bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of self‐reported history of head injury on Alzheimer’s disease biomarker profiles
Authors: Dybing Kaitlyn M , Saykin Andrew J. , Risacher Shannon L 
Published: December 2023

AbstractBackgroundHead injury (HI) as a risk factor for Alzheimer’s disease (AD) has been attracting increased attention thanks to the discovery that concussion is linked to earlier and more severe development of AD (1). HI is prevalent, and a better understanding of how it contributes to AD risk and prognosis is necessary (2). Previous cross‐sectional studies have provided evidence of differences in biomarker levels between individuals with a history of HI and those without (2); this study investigates the effects of a history of HI on longitudinal patterns of AD biomarkers to better understand how HI affects AD risk.MethodUsing the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, we examined longitudinal levels of amyloid β (Aβ), phosphorylated tau (p‐tau), and total tau (t‐tau) in the cerebrospinal fluid (CSF) of 100 individuals with a history of HI and 100 non‐HI controls demographically‐matched on age, sex, race, ethnicity, and years of education. We also analyzed longitudinal levels of blood plasma free plasma (FP) 42, total plasma (TP) 42, pTau181, and NFL.ResultIndividuals with a history of HI had lower CSF Aβ at baseline, lower plasma TP42 at a month 48 follow‐up visit, and lower plasma pTau181 at 72‐ and 96‐month follow‐up visits. There were no differences between the groups on CSF p‐tau or t‐tau levels or plasma FP42 or NFL at any time point.ConclusionLower CSF and plasma amyloid in the HI group may indicate individuals with a history of HI have higher amyloid deposition, given the inverse correlation between CSF/plasma amyloid levels and amyloid deposition on PET (3). The unexpectedly lower plasma pTau in the HI group warrants further analysis. Some of our analyses may be underpowered, as underreporting of HI incidence in ADNI reduces the number of available HI participants. However, despite these limitations, we were able to find significant differences in some biomarkers in individuals with a history of HI. Future studies in expanded samples are needed.1. Fleminger et al. (2003). Journal of Neurology, Neurosurgery & Psychiatry
2. Small et al. (2013). The American Journal of Geriatric Psychiatry
3. Fagan et al. (2006). Annals of Neurology
Enhanced arterial spin labeling in mild cognitive impairment phenotypes
Authors: Umfleet Laura Glass , Cohen Alexander D , Brett Benjamin L , Lancaster Melissa , Obarski Shawn , Mason Lilly , Franczak Malgorzata , Wang Yang 
Published: December 2023

AbstractBackgroundArterial spin labeling perfusion MRI is increasingly proving to be a promising tool for exploring neurovascular changes in neurodegenerative conditions. Using an advanced 3D pseudo‐continuous arterial spin labeling sequence with Hadamard‐encoded multiple post‐labeling delays (eASL), this study evaluated both cerebral blood flow (CBF) and arterial transit time (ATT) alterations in mild cognitive impairment (MCI) phenotypes.MethodMCI patients (N = 19;Mage = 74.63±5.65) and controls (N = 20;Mage = 70.04±7.06) underwent a 3T MR scan with the eASL sequence. ATT and CBF were simultaneously measured. Voxel‐wise group comparisons of CBF and ATT were performed. Results were thresholded at a cluster‐size corrected p<0.001 (a<0.05). A region of interest (ROI) was defined as the overlap of clusters showing a significant difference in CBF and ATT between MCI and controls. Independent t‐tests between MCI phenotypes (amnestic, non‐amnestic) and controls on CBF and ATT ROIs were conducted. Pearson correlations of ROIs with measures of cognition, including executive functioning, were calculated. Correlations informed regression analysis.ResultsVoxelwise analyses (Figure1) demonstrated decreased CBF in MCI compared to controls in the default mode network, middle and superior frontal gyri, inferior parietal lobule, and temporal lobe. Increased ATT was seen in similar regions, with clusters centered in inferior and middle temporal lobe and visual cortex. T‐tests using created ROIs (as described above) revealed group differences between controls and MCI phenotypes in both CBF and ATT (ps≤.01); there was a non‐significant trend for higher ATT in naMCI versus aMCI. The highest correlational values emerged between CBF and ATT ROIs with a measure of executive functioning (TrailsB). IVs in regression analysis were age (step 1) and ATT and CBF overlapping ROI values (step 2, stepwise); TrailsB = DV . Across the entire cohort, CBF (R2 change = .239, p<.001), not ATT, was included in the model.ConclusionAdvanced 3D pCASL with Hadamard encoded multiple PLDs (eASL) can be used to simultaneously measure CBF and ATT in MCI and controls. MCI patients showed different patterns of reduced CBF and prolonged ATT. While CBF and ATT values were significantly correlated with TrailsB, regression analysis revealed that CBF was a more robust predictor of TrailsB. Future research should examine eASL as a biomarker for MCI phenotypes.
Update of the “LIfestyle for BRAin health” (LIBRA) index: Results from an umbrella review and Delphi consensus study on modifiable dementia risk factors
Authors: Rosenau Colin , Köhler Sebastian , van Boxtel Martin P.J. , Deckers Kay 
Published: December 2023

AbstractBackgroundGiven the projected increase in the number of people with dementia and the lack of curative treatment, there is increasing attention to the contribution of modifiable risk and protective factors to dementia risk. In 2015, the “LIfestyle for BRAin health" (LIBRA) index was developed based on the results of a systematic literature review and Delphi expert study (Deckers et al., 2015). LIBRA consists of twelve modifiable risk factors for cognitive decline and dementia. Although this risk index has been well‐validated for cognitive decline and dementia risk in numerous population‐based cohorts and intervention studies, newly emerged risk factors might ask for an update (Deckers et al., 2019; Deckers et al., 2020).MethodTo update LIBRA, we conducted an umbrella review to assess all systematic reviews (SR) and meta‐analyses (MA) on modifiable dementia risk factors published between January 2015 and June 2021 in four databases (Pubmed, Embase, Web of Science, and PsychINFO). In parallel, a two‐round Delphi expert study was conducted. In the first round (May‐June 2022), eighteen dementia experts were asked to evaluate the factors currently included in LIBRA. Additionally, we asked to list new modifiable factors not previously included in LIBRA. In the second round (December 2022‐January 2023), the experts ranked the most important risk factors identified in the umbrella review and first Delphi round.ResultThe search returned 6,540 hits, of which 147 SR/MA were included in our umbrella review. Next to the existing LIBRA factors, new candidate risk factors that were consistently associated with increased risk for cognitive decline and dementia included: low social engagement, hearing impairment, vision impairment, atrial fibrillation, and anxiety. After triangulation of the results of the umbrella review and the first Delphi round, the experts identified hearing impairment, lifecourse inequalities, social contact, atrial fibrillation, and sleep as the most important new modifiable risk factors in the second Delphi round.ConclusionSeveral new modifiable risk factors for cognitive decline and dementia have been identified in this umbrella review and Delphi consensus study. These factors will be used for updating the existing LIBRA index, which will subsequently be externally validated in population‐based cohort studies.
Visit‐to‐Visit Glucose Variability and Global and Regional Brain Volumes: The Multi‐Ethnic Study of Atherosclerosis (MESA)
Authors: Schaich Christopher L. , Brown Elili R. , Bancks Michael P. , Nasrallah Ilya M. , Bryan R. Nick , Heckbert Susan R. , Luchsinger José A. , Hayden Kathleen M. , Mongraw‐Chaffin Morgana , Hughes Timothy M. 
Published: December 2023

AbstractBackgroundHigher visit‐to‐visit fasting glucose variability (GV), indicating worse long‐term glycemic control, is associated with cognitive decline and incident dementia in adults with type 2 diabetes (T2D). We investigated the association of GV with brain volumes in a racially/ethnically diverse cohort of older adults with and without T2D.MethodFasting glucose was measured in MESA participants at six examinations from 2000‐2002 through 2016‐2018. Brain volumes including total gray matter (GM), white matter (WM), hippocampal, limbic, basal ganglia, and frontal and temporal lobe GM were measured by 3T MRI in 2017‐2021 (n = 1,429; 43% of surviving cohort). We calculated the standard deviation (SDG) and average real variability (ARV) of glucose across the six exams, and report standardized differences in brain volumes (95% CI) associated with log2‐normalized GV from multivariable linear regression adjusted for site, intracranial volume, age, sex, race/ethnicity, educational attainment, APOE ε4 status, cardiovascular risk factors, hypertension and lipid‐lowering medication use, mean glucose level during GV assessment, and T2D statusResultParticipants had mean age 73 (8) years; were 53% women, 42% White, 12% Chinese, 27% Black, and 19% Hispanic; and 24% had T2D. Two‐fold increments in SDG and ARV were associated with ‐0.06 (‐0.10, ‐0.02) and ‐0.05 (‐0.09, ‐0.01) lower SD units of adjusted total GM volume, respectively. Higher SDG and ARV were further associated with lower adjusted frontal lobe GM volume (‐0.09 [‐0.14, ‐0.04] and ‐0.07 [‐0.12, ‐0.02] SD units, respectively), but not with temporal lobe, hippocampal, limbic, basal ganglia, or WM volumes. Though not associated with GM volumes itself, T2D appeared to modify associations with regional volumes. For example, higher SDG and ARV were associated with lower limbic area volume (‐0.14 [‐0.23, ‐0.04] and ‐0.08 [‐0.17, 0.009] SD units, respectively) in participants with T2D, but not in T2D‐free participants (‐0.02 [‐0.09, 0.06] and ‐0.02 [‐0.09, 0.05] SD units, respectively). Associations were consistent across race/ethnicity.ConclusionHigher visit‐to‐visit GV over 16‐18 years is associated with a pattern of lower GM volume driven by frontal lobe volume, a key region for governing executive function. GV may have more involvement with GM volumes among individuals with T2D.
Easing the data sharing burden: perspectives and principles to successfully leverage AD data repositories, infrastructures and functionality
Authors: Sivakumaran Sudhir 
Published: December 2023

AbstractCritical Path Institute (C‐Path) is a nonprofit organization that brings together patient groups, academic institutions, the pharmaceutical industry and regulatory agencies from around the world to improve public health. C‐Path provides the legal, scientific, and regulatory infrastructure to generate a unique neutral environment for medical product development, supported by more than a decade of experience in data standards development, platform development and hosting, patient‐level data privacy stewardship, data platform security, and controlled access methodology. The Critical Path for Alzheimer’s Disease (CPAD) is a pre‐competitive consortium that aims to promote, support, and manage a diverse source and format of data and facilitate knowledge sharing from the Alzheimer disease (AD) drug development community. The CPAD database currently contains 65 clinical trials and observational studies, with over 93,000 individual anonymized patient‐level records, with global access to many datasets through the C‐Path Online Data Repository (CODR). The unparalleled breadth, depth and wealth of data will enable us to discover yet‐to‐be identified unmet needs and unanswered questions. Further, CODR is interoperable with the Global Alzheimer’s Association Interactive Network (GAAIN), Vivli and other data platforms. The secure and neutral data sharing framework of CPAD has resulted in the development of several regulatory‐grade tools that help optimize drug development and accelerate bringing new therapies to patients in need. Sufficient case examples of successful data sharing are now available and should inform and encourage future data sharing initiatives.
Staging Neurodegeneration Across the AD Continuum
Authors: Moody Jason F , Dean Douglas C , Alexander Andrew L , Johnson Sterling C , Bendlin Barbara B 
Published: December 2023

AbstractBackgroundWhile amyloid and tau staging are ubiquitous in Alzheimer’s disease (AD), there are no equivalent staging techniques for AD‐related neurodegeneration. Currently, neurodegeneration in AD is commonly assessed with structural MRI measures such as hippocampal volume and cortical thickness. However, recent work suggests that markers for microstructural neurodegeneration derived from diffusion MRI (DWI) may provide crucial additional information related to the onset and progression of AD. Neurite density index (NDI) and return to origin probability (RTOP) are two DWI metrics that have shown promise for characterizing these microstructural alterations.To investigate the utility of DWI for staging neurodegeneration in AD, we implemented logistic regression to compare the abilities of NDI, RTOP, and hippocampal volume to predict AD dementia in 481 late‐middle‐aged participants on the AD continuum.Methods481 participants (383 cognitively unimpaired [CU], 68 Mild Cognitive Impairment [MCI], 30 AD) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center were imaged with T1‐weighted MRI and multi‐shell DWI. After delineating hippocampal volume, average NDI and RTOP values were extracted from the hippocampus and a whole brain white matter skeleton. All measures were fit to a logistic model with age, sex, and scanner as covariates.Corresponding ROC curves were used to derive cutoff values for NDI and RTOP by maximizing the Youden Index.ResultsBox plots and ROC curves are provided in Figures 1‐2 and cutoff values for each DWI metric are provided in Table 1. NDI and RTOP outperformed hippocampal volume in predicting AD across brain regions. The best performing marker was WM NDI (AUC = 0.905), followed closely by WM RTOP (AUC = .878). Meanwhile, hippocampal RTOP (AUC = 0.861) slightly outperformed hippocampal NDI (AUC = 0.844).ConclusionOur work adds to a growing body of literature which suggests that neuroimaging markers of brain microstructure may capture unique signatures of AD progression. Furthermore, the fact that both DWI measures performed best in whole brain WM reinforces WM degeneration as a core feature of AD pathophysiology. Future work will incorporate CSF and PET measures of amyloid and tau to better characterize AD‐specific neurodegeneration.
A perspective on data sharing from potentially registrational trials
Authors: Sink Kaycee M. , Narburgh Lesley , Hu Nan , Tucker Katherine , Doody Rachelle S. 
Published: December 2023

AbstractIt is well recognized that sharing rich and rigorously collected clinical trial data with researchers who were not conducting the study has the potential to accelerate progress in Alzheimer’s disease.. Such data sharing can contribute to an understanding of pathophysiology, natural history, performance of outcome measures, and the profile of response to treatments, and can help researchers to design better studies and health authorities and payors to evaluate the benefits of therapies. The complexities involved in such data sharing include the need to keep up with evolving patient privacy laws, protecting participant anonymity, ensuring trial integrity, and balancing regulatory and publication requirements. In 2012 Roche/Genentech made a commitment to Banner Alzheimer’s Institute and the NIH to share baseline and longitudinal trial data from the Alzheimer’s Prevention Initiative Autosomal Dominant AD trial, a public‐private partnership. We will describe the mechanisms developed to share data from the API ADAD Trial (baseline data now available; longitudinal clinical, imaging, and biomarker data to follow) including methods employed to protect confidentiality and anonymity of participants, and the process for requesting and accessing baseline data. We will also offer learnings from our experiences in sharing data from other neurodegeneration trials.The API ADAD trial was funded by NIA grants RF1‐AG041705, R01‐AG055444, Genentech, Roche, philanthropic contributions to Banner Alzheimer’s Foundation. Florbetapir PET was partly supported by Avid and Lilly.
Baseline and Longitudinal Changes in Lateral Ventricle Volume Predict Cognitive Decline
Authors: Chen Gengsheng , Gordon Brian A. , Wang Qing , Schindler Suzanne E. , McKay Nicole S. , Liu Jingxia , Joseph‐Mathurin Nelly , Keefe Sarah J. , Aschenbrenner Andrew J. , Massoumzadeh Parinaz , Morris John C , Benzinger Tammie L.S. 
Published: December 2023

AbstractBackgroundThe use of biomarkers for early detection of Alzheimer disease (AD) is crucial for developing potential treatments. Previous research has linked structural alterations in specific brain regions to cognitive decline. Lateral ventricle volume can be estimated reliably from various modalities of brain imaging, but this has not been well studied as an AD biomarker. In this study, we tested the hypothesis that baseline and longitudinal changes in lateral ventricle volume as measured by MRI could predict changes in global cognitive composite scores.Method363 Participants enrolled in longitudinal studies at the Knight ADRC at Washington University in St. Louis were included. Magnetic resonance imaging (MRI) data was obtained through OASIS (www.oasis‐brains.org). Participants were required to have at least two cognitive assessments and MRI scans. Lateral ventricular volumes were extracted and corrected for head size using the FreeSurfer intracranial volume. A global cognitive composite score was calculated from the average z‐scores of 10 neuropsychological tests. A random coefficient model was used to calculate longitudinal change in lateral ventricular volumes, and to assess whether these measures predicted cognitive decline when adjusted for age, sex, APOE Ɛ4, and years of education. Spearman correlation was also used to evaluate the relationship between cognitive decline and baseline or longitudinal changes in lateral ventricle volumes.ResultWe found that baseline and longitudinal changes in lateral ventricle volume predicted the rate of change in global cognitive composite (Table 1 and 2, t = ‐4.82, p<0.0001 and t = ‐3.83, p = 0.0001). Additionally, there were significant correlations between baseline and longitudinal changes in lateral ventricle volume and the rate of change in global cognitive composite (Figure 1, R2 = 0.0657, p<0.0001; and R2 = 0.0412, p<0.0001).ConclusionBaseline and longitudinal changes in lateral ventricle volume predicted decline on a global cognitive composite. MRI scanners are widely available world‐wide. Baseline and longitudinal lateral ventricle volumes could potentially be used to stratify risk for cognitive decline for clinical trials.
Association between APOE‐ε4 allele and cognitive function is mediated by Alzheimer’s disease pathology: a population‐based autopsy study in an admixed sample
Authors: Paradela Regina Silva , Paes Vitor Ribeiro , Justo Alberto Fernando Oliveira , Leite Renata Elaine Paraizo , Pasquallucci Carlos Augusto , Grinberg Lea T. , Naslavsky Michel S , Zatz Mayana , Nitrini Ricardo , Jacob‐Filho Wilson , Suemoto Claudia Kimie 
Published: December 2023

AbstractBackgroundApolipoprotein E ε4 allele (APOE‐ε4) is the main genetic risk factor for dementia. APOE‐ε4 is also associated with Alzheimer’s disease (AD) pathology, cerebrovascular disease, and non‐AD neurodegenerative pathologies. Although APOE‐ε4 may influence cognitive impairment through these pathways, less evidence is available from diverse populations, considering that APOE genotype associations seem to vary by race. Therefore, we aimed to evaluate the pathways linking APOE‐ε4 to cognition through AD and non‐AD neuropathology in an autopsy study with an admixed sample.MethodWe used data from the Biobank for Aging Studies of the University of Sao Paulo Medical School. Participants were classified into APOE‐ε4 carriers (at least one ε4 allele) and non‐carriers. Cognitive function was evaluated by the Clinical Dementia Rating Scale sum of boxes. Mediation analyses were conducted to assess the APOE‐ε4 association with cognition through direct and indirect pathways. Indirect pathways included the following mediators: AD‐type pathology, lacunar infarcts, hyaline arteriosclerosis, cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), and TAR DNA‐binding protein 43 (TDP‐43). We used immunohistochemistry to detect AD pathology, CAA, LBD, and TDP‐43. AD pathology was scored using the Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for AD criteria for β‐amyloid plaque. Lacunar infarcts and hyaline arteriosclerosis were evaluated microscopically using hematoxylin and eosin‐stained. All analyses were adjusted for demographic and clinical cofounders.ResultWe included 648 participants (mean age 75±12 y, 52% women, 69% white, and 28% APOE‐ε4 carriers). The association between APOE‐ε4 and cognitive abilities was mediated by the burden of neurofibrillary tangles (β = 0.78, 95% CI = 0.39; 1.22, p<0.001) and β‐amyloid plaques (β = 0.87, 95% CI = 0.39; 1.40, p<0.001). Lacunar infarcts, hyaline arteriosclerosis, CAA, LBD, and TDP‐43 were not mediators in the pathway from APOE‐ε4 to cognitive function. Direct pathways remained significant in the presence of all mediators except TDP‐43 (p = 0.09) and β‐amyloid plaques (p = 0.07).ConclusionThe influence of APOE‐ε4 on cognitive abilities was partially mediated by AD pathology. However, cerebrovascular lesions and non‐AD pathologies were not mediators in the pathway linking APOE‐ε4 to cognition.