bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic predisposition to Alzheimer’s disease is differentially associated with joint volumetric variations in the disease continuum
Authors: Genius Patricia , Calle Maria Luz , Cacciaglia Raffaele , Evans Tavia E , Falcon Carles , Minguillón Carolina , Adams Hieab H.H. , Esteller Manel , Navarro Arcadi , Gispert Juan Domingo , Vilor‐Tejedor Natalia 
Published: December 2023

AbstractBackgroundImaging genetics studies commonly assess the individual association between genetic information and brain features without considering joint brain modulations. The aim of this study was to explore the structural variation of the brain at different stages of Alzheimer’s disease (AD), depending on the genetic predisposition to AD.MethodA total of 351 cognitively unimpaired (CU) middle‐age participants from the ALFA (Alzheimer’s and FAmilies) study and 330 cognitively impaired participants from ADNI (Alzheimer’s Disease Neuroimaging Initiative) with magnetic resonance imaging scans, genetic information and CSF‐amyloid status were included. They were classified as CU Aβ‐, CU Aβ+, (mild cognitive impairment) MCI Aβ+ and AD Aβ+[Table 1]. Freesurfer was used to obtain cortical and subcortical parcellations using the Desikan‐Killiany atlas. A polygenic risk score estimating each participant’s genetic predisposition to AD (PRS‐AD) was calculated including genetic variants at the genome‐wide suggestive level (5×10‐6). Individuals were classified into high/low genetic predisposition groups. Statistical analysis was based on compositional data analysis. First, we computed the optimal multivariate brain structural variation signature (elastic net selection). Then, a logistic regression was performed to determine the association between the optimal signature and the PRS‐AD. Models were stratified by disease stage and adjusted for age and sex.ResultIndividuals at different stages on the AD continuum displayed different brain volumetric modulations associated with higher genetic predisposition to AD [Figure 1]. For instance, the optimal signature associated with an increased risk of AD was mainly characterized by increased hippocampal volumes in Aβ‐ individuals, but decreased volumes in MCI individuals along with the modulation of other temporal regions. Moreover, in AD patients at higher genetic predisposition of AD, the optimal signature was characterized by increased and decreased volumes in frontal regions (e.g. pars triangularis, lateral orbitofrontal vs. medial orbitofrontal, respectively) [Figure 2].ConclusionResults showed AD stage‐specific multivariate volumetric variation associated with an increased genetic risk of AD. Main results suggested that regions that modulated together, although differing according to AD stage, were implicated in the structural brain topology of specific memory networks. The analysis of the joint volumetric variation of brain subregions brings an innovative modeling perspective for neurogenetic studies of AD.
Aging and Alzheimer’s Disease Have Dissociable Effects on Local and Regional Medial Temporal Lobe Connectivity
Authors: Hrybouski Stanislau , Das Sandhitsu R. , Xie Long , Wisse Laura EM , Kelley Melissa , Lane Jacqueline , Sherin Monica , DiCalogero Michael , Nasrallah Ilya M. , Detre John A. , Yushkevich Paul A. , Wolk David A. 
Published: December 2023

AbstractBackgroundThe extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional disruption of the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity (FC) alterations between anterior and posterior regions of the MTL and in MTL‐associated functional communities – the Anterior‐Temporal (AT) and Posterior‐Medial (PM) networks – in normal agers, individuals with preclinical AD, and patients with Mild Cognitive Impairment or mild dementia due to AD.MethodIn this cross‐sectional study, we analyzed data from 179 individuals from the Aging Brain Cohort study of the Penn ADRC. Detailed information about participants is provided in Table 1. For intra‐MTL FC comparisons, the MTL subregions were segmented using the automated segmentation of hippocampal subfields‐T1 (ASHS‐T1) pipeline (Fig. 1a). When modeling the MTL’s interactions with the rest of the cortex, we employed four MTL ROIs (left/right × anterior/posterior) derived from an ex vivo atlas of tau accumulation in the MTL. Our functional datasets were preprocessed using a customized fMRIprep pipeline. Sparse network estimations and modularity‐based consensus clustering were used to reconstruct the AT and PM network systems (Fig. 1b). Age effect analyses and group comparisons along the AD continuum were performed using the General Linear Model within the network‐based statistical framework.ResultThe preclinical stage of AD was characterized by increased FC between the perirhinal cortex and other regions of the MTL, as well as between the anterior MTL and its direct neighbors in the AT network (Fig. 1c‐d). This effect was not present in symptomatic AD. Instead, symptomatic patients displayed reduced hippocampal and intra‐PM connectivity. For normal aging, our results led to three main conclusions (for visuals, see Fig. 2). First, intra‐network connectivity of both the AT and PM networks decreases with age. Second, FC between the anterior and posterior segments of the MTL declines with age. Finally, within the MTL, we observed greater vulnerability of the posterior MTL subregions, particularly the parahippocampal cortex, to age‐associated FC decline.ConclusionTogether, the current results provide evidence for aberrant connectivity in the preclinical stage of AD that may have implications for early AD pathophysiology.
Brain Volumetry‐based Amyloid PET Positivity Prediction in Subjective Cognitive Decline Patients
Authors: Jung Wooseok , Yang Dong Won , Lee Chunghwee , Hong Yun Jeong , Ho SeongHee , Jeong Jee Hyang , Park Kee Hyung , Kim SangYun , Wang Min Jeong , Choi Seong Hye , Lee Dongsoo , Kang Junghyun , Kim Jinyoung , Lee Yeha 
Published: December 2023

AbstractBackgroundAmyloid beta PET screening for subjective cognitive decline (SCD) patients would identify a risk factor of Alzheimer’s disease (AD) at an early stage but is generally infeasible due to the high cost and radiation exposure. Brain volumetry using 3D T1 MRI integrated with genetic information can alternatively suggest amyloid positivity in SCD subjects.MethodIndividuals of age between 60 and 85 feeling cognitive decline and scoring 7% to 50% on the memory test while exceeding 7% of the other tests comprises the SCD dataset via Seoul Neuropsychological Battery (SNSB) scheme (n = 119; 26 Aß+; 24 APOE4+). We measured the volume, volume to intracranial volume ratio, cortical thickness and their normative percentiles of 104 brain subregions, respectively, using VUNO‐Med DeepBrain, an automated brain volumetry and neurodegenerative disease diagnosis‐supporting software. The significance level is set to a = 0.005 to find differentiating regions between amyloid positive and negative groups. Furthermore, four machine learning models (Logistic Regression, Random Forest, XGBoost, TabNet) were trained using the combination of APOE4 information, age, and each of the six different volumetry results to predict amyloid positivity in SCD dataset. The training dataset (n = 102; 36 Aß+; 31 APOE4+) consists of subjects from significant memory concern (SMC) cohort of ADNI2 and ADNIGO studies.ResultSwell of the choroid plexus and shrink of the lingual cortex (both p < .005) are statistically significant in Aß+ SCD patients compared to the Ab‐ patients. The random forest model trained by the volume data plus APOE4 and age information showed the highest performance (accuracy = 0.79, AUROC = 0.75, precision = 0.81, recall = 0.79, F1 = 0.80) in the amyloid positivity prediction task among the 24 models, higher than the model without APOE4 information (accuracy = 0.70, AUROC = 0.71, precision = 0.77, recall = 0.70, F1 = 0.72).ConclusionThe result indicates a statistically significant difference in choroid plexus volume and lingual cortex thickness between Aß+ and Aß‐ SCD patients. In addition, using both APOE e4 information and brain volumetry is crucial for amyloid positivity prediction. This study was supported by a grant from the Ministry of Health and Welfare, HI18C0530.
Intergenerational Social Mobility, Brain Structure, and Cognitive Trajectory: Findings from the Whitehall II Study
Authors: Liu Yingxu , Liu Yinghao , Cui Yuehua , Thyreau Benjamin , Zhang Ye , Taki Yasuyuki , Chen Honglei 
Published: December 2023

AbstractBackgroundPrevious studies on the effects of intergenerational social mobility on cognitive outcomes were not consistent, additionally, underlining brain anatomical variation is unclear. In the present study, we aim to examine the associations of social mobility with brain structure and cognitive trajectories in older adults.MethodThe study included 771 participants, ages 69.8 ±5.2 years, of the Whitehall II ‐ MRI substudy (2012‐2016) with data on their father’s occupation, their own occupation in mid‐life, lifestyle (smoking, drinking, physical activity, social activity, sleep disturbances, auditory difficulty, depression, obesity, hypertension), neuroimaging (T1 structural MRI) and cognitive abilities (global cognition, crystallized cognitive ability, and fluid intelligence). Social mobility was classified into stable high social class, stable low social class, upward mobility and downward mobility group based on occupational shifts from father. We used the ANCOVA tests to assess the association of social mobility with gray matter volume (GMV) and cortical thickness (CT) in various brain regions, and the growth curve modeling (GCM) to evaluate its relations to cognition over 20 years, adjusting for social lifestyle covariates and associated GMV/CT regions identified above.ResultSocial mobility was significantly related to 48 out of the 136 regions of GMV across the frontal lobe, limbic lobe, and temporal lobe; and to 4 out of the 68 regions of CT at the whole‐brain level. Stable high social class preserved the largest GMV and CT value; pair‐wise results suggest upward mobility preserved a larger GMV value than the downward mobility group (average diff. in cm3: 0.121, P<0.05); and similarly a larger CT value (average diff. in cm:0.029, P = 0.051). In GCMs, stable high social class (ref. downward mobility) had a higher entry score of fluid intelligence (b = 2.617, P<0.05), all other comparisons including the entry score and decline rate of cognitive abilities were non‐significant.ConclusionOur results suggest a lack of direct association between social mobility and trajectories of global cognition and crystallized cognitive ability; instead, an indirect effect through preserving the value of brain GMV and CT may occur. Additionally, an adverse causal relationship between social mobility and fluid intelligence might happen.
In vivo tau deposition in the brain stem nuclei and circadian rest‐activity rhythm change in non‐demented older adults
Authors: Jeon So Yeon , Yi Dahyun , Byun Min Soo , Jung Joon Hyung , Kong Nayeong , Chang Yoon Young , Keum Musung , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young 
Published: December 2023

AbstractBackgroundCircadian rest‐activity rhythm (RAR) alterations are common in the early stage of Alzheimer’s disease (AD) disease. Given that the brainstem nuclei, the locus coeruleus (LC) and dorsal raphe nucleus (DRN) in particular, play key roles in modulating arousal and the sleep‐wake cycle, tau pathology in the brain stem nuclei, which occurs even before cortical tau progression, may relate to circadian RAR alteration in older individuals. Therefore, we aimed to test the hypothesis that in vivo tau deposition in the LC and DRN correlates with circadian RAR in non‐demented older adults.MethodA total of 63 non‐demented older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent [11C] PiB PET and [18F] AV1451‐PET. Circadian RAR variables were measured using actigraphy for 8 consecutive days. Tau deposition of the LC and DRN (LC‐tau and DRN‐tau, respectively) was measured in the regions of interest (ROI) masks for each participant prepared in native space using the Harvard arousal network atlas for the LC and DRN. For the purpose of comparison, tau deposition in the substantia nigra (SN‐tau) was also measured in the neuromelanin sensitive MRI‐based ROI for the SN.ResultIncreased LC‐tau and DRN‐tau were significantly correlated with delayed acrophase (ß = 0.303, p = 0.024 for LC‐tau and ß = 0.398, p = 0.003 for DRN‐tau; Table 1 & Figure 1). In contrast, SN‐tau did not related with any RAR variables. Even after controlling for global tau deposition, the significance did not changed (ß = 0.321, p = 0.021 for LC‐tau and ß = 0.367, p = 0.008 for DRN‐tau, Table 1). In addition, Aß positivity showed a significant moderation effect on the relationship between LC‐tau with acrophase. Subgroup analyses showed that increased LC‐tau significantly related with delayed acrophase in Aß‐positivegroup (ß = 0.427, p = 0.004), but did not in Aß‐negative group (ß = 0.099, p = 0.615)(Figure 2)ConclusionOur findings support the possibility that the tau pathology in the LC and DRN underlie circadian RAR alteration, more specifically delayed phase, in non‐demented older adults. In addition, such relationship appears to be more prominent in individuals with brain Aß pathology.
Gray to White Matter Signal Ratio as a novel biomarker of neurodegeneration in Alzheimer’s disease
Authors: Putcha Deepti , Katsumi Yuta , Brickhouse Michael , Flaherty Ryn , Salat David H , Touroutoglou Alexandra , Dickerson Brad C. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized neuropathologically by ß‐amyloid (Aß) plaques, hyperphosphorylated tau neurofibrillary tangles, and neurodegeneration which leads to a phenotypically heterogeneous cognitive‐behavioral dementia syndrome. Our understanding of how these neuropathological and neurodegeneration biomarkers relate to each other is still evolving. A relatively new approach to measuring structural brain change, gray matter to white matter signal intensity ratio (GWR), quantifies the signal contrast between these tissue compartments, and has emerged as a promising marker of AD‐related neurodegeneration. We sought to validate GWR as a novel MRI biomarker of neurodegeneration.MethodTwenty‐nine amyloid‐, tau‐, and neurodegeneration positive patients with atypical syndromes of AD (16 Posterior Cortical Atrophy, 10 logopenic variant of Primary Progressive Aphasia, and 3 Amnestic Dysexecutive phenotype) and 24 amyloid‐negative control participants underwent structural MRI, 11C‐Pittsburgh Compound B (PiB) PET, and 18F‐flortaucipir (FTP) PET scans. Whole‐cortex vertex‐wise general linear models (GLM) were created to identify areas of the cerebral cortex where AD patients showed abnormal signal in each modality, and Pearson’s correlation coefficients were computed to examine the strength of bivariate associations between each pair of modalities at the group level. We then constructed linear mixed‐effects models to test the relative contribution of each non‐FTP modality to explaining the variance in regional FTP uptake.ResultWe found that GWR was associated with cortical thickness, tau PET, and amyloid PET, with GWR showing a larger magnitude of abnormality than cortical thickness. We also found that combining GWR, cortical thickness, and amyloid PET better explained observed tau PET signal than using these modalities alone, suggesting that the three imaging biomarkers contribute independently and synergistically to explaining the variance in the distribution of tau pathology.ConclusionWe conclude that GWR is a uniquely sensitive in vivo marker of neurodegenerative change that reflects pathological mechanisms which may occur prior to cortical atrophy. By using all of these imaging biomarkers of AD together, we may be better able to capture, and possibly predict, AD neuropathologic changes in vivo, which we hope will ultimately contribute to better endpoints to evaluate the efficacy of therapeutic interventions as we move toward an era of disease‐modifying treatments for this devastating disease.
Social engagement, amyloid burden, and dementia: the Atherosclerosis Risk in Communities (ARIC)‐PET study
Authors: Groechel Renée C. , Liu Chelsea , Knopman David S. , Koton Silvia , Kucharska‐Newton Anna M. , Liu Albert C. , Lutsey Pamela L. , Mosley Thomas H. , Palta Priya , Sharrett Richey , Walker Keenan A. , Wong Dean F. , Gottesman Rebecca F. 
Published: December 2023

AbstractBackgroundAlthough amyloid deposition in the brain is often associated with subsequent dementia risk, not everyone with brain amyloid will develop dementia. This discrepancy illustrates the potential importance that risk factors and lived experiences may have in modifying this association. Compared to participants with low social engagement (SE) in mid‐life, we hypothesized that participants with high mid‐life SE will show a weaker association between amyloid burden and incident dementia.MethodWe included data from 310 non‐demented participants of the Atherosclerosis Risk in Communities (ARIC)‐PET study. Social support and isolation were assessed via interviewer‐administered questionnaires (Visit 2; 1990 – 1992). Based upon categorization of both factors, participants were classified as having high, intermediate, or low mid‐life SE (Table 1). Brain amyloid was evaluated with florbetapir PET (Visit 5; 2011‐2014). Elevated amyloid burden was defined as standardized uptake value ratio (SUVR) >1.2 in the global cortex. Incident dementia cases were identified from visit 5 through 2019 through ongoing surveillance utilizing in‐person neurocognitive testing, informant interviews, and hospitalization codes. Relative contributions of mid‐life SE and elevated florbetapir SUVR to incident dementia, independently and with multiplicative interaction terms, were evaluated with Cox regression models, adjusted for demographics, APOEe4 and vascular risk factorsResultAmong 310 participants, 48 developed dementia (median follow‐up: 4.7 years). Mid‐life SE and elevated SUVR each independently predicted dementia risk but did not interact on a multiplicative scale. Participants with high or intermediate mid‐life SE, relative to low mid‐life SE, were less likely to develop dementia (Table 2). Although the interaction between mid‐life SE and elevated SUVR was not significant, stratified models suggested a stronger association between amyloid burden and dementia in participants with high mid‐life SE (Table 3).ConclusionGreater mid‐life SE was associated with lower odds of developing dementia, independent of elevated SUVR. Although protective, there was no strong evidence for effect modification of mid‐life SE on the association between amyloid and dementia risk. Future longitudinal studies evaluating the potential influence of social factors measured throughout the life course are needed to inform our understanding as to what factors may preserve cognition in the presence of elevated brain pathology.
Stress system dysfunction and changes in brain volume and functional connectivity in older adults with subclinical depressive symptoms
Authors: Touron Edelweiss , de Flores Robin , Coulbaut Laurent , Palix Cassandre , Chocat Anne , Kuhn Elizabeth , Landeau Brigitte , Mézenge Florence , Roquet Daniel , Chauveau Léa , Haudry Sacha , Vivien Denis , la Sayette Vincent De , Marchant Natalie L , Chetelat Gael , Poisnel Géraldine 
Published: December 2023

AbstractBackgroundSubclinical depressive symptoms are associated with increased risk of Alzheimer’s disease (AD). This link could be related to stress system dysfunction, known to occur in both depression and AD, and to depend notably on the hippocampus which is particularly sensitive to AD. We aimed at investigating the links between levels of blood stress markers and changes in brain regions involved in the stress response in older adults with subclinical depressive symptoms.MethodCognitively unimpaired older adults with (DepS; n = 73) or without (NoDepS; n = 58) subclinical depressive symptoms (defined using the 15‐item version of the Geriatric Depression Scale), from the baseline data of the Age‐Well trial (NCT02977819) were included. For each participant, levels of cortisol, epinephrine and norepinephrine were obtained from blood sampling. Moreover, the functional connectivity (FC) between, and the gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields were extracted from resting‐state functional, and structural T1‐weighted, MRI. Levels of blood stress markers and neuroimaging measures were compared between groups. Regression analyses were then conducted between levels of blood markers and brain measures. Analyses were corrected for age, sex, education and anxiety symptoms with statistical significance set to p<0.05.ResultHigher blood epinephrine level (p<0.024), and FC between the hypothalamus and the CA1 hippocampal subfield (p<0.040), was found in DepS compared to NoDepS (Fig.1). This higher epinephrine level was associated with greater FC between the hypothalamus and the CA1 (p<0.007) and Subiculum (p<0.013) subfields (Fig.2). Lower GM volume in the CA1 (p<0.008) and DG/CA2‐3‐4 (p<0.013) subfields was also found in the DepS group (Fig.3), but was not associated with epinephrine level. No significant between‐group difference in blood cortisol and norepinephrine levels was observed.ConclusionSubclinical depressive symptoms in aging are associated with higher blood epinephrine level related to greater FC between the hypothalamus and hippocampal subfields (CA1 and Subiculum) – suggesting an increased sympathetic nervous system activity. They are also associated with GM atrophy in specific hippocampal subfields, including the CA1 that is sensitive to AD. These two distinct mechanisms at this preclinical stage of depression may at least partly explain that depression is a risk factor for AD.
Regional cortical hypoperfusion observed in elderly adults prior to development of mild cognitive impairment
Authors: Zhang Linda , Frank Darya , Alfayate Eva , del Ser Teodoro , Medina Miguel , Strange Bryan A 
Published: December 2023

AbstractBackgroundCardiovascular disease is associated with increased risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD), although the underlying mechanisms are not well understood. While it has been theorised that cerebral hypoperfusion caused by heart failure may directly lead to the formation of amyloid plaques and neurofibrillary tangles characteristic of AD, it has also been suggested that decreased perfusion occurs later in disease progression. We used arterial spin labelling (ASL) MRI to compare cerebral blood flow (CBF) between cognitively unimpaired elderly individuals who would remain cognitively stable and those who would later develop MCI to determine if hypoperfusion is detectable at a preclinical stage.Method647 cognitively normal elderly participants with ASL and structural T1‐weighted MRI were selected from the Vallecas Project cohort, a single‐centre longitudinal study currently in its 12th year of annual follow‐up. 586 participants remained cognitively stable (CS) while 61 participants developed MCI over the course of the study. Cortical CBF maps derived from ASL images at the visit before MCI diagnosis were analysed in a voxelwise comparison with CS individuals, with age, sex, and total intracranial volume as covariates.ResultCBF was significantly lower in the right insular cortex in future MCI converters than CS individuals (p<0.05, family‐wise error (FWE) corrected). Hypoperfusion was also significant in the anterior corpus callosum in future converters.ConclusionCerebral hypoperfusion, as measured by ASL, can already be observed in individuals before the onset of clinical symptoms.