bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective sex‐based differences in the association between angiogenic and Alzheimer’s Disease biomarkers in a preliminary cohort of rrAD participants
Authors: Lutshumba Jenny , Wilcock Donna M. , Lee Tiffany , Zhu David C , Scheel Norman , German Dwight C , Zhang Rong , Trout Amanda , Stowe Ann M 
Published: January 2025

AbstractBackgroundVascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD) are the two most common forms of dementia, with overlapping risk factors including cardiovascular risk factors such as hypertension and dyslipidemia. The etiology of both VCID and AD shows sex‐based differences, as well as sex‐based differences in cardiovascular risk factors. However, how sex differences influence AD and angiogenic biomarkers in older adults who have high cardiovascular risk factors is not known.MethodAD and angiogenic biomarkers for VCID were measured from the plasma of a subgroup (n=96) of participants from the ‘risk reduction for Alzheimer’s disease’ (rrAD) two‐year clinical trial (NCT02913664; completed Jan. 2022; n=513 total participants). rrAD participants had a family history of dementia or subjective memory complaints, hypertension, and dyslipidemia. The subgroup in the study included 31 males and 65 females (aged: 71‐85). Baseline values for AD biomarkers: Total tau, pTau181, Aβ40, and Aβ42, angiogenic biomarkers: Tie‐2, VEGF‐A, VEGF‐C, VEGFR1, and VCID biomarkers: bFGF, VEGF‐D, PlGF were analyzed using Meso Scale Discovery (MSD). Nonparametric analysis evaluated the sex differences in biomarkers, linear regression evaluated the relationship between AD biomarkers and angiogenic biomarkers in both sexes.ResultWe found sex‐based differences in AD biomarkers such that females had a higher expression in Total tau and Total tau/Aβ42 (p=0.0021, p=0.0003, respectively) while pTau181 was higher in males (p=0.0216). pTau181/ Aβ42 and Aβ42/40 ratios showed no sex differences, nor did baseline angiogenic biomarkers. There was, however, a selective sex difference in the association between angiogenic and AD biomarkers. In females, Total tau is associated with VEGF‐D (R2= 0.0746, p=0.0277), and Tau/Aβ42 is associated with VEGF‐A and VEGFR‐1(R2= 0.0747, p=0.0275; R2= 0.0973, p=0.0114, respectively). In males, pTau181 and pTau181/Aβ42 are associated with VEGF‐D (R2= 0.2637, p=0.0031; R2= 0.1799, p=0.0174, respectively), Aβ42/Aβ40 is associated with VEGF‐C (R2= 0.1491, p=0.0319), and Tau/Aβ42 is associated with bFGF (R2= 0.1458, p=0.0340).ConclusionThere is a selective sex‐based difference in plasma AD biomarkers and their association with angiogenic biomarkers in this preliminary cohort of older adults with high risks of developing Alzheimer’s disease and related dementias.
“Inhibition of mitochondrial carbonic anhydrases prevents endothelial cell death and blood brain barrier dysfunction in models of amyloidosis.”
Authors: Lemon Nicole L , Vazquez‐Torres Rafael , Canepa Elisa , Rullan Rebecca M Parodi , Ilies Marc A , Fossati Silvia 
Published: January 2025

AbstractBackgroundThe Neurovascular Unit is a multicellular structure of the CNS known to become dysfunctional in Alzheimer’s Disease (AD) and cerebral amyloid angiopathy. Amyloidosis disrupts the function of cerebrovascular endothelial cells (cECs) via extrinsic and intrinsic apoptosis, and induction of blood brain barrier (BBB) permeability. Findings in our lab demonstrated that pan‐Carbonic Anhydrase inhibitors (CAi’s) prevent mitochondria‐mediated apoptotic mechanisms in cECs. Therefore, we hypothesized that the mitochondrial CA isoforms, CA‐VA and ‐VB mediate Aβ‐induced cell death and other deleterious mechanisms in cECs. Importantly, mitochondrial isoform CA‐VB is increased in models of amyloidosis. Thus, we anticipate using a pharmacological selective CA‐Vi will reduce cerebrovascular EC apoptosis and prevent EC activation. We also hypothesize that CA‐VB KO in human cerebral cECs will rescue mitochondrial‐mediated apoptosis and protect from BBB dysfunction. Finally, we anticipated that CA‐Vi prevents cognitive decline/AD pathology in the 3xTG mouse model.MethodHuman cerebral microvascular ECs (hCMECs) were treated with Aβ40‐Q22 Dutch mutant alone, and in combination with CA‐Vi, and we measured outcomes of mitochondria‐mediated apoptosis and BBB function. In parallel to pharmacological inhibition, we employed CA‐VB KO hCMECs to understand the contribution of CA‐VB to mechanisms of EC apoptosis and BBB function. To confirm the findings in vivo, we treated 3xTG AD mice with CA‐Vi from 6 to16 months of age. Mice went through behavior paradigms, and tissue was harvested. We then measured BBB and cell death outcomes, in addition to Aβ and tau levels.ResultInhibition of CA‐V prevented Aβ40‐Q22‐induced mitochondria‐mediated EC death and activation. CA‐VB KO in hCMECs also protected against Aβ‐induced cell death and BBB permeability. Importantly, CA‐Vi prevented cognitive decline, Aβ and tau accumulation, and EC activation in 3xTG mice.ConclusionInhibition of mitochondrial CA‐V is protective in models of amyloidosis and AD in vitro and in vivo through the prevention of mitochondria‐mediated cell death and loss of BBB function. Future studies will aim to understand the cell‐specific mechanisms of CA‐V inhibition.
Unraveling Alzheimer's Disease Heterogeneity: A Comparative Analysis Using HYDRA and CHIMERA
Authors: An Gordon , Benzinger Tammie L.S. , Sotiras Aristeidis , Gordon Brian A. 
Published: January 2025

AbstractBackgroundAlzheimer's Disease can present with heterogenous neurodegenerative patterns. In order to optimize clinical trials and personalized medicine, the identification and characterization of diverse pathological brain patterns associated with AD have become paramount. Optimal approaches to identify such heterogeneity are unknown. The present study employed two distinct clustering approaches, namely HYDRA and CHIMERA, to delineate the spatial pattern of brain atrophy attributable to AD. Methods were applied to MRI scans from the Open Access Series of Imaging Studies (OASIS‐4) project.MethodsHYDRA uses a convex polytope formed by multiple linear hyperplanes that correspond to various pathological patterns, capturing disease subtypes. CHIMERA assesses the pathological transition by transforming NC distribution to separate transformations matching the disease distribution. While both identify spatial patterns, the distinction lies in HYDRA's discriminative analysis of disease subtypes and CHIMERA's generative nature on disease progression through distribution matching.ResultsBoth approaches identified two patterns, or subtypes (Figure 1) with similar CDR results (Figure 2). All subtypes demonstrate marked atrophy within the medial temporal areas, notably the hippocampus. Disparities are evident when assessing subtypes: Subtype‐2 across both methods shows pronounced variations in regions such as superior frontal, middle temporal, parietal cortex, and precuneus, areas paramount in AD pathology. Conversely, HYDRA's Subtype‐1 highlights subtle differences in temporal cortex relative to its Subtype‐2. CHIMERA's Subtype‐1, while mirroring its Subtype‐2 pattern, is less intensified, suggesting an earlier AD stage. Collectively, these patterns concur with recognized AD neuropathological trajectories, pinpointing regions initially impacted in progression. In addition, an in‐depth exploration of subsequent analysis including a longitudinal data evaluation to observe the progression of these patterns over time is slated for later investigation.ConclusionOur findings demonstrate data‐driven approaches to derive clinically meaningful patterns of neurodegeneration. A parallel evaluation of both approaches accentuates the robustness of clustering techniques, revealing consistent and overlapping insights into the intricate pathological landscapes of AD. This convergence in findings bolsters confidence in the reliability of such analytical tools in AD research.
Association of Blood Pressure Mean and Variability with Hippocampal Subfield Volumes in Cerebral Amyloid Angiopathy with Mild Cognitive Symptoms
Authors: SVEIKATA Lukas , Zotin Maria Clara Zanon , Schoemaker Dorothee , Perosa Valentina , Assal Frederic , Greenberg Steven M. , Viswanathan Anand 
Published: January 2025

AbstractBackgroundThe interaction between Alzheimer's pathology and cerebral amyloid angiopathy (CAA), a common cerebral small vessel disease, plays a crucial role in cognitive impairment development in older adults. Recent studies suggest that increased blood pressure (BP) variability may affect subclinical vascular disease and cognitive decline. However, it is currently unknown whether a particular BP profile is linked to hippocampal subfield volumes, which are a significant feature of cognitive decline in neurodegenerative diseases. Therefore, we conducted a study to investigate the relationship between BP profile and hippocampal subfields in nondemented subjects with CAA.MethodWe investigated the relation between BP mean and variability and hippocampal neurodegeneration in a memory clinic cohort of non‐demented participants with possible and probable cerebral amyloid angiopathy (CAA), diagnosed using the modified Boston criteria v1.5. Linear regression models were used to assess the associations between BP profile and hippocampal volumes. The subfield volumes were measured using an automated method on T‐1 weighted sequence using FreeSurfer v6.0. The BP profile was defined using serial outpatient BP measurements five years prior to 3T research MRI. The BP variability was calculated using the coefficient of variation (standard deviation/mean).ResultWe have included 59 participants (74.3 ± 6.8 y, 9/50 F/M) who underwent a median of 12 (IQR 26) outpatient BP measurements five years prior to index MRI. We found a significant association between mean BP and all measured hippocampal subfields, notably the CA1: b=‐032, p=0.008, CA3: b = ‐0.24, p=0.049, CA4: b=‐0.34, p=0.003, and the subiculum: b=‐0.29, p=0.006), adjusted for age and brain volume normalized for total intracranial volume. However, we found no significant association with long‐term BP variabilityConclusionWe found significant associations between mean BP and hippocampal subfields volumes. Our results suggest that elevated BP, but not its variability, is a modifiable risk factor for preventing hippocampal degeneration in the context of CAA‐related cognitive impairment. Further pre‐planned analyses will evaluate the associationa in a subgroup of participants with mild dementia and non‐CAA participants.
Body Mass Index and Brain Aging: Microstructural Effects Mapped with Advanced Diffusion MRI
Authors: Benavidez Sebastian M , Lawrence Katherine E , Nabulsi Leila , Laltoo Emily , Abaryan Zvart , Villalon‐Reina Julio E , Nir Talia M , Gari Iyad Ba , Zhu Alyssa H , Haddad Elizabeth , Jahanshad Neda , Thompson Paul M. 
Published: January 2025

AbstractBackgroundHigh body mass index (BMI) is a risk factor for dementia, and prior diffusion‐weighted magnetic resonance (dMRI) work has shown that higher BMI is associated with lower white matter (WM) integrity. The tensor distribution function (TDF) is an advanced dMRI model that is sensitive to the effects of both healthy aging and Alzheimer’s disease (Nir et al., 2017; Lawrence et al., 2021). Here we use TDF – together with the conventional dMRI model diffusion tensor imaging (DTI) and the advanced dMRI model neurite orientation dispersion and density imaging (NODDI) (Zhang et al., 2012) – to characterize BMI effects on WM microstructure aging in later adulthood in the large‐scale UK Biobank dataset.MethodCross‐sectional dMRI data from 34,763 participants were analyzed (64.7 ± 19.5 years old, 48.4% male) from the UK Biobank dataset. WM metrics were extracted for 20 WM regions of interest (ROI) using the ENIGMA‐DTI protocol and FSL’s tract‐based spatial statistics (TBSS) (Jahanshad et al., 2013; Smith et al., 2006). We examined the interaction between BMI and age (demeaned linear and quadratic age terms) while including standard nuisance covariates. Results were corrected for multiple comparisons across ROIs using the false discovery rate method.ResultSignificant interactions were observed between BMI and age across the deep WM for every dMRI model examined (all corrected p<0.05). When averaging across the full WM, higher BMI was significantly associated with lower fractional anisotropy (DTI‐FA) among older participants (corrected p=0.04). Orientation dispersion (NODDI‐OD) was relatively higher in those with higher BMI in midlife coupled with less pronounced higher values in older adults (corrected p=0.03). Higher BMI was also associated with higher isotropic volume fraction (NODDI‐ISOVF) in middle‐age (corrected p=0.02).ConclusionThese results in a cross‐sectional sample reveal that BMI is significantly associated with age trajectories in older individuals’ brain WM microstructure. This may help elucidate the biological mechanisms of BMI as a risk factor for dementia. Future research should consider longitudinal cohorts that include individuals who convert to dementia, to better understand how BMI affects WM aging.
Dried blood spots as a matrix for measuring AD biomarkers: optimizing parameters of analysis and evaluating technical stability
Authors: Hammerschlag Bruno L. , Fatima Hadia A , Celedon Johanna , Ragas Trevor L , Webster Hannah A , Arnold Steven E , Kivisäkk Pia 
Published: January 2025

AbstractBackgroundAn advantage of blood‐based biomarkers of Alzheimer’s disease (AD) is that collection is easily repeatable and minimally invasive. Repeated biomarker measurements provide greater sensitivity for detecting within‐person change, which in clinical trials can allow for reductions in sample sizes required to detect treatment effects and shorten trial periods. We validated Dried Blood Spots (DBS) as a novel matrix for measuring blood biomarkers of AD, as collection is easily repeatable, less burdensome for participants, and more economical than phlebotomy, and shipment and storage are simplified. Our goal was optimizing collection methods and parameters of measurement, and evaluating the technical stability of repeat measurements and day‐to‐day variability in individual study participants.MethodsWe measured levels of phosphorylated tau 217 (pTau217), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using commercially available electrochemiluminescent immunoassays in DBS and paired plasma samples. Venous blood was obtained from participants in the Massachusetts Alzheimer’s Disease Research Center’s longitudinal cohort study and patients undergoing diagnostic lumbar punctures at Massachusetts General Hospital. DBS samples were prepared by applying whole blood immediately post‐collection to Whatman 903 filter cards and stored at room temperature. Before analysis, DBS samples were punched out of cards and eluted at room temperature overnight.ResultsWe optimized pre‐analytical factors of DBS analysis by investigating differences in elution times and temperatures, and matrix and diluent effects. Using our optimized protocol, GFAP [median (IQR): 4.1 (6.7‐2.2) pg/ml], NfL [29.2 (36.3‐15.2) pg/ml], and pTau217 [4.5 (5.6‐3.3) pg/ml] were detected over the lower limit of quantitation (LLOQ) in all samples. Excellent correlations between plasma and DBS concentrations were observed for GFAP (r=0.90; p<0.0001) and NfL (r=0.96; p<0.0001), while initial validation in a smaller sample size indicated acceptable correlation for pTau217 (r=0.78; p<0.01).ConclusionsWe found measurable levels of three key biomarkers of AD in DBS samples. Concentrations were significantly correlated to levels in paired plasma samples. We are currently evaluating technical repeatability and short‐term variability in capillary DBS levels of pTau217, GFAP, and NfL.
The neural substrate linking olfactory deficits to cognitive decline in MCI
Authors: Karunanayaka Prasanna , Elyan Rommy , Ahmed Biyar , Kanekar Sangam , Peiris Senal , Pang Ran , Eslinger Paul , Yang Qing 
Published: January 2025

AbstractBackgroundA combination of impairments in odor threshold and discrimination, which are both predominantly sensory level functions, and olfactory cognition contribute to age‐related odor‐identification deficits. However, in Alzheimer’s disease (AD), odor identification is more impaired compared to sensory‐level olfactory functions. We, therefore, hypothesized that match and mismatch olfactory fMRI tasks could be used to isolate areas of odor‐identification and that these areas would include primary as well as secondary olfactory structures. We combined functional magnetic resonance imaging (fMRI) with an olfactory detection task to investigate the neural substrates underlying odor identification.MethodTwenty‐five healthy controls and eighteen MCI subjects (Table 1) took part in an olfactory fMRI odor detection task. The task required subjects to press a button with their right index finger to identify an odorant (i.e., oddball) from a list of distractors. An out of magnet olfactory identification and threshold test was also conducted. This multiple‐choice test was used to measure a participants’ ability to identify twenty different odors.ResultA contrast of HC>MCI, for all odor conditions, yielded activation in brain regions shown in Figure 1C. These regions were used in a subsequent correlation analysis. The left supramarginal gyrus was included based on a study where the TPJ area (which includes parts of the supramarginal and superior temporal gyrus) was highly active in the left hemisphere. A correlation analyses using both HC and MCI showed significant positive correlations between activity in the L supramarginal, L superior temporal, L TPJ and L inferior frontal orbital areas, and out‐of‐magnet olfactory identification scores (Figure 2).ConclusionOur novel fMRI task elicited robust activation in higher‐order olfactory structures. Since Lower activation in these regions correlated with lower ID scores across the entire cohort. HC shows greater activity in higher order brain regions, suggesting an impaired top‐down identification mechanism in MCI. There seems to be a separation between HC and MCI in Figure 2. This will be further investigated using a larger sample size.
Associations among Neurofilament light chain (NfL), Depressive Symptoms and Cognition in autosomal dominant Alzheimer´s disease
Authors: Aguillon David Fernando , Vasquez Daniel , Baena Ana Y , Vila‐Castelar Clara , Acosta‐Baena Natalia , Garcia Gloria , Giraldo‐Chica Margarita M. , Tirado Victoria , Muñoz Claudia , Guzman Claudia F , Martinez Jairo E. , Giudicessi Averi , Langella Stephanie , Lopera Francisco , Gatchel Jennifer R. , Quiroz Yakeel T. 
Published: January 2025

AbstractBackgroundDepressive symptoms are associated with neurodegeneration in individuals at increased risk for late‐onset Alzheimer’s disease, but these relationships are less clear in younger individuals and those at risk for autosomal dominant Alzheimer’s Disease (ADAD). Neurofilament light chain (NfL) is a biomarker of axonal damage and neuronal degeneration that becomes abnormal several decades before clinical onset in ADAD. To address this gap, we investigated the associations among depressive symptoms, plasma NfL and cognition in a younger cohort affected by the PSEN1‐E280A genetic variant. Carriers of this variant usually develop dementia by their 50s.MethodA total of 677 carriers (574 cognitively unimpaired and 103 cognitively impaired) and 620 non‐carriers (median age 32 [Interquartile range IQR 24‐42], 55% women, 8 median education years [IQR 4‐11] from the Colombian kindred with ADAD due to the PSEN1‐E280A mutation were included. Participants underwent a neuropsychological evaluation, which included the Mini‐Mental State Examination (MMSE), a Spanish version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) word list learning test (WLL), the 15‐item Geriatric Depression Scale (GDS), and the Functional Assessment Staging Test (FAST) to assess functional independence. Mann‐Whitney‐Wilcoxon test was used to examine group differences, and Spearman’s correlations were used to investigate associations among depressive symptoms, NfL and cognition.ResultCompared to non‐carriers, carriers had higher levels of NfL (carriers=10.98, IQR 5.34‐13.44; non‐carriers=7.41, IQR 4.68‐8.90, p<0.001). There were no group differences in depressive symptoms (carriers =3.44, IQR 1‐5; non‐carriers=2.73, IQR 1‐4, p=0.19). In carriers, higher NfL levels were associated with higher GDS scores (r=0.093; p<0.001). Higher GDS scores were associated with lower MMSE scores (r= ‐0.18; p<0.001) and poorer CERAD WLL performance (r=‐0.17; p<0.001).ConclusionOur study showed that higher NfL plasma levels are associated with higher levels of self‐reported depressive symptoms in individuals with ADAD. These findings support neurodegenerative pathology underlying neuropsychiatric symptoms in ADAD and that these relationships can be detected using plasma measures. Future longitudinal analyses, examining other pathological mechanisms, and GDS‐items are needed to understand these symptoms more clearly in individuals with ADAD and whether they may be useful targets for AD prevention efforts.
The association between IGF‐1 plasma levels and Alzheimer's disease in the Alzheimer’s Disease Neuroimaging Initiative study
Authors: Ross Jermaine , Cha Yoonjeong , Kagalwala Mohamedi 
Published: January 2025

AbstractBackgroundInsulin‐like Growth Factor‐1 (IGF‐1) and its receptor (IGF‐1R) are known to play a role in biological aging. Several studies have explored the correlation between serum levels of IGF‐1 and Alzheimer's‐related dementia (AD). However, conflicting reports exist regarding whether elevated or reduced IGF‐1 levels increase the risk of AD. The focus of this study is to investigate the relationship between IGF‐1 and AD participates in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.MethodsWe analyzed calculated readouts from biomarkers assessed in the study performed by Biomarkers Consortium Plasma Proteomics Project and made available in the ADNI online repository. The study analyzed plasma samples taken from ADNI participants at baseline and 12 months after enrollment. The samples were processed using a 190‐analyte multiplex immunoassay panel, which included a plasma readout for IGF‐1, measured in ng/mL for all 556 subjects. A Cohen's kappa value was calculated to determine an optimal cutoff for distinguishing AD cases compared to controls. A standard t‐test was performed to assess significance between groups.ResultAt baseline, univariate analysis using a t‐test revealed a significant increase in IGF‐1 plasma levels in AD subjects compared to cognitively normal controls (p < 0.05). We also observed higher IGF‐1 levels in mild cognitive impairment (MCI) subjects compared to controls (p < 0.05). There was no significant difference between MCI and AD subjects. These findings are consistent with previous reports showing higher levels of IGF‐1 in animal models of AD, including transgenic mice expressing mutant human amyloid precursor protein and presenilin‐1. The optimal cutoff that maximizes Cohen's Kappa is >9.8 ng/mL of IGF‐1. In contrast, we did not observe any notable difference in IGF‐1 levels in either AD vs normal or MCI vs normal comparisons after 12 months, suggesting a potential temporal nature of the biomarker.ConclusionsIn this study, we found a significant but transient relationship between IGF‐1 and Alzheimer’s‐related dementia. Given current focus on the development of blood‐based biomarkers, these results highlight a putative biomarker for stratifying Alzheimer’s risk, but additional work is required to understand the temporal aspect of IGF‐1 during disease progression.