bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the activated microglia in hippocampal synaptic plasticity alteration in in vitro inflammatory models
Authors: Piccioni Gaia , Mango Dalila , Nisticò Robert 
Published: December 2022

AbstractBackgroundMicroglia cells are primary players in neuroinflammation, which plays a key role in the pathogenesis of Alzheimer's disease (AD). Under pathological inflammatory conditions, microglia activation leads to synaptic alterations thereby influencing the progression of AD. Increased activation of microglial colony stimulating factor 1 receptor (CSF1R) can lead to pathological microglia activation in experimental models of AD (Olmos‐Alonso et al., 2016). Using electrophysiological and immunohistochemical analysis, we investigated hippocampal synaptic transmission and plasticity in experimental models of neuroinflammation. We then tested whether pharmacological manipulation of microglia activation could restore the observed neuroplasticity alterations.MethodC57BL6/J mices of both sexes aged between 30‐ and 40‐days were used. Employing electrophysiological approaches (field and whole cell patch clamp), we recorded in area CA1 in response to stimulation of Schaffer collaterals. We evaluated Long‐Term Potentiation (LTP) induced by theta‐burst stimulation measuring field Excitatory Post‐Synaptic Potentials (fEPSPs) 1 hour after tetanization. We also investigated paired‐pulse ratio (PPR) and spontaneous EPSCs (sEPSCs). Two in vitro inflammatory models were obtained applying Lipopolysaccharide (LPS) (10 μg/ml) or Aβ 1‐42 oligomers (200 nM). As a control, we tested the effect of scrambled Aβ 1‐42. To inhibit the activation of microglia we used Pexidartinib (PLX‐3397) (10μM) and Minocycline (500 nM). For immunohistochemical experiments free‐floating sections were incubated with primary antibodies overnight at 4°C followed by Alexa‐conjugated secondary antibody and DAPI for 2 hours at room temperature in the dark. VGLUT1, Iba1 and CD68 were used as synaptic marker in a triple staining to study pathological pruning and its reversal by PLX‐3397.ResultBoth inflammatory models induced LTP impairment, that was restored by application of a no‐specific blocker, Minocycline, or a specific inhibitor of activated microglia, PLX‐3397.Using whole cell patch clamp recordings, we observed that Aβ produces a reduction in glutamatergic transmission, evaluated as amplitude or frequency of sEPSCs and PPR, that is prevented by PLX‐3397. The data were confirmed using imaging studies, by which count of CA1 microglia and spine remodeling were evaluated.ConclusionOur results demonstrate a functional role of activated microglia in synaptic plasticity alteration that occurs in neuroinflammation suggesting CSF1R as new pharmacological target for AD treatment.
The Specialist Dementia Care Program: Describing and evaluating a novel model of care for people with severe and intractable behaviors in Australia.
Authors: Morris Thomas , Atee Mustafa , Alford Marie 
Published: December 2022

AbstractBackgroundA small proportion of people living with dementia experience very severe and intractable behaviors that cannot be supported by mainstream aged care. As a result, this population often rotates between acute, mental health, and aged care settings, and is at increased risk of inappropriate psychotropic prescribing and hospitalization. This led the Australian Government to announce in 2016 the funding for 35 Specialist Dementia Care Program Units (SDCPUs) across Australia.SDCPUs are purpose built, cottage‐like units staffed by specialist multidisciplinary teams who provide person‐centered care for people with very severe and intractable behaviors and psychological symptoms of dementia (BPSD). SDCPUs aim to reduce BPSD, improve quality of life, reduce inappropriate prescribing, and ultimately successfully transition residents to mainstream care within 12 months. As of January 2022, 10 SDCPUs were operational in 6 of 8 states and territories of Australia.MethodEligibility criteria for admission to SDCPUs include: (1) a diagnosis of dementia; (2) evidence of very severe BPSD (e.g., physical aggression); (3) evidence that the behaviors are enduring (i.e., have lasted at least 3 months); and (4) evidence of intractability to adequate trials of treatment (e.g., nonpharmacological interventions). This session will describe and discuss this assessment process required to access SDCPUs in Australia, the design features and model of care required of their operation, as well as learnings from the first two years of their operation.ResultThis session will also present the first longitudinal results of the impact of SDCPUs on resident behavior and wellbeing. Specifically, we will present the clinical outcomes of 37 residents from two SDCPUs, including BPSD, quality of life, activities of daily living, mood, prescribed psychotropics, rates of hospitalization, and successful transition into mainstream aged care.ConclusionWe will discuss these findings in the context of feasible and effective emerging models of care for BPSD support worldwide.
Rare Genetic Risk in Progressive Supranuclear Palsy
Authors: Chang Timothy , Wang Hui , Lee Wan‐Ping , Kumar Urvashi , Leung Yuk Yee , Dickson Dennis W. , Dalgard Clifton L. , Wang Li‐San , Schellenberg Gerard D. , Geschwind Daniel H. 
Published: December 2022

AbstractBackgroundGenetic risk in common variants have been identified for Progressive Supranuclear Palsy (PSP), but common variants only account for a portion of disease heritability. A proportion of the remaining disease heritability is likely contributed by rare variants identifiable via sequencing. Leveraging whole‐genome sequencing of 1719 PSP cases and 2940 controls from the Alzheimer’s Disease Sequencing Project, we detected single nucleotide variants (SNVs), insertion/deletions (INDELs), and copy number variants (CNVs). Note that all samples are non‐Hispanic whites with identity by descent (IBD) >0.25, and no outlier is >6 standard deviation in the principal component analysis. We conducted association analysis for variants, genes and gene sets to identify rare genetic risk for PSP.MethodAfter quality control (variants and genotypes notated PASS by the calling algorithms), we detected 85,228,234 rare SNVs/INDELs and 163,987 rare CNVs (minor allele frequency (MAF) < 1%). For rare SNVs/INDELs, the Sequence Kernel Association Test Optimized was performed to identify rare genetic PSP risk from protein truncating variants (PTV) and damaging missense variants (MAF<0.01%) in both protein coding genes and gene sets that were previously associated with PSP based on protein co‐expression networks. For rare CNVs, a permutation‐based association test implemented in Plink was performed to identify CNVs associated with PSP.ResultCombining protein truncating variants (PTV) and damaging missense variants, we identified one genome‐wide significant gene, FBXO38 (FDR = 0.0003, OR = 1.78). We also found enrichment of PTVs and damaging missense variants in genes comprising the C2 module, a neuronal module previously identified in post mortem PSP brain (FDR = 0.0016). For CNV analysis, there were 17 significant deletions and 2 significant duplications that were associated with PSP (Padjust < 0.05). The deletion (18:58488230‐58488489) in ALPK2, which has been identified as an Alzheimer’s Disease risk gene, was the only CNV that conferred a higher‐risk for PSP. Particularly, one deletion (17:46009357‐46009595) was in linkage disequilibrium with MAPT H2 haplotype which has been associated various neurodegenerative diseases including PSP.ConclusionWe identified several new genes and a protein co‐expression network in which risk variants were associated with PSP. These genes and pathways provide potential candidate drug targets for future investigation.
MRI Statistical region of interest best differentiates impaired from non‐impaired in the Study of Latinos‐Investigation of Neurocognitive Aging‐MRI (SOL‐INCA‐MRI)
Authors: Fletcher Evan M , Gallo Linda C , Talavera Gregory A , Isasi Carmen R , Kaplan Robert , Lipton Richard B. , Daviglus Martha L , Schneiderman Neil , Gellman Marc D , Stickel Ariana M , Tarraf Wassim , González Hector M , DeCarli Charles S. 
Published: December 2022

AbstractBackgroundWe developed a statistical region of interest (sROI) of gray matter (GM) for which cortical thickness (CT) significantly differed in a “training set” of 100 cognitively normal and 100 individuals with incident dementia in the Framingham Heart Study. sROI significantly predicts incident cognitive impairment and dementia in both FHS and the highly diverse UC Davis Alzheimer’s disease longitudinal cohort. Here we describe a similar analysis of participants of Study of Latinos‐Investigation of Neurocognitive Aging‐MRI (SOL‐INCA‐MRI).MethodsHispanics/Latinos (n=6,377 ages 50‐86) were enrolled in the Study of Latinos ‐ Investigation of Neurocognitive Aging (SOL‐INCA) of which 1,143 also participated in SOL‐INCA‐MRI ancillary study. Cognitive impairment (CI) was defined as any cognitive domain score falling below (<‐1.0 SD) the SOL‐INCA robust internal normative mean and significant cognitive decline (‐0.055 SD/yr), self‐reported cognitive decline and no or minimal functional impairment over 7 years. Participants with dementia were excluded.MRI CT was computed by the DiReCT method. sROI was derived from statistically significant (via 1,000 non‐parametric permutations) clusters of GM voxels having CT group difference t > 2 over the training set (Fig. 1). Extents of sROI overlap with standard atlas GM regions appear in Table 3.Group differences in variables were assessed by t‐test. Logistic regression assessed the impact on cognitive status of MRI factors: total brain, hippocampal, white matter hyperintensities (WMH), sROI volumes and infarction occurrence, controlling for age, sex, education, and background.ResultsThe cohort was 64.4 + 7 years of age, 69% female. Nearly 60% with high school or less education, and 21% CI. Table 1 summarizes demographic and MRI measures for CI and cognitively normal (CN). CI individuals were older, had less education, smaller brains, and greater amounts of WMH. Table 2 summarizes results of logistic regression. Education and sROI mean CT were the only significant predictors of cognitive status.ConclusionCortical thickness within the sROI was strongly associated with cognitive status, even when other commonly used MRI measures were not. sROI may therefore be a sensitive indicator of incipient CI within SOL‐INCA‐MRI where more traditional measures of Alzheimer’s pathology and vascular disease appear insensitive.
IN‐VIVO EVALUATION OF APN‐1808, A TAU SMALL MOLECULE THERAPEUTIC
Authors: Tempest Paul , Lin Yih‐Shyan , Lai Yen‐Ting , Tai Chin‐Yin , Ma Haou‐Tzong , Huang Sheng‐Chieh , Margolin Richard A , Wu Chia‐Lin , Jang Ming‐Kuei 
Published: December 2022

AbstractBackgroundThe high value for Alzheimer’s Disease and other taupathies of a small molecule treatment that can alter disease course is widely acknowledged. We aim to investigate such a therapeutic by leveraging our small molecule CNS aggregated protein discovery platform.MethodOur small molecule discovery platform consists of our proprietary small molecule collection, unique PET imaging biomarkers and cryoEM structures. Our proprietary collection of CNS‐focused aggregated protein binding agents, previously developed by APRINOIA to map the structure‐activity relationship of its tau PET tracer programs, was screened for tau binding and further interrogated for other desirable properties such as selectivity and oral availability. Further efforts derived guidance from the cryoEM structure of our lead compound bound to Tau aggregates. These efforts resulted in our small molecule lead compound APN‐1808.Using rTg4510 mice, which over express 4R tau, we first investigated dose‐response by using in‐vivo PET imaging to measure percent occupancy of APN‐1808. Upon selecting an appropriate dose range, we engaged in 90 day, twice a day dosing of APN‐1808 in rTg4510 mice.ResultMice dosed with APN‐1808 showed improvements both biochemically and phenotypically over vehicle controls. Improvements included increase in synaptic protein level, reduction in overall tau burden, reduction in weight loss and other behavioral observations.ConclusionSeveral readouts showed improvement in the dosed groups compared to controls, including increase of synapse level, reduction of weight loss and reduction of total tau. Further investigations are ongoing.
Exploring mechanisms of synaptic vulnerability and resilience in Primary Age Related Tauopathy
Authors: Kadamangudi Shrinath , Tumurbaatar Batbayar , Taglialatela Giulio 
Published: December 2022

AbstractBackgroundPrimary Age Related Tauopathy (PART) is a sporadic dementia‐related illness, characterized by pathological tau accumulation limited to the hippocampal‐entorhinal region in the absence of Aβ plaques. Studying PART thus presents a unique opportunity to 1) characterize toxic tau species, namely oligomeric (tauO) tau, and to 2) explore molecular mechanisms underlying regional synaptic vulnerability (i.e. hippocampus) and resilience (i.e. neocortex) within a singular tauopathy—such as low‐density lipoprotein receptor 1 (LRP1), recently uncovered as a key mediator of tau uptake and trans‐synaptic spreading.MethodsWe compared levels of tauO, total tau, and LRP1 between the hippocampus and superior medial temporal cortex (SMT) in 7 post‐mortem PART patients. Total homogenate and synaptosomal fractions were prepared for Western Blot; both fractions were probed for total tau (Tau13), and LRP1. TauO were ascribed to high molecular weight tau bands using the total tau probe. p‐tau (AT180) and paired helical filaments (PHF13.6) were also probed in the total homogenate fraction to assess PART neuropathology. The Wilcoxon matched‐pairs signed rank test was utilized to compare regional differences.ResultsWe found elevated levels of p‐tau and PHF in the hippocampus vs. SMT (total homogenate), thus validating previously reported PART neuropathology. We observed a trend towards increased tauO in the hippocampus vs. SMT in PART total homogenate (p=0.11) and synaptosome fractions (p=0.06). Of note, no regional differences were found in total tau levels in either the fractions. In the total homogenate, we found no statistically significant regional differences in LRP1 (p=0.30). Interestingly however, we observed decreased LRP1 in the hippocampus vs. SMT in 6 out of 7 PART patients. On the orher hand, we found no significant differences or notable trends in LRP1 between the hippocampus vs. SMT in the synaptosomal fraction.ConclusionsThis investigation of PART neuropathology is the first to demonstrate accumulation of tauO, restricted to the hippocampus and its synapses. We further report lower levels of LRP1 in the hippocampus of PART patients, a seemingly extra‐synaptic phenomenon, that could potentially mediate regional vulnerability to pathological tau species. Further biochemical and functional assays to characterize tau toxicity and spread are currently under investigation.
Robust prediction of memory and neuroticism in men and women using connectome‐based predictive modeling
Authors: Ju Suyeon , Horien Corey , Constable Todd , Fredericks Carolyn A 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) disproportionately impacts women, yet we have little understanding of the differences in brain circuitry that underlie this vulnerability. We explored aspects of brain connectivity that robustly predict memory performance (measured by RAVLT performance) and neuroticism (measured by NEO‐N) in healthy women vs men by leveraging data‐driven machine learning to model the brain connectome in the Lifespan Human Connectome Project Aging (HCP‐A) dataset.MethodWe used functional MRI scans to create whole‐brain connectivity matrices based on 268 regions‐of‐interest for 725 healthy subjects (319 men, 406 women) aged 36 to 100 enrolled in HCP‐A. Before and after separating the subjects by sex, connectome‐based predictive modeling (CPM) was used with a p‐value threshold of 0.01 and split‐half cross‐validation to identify and implement edges that significantly predicted the neurobehavioral scores to train a predictive model for each group. The models were applied to test sets within each group, outputting the predicted behavioral measures and Pearson correlations between predicted and observed scores.ResultAs anticipated, overall performance in HCP‐A was higher for women than men in RAVLT (p < 1x10‐7) and NEO‐N (p = 0.12). Our model predicted the RAVLT measure (Fig. 1) with accuracies ranging from R = 0.2154 (p < 1x10‐4) to R = 0.4293 (p < 1x10‐4). Our sex‐based models also predicted a high variance in the RAVLT measure between sexes (σ2 = 0.015, Fig. 2). While neuroticism predictors were not as robust for short‐term memory, the models were still able to predict a significant amount of variance (σ2 = 0.023, Fig. 2).ConclusionWe successfully implemented CPM to derive robust brain‐based predictors of memory performance and neuroticism. Models derived separately for each sex differ in their ability to explain variance in these measures. Future analyses will pinpoint specific edges within the connectivity matrices that explain variance in memory performance or neuroticism in men vs women. We anticipate these will yield important insights into why women are at higher risk of developing AD.
Higher body mass and fat composition are related to 1‐year cerebral amyloid accumulation in individuals with elevated risk for Alzheimer’ disease
Authors: Smith Aaron N. , Taylor Matthew K , Sullivan Debra K , Keller Jessica E , Burns Jeffrey M. 
Published: December 2022

AbstractBackgroundAmyloid‐β is a classical hallmark and risk factor for development of Alzheimer’s disease (AD). Observational data suggest that having higher body mass index (BMI) is associated with lower cerebral amyloid burden in cognitively normal adults. However, the influence of body composition on cerebral amyloid deposition has not been investigated. We investigated whether baseline body composition influences 1‐year change in cerebral amyloid in a sample enriched with older adults with elevated amyloid.MethodData from 103 cognitively normal adults with high normal or elevated cerebral amyloid that participated in a 1‐year exercise RCT were analyzed. Cerebral amyloid burden was quantified in 6 cortical regions of interest by Florbetapir F18 PET. Global amyloid burden was calculated by averaging the 6 regions. Total lean body mass and fat mass percentages were measured using DXA. We constructed ordinary least squares regression models to investigate the relationship between our baseline measures of body composition and 1‐year change in regional and global amyloid. All models included age, APOE4 carrier status, study arm, sex, and baseline regional amyloid standard uptake value ratios as covariates.ResultParticipants were 67% female with a mean age of 72.4 ± 5.0 years. Mean BMI was 28.0 ± 5.4, lean body mass percentage was 61% ± 7.5%, and fat mass percentage was 38% ± 7.1%. Higher BMI was related to less 1‐year amyloid accumulation in 5 regions (anterior cingulate gyrus, precuneus, inferior medial frontal gyrus, lateral temporal lobe, and superior parietal lobe) and globally (β range = ‐0.003 to ‐0.004, p<0.03 for all). Higher fat mass percentage was related to less amyloid accumulation in all 6 brain regions and the global average (β range = ‐0.25 to ‐0.34, p<0.03 for all). Higher lean body mass percentage was related to less amyloid accumulation in the lateral temporal lobe (β = ‐0.003, p = 0.01).ConclusionIn this study, having larger body stature and higher fat mass percentage were related to less amyloid accumulation in individuals with elevated risk for AD. Further studies are necessary to explore these relationships in greater detail and to ascertain if these findings are modulated by other biological variables.
PROGRESS IN DEVELOPING A LIGHT‐STABLE 4R TAU PET IMAGING AGENT: APN‐1701 FIH
Authors: Tempest Paul , Lin Yih‐Shyan , Tai Chin‐Yin , Ono Maiko , Russell David S , Sandiego Christine M , Gunn Roger N , Carroll Vincent , Margolin Richard A , Kao Tzu‐Huei , Higuchi Makoto , Jang Ming‐Kuei 
Published: December 2022

AbstractBackgroundThe need for a light stable 4R tau PET tracer for use in diverse tauopathies is widely appreciated. We aimed to assess the initial human imaging profile of [18F]APN‐1701 as such a tracer and to compare its imaging profile to the well‐established but light‐sensitive tracer [18F]‐APN‐1607 that can detect 4R aggregates as well as 3R and mixed 3R/4R aggregates. [18F]APN‐1607 has progressed to a multicenter Phase 2 clinical trial for Alzheimer’s disease (AD); therefore, prior imaging data with it was considered valuable for comparison.MethodOne cognitively normal (CN) subject (male, 73yo) and one AD subject (female, 58 yo), who had undergone prior amyloid profiling using [18F]florbetapir PET and subsequent imaging with [18F]APN‐1607 in a proof‐of‐concept study and a test‐retest study, respectively, participated in the current study. Dynamic imaging with [18F]APN‐1701 was performed over 180 min to obtain kinetic data.ResultOverall, for both subjects [18F]APN‐1701 generally matched [18F]APN‐1607 findings, i.e., peak SUV values reached similar levels. The CN subject, who was amyloid negative, had slight, uniform cortical [18F]‐APN‐1701 uptake and more substantial uptake in the pallidum, pons and midbrain. SUVr images for the AD subject showed retention in similar brain regions for both tau tracers with the same rank order of regional SUV/SUVr. Notably, for this subject [18F]APN‐1701 continued to accumulate up to the end of image acquisition.Conclusion[18F]APN‐1701 demonstrates cortical uptake generally similar to [18F]APN‐1607 but its slow kinetics are unfavorable for further development.
Body mass index and 2‐year change of in vivo Alzheimer's disease pathologies in cognitively normal older adults
Authors: Lee Seunghoon 
Published: December 2022

AbstractBackgroundMultiple studies supported that low body mass index (BMI) or underweight status in late‐life was associated with increased risk of dementia. We tried to test the hypothesis that lower late‐life BMI is related with greater increase of in vivo AD pathology including Aβ and tau deposition for two years in cognitively healthy individuals. Additionally, we explored the same relationship in each sex separately, considering previous reports that showed prominent sex differences for the relationship between BMI and AD dementia risk.MethodTotal 194 cognitive normal older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent comprehensive clinical assessment including BMI measurement, [11C] Pittsburg compound B and [18F] AV‐1451 PET at baseline. The same brain imaging scans were repeated at a year follow‐up assessment. The association of baseline BMI with longitudinal changes of AD biomarkers were analyzed using linear mixed effect models.ResultLower BMI at baseline was significantly associated with greater increase of tau deposition in AD‐signature region for 2 years. In contrast, BMI was not related with 2‐year change of global Aβ deposition. In additional exploratory analysis for each sex, lower baseline BMI was associated with greater increase of both Aβ and tau deposition in male, whereas neither Aβ nor tau change was not related with baseline BMI in female.ConclusionThe present study suggest that lower late‐life BMI may accelerate the accumulation of AD pathology in the brain, especially in male. To prevent AD, more attention is needed to be paid to avoiding underweight in old age and maintaining an appropriate BMI status.