344mm, average tracer dose = 299.70 MBq. 8 cognitively‐normal, 3 Mild Cognitive Impairment (MCI), and 1 Alzheimer’s disease (AD). Regions of interests were drawn in the middle descending aorta and eroded to exclude the vessel walls to derive IDIFs (Fig.1). Next, regional brain analysis including PET image matching to previously acquired T1‐weighted MRI, normalization, and segmentation were performed in PMOD (v4.2) using the AAL atlas. PET SUVR (90‐110min) means were calculated from 7 index regions (lateral frontal, medial frontal, anterior cingulate, posterior cingulate, lateral temporal, lateral parietal, and precuneus) and the cerebellar gray matter. Dynamic time activity curves (TACs) from the same brain regions were fit to the two‐tissue compartment model (2TCM) using population metabolite‐corrected IDIFs; and the Multi‐linear Reference Tissue Model (MRTM) to calculate distribution volume ratio (DVR) with reference to cerebellar gray (Ichise, JCBFM 2003).ResultAmyloid‐positive patients showed the highest SUVR in brain index regions (Fig.2). High quality dynamic kinetic modeling was achieved (Fig.3), with high SUVR accumulation in index regions compared to cerebellum at later time points in amyloid‐positive cases. SUVR and DVR from kinetic models were strongly correlated; with slight overestimation of SUVR compared to DVR (Fig.4). DVR values from the MRTM were lower than (86.7% of) DVR quantified by 2TCM.ConclusionsAbsolute quantification of amyloid binding from total‐body [18F]‐florbetaben PET data is feasible using aorta IDIFs with high agreement between dynamic binding parameters compared to SUVR in discriminating positive and negative scans.
Positive association of Cerebral Amyloid Angiopathy (CAA) with R2 Relaxation rate: A study of ex‐vivo MRI and pathology
Authors: Yasar Md Tahmid , Tazwar Mahir , Tamhane Ashish A , Evia Arnold M , Bennett David A , Schneider Julie A , Arfanakis Konstantinos 
Published: December 2022

AbstractBackgroundCerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid‐β in the walls of cortical and leptomeningeal small vessels. CAA is common in older adults and has been associated with cognitive decline and dementia. In this work, the association of CAA with the transverse relaxation rate R2 values in a large community‐based cohort of older adults was investigated.MethodCerebral hemispheres from 797 participants of three cohort studies of aging, the Rush Memory and Aging Project, the Minority Aging Research Study, and the Religious Orders Study (Figure 1) were included in this work. All hemispheres were imaged ex‐vivo at approximately 30 days postmortem using 3T clinical MRI scanners. Each scan included a multi‐echo spin‐echo sequence, and in each voxel, the signals from the different echoes were used to fit a mono‐exponential T2 decay equation (R2 is the reciprocal of T2). The resulting R2 maps were registered to an ex‐vivo brain hemisphere template using ANTS. Following the MRI scan, each hemisphere underwent thorough neuropathologic evaluation (Figure 2). The assessed pathologies were: CAA, Alzheimer’s pathology, LATE‐NC, hippocampal sclerosis (HS), Lewy bodies, arteriolosclerosis, atherosclerosis, gross and microscopic infarcts.Voxel‐wise linear regression was conducted to test the association of R2 with CAA, controlling for all other neuropathologies listed above, demographics (age at death, sex, education), and other variables (postmortem interval to immersion in fixative, postmortem interval to ex‐vivo MRI, scanners). Statistical analysis was done using PALM with tail‐accelerated 1000 permutations, threshold‐free cluster enhancement, and family‐wise error rate correction. Statistical significance was set at p<0.05.ResultThe voxel‐wise analysis revealed a spatial pattern of higher R2 values for higher CAA burden (Figure 3). The pattern included subcortical structures such as the caudate, putamen, nucleus accumbens, hippocampus, regions in the insula, anterior cingulate cortex, orbitofrontal cortex, and superior frontal cortex (Figure 3). No voxel showed a negative association between R2 values and CAA burden.ConclusionOur work showed that CAA is associated with higher R2 among older adults, independent of other neuropathologies and demographic factors. The spatial pattern for this association derived from the voxel‐wise analysis included subcortical and frontal lobe structures.
Microglial state changes in response to LM11A‐31 promote recovery in a tauopathy mouse model of Alzheimer’s Disease
Authors: Butler Robert R. , Yang Tao , Tran Kevin C , Johnson William A , Liu Harry , Leng Song Albert , Massa Stephen M. , Longo Frank M. 
Published: December 2022

AbstractBackgroundTau pathologies in Alzheimer’s Disease (AD) contribute to neurodegeneration and synaptic degeneration via a variety of mechanisms. Neurotrophic signaling pathways present an avenue to counteract degenerative mechanisms via receptor modulating compounds, such as the p75NTR‐targeted small molecule LM11A‐31 (C31). Treatment with C31 in tauopathy models causes reductions in tau aggregation and microglial activation, restoration of synaptic plasticity, and prevention of synaptic spine loss. Using tauopathy model tauP301S mice (PS19), we examined the impact of long‐term dosing with C31 at the single‐cell transcriptional level to better understand the cell types and cellular mechanisms affected by treatment.MethodsPS19 and age‐matched (Wt) mice were dosed with either C31 or vehicle for 3 months starting at 6 months of age, when tau pathology was well established. Whole cortex was isolated for nuclear extraction and single‐nucleus RNA‐sequencing. AnalysisResultsClustering microglia for cell type annotation revealed treatment group‐specific microglial subclusters (Figure 1). Further, microglial gene expression across experimental groups showed a strong inverse correlation (R = ‐0.647; p < 1.01e‐78) between C31 differential expression and PS19 differential expression in genes nominally significant (p < 0.05) for both (Figure 2). In particular, microglial genes that were downregulated in the PS19 tauopathy model and upregulated by C31 were enriched for those falling into GO categories including “synapse organization” and “cell junction organization” (p‐adj: 8.95e‐20, 2.66e‐17). Conversely, expression that was up in PS19 tauopathy and down in C31 showed enrichment for “small GTPase mediated signal transduction”, and “cell junction disassembly” (p‐adj: 8.59e‐05, 0.0431).ConclusionThese findings demonstrate differences in microglial gene expression between Wt and PS19 mice some of which may be reversed by C31. Loss of homeostatic microglia has been previously associated with AD neurodegeneration, improper dendritic spine formation and inability to maintain synaptic structure. Our findings support the hypothesis that loss of homeostatic microglia exacerbates synaptic dysfunction, and their recovery may be one potential mechanism by which C31 can restore synaptic plasticity.
Identifying Pathways of Physiological Deterioration to Understand Racial Disparities in Cognitive Status: A 4‐way Mediation‐Interaction Decomposition Analysis
Authors: Higgins Cesar , Ware Erin B , Hicken Margaret , Zawistowski Matthew , Kobayashi Lindsay C , Muhkerjee Bhramar , Bakulski Kelly M 
Published: December 2022

AbstractBackgroundExposure to interpersonal and structural racism may increase the risk of adverse cognitive aging in racialized groups. Physiological deterioration may lie on the causal pathway leading racism to cognitive aging, but this potential mediating role has never been investigated. We quantified the extent to which the racial disparity (a proxy measure of exposure to racism) in cognitive status was mediated through physiological biomarkers of inflammation, glucose homeostasis, cholesterol ratios, and renal functioning.MethodsData were from the US Health and Retirement Study in 2006 and 2008. We performed cross‐sectional (n = 9,107) and 2‐year follow‐up analyses (n = 6,147) to explore the mediating roles of four physiological biomarkers in racial/ethnic disparities in prevalent and incident dementia. We used self‐reported race/ethnicity as a proxy for exposure to structural and interpersonal forms of racism. Mediators were serum biomarkers of systemic inflammation (hsCRP), glucose homeostasis (HbA1C), cholesterol processing and atherosclerosis risk (TC/HDL‐C ratio), and renal functioning (cystatin C). We performed a 4‐way decomposition analysis that accommodated exposure‐mediator interactions to identify natural direct and indirect effects.ResultsIn this sample, the prevalence of dementia was 2.2% among non‐Hispanic White, 8.5% among non‐Hispanic Black, and 6.0% among Hispanic participants. Among non‐Hispanic Black relative to non‐Hispanic White participants, the mediating effect of HbA1C on prevalent dementia was 6% (95% CI: ‐4%, 16%) and the interaction effect with race was 11% (95% CI: ‐11%, 34%) (Table 1). Similarly, we estimated a mediating effect of cystatin C on prevalent dementia of 0% (95% CI: ‐2%,2%) and an interaction effect with race of 10% (95% CI: ‐5%, 25%). For incident dementia, among non‐Hispanic Black relative to non‐Hispanic White participants, the mediating effect of hsCRP on incident dementia was 18% (95% CI: ‐6%, 41%), and the interaction effect with race was 45% (95% CI: ‐20%, 110%) (Table 2). Results were similar for Hispanic relative to non‐Hispanic White participants.ConclusionsThe relationships between race/ethnicity and prevalent and incident dementia were not mediated by or interacted with serum biomarkers of physiological deterioration. Racial disparities in cognitive status in mid‐to‐later life may be attributable to structural factors to racism and the mediating effects of other biomarkers.
Alzheimer drug candidate NA‐831 for the treatment of Dementia caused by Covid‐19‐ A Phase 2/3 clinical trial methodology
Authors: Tran Lloyd , Kurkinen Markku 
Published: December 2022

AbstractBackgroundMore than one third of Covid‐19 patients at the time of discharge from hospitalization have evidence of cognitive impairment and motor deficits. Patients surviving COVID‐19 are at high risk for subsequent development of neurological disease, particularly Alzheimer’s disease.MethodThe clinical Phase 2/3 evaluates the safety and efficacy of NA‐831 alone, and a combination therapy comprises NA‐831 with an anti‐viral drug Atazanavir, NA‐831 with an anti‐inflammatory drug, and a potential synergy between Atazanavir and Dexamethasone.The Clinical Protocol:Study Type: Interventional Phase 2/3Estimated Enrollment: 525 participantsAllocation: RandomizedThere will be daily symptom surveys for 14 days, then weekly thereafter for 3 weeks resulting in a total duration of follow up of 36 days.Status: is recruiting and the study is expected to be completed by December 15, 2023Result
Primary Outcome Measures
Time from randomization to recovery defined as1) absence of fever, as defined as at least 48 hours since last temperature ≥ 38.0°C without the use of fever‐reducing medications2) absence of symptoms of greater than mild severity for 24 hours3) not requiring supplemental oxygen beyond pre‐COVID baselineAND 4) freedom from mechanical ventilation or death
Secondary Outcome Measures
1) Brief Cognitive Rating Scale (BCRS) and2) Clinician’s Interview‐Based Impression of Change plus caregiver input (CIBIC‐plus) after 24 weeks.ConclusionThe progress of the clinical trials will be presented discussed.