bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repetitive mild traumatic brain injury induces hippocampal neural immune signaling linked to astrocyte reactivity
Authors: Pybus Alyssa F , Bitarafan Sara , Brothers Rowan , Rohrer Lilly , Udeshi Kareena , Davies Brae , Khaitan Arushi , Li Chenxing , Buckley Erin , Wood Levi B 
Published: June 2023

AbstractBackgroundRepeated mild traumatic brain injuries (mTBIs) sustained within a “window of vulnerability” can lead to a cumulative severity of outcomes such as memory impairment, depression, and long‐term development of amyloid beta (Aβ) pathology and neurofibrillary tangles. We previously reported that acute increases in neural immune signaling within the MAPK pathway and expression of pro‐inflammatory cytokines were associated with low cerebral blood flow (CBF) and worse long‐term spatial learning and memory in a weight‐drop mouse model of repetitive mTBI. We hypothesized that an increasing number of injuries would lead to an increase in neural immune signaling, pathological markers, and glial activation in the hippocampus.MethodFemale 3xTg mice at 3‐4mo of age were subjected to 1x, 3x, or 5x weight‐drop closed head injuries (CHI) spaced once‐daily. Animals were sacrificed and brains harvested at 30min, 4h, 24h, or 1‐month after the final CHI (n = 7‐10/time point/injury group). 32 cytokines, 10 MAPK phospho‐proteins, Aβ42, Aβ40, phospho‐tau (pThr181), and total tau were measured by Luminex in hippocampal tissues. GFAP was measured by ELISA. CBF was non‐invasively measured immediately prior to sacrifice.ResultWe observed a steady increase in both total tau and phospho‐tau and a trend of increased GFAP in the hippocampus after repeated injuries. We then identified groups of cytokines and MAPK phospho‐proteins which co‐vary with either GFAP or phospho‐tau. GFAP‐associated cytokines showed a rapid acute increase after injury then a return to basal levels by 24h, while GFAP‐associated MAPK dynamics changed with repeated injury. Cytokines and MAPK phospho‐proteins showed a notably high degree of cross‐correlation 4h after repeated injury, when GFAP levels were at their highest. Multivariate analysis revealed that high levels of GFAP were associated with low CBF while increased phospho‐tau in the frontal cortex was associated with high CBF.ConclusionTogether, our data indicate an increase in hippocampal neural immune signaling and astrocyte reactivity after repetitive brain injury. Immune signaling changes may be causally linked to spatial learning and memory deficits after repetitive mTBI.
Computational CRISPR deep learning simulation of the likelihood of Alzheimer’s disease using chromosome 19 GWAS
Authors: Bae Jinhyeong , Acri Dominic J , Nho Kwangsik , Saykin Andrew J. , Penchev Valentin , Apostolova Liana G. 
Published: June 2023

AbstractBackgroundSeveral genetic variants in chromosome 19 have been determined as independent Alzheimer’s disease (AD) risk factors. It is presumed that different combinations amongst them would further impact AD risk and progression at the individual level. In order to advance AD precision medicine, it is critical to understand the underlying complex genetic mechanisms. Deep learning technology is capable of not only identifying such variants but also defining complicated interactions that could further influence disease progression.MethodWe applied a novel deep learning model to the 266,161 SNP chromosome 19 data of 313 AD and 457 cognitively unimpaired (CU) ADNI patients. By using occlusion mapping we identified the SNPs that contributed to predictive accuracy of AD vs. CU and sequentially replaced each of them with all other biologically plausible alleles to most precisely measure the impact of the variability at the SNP level. Next, we examined the possible epistatic interactions on the SNP level on AD likelihood by co‐occlusion of pairs of SNPs and investigating the additional changes on predictive accuracy.ResultRs56131196 (APOC1) emerged as the most powerful chromosome 19 AD SNP. 79.69% (51/64) of the predicted AD patients were heterozygous, i.e., AG, at this locus. In contrast, 88.89% (80/90) of the predicted CU patients had GG genotype at rs56131196. Substituting AG for GG in predicted AD participants resulted in changing the diagnostic prediction to CU in 36% of the cases. Substituting GG for AA in predicted CU participants resulted in changing the diagnostic prediction to AD in 6% of the cases. The model further identified that AG→GG replacement further affects the likelihood of AD by interactions with SNPs in other genes including APOC1/APOC1P1, TOMM40, and ERCC1/CD3EAP.ConclusionWe tested the APOC1 rs56131196 genotype risk for AD by creating a simulator analogous to CRISPR. This innovative approach could provide a potential in silico CRISPR predictive modeling and help advance personalized preventive gene therapy for AD.
The association of amyloid‐beta, tau, and cerebrovascular biomarkers with neurodegeneration in dementia with Lewy bodies
Authors: Ferreira Daniel , Przybelski Scott A. , Lesnick Timothy G. , Schwarz Christopher G. , Diaz‐Galvan Patricia , Graff‐Radford Jonathan , Senjem Matthew L. , Fields Julie A. , Savica Rodolfo , Ferman Tanis J , Graff‐Radford Neill R , Lowe Val J. , Jack Clifford R. , Petersen Ronald C. , Westman Eric , Boeve Brad F. , Kantarci Kejal 
Published: June 2023

AbstractBackgroundDementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, after Alzheimer’s disease (AD). While alpha‐synuclein pathology is the hallmark of DLB, AD and cerebrovascular pathologies are common in DLB patients. However, the contribution of these pathologies towards neurodegeneration in DLB is largely unknown. We investigated associations of amyloid‐beta, tau, and cerebrovascular biomarkers with regional gray matter (GM) volume in DLB patients and cognitively unimpaired (CU) controls.MethodWe included 30 DLB patients (69.3±10.2 years old, 87% men) and 100 CU individuals balanced on age and sex (Table 1). We used 11C‐Pittsburgh Compound‐B (PiB) and 18F‐Flortaucipir positron emission tomography (PET) to assess amyloid‐beta and tau in‐vivo. We used structural MRI to assess white matter hyperintensity (WMH) volume, a marker of cerebrovascular lesion load, and regional GM volume (a marker of neurodegeneration). We used correlations and ANCOVA in the whole dataset and structural equation modelling in the DLB patients to investigate associations of WMH volume and regional amyloid‐beta and tau PET standardized uptake value ratios (SUVRs) with regional GM volume.ResultDLB patients showed lower GM volume across all cortical and subcortical regions except for cuneus, putamen, and pallidum (Fig.1). Greater WMH volume was associated with lower volume in the medial and orbital frontal cortices, insula, fusiform cortex, and thalamus in DLB patients (Fig.2). Greater PiB SUVR was associated with lower volume in the inferior temporal cortex, while Flortaucipir SUVR did not correlate with GM volume (Fig.2). Structural equation modelling showed that higher age and positivity for the APOE e4 genotype were significant predictors of greater WMH, and WMH in turn was a significant predictor of GM volume in medial and orbital frontal cortices, insula, and inferior temporal cortex (Fig.3). In contrast, we observed two distinct paths for the fusiform cortex, with age having an effect through PiB and Flortaucipir SUVRs on the one path, and through WMH on the other path (Fig.3).ConclusionDLB patients have widespread cortical atrophy, most of which likely is influenced by alpha‐synuclein pathology. Although amyloid‐beta, tau, and cerebrovascular pathologies often coexist in DLB, their contributions to neurodegeneration seem to be region specific.
Increased Expression of Kif11/Kinesin‐5 mRNA Offsets Cognitive Deficits In An Alzheimer’s Mouse Model, Blocks Aβ‐Mediated Decreases in Long‐Term Potentiation and Spine Density, and is Associated With Better Cognitive Performance in Alzheimer’s Patients
Authors: Lucero Esteban M , Freund Ron , Smith Alexandra N. , Johnson Noah R , Dooling Breanna , Sullivan Emily , Prikhodko Olga , Ahmed Md. Mahiuddin , Bennett David A , Hohman Timothy J. , DellAcqua Mark , Chial Heidi J , Potter Huntington 
Published: June 2023

AbstractBackgroundInteractions between the Aβ with intra‐ and extra‐cellular molecules disrupt neuronal structures and functions, leading to cognitive dysfunction in Alzheimer’s disease (AD). We previously have shown that Aβ competitively inhibits the microtubule motor protein KIF11 (Kinesin‐5/Eg5), which regulates microtubule dynamics, cellular trafficking, neuronal migration, and neuronal structures important for learning and memory. In vitro cell culture and ex vivo electrophysiology experiments later revealed that the inhibition of KIF11 by Aβ underlies multiple phenotypes associated with AD, including decreases in LTP, breakdown of the microtubule network, and deficits in neurotransmitter receptor localization and function. Here we aimed to determine whether increased Kif11 expression overrides phenotypes associated with AD.MethodsKif11 overexpressing mice were crossed with the 5xFAD mouse model of AD to generate 5xFAD mice that overexposes Kif11. Learning and memory of these mice was measured through the performance of 6‐8 month old mice in the radial‐arm water maze and LTP was measured by the fEPSP response to high‐frequency stimulation of the CA1 region in hippocampal slices of our transgenic mice. Primary rat neurons were transiently transfected to express human APP harboring the Swedish mutation (APPswe) with or without Kif11 overexpression to determine whether increased Kif11 expression affects Aβ‐mediated decreases in dendritic spine, We then evaluated cognitive function in amyloid positive individuals in the ROS/MAP study with their KIF11 mRNA expression in 4 brain regions, the DLPFC (N = 939), PCC (N = 527), and the CN (N = 715).ResultsKIF11 overexpression overrides Aβ toxicity and rescues Aβ‐mediated decreases in LTP in hippocampal slices and dendritic spine density in cultured neurons. Furthermore, we found that spatial and working memory deficits were prevented in a 5xFAD Alzheimer’s mouse model that overexpresses Kif11. Analyses of RNAseq data from human participants in the Religious Order Study and Memory and Aging (ROS/MAP) revealed that higher KIF11 expression in AD patients correlated with better cognitive performance.ConclusionKIF11 is essential for maintaining synaptic structures and functions critical for learning and memory in AD, and preventing or overriding the inhibitory interaction of Aβ with Kif11 could be a promising therapeutic target for multiple AD phenotypes.
Neuropsychiatric symptom progression in predementia frontotemporal dementia mutation carriers
Authors: Lee Hyunwoo , Chatterjee Atri , Mackenzie Ian R , Lapid Maria I. , Huey Edward D. , Wittenberg Dana , Rosen Howard J. , Boeve Brad F. , Boxer Adam L , Rankin Katherine P , Hsiung Ging‐Yuek Robin ,   the ALLFTD Consortium
Published: June 2023

AbstractBackgroundNeuropsychiatric symptoms (NPS) often occur during the prodromal stage of frontotemporal dementia (FTD), as evidenced by the presence of early psychiatric diagnosis in approximately 50% of bvFTD patients prior to their dementia diagnosis. We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased baseline burden and rates of progression of NPS compared to non‐carrier individuals prior to onset of dementia symptoms based on the Clinical Dementia Rating (CDR) scale.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. NPS were assessed with Neuropsychiatric Inventory‐Questionnaire (NPI‐Q), Geriatric Depression Scale (GDS), Interpersonal Reactivity Index (IRI), Social Behaviour Checklist (SBOCL), and Behavioral Inhibition Scale (BIS) annually for up to five years. We selected participants with CDR scores of 0 and 0.5. If a participant’s CDR changed to above 0.5 during the follow‐up, we only analyzed observations collected before the conversion. We used mixed effects models to compare the baseline burden and the longitudinal progression of NPS measures between carriers and controls, adjusted for baseline age, sex, education, and baseline Montreal Cognitive Assessment (MoCA) scores.ResultWe analyzed data from 607 participants (111 C9orf72+, 47 GRN+, 67 MAPT+ and 382 non‐carrier controls). There were no significant group differences in baseline demographic features, except that MAPT+ was significantly younger than other groups (average age: C9orf72+ = 45, GRN+ = 53, MAPT+ = 41, controls = 54). Baseline NPS scores were not significantly different between carriers and controls, except that C9orf72+ had significantly lower GDS compared to controls (p = 0.002). Longitudinally, GRN+ (p = 0.02) and MAPT+ (p = 0.009) had significantly higher rates of NPI‐Q increases compared to controls, while the progression of NPI‐Q in C9orf72+ was comparable to controls. The rates of GDS, IRI, SBOCL and BIS progression were not significantly different between carriers and controls.ConclusionPrior to the onset of dementia, GRN+ and MAPT+ have a faster progression of NPS, as measured by NPI‐Q, compared to controls. Future work will investigate whether different mutation carriers are affected by specific type/cluster of symptoms.
Altered ubiquitination of phospholipase D3 contributes to lysosome dysfunction in Alzheimer’s Disease
Authors: Fernandez Wilber Romero , Antunes Lissa Ventura , Katdare Ketaki A. , Balotin Kylie M. , Prusky Alex , Solopova Elena , Shostak Alena , Wang Emmeline , Lippmann Ethan S , Schrag Matthew 
Published: June 2023

AbstractBackgroundProteinopathy is a common feature of multiple neurodegenerative diseases. Recent studies have demonstrated lysosomal dysfunction is closely linked to neurodegenerative proteinopathies. In the context of Alzheimer’s disease (AD), the lysosomal protein phospholipase D3 (PLD3) has been identified as a potential molecular player, but PLD3’s distinct role in lysosome function is not completely understood.MethodWe used immunohistochemistry, western blot, and proximity ligation assays to determine PLD3’s localization, expression level, post‐translational modification and protein‐protein interaction profile. Experiments were performed using iPSC‐neuron cultures and human brain tissue obtained from patients with AD and neurological controls through the Vanderbilt Brain and Biospecimen Bank.ResultPLD3 is neuronal widely distributed throughout brain regions relevant to memory and cognition and PLD3 levels were significantly lower in AD brains compared to the controls. We discovered that PLD3 ubiquitination was significantly increased in AD brains relative to the controls, providing a possible explanation for the PLD3 reduction and localization into hallmark pathological structures of the AD brain. Furthermore, PLD3‐ubiquitin complexes were enriched in parenchymal β‐amyloid deposits and intraneuronal tau pathologies, both neuropil threads and neurofibrillary tangles.We provide the first experimental evidence for the physical interaction between PLD3 and Cathepsin D (CTD), both in human brain tissue and iPSC neurons. The interaction between PLD3/CTD was promoted by exposure of iPSC‐neurons to human Aβ seeds isolated from post‐mortem brain, suggesting this protein‐protein interaction is relevant to Aβ pathology. We found this heterodimer was dramatically reduced in AD brain, especially in dystrophic neurites. The loss of this interaction in dystrophic neurites is notable because even though PLD3 levels are reduced in the AD brain, both PLD3 and CTD are present in abundance around β‐amyloid plaques. The loss of PLD3/CTD interaction observed in AD brain is only partly explained by reduced expression of both proteins, so it is likely that an alteration in lysosome function is impacting this protein‐protein interaction.ConclusionThis study revealed an important role for both PLD3 ubiquitination and as an interaction partner for CTD within lysosomes. It will be interesting to further dissect the molecular mechanisms underlying the PLD3/CTD interaction.
Interaction effect of sex and diagnosis on functional connectivity within the default network in healthy controls, mild cognitive impairment and Alzheimer Disease
Authors: Cieri Filippo , Yang Zhengshi , Cummings Jeffrey , Kinney Jefferson W , Cordes Dietmar , Caldwell Jessica ZK ,   ADNI study
Published: June 2023

AbstractBackgroundAge and sex are major risk factors for late onset Alzheimer’s disease (AD). Almost 70% of AD patients are women, but reasons for sex disparities are not well understood. One potential avenue of inquiry is investigation of default network (DN) functional connectivity (FC) differences between men and women.MethodWe studied amyloid positive individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), clinically diagnosed as healthy elderly controls (HCs), Mild Cognitive Impairment (MCI) and AD, with resting‐state functional Magnetic Resonance Imaging available at the diagnostic and cognitive testing visit (Table 1). We selected seven regions of interest (ROIs) in the DN (Figure 1), including bilateral angular gyrus (ANG), calcarine (CAL), precuneus (PCUN), medial orbital frontal gyrus (ORBmed) and bilateral middle occipital gyrus (MOG). Pearson’s correlation characterized FC between ROIs. Linear mixed effect models adjusted for covariates (education, handedness, presence of apolipoprotein [APOE] ε4 and intra‐subject effect), and analysis of variance (ANOVA) evaluated the effects of diagnosis, sex and their interaction, using Bonferroni correction.ResultsANOVA showed significant differences between diagnostic groups in FC of left ANG – PCUN/CAL and bilateral MOG – CAL. Significant diagnosis by interaction effects were observed in FC especially at the level of posterior‐ventral DN. Specifically, between ANG‐CAL, and PCUN‐MOG (Table 2). Post‐hoc analysis demonstrated distinct effect sizes and/or opposite direction effects in women compared to men (Figure 2). Left ANG – CAL and left ANG – PCUN connectivity had medium effect (|d| >0.5) for men in the MCI versus HC comparison, although small effect (|d| <0.2) across sexes. The discrepancies between women and men were observed in the AD versus MCI comparison, such as the left ANG – left MOG and right ANG – CAL, where they show an opposite direction of FC.ConclusionsOur study found that the sex differences in DN FC did not remain consistent across the clinical AD spectrum. Instead, significant sex by diagnosis interaction effects suggest that treating sex as a covariate overlooks sex‐specific pathological changes in brain FC.
Deformation‐based morphometry analysis shows early degeneration in Nucleus basalis of Meynert in Subjective Cognitive Decline
Authors: Shafiee Neda , Morrison Cassandra , Dadar Mahsa , Fonov Vladimir S , Spreng R. Nathan , Collins D Louis 
Published: June 2023

AbstractBackgroundPeople with subjective cognitive decline (SCD+) are thought to be at greater risk of Alzheimer’s disease (AD). The Nucleus basalis of Meynert (NbM) has been shown to change early in AD (Fernández‐Cabello et al., 2020), and it is the main source of cholinergic projection to entorhinal cortex (EC) (Mesulam et al., 2013). We thus investigated if there was evidence of degeneration in the NbM, or EC in SCD+ participants compared to those without (SCD‐), and if there was a relationship between changes in these regions and SCD status using deformation‐based morphometry (DBM).MethodData included baseline visit MRI scans of 232 cognitively healthy older adults (148 SCD‐; 84 SCD+) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (using only ADNI2). SCD status was extracted based on the cognitive change index (CCI) of the subjects reported in ADNIMERGE data (CCI ≥16). MRI resolution was increased to 0.5 mm isotropic voxel‐size before non‐linear registration to an ADNI‐based unbiased symmetric template. The resulting deformation fields were used to compute the Jacobian determinant map for each subject as a proxy for local volume. NbM, and EC masks were mapped to our high‐resolution template and mean determinant values inside these masks were estimated, and sex‐ and age‐corrected z‐scores were calculated. Two‐sample t‐tests were then used to compare the SCD+:SCD‐ differences.ResultFigure 1 shows the mean z‐score values for NbM and EC regions for both SCD+ and SCD‐ groups. Results for left NbM showed a significant difference between two groups (p = .007), but not for the right NbM (p = .12). However, z‐scored EC volumes did not show any statistically significant difference between groups for either left (p = .58) or right region (p = .41).ConclusionOur results suggest that in SCD+ subjects, while the EC is still intact, neurodegeneration in the NbM appears to have already begun. Quantifying degeneration in the NbM may allow for early diagnosis of AD. Further research is needed to evaluate if such differences can be computed on an individual subject basis for use as a biomarker.
Description of the ARMADA (assessing reliable measurement in Alzheimer’s disease) general population study cohorts
Authors: Karpouzian‐Rogers Tatiana , Ho Emily , Novack Miriam , Chinkers Miriam , Wortman Katy , Nowinski Cindy J. , Dodge Hiroko H , Giordani Bruno , Gershon Richard C. , Weintraub Sandra 
Published: June 2023

AbstractBackgroundGiven the growing population of aging adults, and subsequently individuals with dementia, there is a need for instruments that can detect cognitive impairment in early stages. The NIH Toolbox® for Assessment of Neurological and Behavioral Function (NIHTB) is a computerized battery of assessments measuring multiple domains cognition, emotion, sensation, and motor abilities. The goal of the ARMADA study is to validate the NIHTB in individuals with mild cognitive impairment (MCI) and dementia of the Alzheimer type (DAT). Here, we describe the demographic and clinical characteristics of participants ages 65 to 85 from the general population sample.MethodNormal control (NC), MCI, and DAT groups racially proportional to the US population were recruited from existing cohorts across nine Alzheimer’s Disease Research Centers and sites with cognitive aging studies. Diagnoses were based on the Uniform Data Set methodology, and included multiple clinical and cognitive assessments. Participants completed the NIH Toolbox at baseline, 12‐, and 24‐month visits.ResultGroups were matched with respect to multiple demographic characteristics. There were some differences in age and sex, such that the NC group had more female participants and was the youngest. Dementia severity levels differed as expected, with the DAT group demonstrating greater cognitive and functional impairment compared to the MCI group, and the NC group demonstrating minimal cognitive or functional symptoms. Additionally, the DAT group reported more neuropsychiatric symptoms compared to the NC and MCI groups. There was no difference in reported family history of cognitive impairment across groups. Many participants across groups had at least one Alzheimer biomarker collected.ConclusionThe study cohorts included in the ARMADA study accurately reflect their respective clinical syndromes for validating the NIHTB across the cognitive aging spectrum. The goals for the ARMADA study include comparing performance on all four modules of the NIHTB across groups, evaluating the relationship between Alzheimer biomarkers and NIHTB measures, and measuring changes in performance longitudinally. Special emphasis groups, including individuals over age 85, African American participants, and Spanish‐Speaking participants, were also recruited and are reported elsewhere.