bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intra‐ and post‐procedural lumbar puncture symptoms in a sample of Black/African American, American Indian/Alaska Native, and White middle age older adults
Authors: Cole Aleshia , Van Hulle Carol A. , Eierman Allison C , Rovner Sarah , Chin Nathaniel A. , McLester‐Davis Lauren W. Y. , Johnson Sterling C , Bendlin Barbara B , Okonkwo Ozioma , Gleason Carey E. , Edwards Dorothy F. , Asthana Sanjay , Carlsson Cynthia M 
Published: December 2023

AbstractBackgroundCerebral spinal fluid (CSF) as a biomarker of Alzheimer’s disease (AD) is a helpful tool in diagnosing preclinical disease. While blood‐based biomarkers are becoming increasingly used for early detection, CSF collection is still necessary for validation of AD blood‐based biomarkers and for identification of biomarkers for other types of dementias, including those that commonly co‐occur with AD. Attitudes and beliefs surrounding lumbar punctures (LPs) vary, and differing techniques as well as side effect rates might dissuade both clinicians and participants from considering LPs as a viable biomarker option. The aim of this analysis was to examine intra‐ and post‐procedural symptoms of a specific technique for collecting CSF from adult volunteers enrolled in the Wisconsin Alzheimer’s Disease Research Center.MethodLPs were performed on 587 volunteers using a standardized LP technique with atraumatic needle. Up to 22 milliliters of cerebral spinal fluid was obtained using gentle syringe aspiration of fluid. Clinician notes documenting the procedure were used to assess intra‐procedural symptoms. A follow‐up phone call the next day was used to evaluate any post‐procedural symptoms. The association between participant characteristics and LP intra‐procedural symptoms, post‐procedural symptoms, and LP success were tested using linear regression.ResultThe majority of participants did not report any intra‐procedural (59%) or post‐procedural (77%) symptoms. Being female was associated with experiencing increased intra‐procedural symptoms among Black / African American and White participants; younger age and lower waist‐to‐hip ratio were associated with higher rates of intra‐procedural symptoms among White participants. Participant characteristics were not associated with post‐procedural symptoms. LP success was high for all groups (67% to 90%). Among White participants, pain and vasovagal responses were associated with terminating the LP before sufficient fluid was collected. Among Black / African American participants, pain was associated with terminating the LP procedure before sufficient fluid was collected. Among American Indian / Alaska Native participants, no intra‐procedural symptoms were associated with early LP termination.ConclusionWe provide rates of LP intra‐procedural and post‐procedural symptoms in a diverse sample of middle‐aged and older adults. These data suggest that LPs are safe and well tolerated across a diverse group of participants.
Scholars reflect on first ADRC‐REC cycle
Authors: Spensley Sheryl , Bendlin Barbara B , Head Elizabeth , Cavazos José E. , Yassine Hussein N. 
Published: December 2023

AbstractBackgroundIn 2018, the National Institute on Aging introduced Research Education Components (RECs) within the Alzheimer’s Disease Research Centers (ADRCs) to support educational activities to complement the training of a workforce to meet the nation’s needs in AD and related dementias, and develop the next generation of scientists to lead cross‐disciplinary, translational, team‐science projects on AD or AD‐related dementias.MethodsIn April 2023, the ADRC REC National Steering Committee surveyed current and former REC scholars from the 37 ADRCs to learn about their experiences.ResultsWe had responses from 26 of the 37 centers (70%) and 52 of the 55 REC scholars who completed the survey gave us permission to share their responses. Scholars ranged from graduate students to tenured faculty. The most common areas of research focus were basic or discovery science (42%) and neurosciences (35%). The least common areas of focus were social policy (2%), neuropsychology (2%) and pharmacology/drug discovery (6%). Regarding support, the most common responses were that their REC program provided them with funds to support a research project (79%), provided mentor support (71%), provided training to develop their research (65%), and helped them understand how Alzheimer’s Disease Research Centers worked (65%). Some scholars reported that their programs have standard training courses for all scholars (35%), while other programs have training that is unique to each scholar’s needs (54%). Forty‐nine scholars (94%) said they would have benefited from earlier REC support and training during their graduate and post‐doc stages.A goal of the REC is to diversify the field of ADRD researchers. This survey showed the demographic breakdowns included White (52%), African American (13%), Hispanic or Latinx (13%), East Asian (12%), South Asian (8%), and some chose not to report (2%). More respondents identified as females (48%) than males (37%).ConclusionThere is a heterogeneity of approaches to develop REC scholars with an emphasis on funding, mentoring and networking. The most common request from scholars was for more collaboration and networking between scholars from other ADRCs. REC Scholars seek more connections and clear definitions of the expected outcomes of the REC scholar initiative.
Astrocyte signaling regulates microglial and oligodendrocyte subpopulation changes in a diet‐based model of small cerebral vessel disease
Authors: Norris Christopher M. , Lee Sangderk , Gollihue Jenna L , Goulding Danielle S. , Sompol Pradoldej , Wilcock Donna M. , Morganti Josh M. 
Published: December 2023

AbstractBackgroundVascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzhiemer’s disease. Hyperhomocysteinemia (HHcy)‐inducing diets in mice recapitulate aspects of VCID including small cerebrovessel pathology, vascular inflammation and cognitive decline. Recently, we found signs of astrocytic Ca2+‐dysregulation and hyperactivation of calcineurin/NFAT activity in mice treated with HHcy diet (Sompol et al., 2023 J Neurosci 43:1797). Inhibition of astrocytic NFATs normalized cerebrovascular, synaptic, and cognitive function in HHcy mice, suggesting that reactive astrocytes alter the brain milieu during development of HHcy and small cerebrovessel pathology. Here, we used scRNA‐seq to further characterize the impact of astrocytic calcineurin/NFATs on multiple brain cell types in the context of HHcy.MethodSeven‐to‐eight week‐old male C57BL/6J mice received intrahippocampal injections of AAV2/5‐Gfa2‐EGFP (control) or AAV expressing the NFAT inhibitor VIVIT (i.e. AAV2/5‐Gfa2‐VIVIT‐EGFP). Mice were then fed with control chow(CT) or HHcy‐inducing chow enriched in methionine and deficient in folate and vitamins B6 and B12. After15 weeks of diet, brains were extracted and hippocampi dissected away, pooled and dissociated for transcriptional analyses. scRNA‐seq was used to identify diet and AAV‐dependent cell specific gene expression changes according to our previous work (Lee et al, 2023, Cell Reports, 112196).Result31 cell clusters were identified and assigned to 1 of 12 unique cell types using established gene markers. Analysis of differentially‐expressed genes showed that microglia and oligodendrocytes were most sensitive to diet and/or AAV treatment. In HHcy mice treated with control AAV (HHcy–EGFP), predominant microglial subpopulations exhibited upregulation of several disease‐associated microglial genes (e.g. Apoe, Il1b, Ccl5, Cebpb, Cybb) and downregulation of common homeostatic genes (e.g. P2ry12, Gpr34, Fcrls, Sparc). Oligodendrocyte subpopulations in the same mice also exhibited upregulation of disease related genes (e.g. Serpina3n, H2‐D1, C4b, Klk6). However, these patterns were mitigated in HHcy mice treated with AAV‐Gfa2‐VIVIT, who exhibited expression patterns in line with CT diet mice. Analyses of DEGs in other cell types and association with immunometabolic pathways are in progress.ConclusionResults suggest that reactive astrocyte signaling strongly regulates molecular phenotypes of other local glial cells and provides a potential target for preventing/resolving pathologic glial activity in VCID and other ADRDs.
Distinct cultured microglia characteristics distinguish cognitive SuperAgers from their cognitively normal peers
Authors: Taefi Erfan , Bahrami Atousa , Garcia Donte , Ayala Ivan , Hickman Suzanne E , Gefen Tamar , Huentelman Matthew J , Mesulam Marsel , Rogalski Emily J , Khoury Joseph El , Geula Changiz 
Published: December 2023

AbstractBackgroundSuperAgers are individuals ≥80 years with exceptional episodic memory equal to or better than individuals 20 to 30 years their junior. SuperAgers display resistance to age‐related neurofibrillary degeneration. Qualitative observations suggested that SuperAger cultured microglia display higher rates of proliferation compared to age‐matched controls. The purpose of this study was a comprehensive and quantitative investigation of potential differences between SuperAger and control microglia.MethodApproximately 6.6×103 microglia from the frontal cortex of 5 SuperAgers and 5 controls were seeded and allowed to proliferate to 80% confluence prior to passage (P). Number of cells at confluence, number of days to confluence, and highest passage reached were recorded. Gene expression profiles were investigated in P4 cultures. RNASeq libraries were prepared using the Lexogen QuantSeq 3’ RNA Library kit and assessed using the Agilent High Sensitivity DNA chip. Bioinformatic analysis was performed using the BlueBee integrated data analysis pipeline. Microglia function was assayed through uptake of fluorescently tagged oligomeric and fibrillar amyloid‐β (Aβ42) and production of reactive oxygen species (ROS) in response to the two Aβ conformations.ResultAt each passage, SuperAger cultures contained greater numbers of microglia when compared with controls (by 150% at P5, p<0.01) and reached 80% confluent faster (by 108%). On average, control microglia ceased proliferating at P9, while SuperAger microglia proliferated up to P12. RNAseq analysis identified 434 genes differentially expressed in the two groups (p<0.05). Upregulated genes in SuperAgers included genes involved in DNA repair and in membrane trafficking. SuperAgers exhibited downregulation of several transcripts involved in age‐related disease pathogenesis, including Adap2, MAP2, RBM20, CNTN3, and genes that regulate mitochondrial oxidative burst. Preliminary functional analysis revealed more efficient uptake and response to oligomeric when compared with fibrillar Aβ. SuperAger microglia displayed greater ROS production when compared with controls. No differences were observed in Aβ uptake.ConclusionThese results point to distinct characteristics of microglia that may contribute to the biological bases of the SuperAging phenotype. Upregulation of genes involved in DNA repair is likely to slow microglia senescence, allowing increased proliferation in SuperAgers. Additional studies are needed to validate and extend these findings.
Association of ambient air pollution with cognitive functioning and structural brain damage: The Maastricht Study
Authors: Soeterboek Jens , Deckers Kay , van Boxtel Martin P.J. , Backes Walter H. , Eussen Simone J.P.M. , van Greevenbroek Marleen M.J. , Jansen Jacobus F.A. , Koster Annemarie , Schram Miranda T. , Stehouwer Coen D.A. , Wesselius Anke , Lakerveld Jeroen , Köhler Sebastian 
Published: December 2023

AbstractBackgroundDementia prevention poses one of the biggest challenges to our ageing society (1,2). Next to individual modifiable risk factors, shared environmental risk factors have been linked to dementia risk. Exposure to air pollution has been identified as a new candidate risk factor which on a population level carries more risk than well‐established risk factors such as hypertension and type‐2 diabetes (1). This study aimed to investigate the association between exposure to air pollutants with cognitive functioning and markers of structural brain damage next to and above individual risk factors.MethodCross‐sectional data from the population‐based cohort (N = 4,154; mean age 59.27±8.54 years, 50.12% women) of The Maastricht Study (3) was used and matched to address‐based data from the Geoscience andHealth Cohort Consortium of average exposure to particulate matter (<2.5mg and <10mg), NO2 and soot over the years 2013‐2018. Cognitive functioning was assessed through a neuropsychological test battery. Standardized volumes of grey matter, white matter, cerebrospinal fluid, and presence of cerebral small vessel disease were derived from 3‐Tesla MRI. Individual risk factors were added as one covariate, using the validated Lifestyle for Brain Health score (4). Binary logistic and multiple linear regression analyses tested the associations between air pollutants and the outcome measures. Likelihood‐ratio tests were performed to compare the extensive models.ResultWe found a curvilinear association relating particulate matter exposure in the mid to higher range to lower grey matter and higher cerebrospinal fluid volume, independent of age, sex, education, and LIBRA score. There was no association between air pollutant exposure and cognitive functioning or markers of cerebral small vessel disease.ConclusionIn this population‐based cohort, average to high exposure to particulate matter was related to an increase in markers of brain atrophy, showing important implications for environmental and public health policymaking.
Generalized Calibrated BOLD fMRI for the Relationship between Cerebral Metabolism and Hypertensive Status
Authors: Zhang Anqi , Kim Donghoon , Hong Sarah Y. , Hughes Timothy M. , Lipford Megan E. , Lockhart Samuel N. , Craft Suzanne , Baker Laura D , Whitlow Christopher T , Okonmah‐Obazee Stephanie E. , Hugenschmidt Christina , Bobinski Matthew , Jung Youngkyoo 
Published: December 2023

AbstractBackgroundElevated blood pressure levels during mid‐life have been found to be associated with an increased susceptibility to developing dementia later in life, particularly vascular dementia. Quantitative imaging biomarkers, such as Oxygen Extraction Fraction (OEF) and Cerebral Metabolism Rate of Oxygen (CMRO2), can be indicators of impaired cerebral metabolism. Calibrated Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) is a multi‐parametric approach utilizing hyperoxic and hypercapnic gas challenges (Figure 1). The impact of hypertension on OEF and CMRO2 has been investigated.MethodA cohort of 84 participants was recruited from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core (Table 1). Among all the covariates, participants with prediabetes and diabetes were considered diabetic, and those who exhibited high blood pressure or were using medication to manage hypertension were classified as hypertensive. The MRI was conducted using a 3T Siemens Skyra MRI scanner with a 32‐channel head coil. Dynamic Pseudocontinuous Arterial Spin Labeling (PCASL) was used to acquire cerebral blood flow (CBF) and BOLD images during respiratory challenges with an end‐tidal forcing system. The ROI values in the frontal lobe, temporal lobe, parietal lobe, and occipital lobe regions were chosen. The correlation between hypertensive status and OEF and CMRO2 in the ROI was analyzed with a linear mixed model, with covariates of age, sex, cognitive status, APOE genotype, diabetic status, and hypertensive status.ResultA negative correlation was found between CBF, OEF, and CMRO2 with hypertensive status in frontal lobe region (Figure 2). Statistical significance was observed for OEF and CMRO2 (p = 0.049 and p = 0.028, respectively), indicating the potential influence of hypertensive status on these biomarkers.ConclusionThe study concludes that there is a significant negative association between hypertensive status and both OEF and CMRO2, particularly in the frontal lobe region. The observed reduction in OEF and CMRO2 is not solely due to decreased CBF, but rather complex and multifactorial processes involving vascular remodeling and altered oxygen metabolism. Additional research is necessary to fully understand the underlying pathophysiological mechanisms that link hypertension to decreased OEF and CMRO2, particularly in the context of regional specificity.
Significant dose‐dependent reduction in neurofilament light chain concentration in plasma with oral tau aggregation inhibitor hydromethylthionine mesylate
Authors: Wischik Claude M , Schelter Bjoern , Penny Lewis Kirk , Miller Sonya , Stefanacci Richard , Heslegrave Amanda , Zetterberg Henrik 
Published: December 2023

AbstractBackgroundHydromethylthionine mesylate (HMTM) is a potent oral tau aggregation inhibitor. Recent results from Study TRx‐237‐039 (LUCIDITY) suggest strong effects on cognitive and functional decline and progression of brain atrophy. We investigated the effect of HMTM on change in the plasma biomarker neurofilament light chain (NfL) in LUCIDITY. NfL is a clinically accessible and established biomarker for neurodegeneration that is known to be correlated with measures of clinical decline and brain atrophy in AD and MCI due to AD (MCI‐AD).MethodLUCIDITY is a double‐blind randomised controlled Phase 3 clinical trial comparing change over 12 months in cognitive, functional and brain atrophy outcomes at HMTM doses of 16 mg/day, 8 mg/day and methylthioninium chloride (MTC) at a dose of 4 mg twice weekly as a control in a 4:1:4 randomisation, with a subsequent 12 month blinded open‐label extension phase in which all participants received 16 mg/day.ResultBaseline and 12‐month NfL plasma levels were available as randomised in 161/185 participants receiving HMTM 16 mg/day, 38/48 receiving HMTM 8 mg/day and 136/185 receiving MTC 8 mg/week. The corresponding prespecified analysis model showed a 93% reduction in the change in NfL levels relative to control for HMTM 16 mg/day overall (p = 0.0278). Reduction in NfL change in the MCI‐AD subgroup was significant also at HMTM 8 mg/day (p = 0.0242). In the AD subgroup, there were directional dose‐dependent trends that did not reach statistical significance. Change in NfL level at 12 months was significantly correlated with change in ADAS‐cog11 (p = 0.0038) and whole brain volume (p = 0.0359) over 24 months.ConclusionThese results demonstrate that the orally administered tau aggregation‐inhibitor, HMTM, is able to produce a significant dose‐dependent reduction in neurodegeneration in AD as measured by change in plasma NfL levels.
Predictors of Successful Brain Aging: An Autopsy Study
Authors: Iida Megan A , Marx Gabe , Kauffman Justin , McKenzie Andrew T , Koenigsberg Daniel , Richardson Timothy E. , Walker Jamie M. , White Charles , Farrell Kurt W. , Crary John F. 
Published: December 2023

AbstractBackgroundThe neuropathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques and neurofibrillary tangles, also accumulate in the brains of aging individuals. However, some individuals are able to age successfully without significant degenerative neuropathology or cognitive impairment, a phenomenon referred to as “successful aging”. The predictors of successful “neuropathologic” and “cognitive” aging are not fully understood, creating a critical knowledge gap. Factors such as resistance, resilience, and reserve are believed to play important roles. Furthermore, the relationship between neuropathological changes, such as tau pathology and amyloid pathology, and cognitive impairment in the oldest old population remains unclear, and the concept of amyloid plaques causing tau pathology may not be universally valid. The association between amyloid plaques and dementia also continues to be debated.MethodsIn this study, we utilized a collection of 414 post‐mortem brain tissues (171 female, 241 male) from aged individuals (average age 90, range 80‐108) with neuropathological and clinical data (215 without cognitive impairment and 161 with cognitive impairment) to perform a cross‐sectional analysis. Our cohort included subjects who had cognitive assessments available and included those with no amyloid plaque pathology or mild burden based on neuropathological criteria. Variables (including new traits derived from A.I. based feature extraction) associated with the cognitive measures were determined using multivariable logistic regression.ResultsOur results revealed that age of death and Braak neurofibrillary tangle stage were significant predictors of cognitive impairment (p<0.05), while amyloid positivity was not. These findings suggest that tau pathology may have a stronger association with cognitive impairment in the oldest old population compared to amyloid plaques.ConclusionUnderstanding the neuropathological factors associated with successful brain and cognitive aging will contribute to our knowledge of the underlying mechanisms and may pave the way for the development of interventions to promote successful aging and prevent cognitive decline in old age. Further research in this area is warranted to elucidate the complex relationship between neuropathology, cognitive function, and aging in the oldest old population.
Bio‐Hermes study topline results: Aß 40/42 and p‐tau181/217/231 blood‐based biomarkers compared to amyloid PET and CSF in a diverse, community‐based population
Authors: Beauregard Douglas W. , Gaudioso Jennifer , Mohs Richard , Hollingshead Sarah , Dwyer John , Bork Jason , Kerwin Diana R. 
Published: December 2023

AbstractBackgroundResearch of blood‐based biomarkers to indirectly assess amyloid presence in the brain has mainly been conducted in special populations (e.g., those enrolled in autopsy programs or single site populations selected for genetic vulnerability). To more accurately reflect clinical trial populations and to increase diversity, the Bio‐Hermes study used 17 sites and monitored recruitment to achieve ≥19% underrepresented minorities (URM) in each of the 3 clinical trial cohorts of Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and Mild AD. In addition to blood‐based biomarkers and the presence of amyloid plaques identified through brain amyloid PET and CSF, numerous digital tests and genetic assays were performed resulting in a robust Bio‐Hermes database.MethodWithin 18 months, 17 sites enrolled 1,001 participants (60‐85 y/o) in clinically defined cohorts of: CN (N = 417), MCI (N = 312), and Mild AD (N = 272). Traditional and digital cognitive testing, amyloid PET imaging, biospecimen collection, and speech analytics were performed. A subset of participants received a retinal exam. Blood biomarkers included Aß 42/40, p‐Tau181/217/231, NfL, GFAP, full genome sequencing, including APOE status, and proteomics. Digital biomarkers included memory recall, executive functions, and drawing‐based and speech elicitation tasks. Blood biomarkers’ relationship to amyloid PET was measured using Spearman’s rank correlation. A ROC curve analysis assessed the sensitivity and specificity of each biomarker and combination of biomarkers compared with amyloid positivity from PET and CSF.ResultBrain amyloid positivity results were 21%, 34%, and 61% for the CN, MCI, and Mild AD cohorts, respectively. Initial data analysis by Global Alzheimer’s Platform Foundation® (GAP) compared results of blood Aß 42/40, t‐tau, and p‐tau181/217/231 tests with brain amyloid positivity. ROC analysis showed more favorable AUC for Aß 40/42 and p‐tau181 (0.8268), Aß 40/42 and t‐tau (0.7922), and Aß 40/42 (0.7918). For Black/African Americans, brain amyloid positivity was 24%, 23%, and 38% for the CN, MCI, and Mild AD cohorts, respectively, and for Hispanic/Latinos results were 4%, 37%, and 53%, respectively. Additional correlation and URM data will be available July 2023.ConclusionInitial topline results show blood‐based AD biomarkers are associated with brain amyloid positivity warranting further analysis of the Bio‐Hermes community‐derived database of blood‐based and digital biomarkers.