bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of cardiovascular comorbidities to Alzheimer’s Disease (AD) among older adults with low plasma AD biomarker level
Authors: Gu Yian , Bahl Aanya , Honig Lawrence S. , Kang Min Suk , Mayeux Richard 
Published: January 2025

AbstractBackgroundThere has been a great advancement in clinical application of blood‐based biomarkers of Alzheimer’s Disease (AD) over the past years. We aimed to examine whether cardiovascular comorbidities may contribute to clinical cognitive impairment in individuals with low level of these biomarkers.MethodThe current cross‐sectional study included 969 elderly [562 cognitively unimpaired, 407 cognitive impairment (104 amnestic MCI and 303 AD)] participants of the Washington Heights, Hamilton Heights, and Inwood Columbia Aging Project (WHICAP) study. We used Quanterix SIMOA HD‐X platforms to measure phosphorylated Tau‐181 (P‐tau181), total (T‐tau), Amyloid beta (Aβ) 40, Aβ42, Glial Fibrillary Acid Protein (GFAP), and Neurofilament Light Chain. Individuals were characterized as ‘biomarker positive’ or ‘biomarker negative’ based on combined GFAP and P‐tau181/Aβ42 cut scores. Clustering of cardiovascular comorbidities was defined as the total number of conditions including diabetes, hypertension, heart disease, and stroke. The association between the cardiovascular comorbidities and cognitive impairment was examined using logistic regression, adjusted for age, sex, ethnic group, and years of education.ResultAmong individuals with 0 ‐ 4 cardiovascular comorbidities, 20%, 43%, 42%, 52%, and 70% had cognitive impairment, respectively (p<0.001). Individuals with more cardiovascular conditions were more likely to be Hispanics, but not different in biomarker positivity status, sex, age, or education. Based on GFAP and P‐tau181/Aβ42, 188 (19.4%) were biomarker positive. As expected, being biomarker positive was associated with higher odds (OR=2.0, 95%CI=1.3‐3.2, P=0.002) of having cognitive impairment, after adjusting for age, sex, ethnic group, and years of education, and comorbidities score. Still, 37% of the 781 biomarker negative individuals had cognitive impairment. We further found that among these biomarker negative individuals, having more comorbidities (OR=1.40, 95%CI=1.02‐1.92, P=0.035) was associated with higher odds, while education was associated with lower odds (OR=0.80, 95%CI=0.75‐0.85, P<0.001), of having cognitive impairment. No association of comorbidity and cognitive impairment (OR=1.2, 95%CI=0.68‐2.15, P=0.52) was found in biomarker positive individuals.ConclusionPlasma AD‐related biomarkers were associated with clinical cognitive impairment. Older adults with low level of AD biomarkers may still be at risk of developing cognitive impairment if they have high burden of cardiovascular comorbidities.
Short‐term Sirolimus Treatment Restores Hippocampus and Caudate Volumes and Global Cerebral Blood Flow in Asymptomatic APOE4 Carriers Compared with Non‐carriers
Authors: Flemister Abeoseh , Xing Xin , Overschmidt Jessica , Cassani Joanne , Green Stefan J. , Beversdorf David Q. , Woods Carter , Grinstead John W. , Altes Talissa A. , Lin Ai‐Ling , Govindarajan Maalavika 
Published: January 2025

AbstractBackgroundApolipoprotein ε4 allele (APOE4) is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). Compared with non‐carriers, cognitively normal APOE4 individuals have shown brain atrophy and lower cerebral blood flow (CBF) decades before AD pathological and clinical symptoms appear. The goal of the study is to determine if using Sirolimus, an FDA‐approved mTOR inhibitor, could restore the brain volumes in structures related to cognitive functions and global CBF (gCBF) for asymptomatic APOE4 carriers compared with non‐carriers.MethodThe study was performed at the University of Missouri. Low dose Sirolimus (1 mg/day) was given for 4 weeks to three middle‐aged, cognitively normal APOE4 carriers (F:M = 2:1) and two female APOE3 individuals (45‐65 yrs; MOCA > 27). Oral swabs were used to determine APOE status. 3T MRI‐based structural MPRAGE and T1‐weighted images, and pseudo‐continuous arterial spin‐labeled (PCASL, 1.7x1.7x4mm resolution) were acquired at baseline (pre‐treatment) and Post‐Sirolimus (the end of treatment). FreeSurfer 7.4 was used to automatically generate segments for volumetric analysis and PCASL images were analyzed via MANGO software for perfusion weighted gCBF.ResultAPOE4 carriers had significantly increased Caudate and Hippocampal volumes (Figure 1A) and gCBF (Figure 1B) after 4 weeks of Sirolimus treatment. These differences were not found in the non‐carriers (APOE3 participants). The quantitative data is shown in Table 1. It also shows that APOE4 carriers had significantly lower Hippocampal volume and gCBF at baseline compared with that of APOE3 participants (indicated by “**”), and Sirolimus tends to restore the values to closer to those of the non‐carriers. No side effects were observed, and no changes in blood glucose and HbAc1 levels were found in all the participants.ConclusionWe show that short‐term Sirolimus treatment can effectively restore brain volumes and gCBF for asymptomatic APOE4 carriers. Specifically in the caudate and hippocampus, which play many roles integral in normal cognitive functioning including memory, learning, and emotional regulation, has considerable atrophy in AD. The findings imply that Sirolimus may be useful and effective to mitigate or prevent AD developments for asymptomatic APOE4 carriers.
Connectomic differences in cognitively normal APOE4 versus non‐APOE4 carriers at risk for Alzheimer’s Disease
Authors: Stout Jacques Andrew , Mahzarnia Ali , Moon Hae Sol , Han Zay Yar , Johnson Kim G , Badea Alexandra 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) causes a steady degradation of connections inside the brain. The apolipoprotein E is a protein where one of its subtypes, APOE4, is a major genetic risk factor for developing late onset AD. Using a combination of tensor network PCA (TN‐PCA) and bundle analysis, we sought to determine which specific connections differentiate APOE4 individuals relative to non‐APOE4 carriers, and whether these changes increase with age.MethodOur study included 77 individuals from 20 to 83 years old, 37 male and 40 female, 41 possessing only the APOE3 allele and 36 with at least one APOE4 allele. Imaging was done using diffusion weighted imaging, with a T1w anatomical scan also obtained for atlas based labeling and co‐registration. The tracts were modeled in subject space using mrtrix with anatomically constrained tractography and brought into the same template image space using our SAMBA registration pipeline. Connectomes of number of streamlines and the average FA were calculated with mrtrix. FA connectomes were used with TN‐PCA, determining which connections had higher weight for separating the genotype groups between APOE3 and APOE4. Streamlines of specific connections were split into bundles using dipy quickbundles. Statistical analysis compared linear and quadratic models for age, genotype and the interaction of the two.ResultTN‐PCA results indicate that connections of precuneus to other structures had an important weight in APOE3 to APOE4 differentiation, particularly their inter‐hemispheric connection, their connection to the superior‐parietal region. Linear modeling showed the FA of precuneus connected streamlines had noticeable differences between APOE3 and APOE4 groups. These differences were exacerbated in specific bundles: precuneus‐right to precuneus‐left, and precuneus‐left to superiorparietal‐left connection.ConclusionOur results indicate that the precuneus connections differentiate between APOE4 and non‐APOE4 carriers. Future studies will address separately the white matter and grey matter streamline sections, and we will add further analysis along the streamlines for increased specificity.
Inflammation links in Alzheimer’s Disease: connecting fluid proteomics and TSPO PET
Authors: Pola Ilaria , Ashton Nicholas J. , de Bastiani Marco Antônio , Brum Wagner Scheeren , Rahmouni Nesrine , Servaes Stijn , Stevenson Jenna , Tissot Cécile , Therriault Joseph , Pascoal Tharick A. , Blennow Kaj , Zimmer Eduardo R. , Zetterberg Henrik , Rosa‐Neto Pedro , Benedet Andrea L. 
Published: January 2025

AbstractBackgroundEmerging evidence underscores the importance of neuroinflammation in the progression of Alzheimer’s disease (AD) pathophysiology. Recent studies indicate the involvement of the inflammatory mechanisms both in amyloid‐ β (Aβ) and tau deposition in the brain. Nevertheless, due to the complexity of the immune responses and the intricate interplay between the peripheral and the central nervous systems, identifying biomarkers that reflect the brain´s inflammatory state in AD has been a challenge. For this reason, the characterization of immune‐related proteins in cerebrospinal fluid (CSF) and plasma would contribute to the understanding of the role of neuroinflammation in the progression of AD.MethodParticipants from the Translational Biomarker for Aging and Dementia Cohort (TRIAD) incorporating within the AD spectrum, and with available amyloid Aβ ([18F]AZD4694), tau ([18F]MK6240) and TSPO ([11C]PBR28) PET data (positivity = 2.5 SD > mean ROI‐SUVR of young participants), had plasma (n= 151) samples analyzed with the NULISA technology (Alamar Biosciences®). Inflammation‐related proteins (n=72) were selected and included in our analysis, which differential expression was evaluated with linear models (LIMMA) contrasting TSPO groups. After FDR correction for multiple comparisons, the differentially expressed proteins were selected for further analysis, where protein levels were correlated with the PET uptake of 45 anatomical brain regions.ResultThe differential expression analysis unveiled 5 proteins that are in higher concentrations in the plasma of TSPO positive in comparison with TSPO negative participants (Figure 1): GFAP, CHI3L1, CST3, FABP3, and CHIT1. The correlation analysis between the plasmatic proteins and PET uptake showed significant overlapping correlations with TSPO, Aβ and tau PET in brain regions such as inferior frontal gyrus, inferior occipital gyrus and amygdala (Figure 2).ConclusionThese preliminary findings underscore the relevance of GFAP, CHI3L1, CST3, FABP3, and CHIT1 at proxying immune‐related processes in AD, by linking peripherally quantified proteins to brain pathology, as suggested by the colocalized correlations with amyloid, tau and TSPO PET uptake. Further replication of this analysis on the CSF proteomic data of these participants will support the potential significance of these proteins as valuable indicators of neuroinflammation in AD pathology.
Compression and expansion in the aging brain is associated with clinical and cognitive outcomes
Authors: Adams Jenna N. , Escalante Yuritza Y , Yassa Michael A. , Janssen Niels 
Published: January 2025

AbstractBackgroundThe brain undergoes structural changes during aging, such as gray matter loss, enlarged ventricles, and sulcal widening. However, previous studies have primarily investigated these changes in isolation, without describing the complex spatial relationships between overall brain shape and regions. Here, we tested how gradients of expansion and compression of the global shape of the brain as well as between homologous brain regions across hemispheres are affected by age, and whether these changes further contribute to clinical impairment and cognitive deficits in older adults.MethodWe analyzed 2,039 structural MRIs from the Open Access Series of Imaging Studies (OASIS) dataset (42‐97 years; 56%F). MRIs were preprocessed using Freesurfer version v6.0. Gradients of whole‐brain expansion and compression were quantified by placing equally spaced points on the outer cortical surface (n=400) along inferior‐superior and anterior‐posterior directions (Figure 1A). To assess regional changes, we measured the Euclidean distance between left and right hemisphere homologues (Figure 1B). Age effects were evaluated continuously and by comparing groups of increasing age to a young control group (42.7‐59.9 years). Clinical impairment was defined as a Clinical Dementia Rating (CDR) >0, and neuropsychological testing were used to probe cognitive deficits.ResultIncreasing age was associated with global expansion in inferior‐anterior regions and with compression in posterior‐superior regions (Figure 2A). Cross‐hemisphere distances between regional homologues showed a progressive pattern of expansion in subcortical and medial/lateral temporal lobes and compression in posterior parietal areas across increasing age groups (Figure 2B). Controlling for age, these patterns were exacerbated in clinically impaired older adults (CDR>0) and related to episodic memory and executive function scores in a regionally‐specific manner (Figure 3). Global and regional results replicated in an independent sample of older adults (Cambridge Centre for Ageing and Neuroscience dataset; N=564, 30‐88 years, 51%F).ConclusionDuring aging, the overall shape of the brain undergoes patterns of expansion within inferior‐anterior and subcortical regions, and compression within superior‐posterior regions, that further contribute to clinical impairment and cognitive deficits. This suggests that changes to the complex spatial anatomy and geometry of the aging brain may impact its ability to function efficiently and lead to cognitive dysfunction in older adults.
Longitudinal change of cerebral amyloid and tau and its association with plasma biomarkers in preclinical Alzheimer's disease
Authors: Fajardo Alfonso , Yakoub Yara , Rudolf Jonathan Gallego , Remz Jordana , Soucy Jean‐Paul , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Breitner John C.S. , Poirier Judes , Villeneuve Sylvia ,   PREVENT‐AD Research Group
Published: January 2025

AbstractBackgroundFor medical purposes, amyloid‐beta (Aβ) and tau biomarkers are typically dichotomized into positive (+) and negative (‐) status to define individuals with Alzheimer’s disease (AD) pathology. Nevertheless, such AD proteinopathies start accumulating years before reaching clinically‐defined abnormality thresholds. We examined longitudinal change in PET Aβ and tau in cognitively unimpaired (CU) individuals; then we explored their baseline plasma levels and demographic characteristics. Finally, we assessed the association between plasma/demographics and annual rate of change (aRC) of AD pathology.MethodWe included 110 CU participants from the PREVENT‐AD cohort who underwent longitudinal Aβ and tau PET scans (mean time between scans = 4.33 years, 0.44 SD). We created four accumulator groups: 1) a non‐accumulators group, 2) an Aβ‐only group which included individuals classified as Aβ+ at baseline (SUVr threshold of 1.25, 18 CL) plus those with an Aβ aRC > 2.19 CL, 3) a tau‐only group which included individuals classified as tau+ at baseline (2 SDs above the mean of young participants, SUVr=1.23) plus those with a temporal meta‐ROI aRC > 0.022 (a GMM‐derived cut‐point), and 4) an Aβ & tau accumulator group. We then compared demographic characteristics and baseline plasma biomarker levels of Aβ42/40, GFAP, NfL, pTau181 and pTau217 across the four groups. Finally, we fitted linear regression models to predict Aβ/tau aRC as continuous variables from demographics or baseline plasma, including age and sex as covariates.ResultsAβ accumulator groups included a higher proportion of APOE4 carriers (Table 1). Compared to non‐accumulators or tau‐only accumulators, Aβ‐only accumulators and Aβ & tau accumulators showed higher baseline plasma levels of NfL and GFAP. When aRC was treated as a continuous value, APOE4 status and age were positively associated with higher rate of Aβ accumulation. Finally, higher baseline GFAP levels were associated with faster accumulation of both Aβ and tau in the brainConclusionsAPOE4 status, increased age and plasma GFAP levels were closely related to faster Aβ aRC. Higher plasma GFAP levels were further associated with faster tau aRC. Therefore, GFAP might be an indicator of AD pathophysiological processes.
Inflammation in the white matter relates to core Alzheimer's disease pathophysiological processes
Authors: Ottoy Julie , Kang Min Su , Yin Eric , Rahmouni Nesrine , Stevenson Jenna , Soucy Jean‐Paul , Benedet Andrea L. , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Gauthier Serge , Black Sandra E , Rosa‐Neto Pedro , Goubran Maged 
Published: January 2025

AbstractBackgroundIn‐vivo PET imaging studies have demonstrated neuroinflammation (microglia reactivity) in the neocortex of Alzheimer’s disease (AD) patients. However, the extent and implication of microglia reactivity in white matter regions remains unclear. Here, we explored microglia reactivity in white matter using PET imaging of the translocator protein (TSPO) in relation to core AD biomarkers (amyloid, tau, and astrogliosis), microstructural damage, and cognitive decline.MethodNinety‐one participants from the Translational Biomarkers in Aging and Dementia cohort (45% Aβ‐positive, 39% cognitively impaired) underwent diffusion‐weighted MRI, TSPO‐PET (11C‐PBR28), amyloid‐PET (18F‐NAV4694), tau‐PET (18F‐MK6240), and plasma Aβ42/40, ptau181, ptau217, and ptau231. We investigated the associations of TSPO‐PET SUVR in white matter lobes (eroded by 2mm3) with each of the AD biomarkers, diffusion metrics, and cognition, adjusted for demographics and global cortical TSPO‐PET. Longitudinally, we investigated the interaction between time (up to 2y) and baseline white matter TSPO‐PET SUVR on cognitive decline, adjusted for demographics and cortical amyloid.ResultWhite matter TSPO‐PET was increased globally with older age and frontally with male sex (p<0.05). In impaired individuals, TSPO‐PET was elevated in temporo‐occipital white matter regions compared to controls (p=0.01‐0.02). The occipital increases were associated with reactive astrogliosis (p=0.011) and higher‐Braak tau‐PET (p=0.003‐0.034 for Braak3‐4) and plasma ptau181 (p=0.014) (Figure 1A‐B), but not with Aβ, ptau231 or ptau217. In addition, higher occipital TSPO‐PET was associated with lower fibre integrity (fractional anisotropy, p=0.025) but not free water. Finally, in relation to cognition, higher occipital and parietal TSPO‐PET was significantly associated with impaired memory and language, respectively, independent of Aβ (Figure 1C). Longitudinally, within the same patient, higher white matter TSPO‐PET at baseline was significantly associated with favorable clinical outcome over time (Figure 1D).ConclusionIncreased microglia reactivity (TSPO‐PET) in posterior white matter may indicate later‐stage AD associated with astrogliosis, tau, and dysfunction of the memory and language domains. Another novel finding is that individuals with higher white matter TSPO‐PET at baseline displayed better clinical prognosis over time. As such, assessing white matter inflammation could be promising to evaluate target engagement in clinical trials of anti‐inflammatory drugs and to subtype patients for better patient‐centric treatment outcome.
MRI findings in a dementia center from Recife, Brazil: applicability of the Fazekas’ score
Authors: Neto Francisco Sabino de Oliveira , Calixto Lucas Henrique , Soares João Pedro Wanderley , Arteiro Pedro Jatobá , Gondim Alice Batista , Araújo Luziany Carvalho , Barbosa Breno José Alencar Pires 
Published: January 2025

AbstractBackgroundData about dementia in Brazil are scarce and subnotified. Until 2018, 1,3 million people were estimated to have been affected. neuroimaging has a crucial importance to provide detailed information about cerebral structures and characteristics patterns of different types of dementia even as the progression of these injuries. One of the most used imaging scales since 1987 is the Fazekas’ scale, which graduate the lesions according to their distribution in cerebral parenchyma. we aimed to analyze the encephalon’s MRI from patients that are in outpatient follow‐up and caracterize main radiology white matter findings.MethodIt’s a transversal, retrospective and descriptive study about long‐sufferings which were in outpatient between 2017 and 2022 in a North East reference service. Were selected those which the MRI has been done in this service and evaluated by a neuroradiologist using the HORUS™ image analysis software, determining radiologic patterns using Fazekas’ scaleResultAmong ninety‐nine medical records evaluated, there were 26 CT Scans, 15 PET‐CT and 76 MRIs. From this exams, only 35 patients had MRI scans at this service. Two patients were excluded from the study because of the incomplete sequences, with no possibility of evaluation. About the 33 remaining patients, 3 of them had incomplete image sequences, but with an evaluable flair. The mean age was 64.9 years old (+/‐ 12.9), which 57% were female. About the associated comorbities, there were 18 cases of Hypertension (ASH), 4 of diabetes mellitus (DM), 9 of alcoholism and 10 of smoking. The Fazekas Score in these patients were: 0 in 2 patients, 1 in 14 patients, 2 in 9 patients and 3 in 8 patientsConclusionAlthough it’s an old instrument, the Fazekas’ scale is still an actual and with considerable applicability way to graduate lesions in patients with dementia and risky factors using of a simplified way.
Acute Aβ12‐28P administration targeting apoE/Aβ interaction rescues synaptic function and cognitive decline in advanced‐stage Alzheimer’s disease
Authors: Chen Shuo , Lam Nikolas , Li Zhiheng , Wang Ding , Liu Pengfu , Berbano Victoria , Xie Yu , Nguyen Tyra , Xu Yvonne , Yang John , Ha Karen , Semana Leonardo , Dias Rachel , Masurkar Arjun V. , Wisniewski Thomas 
Published: January 2025

AbstractBackgroundApolipoprotein E4 (apoE4) has been identified as the major genetic risk factor for late onset Alzheimer’s disease (AD). Our lab has demonstrated that chronic administration of Aβ12‐28P, a synthetic peptide that blocks apoE4/Aβ binding, in middle‐aged transgenic AD mice significantly ameliorates pathology progression, resulting in reduced Aβ plaques deposition and cerebral amyloid angiopathy (CAA) along with improved memory and cognition. However, whether blocking apoE4/Aβ interaction by Aβ12‐28P also has an ameliorating effect on the neuronal and cognitive function of old AD mice where Aβ pathology has been extensively developed remains unknown.MethodGeriatric SwDI/APOE4 mice (18‐24 months old) were intraperitoneally injected daily with Aβ12‐28P, while control mice received only saline. Behavioral tests including anxiety in open field, locomotor activity, T‐maze, object recognition, and radial arm maze were performed 2 hours post‐injection to assess the acute effect of Aβ12‐28P. After 3 weeks of behavioral testing with daily treatment, acute hippocampal slices were prepared and subjected to in vitro physiology experiments to evaluate long‐term potentiation (LTP) of Schaffer collateral input to CA1. On the recording day Aβ12‐28P or saline was injected 2 hours before slice preparation.ResultAcute Aβ12‐28P treatment resulted in significant cognitive improvement. While the treated mice did not show differences in locomotor activity, significantly enhanced cognitive performances were observed, including improved performance in one‐day T‐maze test (n = 10/group, p = 0.0005), one‐day novel object recognition test (n = 6/group, p = 0.018), and multiple‐days radial arm maze test (n = 8‐9/group, p = 0.0008). Aβ12‐28P administration also significantly reduced anxiety in open field (n = 6/group, p = 0.0081). We further compared the hippocampal Schaffer collateral LTP in slices from Aβ12‐28P‐treated versus non‐treated mice. Slices from the treated animals showed significantly enhanced LTP (n = 9‐10/group, p < 0.0001), suggesting rescued synaptic plasticity.ConclusionThese results suggest that acute Aβ12‐28P administration blocking apoE/Aβ binding rescues synaptic plasticity and cognitive decline in old AD mice where extensive Aβ pathology has been developed. Our finding opens the possibilities to apply the strategy of targeting apoE/Aβ interaction for alleviating advanced‐stage AD symptoms in addition to ameliorating Aβ deposition during AD progression.