bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infusion of neural precursors improves memory impairment in mouse models of Alzheimer’s disease
Authors: Ruiz Nazaret Gamez , Fuentes Enrique Antonio Armijo , Gomez‐Gutierrez Ruben , Soto Claudio , Moreno‐Gonzalez Ines 
Published: December 2020

AbstractBackgroundCurrently available treatments for Alzheimer’s disease (AD) are essentially symptomatic and not disease‐modifying, positioning it as a serious global health problem with the increase of the elderly population. This disease is clinically characterized by progressive memory impairment and cognitive dysfunction. The neuropathological hallmarks of AD are the accumulation of extracellular β‐amyloid (Aβ) peptide in senile plaques, intracellular deposition of hyper‐phosphorylated tau as neurofibrillary tangles (TNF), neurodegeneration, synaptic loss throughout the brain, and a neuroinflammatory process governed by the activation of glial cells. Recently, stem cell therapy has provided great potential in treating AD patients. However, there is an urgent need to replace the conventional intracerebral stem cell therapy for a less invasive method to avoid some of the technical challenges. Our recently published results indicated that peripheral treatment with neural precursors (NPs) ameliorates clinical symptoms by reducing the disease‐associated neuroinflammation in a mouse model of Parkinson’s disease. Therefore, we hypothesize that intravenous administration of NPs and their released neurotrophic factors can be used as a non‐invasive therapy to ameliorate memory impairment in mouse models of AD.MethodIn this pre‐clinical study, NPs derived from mesenchymal stem cells (MSC‐NPs) and induced pluripotent stem cells (iPSC‐NPs) were intravenously injected into APP/PS1 and P301S mice at 3 and 6 months old (before and after brain pathology is established). Before treatment and at the age of 7 months old, experimental and control (PBS) animals were subjected to Barnes maze task, novel object recognition and rotarod test.ResultNPs treated mice displayed an amelioration in memory dysfunction compare to the PBS‐injected animals. In addition, P301S mice injected with NPs showed improved motor function to rotarod coordination test in comparison to the control group.ConclusionPeripheral inoculation using NPs could be used as a treatment to reduce AD‐related clinical signs.
Multiple pathologies in an amateur soccer player with severe chronic traumatic encephalopathy
Authors: Rodriguez Roberta Diehl , Suemoto Claudia K. , Brucki Sonia Maria Dozzi , Leite Renata P. , Nowinski Christopher , de Lucena Ferretti‐Rebustini Renata Eloah , Jacob‐Filho Wilson , Pasquallucci Carlos Augusto , Nitrini Ricardo , Grinberg Lea Tenenholz 
Published: December 2020

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a tauopathy associated with repeated brain injuries. The presence of co‐pathologies is not uncommon in individuals with CTE. Here, we described clinical and neuropathological findings of amateur soccer with a history of progressive parkinsonism and dementia.Method63‐years old male with no family history of neurodegenerative disease or alcohol abuse. He played amateur soccer as a goalkeeper for 42 years. Episode of concussion with loss of conciseness at age of 20, without symptoms afterward. He denied any non‐soccer related episodes of brain trauma. At the age of 65, he started with REM behavior disorder, followed by apathy. At age 67, he developed asymmetric bradykinesia, limb rigidity, and complete anosmia. At the age of 73, a neurological examination demonstrated asymmetric parkinsonism, worse in the left. He denied motor fluctuations or hallucinations. At age 75, cognitive impairment was observed and his MMSE score was 22/30 with temporal disorientation, executive and delayed recall impairments. The working diagnosis was Parkinson's disease dementia. He died at age of 81.ResultNeuropathological examination showed prominent frontal and temporal atrophy, hippocampal asymmetry and moderate depigmentation of substantia nigra, and locus coeruleus. Hematoxylin and eosin staining showed left hippocampal sclerosis and white matter arteriolosclerosis. Immunohistochemistry evaluation showed aggregates of hyperphosphorylated tau in neurons, astrocytes and cell processes in a patch distribution around vessels, with deep sulcal accentuation in several cortical regions fulfilling criteria for CTE stage III. Additionally, neurofibrillary pathology was found in subcortical and cortical areas (BRAAK stage V) and Aß plaques were distributed in cortical, limbic and diencephalon areas (Thal 4), altogether meeting criteria for an intermediated ADNC. Also, phosphorylated TDP‐43 immunoreactive dot‐like and neuronal cytoplasmatic inclusions were found in entorhinal cortex, amygdala and hippocampus (LATE stage 3). Moreover, diffuse Lewy pathology was observed (Braak 5 of Parkinson´s disease).ConclusionDespite showing multiple co‐pathologies, former soccer players may develop CTE changes. This case adds to the increased number of former soccer players showing dementia due to multiple pathologies and CTE. If soccer‐related brain trauma triggers multiple neuropathological processes or if they develop independently remains an open question.
Structural characterization of rare missense variants within known neurodegenerative disease proteins
Authors: Palmer Ellen L. , Moth Christopher , Benchek Penelope , Wheeler Nicholas R. , Kunkle Brian W. , Hamilton‐Nelson Kara L. , Griswold Anthony J. , Naj Adam C. , Farrer Lindsay A. , Martin Eden R. , Pericak‐Vance Margaret A. , Haines Jonathan L. , Sheehan Jonathan H. , Capra John A. , Bush William S. 
Published: December 2020

AbstractBackgroundRecent work suggests unexplained heritability of Alzheimer’s Disease (AD) may involve rare variants in genes implicated in other neurodegenerative disorders. However, existing gene‐based tests have insufficient power to detect true associations when neutral variants are included. Therefore, identifying variants with potentially high impact on protein function before computing gene‐based statistical associations is critical.MethodWe employed the Phenotype Consensus ANalysis (PCAN) approach to identify genes with Mendelian associations to neurodegenerative disorders using semantic similarity, resulting in a candidate gene list of 24 genes not associated with AD and two previously associated genes (PSEN1 and TREM2). We applied the PathProx algorithm to identify Alzheimer’s Disease Sequencing Project (ADSP) Discovery Phase variants significantly clustered with known pathogenic variants compared to benign variants within 3D protein structures. Pathogenic variants for Mendelian neurodegenerative disorders were curated from ClinVar and benign variants from ExAC. Additionally, we predicted the impact of each ADSP variant on protein stability (vs. canonical wildtype amino acid) via change in free energy of folding (∆∆G) estimated by Rosetta software.ResultOut of 1,365 ADSP missense variants in 26 genes, we identified 230 that were proximal (using PathProx) to known pathogenic variants. A total of 230 variants had ∆∆G values indicating their potential to thermodynamically destabilize a protein’s structure (91 variants were also proximal to known clinical variants). Gene‐based testing using these predicted functional variants identified two novel genes (CSF1R, and SERPINI1) associated with AD risk. Finally, models for PSEN1 and TREM2 using the PathProx or ∆∆G‐identified variants remained statistically significant with similar p‐values to models using all missense variants.ConclusionWe have identified subsets of missense variants likely to impact the function of proteins associated with neurodegenerative diseases in the ADSP. These annotations can be used in multiple ways, such as highlighting variant sets for use in gene‐based testing and prioritizing variants for in vitro testing. Additionally, functional characterization of rare variants using PathProx and ∆∆G could aide in in heterogeneity testing of multifactorial diseases like AD. Finally, our methodology is phenotype‐centric and applicable to other diseases with overlapping phenotypes to identify candidate genes in a variety of neurological disorders.
Emerging effects of APOE in the Wisconsin Registry for Alzheimer’s Prevention
Authors: Vasiljevic Eva , Koscik Rebecca L. , Jonaitis Erin M. , Betthauser Tobey J. , Christian Bradley T. , Johnson Sterling C. , Engelman Corinne D. 
Published: December 2020

AbstractBackground
APOE ε4 allele status predicts both age of late‐onset Alzheimer’s disease (LOAD) onset and rate of cognitive decline leading up to LOAD. However, most of those studies have been done in older samples and with LOAD diagnosis absent biomarker data. There is less known about when APOE related differences in cognition and LOAD biomarkers emerge. Moreover, modeling APOE using ε4 allele status does not account for non‐linear risk between combinations of ε2, ε3, and ε4 alleles (Belloy et al. 2019, Neuron). Our first objective was to identify if the rate of cognitive decline and the level of amyloid‐beta (Aβ) differ by the APOE score, a composite score of the six APOE allele combinations weighted by the log odds of their association with LOAD (Darst et al., 2017 J. Alzheimers Dis.). Our second objective was to estimate the time that the APOE effect on cognition and Aβ emerges.MethodWe analyzed cognitive trajectories (n=1141) and Aβ (n=219) across APOE scores of participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP). WRAP is a longitudinal study of adults age 40‐70 and non‐demented at baseline who were followed for up to 16 years with assessments every 2 years. We compared the rates of decline across the APOE score for four neuropsychological composite scores using a mixed effects regression model for longitudinal change with age. We estimated average Aβ (PiB‐PET DVR) at ages 55, 65 and 75 using a linear regression model with a person’s last scan.ResultWe found a significant age‐by‐APOE interaction in predicting cognitive decline such that the rate of cognitive decline for all four composite scores was greatest for people with the highest APOE score (Figure 1, Table 1). There was also a significant age‐by‐APOE interaction for predicting Aβ burden in the brain such that the average global Aβ was greatest for individuals with the highest APOE score (Figure 2).ConclusionWe are currently analyzing timing of the emerging APOE effect on cognition. These results indicate that Aβ onset occurs earliest and the rate of cognitive decline is greatest for people with highest APOE risk in the WRAP sample.
Development of an orally bioavailable stress kinase inhibitor with brain exposure that targets the neuroinflammation‐synaptic dysfunction pathophysiology axis
Authors: Watterson Daniel Martin , Arancio Ottavio , Windisch Manfred , Pelletier Jeffrey , Roy Saktimayee M. 
Published: December 2020

AbstractBackgroundAn ambitious primary goal of NAPA is to identify disease modifying interventions, a goal complicated by the nearly complete failure of all clinical trials. However, a common yet neglected target is the pathophysiology progression theme of synaptic dysfunction associated with aspects of neuroinflammation that contribute to synaptic dysfunction. The neuroinflammation‐synaptic dysfunction hypothesis posits that certain aspects of this axis are amenable to therapeutic intervention. The druggable stress kinase p38αMAPK is a key target in the neuroinflammation‐synaptic dysfunction pathophysiology progression axis. Increased activity in activated glia results in dysregulated innate immunity as evidenced by increased levels of proinflammatory cytokines. Increased activity in neurons results in altered axonal transport and synaptic dysfunction. Neuronal dysfunction, in turn, results in further stimulation of the evolving stress cycle. Concurrent inhibition of the single target p38αMAPK in distinct cells of the pathophysiology axis could provide a novel form of potential pleiotropic intervention with increased potential for efficacy.MethodA fragment‐based, secondary pharmacology‐filtered experimental approach allowed the custom design and production of a novel p38αMAPKI drug candidate, MW150 (= MW01‐18‐150SRM), with exceptional molecular selectivity and concurrent avoidance of dose limiting barriers identified in prior clinical candidates. IND‐enabling preclinical toxicology integrated with preclinical pharmacokinetics and pharmacodynamics documented a potential for first‐in‐human clinical evaluation (summarized in Roy, S. M., et al., 2019, J.Med.Chem., Drug Annotation: A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction)ResultMW150 is a unique, orally bioavailable, stress kinase inhibitor that exhibits brain exposure and efficacy in diverse CNS disease models characterized by a neuroinflammation‐synaptic dysfunction axis. Promising results from ongoing studies suggest MW150 may be phase 2‐ready clinical asset available in Q3 2020: 1) phase 1a (SAD) and 1b (MAD) clinical trials; 2) six‐ and nine‐month preclinical toxicology; 3) commercial scale GMP clinical drug suitable for phase 2 and 3 clinical trials.ConclusionMW150 has the potential to provide a new therapeutic intervention mechanism for neurologic disease modification. There are no clinical trials of drugs with MW150’s unique profile of molecular recognition, pharmacological selectivity and safety.
Shared imaging biomarkers across Alzheimer’s and Parkinson’s disease
Authors: Zhao Yuji , Kurmukov Anvar , Goldman Jennifer , Gutman Boris A 
Published: December 2020

AbstractBackgroundAlzheimer's disease (AD) and Parkinson's disease (PD) are the two of the most common neurodegenerative diseases [1]. In previous studies, AD and PD demonstrate overlap in clinical syndromes, including presence of cognitive impairment, dementia in PD, and post‐mortem studies with regional atrophy and amyloid and tau deposition [2][3]. Here, we propose a novel morphometric‐feature based machine learning model to explore shared degenerative patterns in AD and PD on neuroimaging.MethodWe used T1‐weighted (T1w) MRI data from (PPMI) 166 controls/356 de novo PD patients, and (ADNI‐1) 242 controls/199 AD patients. As a baseline model we trained sparse spatially regularized (TV‐L1) logistic regression [6][7] using subcortical shape and cortical thickness [4][5] from T1w MRI. To train the two models jointly, we constrain the optimization with a cross‐disorder (CD) agreement term: the L2 model difference, weighted by the models’ local normalized mutual information (MI). The CD‐MI term allows the models to guide each other’s optimization, dynamically amplifying information sharing where degenerative patterns are most similar and minimizing sharing where they are dissimilar. We evaluate all models’ ROC area‐under‐the‐curve (ROC AUC) using nested cross‐validation and a shuffle‐split bootstrap test to assess model stability. For subcortical regions, we trained models using all regions, as well as individual models for each region (L/R thalamus, putamen, caudate, pallidum, hippocampus, amygdala, accumbens).ResultInformation sharing significantly improved predictive power for cortical thickness‐based, L amygdala, L caudate, and bilateral putamen models (Table 1, Figure 4). Weight maps of AD and PD models (Figures 1a,b,2) show areas of similar degenerative patterns in frontal and parietal association areas, thalamus caudate and putamen, confirmed by the mutual information maps (Figures 1c,3).ConclusionWe designed a novel machine learning model to explore joint imaging biomarkers between Alzheimer's and Parkinson’s disease. Our findings on neuroimaging suggest shared topography of frontal, parietal, temporal, and cingulate changes for AD and PD. This may signify overlap of underlying pathologies with co‐existent amyloid and tau burden in both AD and PD.
Association of TREM2 variants and sphingolipid levels with AD in blood and brain
Authors: Proitsi Petroula , Ebshiana Amera A , Hodges Angela , Legido‐Quigley Cristina 
Published: December 2020

AbstractBackgroundThe TREM2 gene has an effect on AD risk similar to that of ApoE ε4. TREM2 is a microglial receptor, sensitive to lipids associated with neurodegeneration, such as glycerophospholipids and sphingomyelins (SM). Reduced levels of S1P in AD brain and elevated ceramides (CER), likely contribute to disease pathogenesis. The ability to respond to this signal may have important implications for AD. However, the extent to which TREM2 genetic variants affect the relationship between lipid levels and AD has not been examined. Here we investigated the association of lipid levels with AD in post‐mortem brain samples and blood and we interrogated how TREM2 genetic variants modify these associations.MethodBrain tissue from the hippocampus and BA9 was collected from 48 AD patients and 24 controls, and blood was collected from 58 AD patients, 21 controls and 16 participants with Mild Cognitive Impairment (non‐overlapping). All participants were genotyped for TREM2 AD‐related variants. LCMS analyses were performed on both brain and blood and >250 lipid species were annotated. Linear and mixed effects regression models adjusted for age, sex, APOE ε4 allele, and post‐mortem delay (in brain samples), were used to investigate the association of lipids with AD and to examine whether TREM2 variants modified these associations.ResultOverall CER and SM levels, especially those of shorter chain lengths, were increased in AD in both hippocampus and BA9 (e.g. AD patients had 1.02 SD higher Cer.d36.1 levels compared to controls (P‐value<1x10‐4 ; pooled estimate across the two brain regions ). TREM2 seemed to modify the associations of specific CER and SM with AD, with lipid levels of AD TREM2 carriers resembling those of controls. Although the associations of lipids with AD in blood were not as strong (with some in opposite direction) the way TREM2 affected association of some lipids with AD was analogous to that in brain.ConclusionThis is the first study to investigate how TREM2 variants contribute to disease vulnerability through changes in lipid levels in post‐mortem brain tissue and blood. These results could hold special value in AD as they suggest vulnerable processes that could be targeted for therapeutic development.
Biopsychosocial effects of mindfulness intervention on older adults with mild cognitive impairment: A review
Authors: Tan Xiang Ren , Ho Elaine QY , Kua Ee‐Heok , Mahendran Rathi , Ng Ted Kheng Siang 
Published: December 2020

AbstractBackgroundFueled by the repeated failures of pharmaceutical compounds in clinical trials, the dementia field has recently moved towards validating preventive intervention of behavioral nature, such as mindfulness practice, to prevent and delay cognitive impairment. Despite the known cognitive benefits of mindfulness in healthy individuals, the effects on delaying cognitive decline in older adults with MCI (mild cognitive impairment) are largely unknown.MethodWe conducted a literature review on randomized controlled trial (RCT) studies to critically appraise the bio‐psycho‐social effect of mindfulness intervention on older adults aged ≥60 years old with MCI.ResultA myriad of mindfulness studies have been conducted in Western countries. A total of five RCTs examining subjects with MCI were identified. Four studies showed improved neurocognitive assessments, three studies demonstrated improved neuroimaging measures, one study showed improved bio‐fluid markers and one study showed improved psychosocial well‐being. Most studies had small sample size (N20) and short duration of follow‐up (≤8 weeks), often with inadequate methodological rigor and mostly speculative post‐hoc interpretations.ConclusionThe MCI population is severely understudied in the field of mindfulness intervention. Given the overall positive preliminary findings, it is time to move towards conducting large scale RCT of high‐quality, comparing the effects of mindfulness between Western and Eastern societies. A number of critical future directions include conducting high‐quality RCTs with more standardized mindfulness interventions, examining dose‐response relationship, longer follow‐up period to examine sustainability, differentiation of the specific effects of mindfulness, and the use of objective measures, particularly bio‐fluid markers.
ApoE ε4 status in pre‐dementia risk states, mild behavioural impairment and subjective cognitive decline, and the risk of incident cognitive decline
Authors: Nathan Santhosh , Gill Sascha , Ismail Zahinoor 
Published: December 2020

AbstractBackgroundDementia has an increasing global burden with over 40 million affected individuals. With sub‐optimal advances in drug development, there is an increasing shift to determine risk of dementia in the non‐demented population. Assessment of neuropsychiatric symptoms (NPS) may offer an opportunity to capture the at‐risk group earlier. Mild Behavioural Impairment (MBI) is a validated neurobehavioural syndrome, characterized by the emergence of sustained NPS in older adults as an at‐risk state for dementia. Cognitively, subjective cognitive decline (SCD) is a dementia at‐risk group in which cognitive symptoms are reported in the absence of objective findings. The apolipoprotein epsilon 4 (ApoE ε4) gene is a well‐known risk marker for dementia. We aim to determine the frequency of ApoE homozygosity in SCD, stratified by MBI status cross‐sectionally, and calculate the hazard of incident cognitive decline in this group longitudinally.MethodData from 5005 participants in the National Alzheimer’s Coordinating Center (NACC) were used to capture older adults who were cognitively normal, but had subjective cognitive complaints (SCD). We determined MBI status (+/‐) using a previously published transformation algorithm of NPI‐Q scores. We tabulated ApoE genotype in both groups. We compared proportion of ApoE homozygousity (APOE ε4+/+)in the MBI+ versus the MBI‐ group. Additionally, a Cox proportional hazards regression will be done to capture hazard of incident mild cognitive impairment in MBI+ versus MBI‐.ResultA two‐sample test of proportions of MBI+/‐ status stratified by ApoE ε4+/+resulted in significant differences between groups with homozygosity more frequent in MBI+ versus MBI‐ (p<0.001). We will also present the results of the Cox proportional hazards regression analysis.ConclusionIn older adults with subjective cognitive decline, ApoE ε4 allele homozygosity was more frequently seen in the MBI+ group. These findings provide additional evidence for the utility in determining MBI status in SCD.