bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Good Life program for healthy brain aging is an active registry for clinical research recruitment
Authors: Johnson David K 
Published: January 2025

AbstractBackgroundThe Good Life program for healthy brain aging (TGL) is an online program for positive lifestyle change that is made up of exercise, diet and social support classes. Since 2020, The Good Life has served thousands of older Californians. Currently, we host 17 classes weekly for our 750 active members (in both English and Spanish). Our exercise and cooking classes are our most watched content. Exercise classes attendance is 20‐70 participants per show (x11 weekly). Our x3/week cooking classes attendance is 20‐50 participants per show. We provide The Good Life freely and, in the process, engender goodwill ‐ a proven pathway to rebuilding trust and fostering reciprocity. The Good Life enjoys funding support from the State of California as public health program to support Black and Latinx healthy aging. In 2023 it expanded broadly across 13 California counties participating in the CDC’s Healthy Bain Initiative, providing TGL to all California residents. Three of the 13 counties are now creating local content tailor made to their specific ethno‐geographies.MethodTGL is implementing a 9‐step infrastructure building plan to (1) Extend this California program to scale nationally to serve large numbers of participants in NIA clinical research and training network centers; (2) Engage Black and Latinx American communities across the nation in a thoughtful, fun, and clinically meaningful health education campaign with messaging that will facilitate recruitment and enhance retention; (3) Evaluate the success of our precision engagement program using empirical metrics: (i) participant enrollment into clinical trials, (ii) time spent watching content per digital segment, (iii) number of clicks into subsequent public health messaging. These metrics will be correlated with participant data describing changes in attitudes re (a) Trust in Biomedical Research and (b) Stages of Research Volunteerism.ResultSince May 2023, TGL has recruited 260 Black Americans into 3 academic clinical research programs.ConclusionTGL is a scalable internet‐based program with potential reach well beyond its large existing membership.
Synthesis and biological evaluation of some novel coumarin‐oxadiazole conjugates as potential candidates for the treatment of cognitive decline
Authors: Arora Geetakshi , Piplani Poonam 
Published: January 2025

AbstractBackgroundThe present study demonstrates the design, synthesis and pharmacological evaluation of coumarin‐oxadiazole hybrids as potential molecules of therapeutic significance for the treatment of cognitive dysfunction.MethodEight novel coumarin‐oxadiazole hybrids have been synthesized by employing suitable synthetic procedures and characterized by various spectral techniques i.e. FT‐IR, 1H NMR and 13C NMR. All synthesized compounds were evaluated for their in‐vitro acetylcholinesterase (AChE) inhibition at five different concentrations. After in vitro studies, the compounds have been evaluated against behavioural alterations using step down passive avoidance and escape learning protocol at a dose of 2.0 mg/kg with reference to standard drug, rivastigmine. These compounds were further evaluated for their ex vivo acetylcholinesterase inhibition using mice brain homogenate as a source of the enzyme. Biochemical estimation of markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione, catalase) has been carried out to access the role of synthesized molecules on the oxidative damage induced by scopolamine.ResultThe compounds 114, 117 and 120 were found to be the most promising in amelioration of cognitive impairment due to scopolamine as evidenced in both the behavioural animal model and ex vivo acetylcholinesterase assay. The coumarin‐oxadiazole based analogues have been found to exhibit promising antioxidant effects as indicated by the assessment of various biochemical parameters.ConclusionOur results depicted that the anti‐amnesic effect of the synthesized conjugates on scopolamine‐induced memory impairment may be related to the mediation of the cholinergic nervous system and their effective antioxidant activity.
Attention Network Dysfunctions in Lewy Body Dementia and Alzheimer's Disease
Authors: Su Li 
Published: January 2025

AbstractBackgroundAttention deficits are notable in Lewy body dementia (LBD) and in Alzheimer’s disease (AD), however, its underlying neurobiology and neuropathology are unclear. Functional magnetic resonance imaging (fMRI) and electroencephalograph (EEG) provides information about attention deployment and regional neural oscillatory deficits in LBD and AD. In this study, we combined fMRI and EEG to detect neural correlates of attention dysfunctions in LBD and AD.MethodWe recruited 33 patients with LBD, 15 patients with AD and 19 elderly healthy controls. All participants underwent a 3T fMRI scanning and a subsequently EEG recording. During fMRI and EEG, participants performed the same modifiedAttention Network Task (ANT) to investigate the alert, orient, executive and conflict attention dysfunctions. Here, we have focused on the EEG part of the study while using the fMRI data to localise the EEG signal on the cortex.ResultBehaviourally, although both LBD and AD maintained a relative normal executive/conflict attention, we found that LBD had alert attention deficits and AD showed apparent orient attention dysfunctions. Based on source‐level EEG analyses, LBD had frontal‐central deficits for alert attention while AD showed inferior frontal and precentral impairments for orient attention. In addition, the insular and inferior frontal areas was hyper‐activated in LBD and AD for executive/conflict attention. Apart from these areas, LBD showed complementary temporal‐central‐occipital network for the modified ANT task. Furthermore, the oscillational sources for the ANT effects indicated that alpha and theta bands were partly impaired in dementia patients.ConclusionIn summary, using source localised EEG, we found that attention dysfunctions in LBD and AD have engaged different neural networks. This has important implications in understanding the symptomology in LBD such as recurrent visual hallucinations and cognitive fluctuation.
Red Light Therapy Attenuates Prolonged LED light Exposure‐Associated Neuropathology and Mediates Circadian Clock Genes ‐ Per1 and Bmal1 Expression in Rats' Basal Ganglia
Authors: Obajuluwa Adejoke Olukayode , Babafemi Laoye John , Ndianefo Ogochukwu Jessica , Obajuluwa Tiwalola Madoc , Lech James Chrystopher , Okiki Pius Abimbola 
Published: January 2025

AbstractBackgroundProlonged exposure to LED‐light has been associated with impaired sleep quality and pathogenesis of various diseases, including Alzheimer’s Disease (AD). Red light therapy has been indicated as a non‐invasive way of reducing anxiety, mood and sleep optimization in neurodegenerative disorders but its endogenous mechanisms are insufficiently comprehended. Hence, we assessed the effects of scheduled red‐light exposure on clock genes‐Bmal1 and Per 1 expression, feacal boli frequency, and anxiety‐like responses in prolonged LED‐light exposed rats.MethodAnxiety‐like indices of male rats was assessed using standard neurobehavioural methods under various light settings exposures (n=5) in groups: I) 12‐hour light/12‐hour dark (NC), II) 12‐hour light and 12‐hour dark + scheduled red light (PC), III) 24‐hour LED light, and IV) 24‐hour LED light + scheduled red light; every two weeks for a total of 60 days. Total RNA was isolated from the rats' basal ganglia and reverse transcription was performed with the ProtoScript cDNA synthesis kit. Quantification and purity of cDNA were assessed using 1µl in a DeNovix spectrometer. Sequenced primers were utilized for the analysis of mRNA expression levels of Bmal1, Per1, and the housekeeping gene (GAPDH) through real‐time PCR. The PCR products were resolved by electrophoresis on 1.5% agarose gels and visualized by SafeView staining.ResultFeacal bolus frequency (p<0.001), closed arm entries (p<0.05), and time spent in the dark area of the light‐dark box (p<0.001) were significantly reduced in the 24‐h LED light+scheduled red light and control groups rats compared to the 24‐h LED light. Real‐time gene expression analyses of Per1 showed a significant decline in the 24‐hour LED‐exposed rats, as indicated by decreased mRNA expression levels (p<0.05), when compared to other groups. Bmal1 gene expression remained unchanged in groups I and II while AGE revealed 100bp and 150 bp banding patterns for Bmal1 and Per1, respectively.ConclusionThe findings from this study revealed that red light therapy attenuates LED light‐exposure‐induced anxiogenic responses and Per1 gene expression impairment. Consequently, these findings have the potential to inform the development of non‐invasive treatment strategies targeting the improvement of sleep quality in the management of neurodegenerative disorders. However, safety assessments should be ensured for its validation.
Longitudinal loneliness changes are associated with cognitive decline and brain structure alterations: evidence from the Whitehall II cohort study
Authors: Zhang Ye , Tatewaki Yasuko , Liu Yingxu , Tomita Naoki , Thyreau Benjamin , Taki Yasuyuki 
Published: January 2025

AbstractBackgroundLoneliness has been linked to cognitive decline and an elevated risk of Alzheimer's disease (AD). Previous studies measured loneliness at a single point time, which may not accurately capture the longitudinal changes of different loneliness types (e.g., recover form loneliness; persistent loneliness) and their impact in the neuropathology of AD. This study investigates five‐year longitudinal changes of loneliness and their associations with cognitive function and brain structure alterations using data from the Whitehall II cohort study.MethodThis study included 5346 participants with mean age = 65 year (Female:26.68 %) at baseline (2007‐2009). Loneliness was measured using one item form the Center for Epidemiologic Studies Depression Scale, and longitudinal loneliness changes were defined from two time points (2002‐2004; 2007‐2009). Linear mixed‐effect models were used to examine the association between different loneliness types and eight‐year changes of different cognitive domains (global cognition, reasoning, verbal fluency, and verbal memory). Robust linear regression models were employed to assess loneliness types and gray matter volumes (GMVs) in selected brain regions five‐year later (2012‐2012) using the Whitehall IIMRI substudy (N=711).ResultWe defined four types of loneliness changes: “No loneliness”, “Transient loneliness”, “Incident loneliness” and “Persistent loneliness”. Compared to no loneliness, persistent loneliness was associated with decline in cognitive function (global cognition: b= ‐0.20, p<0.001; reasoning: b= ‐0.29, p<0.001; verbal memory: b= ‐0.11, p<0.007; verbal fluency: b= ‐0.15, p=0.001;) after controlled for age, sex, education, and objective social isolation. Compared to no loneliness, persistent loneliness was associated with decreased GMVs in right posterior cingulate cortex (b= ‐0.17, pFDR‐corrected=0.041); transient loneliness was associated with increased GMVs in rostral anterior cingulate cortex (b= ‐0.48, pFDR‐corrected=0.025).ConclusionPersistent loneliness was associated with both longitudinal cognitive decline and decreased brain regions involved in emotional regulation, suggesting persistent loneliness feelings, no incident loneliness, could be a risk factor in the neuropathology of AD. Moreover, recovery from loneliness feeling (transient loneliness) could be protective in future brain structure alterations. Our study suggests that identifying participants has long‐term loneliness and developing strategies to overcome loneliness feeling could be important for AD prevention.
Implementation and Validation of Face De‐Identification (de‐facing) in ADNI‐4
Authors: Schwarz Christopher G. , Tosun Duygu , Yushkevich Paul A. , Choe Mark , Rossi Stephanie , Das Sandhitsu R. , Ittyerah Ranjit , Fletcher Evan , Maillard Pauline , Singh Baljeet , Harvey Danielle J. , Malone Ian B. , Prosser Lloyd , Senjem Matthew L. , Matoush Leonard C. , Ward Chadwick P. , Prakaashana Carl M. , Decarli Charles , Weiner Michael S. W. , Jack Clifford R. 
Published: January 2025

AbstractBackgroundRecent advances in automatic face recognition have increased the risk that de‐identified research imaging data could be re‐identified from face imagery in brain scans.MethodAn ADNI committee of independent imaging experts evaluated 11 published techniques for face‐deidentification (“de‐facing”) and selected four algorithms (FSL‐UK Biobank, HCP/XNAT, mri_reface, and BIC) for formal testing using 183 longitudinal scans of 61 racially and ethnically diverse ADNI participants, evaluated by their facial feature removal on 3D rendered surfaces (confirming sufficient privacy protection) and by comparing measurements from ADNI routine image analyses on unmodified vs. de‐faced images (confirming negligible side effects on analyses).ResultEffects of the de‐facing methods on FreeSurfer at UCSF (Figure 1‐top), ASHS at University of Pennsylvania (Figure 1 bottom‐left), and longitudinal atrophy at Mayo Clinic (Figure 1 bottom‐right) were comparable with each other and sufficiently small vs. unmodified scans to recommend de‐facing in ADNI‐4. The FSL and mri_reface methods were more thorough in removing facial features, partly because these also removed ears (Figure 2‐top). mri_reface was recommended for ADNI‐4 primarily because fewer (zero) images had modified brain (Figure 2‐bottom), and ADNI leadership approved de‐facing with mri_reface. ADNI performed a second validation of its latest version on another diverse sample of 100 ADNI‐3 participants. These analyses included: boundary shift interval at University College London, where average differences in measurements were all <0.05%; cortical white matter hyperintensities at UC Davis, where they found “minimum impact” (R>0.97); and others.ConclusionADNI‐4 de‐faces all indicated image types (Table 1) before subsequent pre‐processing, analyses, and public release. Sites upload images to the central repository (LONI), where they are queued to the MRI Core at Mayo Clinic for de‐facing. Image types requiring de‐facing are de‐faced using mri_reface. Trained analysts inspect de‐faced images to confirm complete removal of the face and complete non‐modification of the brain, and any flagged images are re‐processed manually until issues are resolved. De‐faced images are converted back to DICOM and re‐uploaded for further distribution. Image types not requiring de‐facing are indicated to proceed directly to subsequent steps. In summary, ADNI‐4 has adopted mri_reface because it successfully de‐faces without substantially affecting brain measurements.
The genetic architecture of the human anterior commissure and its potential role as biomarker of neurodegeneration
Authors: Ochoa‐Rosales Carolina , Adams Hieab H.H. 
Published: January 2025

AbstractBackgroundCommissural tracts are the white matter fibre bundles intercommunicating left and right brain hemispheres. They integrate many cognitive functions such as memory, verbal processing, motor and perceptual skills. Also, commissures connect specific layers of cortical neurons that are also lost in Alzheimer’s disease (AD) and other neurodegenerative disorders. Although highly heritable, commissures´ specific genetic determinants remain obscure. We aim to investigate the genetic determinants of the human anterior commissure. Given its presumed role in neurodegeneration, we aim to further provide mechanistic insights into neurological conditions that may result from its dysfunction.MethodTwo‐stage genome‐wide association study, (GWAS) (N=18,828) of the size of the anterior commissure. The discovery sample included seven cohorts (N=7,935) and was meta‐analyzed with ten replication cohorts (N=10,893). The size of the anterior commissure was manually derived from magnetic resonance imaging (1.5T/3T) with at least T1/T2‐weighted sequences. The genetic data was assessed through genotyping using SNP microarrays. We used voxel‐based morphometry to determine which regions are connected by the anterior commissure. To prove a functional validation of the identified variants, we performed a series of in silico experiments, including the study of the spatial expression patterns in human brains, quantitative trait loci (QTL), enrichment analysis and pleiotropy with neurodegenerative diseases.Resultwe identified six independent variants at four loci (p‐values from 4.1x10‐8 to 9.4x10‐22). We mapped the loci to probable causal genes involved in axon guidance (EPHA3 and SEMA6A), cognitive disorders (CTNND2), and growth factor signaling (RIT2). Voxel‐based morphometry revealed distinct associations of the variants with connected grey matter regions in the brain. We found enrichment for H3K4me1 peaks (marking enhancer sites), introns, and conserved sequences, as well as cell‐type‐specific annotations from the central nervous system and cardiovascular system. Furthermore, we identified pleiotropy between genes known to increase risk of neurodegenerative conditions including frontotemporal lobar degeneration gene TMEM106B. Variants associated to this gene have been related to dementia development.Conclusionthese results shed light on the genetic architecture of commissural tracts and establish the size of the anterior commissure as a relevant biomarker of neurodegeneration.
Links Between Microvascular and AD‐related pathology in the Medial Temporal Lobe
Authors: Perosa Valentina 
Published: January 2025

AbstractBackgroundCerebral small vessel disease (CSVD), which includes cerebral amyloid angiopathy (CAA) and arteriolosclerosis, often co‐occurs with Alzheimer’s disease (AD) pathology. The medial temporal lobe (MTL) is susceptible to hosting multiple AD pathologies, such as neurofibrillary tangles (NFTs), amyloid‐ß plaques, phospho‐Tar‐DNA‐Binding‐Protein‐43 (pTDP‐43), as well as CSVD. Whether a causal relationship between these pathologies exists remains largely unknown, but one potential linking mechanism is the dysfunction of perivascular clearance. Our objective was to examine the burden of CSVD in the MTL of a pathological AD cohort and to establish the associations between CSVD and AD‐related pathologies, as well as between CSVD and enlarged perivascular spaces (EPVS), a potential indicator of clearance dysfunction.MethodThe study included 156 autopsy cases (mean age at death 79.4±10.9 years, 90 females) from the Massachusetts Alzheimer’s Disease Research Center (MADRC). One hemisphere was preserved in formalin, and 5 µm‐thick sections were cut from predefined regions of the hippocampal body and entorhinal cortex. These sections were subsequently stained using luxol fast blue with hematoxylin&eosin (LHE), and antibodies against amyloid‐ß, hyperphosphorylated tau (At8), and pTDP‐43, following standard histological and immunohistochemical protocols. Utilizing deep‐learning models (Aiforia®), we computed the burden of CAA, amyloid‐ß plaques, NFTs, and pTDP‐43 inclusions (Figure 1). Additionally, the severity of arteriolosclerosis and the % area of EPVS were evaluated on the LHE sections.ResultIn linear mixed effects models CAA was positively associated with the density of NFTs (Est=7.21; p=0.024; R2=69%) and amyloid‐ß plaque burden (Est=3.01; p<0.001; R2=61%) in all regions of interest. Arteriolosclerosis had no direct effect on parenchymal AD‐related pathologies but showed a positive interaction with CAA in the association with PVS enlargement. There was no relationship between pTDP‐43 inclusions and arteriolosclerosis.ConclusionThese results point towards an association between microvascular pathology and AD‐related pathology, possibly mediated by clearance dysfunction.
Spatial Characterization of White Matter Hyperintensity Pathophysiology Across Disorders
Authors: Parent Olivier , Devenyi Gabriel A. , Bussy Aurelie , Pigeau Grace , Costantino Manuela , Fouquet Jérémie , Rodriguez Daniela Quesada , Dadar Mahsa , Chakravarty Mallar M. 
Published: January 2025

AbstractBackgroundWhite matter hyperintensities (WMHs) are age‐related radiological abnormalities indicative of small vessel disease. It is unclear if WMHs in different regions represent similar pathophysiology and etiology. Here, we developed a framework to estimate WMH pathophysiology in vivo, which allowed us to precisely characterize spatial patterns of WMH tissue alterations associated with four disorders.MethodWe used data from 32,014 UK Biobank (UKB) participants. WMHs and normal‐appearing white matter (NAWM) were automatically segmented. Diffusion‐ and susceptibility‐weighted images were used to derive fluid‐, fiber‐, myelin‐ and iron‐sensitive microstructural markers. We calculated voxel‐wise normative models of NAWM microstructure using Bayesian linear regression with age (4th order B‐spline) and sex predictors in a custom UKB template space derived using multi‐spectral registration of T1w and fractional anisotropy (FA) images (Fig. 1A‐B). Within‐subject WMH pathophysiology was estimated as the difference between WMH microstructure and predicted NAWM microstructure (Fig. 1C).ResultFirst, from between‐subject averages of WMH microstructural abnormality (Fig. 2A), we used spectral clustering to derive spatial patterns of WMHs that share similar pathophysiological properties (Fig. 2B). The first cluster (periventricular) has low abnormality. The second (posterior) and third (anterior) cluster both show fluid accumulation, fiber alterations, and myelin and iron loss, while the anterior cluster shows higher abnormality. Second, we assessed the differences between four disorders and age‐ and sex‐matched controls in terms of all WMH features with Cohen’s D. Ischemic heart diseases (n=2320) and hypertensive diseases (n=9852) demonstrated small but significant effects across measures, which were slightly higher in anterior regions. Stroke (n=320) demonstrated larger effects, which were more prominent in anterior regions. On the other hand, dementia (n=46) demonstrated smaller effects compared to stroke, reaching significance mostly in posterior regions despite the smaller sample size. Interestingly, the fractional anisotropy and orientation dispersion markers showed drastically inverted patterns of effects between stroke and dementia.ConclusionOur results separating anterior and posterior WMHs are consistent with accumulating evidence showing that posterior WMHs may be linked to Alzheimer’s pathology, whereas anterior WMHs may be associated with vascular pathologies. MRI pathophysiological markers may further help in distinguishing these etiologies.