bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility of comprehensive heart‐brain MRI for investigating hemodynamic coupling in aging
Authors: Jarvis Kelly , Martersteck Adam , Richter Adam , Moore Jackson E. , Sridhar Jaiashre , Aristova Maria , Jin Ning , Schnell Susanne , Russell Eric , Markl Michael , Ragin Ann , Rogalski Emily J 
Published: December 2023

AbstractBackgroundCardiovascular risk factors have been linked with dementia risk in aging adults. However, mechanisms underlying heart‐brain hemodynamic coupling and effects on the brain remain unclear. 4D flow MRI is uniquely poised to systematically evaluate complex hemodynamics along the heart‐brain pathway. Owing to advancements yielding shorter scan times, 4D flow MRI can be acquired in approximately 7 minutes (heart) and 10 minutes (brain). This supports practical add‐on of 4D flow MRI to neuroimaging scans for comprehensive heart‐brain MRI evaluation in under an hour. We aimed to build a heart‐brain MRI acquisition and analysis framework to study relationships between hemodynamics and brain structure with age.Method17 healthy participants (age = 53.5±16.3[24‐76] years) underwent heart‐brain MRI at 3T (MAGNETOM Prisma, Siemens, Erlangen, Germany), including a free‐breathing whole‐chest 4D flow MRI research sequence, intracranial dual‐venc 4D flow MRI research sequence, and T1‐ and T2‐weighted structural neuroimaging. Participants were cognitively healthy and screened for history of cardiovascular and cerebrovascular problems that may influence blood flow. 4D flow MRI was used to evaluate blood flow velocities in the aorta and Circle of Willis (Figure 1: left). Mean velocity was determined on a voxel‐wise basis over the entire cardiac cycle. Volumetric and cortical thickness analysis was performed with FreeSurfer (v7.3; Figure 1: right). Left and right hippocampal and amygdala volumes were averaged and corrected for intracranial head size. We examined relationships between hemodynamics, volume and thickness measures, and age using Pearson correlations and multiple regression.ResultMean aortic velocity was associated with age (r = ‐0.59, p = 0.012), hippocampal volume (r = 0.68, p = 0.003), amygdala volume (r = 0.59, p = 0.012), and inferior temporal thickness (r = 0.49, p = 0.044). Figure 2. Mean velocity in the Circle of Willis (r = ‐0.49, p = 0.048), amygdala volume (r = ‐0.66, p = 0.004) and inferior temporal thickness (r = ‐0.60, p = 0.010) were also associated with age. Using multiple regression, mean aortic velocity was associated with hippocampal volume (p = 0.018) adjusting for age.ConclusionThis study demonstrates capture of comprehensive heart and brain data in a single imaging exam for assessment of age‐related relationships in hemodynamics and brain structure. Heart‐brain MRI is a promising tool for evaluation of hemodynamic coupling along the entire heart‐brain pathway. Grant support: NIH NIA P30AG059988, P30AG072977, K01AG080070; NINDS R21NS122511:
Non‐AD pathologies, as measured using a mismatch index between regional brain metabolism and tau PET signal, are associated with age, sex, and amyloid burden
Authors: Malotaux Vincent , Colmant Lise , Dricot Laurence , Quenon Lisa , Huyghe Lara , Gérard Thomas , Ivanoiu Adrian , Lhommel Renaud , Hanseeuw Bernard J 
Published: December 2023

AbstractBackgroundBrain hypometabolism in the absence of tauopathy may indicate the presence of non‐AD pathologies. We aimed to investigate the mismatch between regional tau pathology and brain metabolism to characterize the profile of patients suspected to have co‐pathologies.MethodSixty‐one clinically impaired patients, attending the Memory Clinic, performed both a [18F]‐Fluorodeoxyglucose‐PET to assess brain metabolism and a [18F]‐MK6240 Tau‐PET to estimate tau burden. To compare these images, we normalized them using data from clinically normal older adults (n = 30), resulting in FDG and tau z‐scores for 74 FreeSurfer‐defined regions. We computed intra‐subject correlation coefficients between tau and FDG data as a mismatch index between tau and metabolism. We then compared FDG and tau z‐scores using intra‐individual paired sampled t‐tests and identified patients with hypometabolism exceeding tau pathology (suspecting co‐pathologies). To increase sensitivity, the same analysis was repeated using temporal regions only. We finally evaluated demographics, cognition, and amyloid burden in the group of patients with suspected co‐pathologies.ResultIn the entire cohort, the intra‐subject FDG‐Tau correlation was significantly negative in the temporal lobe (r = ‐0.27, p<0.05), but not in the entire neocortex (r = ‐0.11), demonstrating closer association between modalities in the temporal lobe, and greater mismatch in the other regions. Twenty‐five (41%) patients had significantly greater FDG z‐scores than tau z‐scores, including thirteen (21%) with greater hypometabolism than tau pathology in the temporal lobe. These patients were older and more frequently male than patients with greater tau pathology; those with a temporal mismatch also had lower amyloid pathology (Table 1). Older ages and better cognition were associated with the mismatch index in the entire neocortex (r = 0.25/0.49, p<0.05); in addition, lower amyloid burden was associated with the temporal mismatch index (r = 0.27, p<0.05, Fig.1).ConclusionPatients with greater temporal hypometabolism than tau deposition are older, more frequently males, and have lower amyloid burden than patients with greater temporal tau deposition. These patients are suspected to have temporal non‐AD pathologies.
CSF Aβ42/40 is associated with neurodegeneration independently of CSF p‐tau in the earliest AD continuum
Authors: Cacciaglia Raffaele , Falcon Carles , Shekari Mahnaz , Salvadó Gemma , Milà‐Alomà Marta , Huguet Jordi , Garcia Marina , Kollmorgen Gwendlyn , Carboni Margherita , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo 
Published: December 2023

AbstractBackgroundSoluble Aß dyshomeostasis is thought to be the earliest detectable alteration in AD, but is believed to have little impact on neurodegeneration. Conversely, the onset of tau pathology in the presence of Aß drives subsequent neurodegeneration. Here, we aimed to assess the independent contribution of soluble Aß and tau dyshomeostasis to neurodegeneration, in the earliest stages of the AD continuum.MethodThe first 330 consecutive participants of the ALFA+ study with available longitudinal (3.45±0.24 y) MRI, CSF Aß42, Aß40, p‐tau181, and NfL at baseline were included. CSF biomarkers were assessed with the Roche NeuroToolKit robust prototype immunoassays and p‐tau181 with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (Roche Diagnostics International Ltd). Gray matter volume (GMv) changes were computed voxelwise using SPM12 on T1w scans. Hippocampal subfields were segmented using ASHS on high‐resolution acquisitions. To detect regions showing early neurodegeneration, correlations between CSF NfL and GMv changes were sought. Then, GMv and hippocampal subfields changes were sought in association with CSF Aß42/40 and CSF p‐tau181, both alone and after controlling for the other biomarkers. The interactive effect of CSF p‐tau181 and Aß status (CSF Aß42/40 < 0.071) on brain structure was determined.ResultTable 1 shows sample’s characteristics. CSF NfL concentrations were associated with longitudinal GMv atrophy in the medial and inferior temporal areas (Fig. 1A). CSF Aß42/40 significantly predicted GMv atrophy in the hippocampus bilaterally, alone and when controlling for CSF p‐tau181 and NfL (Fig. 1B‐C). CSF p‐tau181 interacted with Aß status to predict GMv atrophy in the posterior hippocampus bilaterally (Fig. 1D). Longitudinal GMv atrophy in the hippocampal subfields were confirmed in association with CSF Aß42/40 in the bilateral CA1, dentate gyrus and BA35 (Table 2).ConclusionIndependently of p‐tau, early Aß dyshomeostasis is associated with longitudinal GMv atrophy in AD‐sensitive brain areas in the early AD continuum. As expected, tau levels were associated with additional atrophy in these regions in Aß+ individuals. Pathophysiological alterations other than Aß, but correlated with CSF Aß levels, might contribute to the observed atrophy patterns. Control of the earliest pathophysiological alterations in AD may have a relevant impact on neurodegeneration, even at the earliest preclinical stages.
Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort
Authors: Lorenzini Luigi , Maranzano Alessio , Tranfa Mario , Collij Lyduine E. , Sudre Carole H , Wolz Robin , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Chetelat Gael , Waldman Adam , Wardlaw Joanna M , Fox Nick C , Ritchie Craig W , Scheltens Philip , Visser Pieter Jelle , Wink Alle Meije , Mutsaerts Henk‐Jan , Gispert Juan Domingo , Ingala Silvia , Barkhof Frederik 
Published: December 2023

AbstractBackgroundThe role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.MethodWe included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aß1‐42; CSVD indices (visual assessment for perivascular spaces [PVS] in the basal ganglia [BG] and centrum‐semiovale [CS], periventricular and deep white matter hyperintensities [WMHs], presence of lobar or deep cerebral microbleeds [CMBs], and lacunes, and quantification of global and lobar WMH volumes) and Aß1‐42 and p‐Tau181, including an interaction between CSVD indices and Aß1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.ResultHigher FRS scores were associated with lower CSF Aß1‐42 (ß = ‐0.18; p<0.001) and higher P‐tau181 (ß = 0.21; p<0.001). Aß1‐42 was negatively associated with all CSVD markers (all p<0.001; Figure‐2). We found stronger association between Aß1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction<0.005) scores, and higher regional WMH (all p‐interactions<0.005) volumes. Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aß1‐42 (indirect effect: ß = ‐0.03; p<0.001). Aß1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aß1‐42 on P‐tau181 levels (ß = ‐0.14; p<0.001) and HCV (ß = 0.06; p<0.05), and of P‐tau181 levels onto HCV (ß = ‐0.05; p<0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: ß = 0.36; p < 0.05) and HCV (indirect effect: ß = ‐0.24; p < 0.05) through Aß1‐42 was observed.ConclusionExpression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.
Cerebral microbleeds in traumatic brain injury associated with differential risk factors and clinical outcomes: the PREVENT‐Dementia study
Authors: Low Audrey , McKiernan Elizabeth , Prats‐Sedano Maria A , Carter Stephen F , Stefaniak James D , Su Li , Dounavi Maria‐Eleni , Muniz‐Terrera Graciela , Jenkins Natalie D , Ritchie Karen , Lawlor Brian , Naci Lorina , Malhotra Paresh A , Thayanandan Tony , Mackay Clare , Koychev Ivan , Raymont Vanessa , Ritchie Craig W , O'Brien John T 
Published: December 2023

AbstractBackgroundCerebral microbleeds (CMB) are predictive of increased risk of dementia and stroke. Although commonly regarded as vascular markers, CMB can also stem from non‐vascular aetiologies like head injuries or traumatic brain injury (TBI), although these are often overlooked. Therefore, this study examines CMB in relation to TBI, and their differential causes (i.e., risk factors) and consequences (i.e., clinical outcomes).MethodIn 605 healthy middle‐aged adults (aged 40‐59), CMB were rated on 3T susceptibility weighted imaging (SWI) MRI. TBI was assessed using the Brain Injury Screening Questionnaire (BISQ). TBI+ was defined as at least one blow to the head resulting in loss of consciousness (36.0%; n = 217). Memory was assessed using the COGNITO battery. Interaction analyses examined TBI*CMB interactions on hypertension, gait, and memory. Dominance analysis examined the relative contribution of TBI and vascular risk factors on predicting gait disturbances and memory. All models adjusted for sex, age, education, and study site.ResultTBI was related to higher CMB count (t = 2.06, p = .039), and were more common in males (48.3%) than females (28.0%) (Χ2 = 28.91, p<.001). Number of TBI events related to poorer memory (t = ‐2.62, p = .009) and gait disturbances (t = 3.54, p<.001). Interaction analyses demonstrated that hypertension (t = ‐2.26, p = .024), memory (t = 2.70, p = .007) and gait (t = ‐2.29, p = .023) were less closely related to CMB in individuals with greater number of TBI events, relative to those with fewer TBIs. Regionally, these interactions were significant for lobar CMB, but not deep subcortical CMB. Within the TBI+ group, dominance analysis demonstrated that number of TBI events outperformed vascular risk factors in predicting gait disturbances (Contribution to R2: TBI = 52.9%, vascular risk = 32.6%) and memory (TBI = 28.7%, vascular risk = 1.2%).ConclusionCMB appeared to differ aetiologically and clinically in those with and without TBI. In individuals with TBI, TBI itself was the dominant driver of clinical deficits. When compared to CMB of presumed vascular origins cross‐sectionally, TBI‐related CMB may appear to be less detrimental. However, longitudinal analysis is required to determine how TBI‐related CMB differ in clinical trajectory and downstream pathologies. This study highlights the importance of differentiating between CMB of vascular origins vs. TBI in both research and clinically to aid prognosis and treatment decisions.
Association of cognitive reserve indicator with cognitive decline and structural brain differences in mid‐ and late life: a large population‐based cohort study
Authors: Yang Wenzhe , Wang Jiao , Guo Jie , Dove Abigail , Qi Xiuying , Xu Weili 
Published: December 2023

AbstractBackgroundCognitive reserve (CR) contributes to preserving cognition when facing brain aging and damage. CR has been linked to reduced dementia risk in late life. However, the association between CR and brain imaging measures, especially in mid‐life, is unclear. We aimed to explore the association of CR with cognitive decline and structural brain differences in mid‐ and late life.MethodWithin the UK Biobank, 42,301 dementia‐free participants aged 40‐70 were followed for a median of 9 (interquartile range: 8 to 10) years. Latent class analysis was used to generate an indicator of CR (categorized as high, moderate, and low) based on education, occupation, and multiple cognitively stimulating activities at baseline. Cognitive tests for global and domain‐specific cognitive function were administrated at baseline and follow‐up. A subsample (n = 34,041) underwent brain magnetic resonance imaging (MRI) scans at the follow‐up examination. Volumes of total brain, white matter, grey matter, hippocampus, and white matter hyperintensities (TBV, WMV, GMV, HV, and WMHV) were assessed. Data were analyzed using mixed‐effects models and linear regression.ResultAt baseline, 16,032 (37.90%), 10,709 (25.32%), and 15,560 (36.78%) participants had low, moderate, and high levels of CR, respectively. In multi‐adjusted mixed‐effects models, compared to low CR, high CR was associated with a slower decline in global cognitive function (ß [95% confidence interval, CI]: 0.10 [0.08, 0.11]), prospective memory (0.10 [0.06, 0.15]), fluid intelligence (0.07 [0.04, 0.10]), and reaction time (0.04 [0.02, 0.06]). In MRI data analysis, high CR was related to lesser TBV (‐0.03 [‐0.04, ‐0.02]), WMV (‐0.03 [‐0.04, ‐0.02], GMV (‐0.02 [‐0.04, ‐0.01]), and WMHV (‐0.03 [‐0.05, ‐0.002]), but greater HV (0.04 [0.02, 0.06]) compared to low CR. In analyses stratified by baseline age, the significant associations between high CR and global cognition and TBV were present among both mid‐life (<60 years) and late‐life ( = 60 years) participants. The CR‐cognitive decline association remained significant after additional adjustment for MRI measures.ConclusionHigher CR is associated with slower cognitive decline, lesser TBV, greater HV, and lower microvascular burden, especially in mid‐life. The protective role of high CR on cognition is independent of structural brain differences.
PET Imaging of Rho‐Associated Protein Kinase 2 in A Mouse Model of Alzheimer’s Disease
Authors: Zheng Chao , Nicholson LaShae , Chen Baosheng , Toyonaga Takuya , Liu Michael , Strittmatter Stephen M , Carson Richard E. , Huang Yiyun , Cai Zhengxin 
Published: December 2023

AbstractBackgroundRho‐associated protein kinase 2 (ROCK2) activity is implicated in Alzheimer’s disease (AD) and other central nervous system (CNS) disorders 1. In this study, we investigated the relative expression levels of ROCK2 in APP/PS1 transgenic AD mice and age‐matched wild‐type (WT) C57BL/6J mice using the ROCK2‐specific PET radioligand, [11C]ROCK201.MethodThe ROCK2 tracer [11C]ROCK201 was synthesized according to the previously published procedure 2. PET scans were performed in a Focus‐220 scanner on 12‐month‐old APP/PS1 transgenic mice (n = 8) and WT controls (n = 5). Self‐blocking scans were performed 10 min post injection (p.i.) of the unlabeled ROCK201 (i.v., 3.3 mg/kg). Regions of interest (ROIs) were extracted from the Ma‐Benveniste‐Mirrione mouse brain atlas and regional time‐activity curves (TACs) were obtained by applying template ROIs to the averaged PET images (0 to 60 min p.i.). Distribution volume ratio (DVR) values were generated using the simplified reference tissue model 2 (SRTM2) on the 60‐min dynamic PET imaging data, with cerebellum (CB) as the reference region. ROCK2 protein expression levels were assessed immunohistochemically in brain tissues of 12‐month‐old APP/PS1 (N = 3) and WT (N = 3) mice.ResultUptake of [11C]ROCK201 was observed throughout the mouse brain, with peak SUV of 2.6. TACs were consistently higher in the hippocampus of APP/PS1 mice than controls, within 20 min p.i. (Fig. 1a). Reduced uptake was observed in self‐blocking studies, indicating specific binding of [11C]ROCK201 in the rodent brain (Fig. 1a). TACs were well fitted with SRTM2. Compared with age‐matched WT controls, the DVR(CB) in the hippocampus of APP/PS1 mice was 9.3% higher than that of WT mice (p = 0.03) (Fig. 1b). Consistent with PET imaging results, ROCK2 protein expression is elevated by 49±2% in the CA1 of APP/PS1 mice compared to that of WT mice (Fig. 1c).ConclusionWe demonstrated the uptake and detection sensitivity of the radioligand [11C]ROCK201 in the mouse brain, with higher tracer uptake in the hippocampi of APP/PS1 mice as compared to WT mice, supporting the use of [11C]ROCK201 in preclinical AD drug discovery and development.
MIITRA atlas: high resolution FOD template of the older adult brain
Authors: Wu Yingjuan , Ridwan Abdur Raquib , Niaz Mohammad Rakeen , Bennett David A. A , Arfanakis Konstantinos 
Published: December 2023

AbstractBackgroundHigh quality fiber orientation distribution (FOD) template of the older adult brain facilitates white matter studies in older adults. This work compared several methods to construct an FOD template of the older adult brain in the space of the MIITRA atlas(Wu et al.,2022).MethodT1w and DWI data from 400 non‐demented older adults (50% male;64.9‐98.9 yrs;54% white,43% black)(Bennett et al.,2018;Barnes et al.,2012) participating in the construction of the MIITRA atlas were used. Method 1: FOD‐based single modality registration(cost function:mean squared difference)(MRtrix3). Method 2: The nonlinear transformations generated from MIITRA T1w and DTI template construction were applied to the FODs(Wu et al.,2021). Method 3: Multichannel registration based on T1w, T2w, FA and MD information with equal weights(cost function:cross‐correlation)(ANTs). Method 4: Multichannel registration based on T1w and FOD information with equal weights(cost function:cross‐correlation)(MRtrix3). Method 5: Multichannel registration based on T1w, FA and FOD information with weights of 4,3,3 respectively(cost function:cross‐correlation)(MRtrix3). Method 6: Same as Method 5 followed by FOD registration performed on the FOD data that were already transformed by Method 5(cost function:cross‐correlation)(MRtrix3). The FOD templates generated with different methods were compared by visual inspection, image sharpness of the total apparent fiber density (AFD) map, precision of spatial normalization of FOD data used in template construction, and spatial matching with the existing MIITRA T1w and DTI templates.ResultThe FOD templates generated with Methods 2, 3 and 6 exhibited higher image sharpness(Fig.1A). Fiber crossings were more clearly defined in the FOD templates generated with Methods 1,4,5,6(Fig.1B). Method 6 allowed higher ACC and lower MSD of spatially normalized FOD data, indicating higher precision in spatial normalization(Fig.2A,B). Method 2 provided the highest spatial matching with the existing MIITRA templates, followed closely by Methods 4,5,6(Fig.2C,D). Overall, the FOD template generated with Method 6 achieved high image quality, was constructed based on precisely matched FOD data, and exhibited high spatial matching to the existing MIITRA templates(Fig.3).ConclusionAn FOD template of the older adult brain was constructed for the MIITRA atlas. The new template exhibits high image quality, is constructed based on precisely matched FOD data, and exhibits high spatial matching to other existing MIITRA templates.