bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Background

Cerebral 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).

Method

In 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.

Result

TBI 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%).

Conclusion

CMB 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

Background

Cognitive 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.

Method

Within 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.

Result

At 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.

Conclusion

Higher 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

Background

Rho‐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.

Method

The 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.

Result

Uptake 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).

Conclusion

We 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

Background

High 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).

Method

T1w 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.

Result

The 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).

Conclusion

An 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.
Altered patterns of brain activity during a fMRI memory task in cognitively normal adults carrying the APOE ε4 allele
Authors: Corbo Daniele , Quattrini Giulia , Saglia Silvia , Agnelli Giancarlo , Mega Anna , Marizzoni Moira , D'Aprile Ilari , Cattaneo Annamaria , Bortoletto Marta , Gasparotti Roberto , Pievani Michela
Published: December 2023

Background

The e4 allele of the Apolipoprotein E gene (APOE) is a well‐established risk factor for Alzheimer’s disease (AD), e4 carriers showing earlier onset and more severe memory impairment than non‐carriers. Neuroimaging evidence suggests that APOEe4 may modulate neural activity in AD since early stages. The purpose of this study was to determine whether APOEe4 influences brain activity in the memory circuit in older cognitively unimpaired individuals.

Method

Thirty cognitively unimpaired participants (n = 10 APOEe4 heterozygous carriers, age = 65± 5 years, 50% females, MMSE score = 29±1; n = 20 APOEe4 non‐carriers, age = 68±5 years, 35% females, MMSE score = 30±1) were recruited and underwent multidomain (i.e., memory, visuospatial abilities, language, attention) neuropsychological exams and functional MRI scan during an associative memory task, which consisted of two phases: (i) encoding of face‐name associations; (ii) recognition of the name associated to each face. Image preprocessing and voxel‐wise comparisons were conducted using the Statistical Parametric Mapping (SPM, v12). Clusters were considered significant at an uncorrected threshold of p<0.001.

Result

Participants were comparable for demographic and cognitive features (p>0.10) and performed similarly on the in‐scanner face‐name association memory task (p>0.10). Compared to e4 non‐carriers, carriers showed (i) greater activation during the encoding task in the left temporo‐occipital cortex/fusiform gyrus, (ii) greater activation during the recognition task in the middle temporal gyrus/temporo‐occipital cortex bilaterally and in the right cerebellum, and (iii) lower activation during the recognition task in the medial supplementary motor area.

Conclusion

These preliminary results confirm that the APOE e4 allele is associated with a different pattern of brain functional activity during an associative memory task in cognitively unimpaired older. Given the similar cognitive performance between groups, higher activation in temporo‐occipital regions might reflect a compensatory process in regions vulnerable to AD pathology.
White matter hyperintensity shape in relation to long‐term small vessel disease progression in community‐dwelling older adults
Authors: Keller Jasmin Annica , Sigurdsson Sigurdur , van Buchem Mark A. , Launer Lenore J J. , Van Osch Matthias J.P. , Gudnason Vilmundur , de Bresser Jeroen H.J.M.
Published: December 2023

Background

White matter hyperintensity (WMH) shape was recently introduced as a novel small vessel disease (SVD) marker that may provide a more detailed characterization of WMH than volume alone. We aimed to investigate the association between baseline WMH shape and cerebrovascular disease progression over 5 years in community‐dwelling individuals.

Method

Data from the Age, Gene/Environment Susceptibility‐Reykjavik (AGES) study (n = 2297) was used in the current study. FLAIR and T1‐weighted brain MRI scans were acquired at baseline from 2002 to 2006 on a 1.5 Tesla Signa Twinspeed system (General Electric Medical Systems, Waukesha, Wisconsin). Five years later, follow‐up MRI scans were acquired from 2007 to 2011 with the same protocol. Baseline WMH shape was assessed using an in‐house developed pipeline (see figure 1).

Result

A more irregular shape of periventricular/confluent (solidity, convexity, concavity index, fractal dimension) and deep WMH (eccentricity, fractal dimension) at baseline were associated with increased progression of WMH volume over 5 years (see figure 2). A more irregular shape of periventricular/confluent WMH (solidity, convexity, concavity index, fractal dimension) was associated with new subcortical infarcts and new microbleeds at the 5 year follow‐up (see figure 3).

Conclusion

Our findings indicate that a more irregular WMH shape is associated with SVD progression and may aid prediction of disease progression.
Stability of Magnetoencephalography and Electroencephalography Spectral Features in Mild Cognitive Impairment
Authors: Kinnunen Antti S , Kulashekhar Shrikanth , Saarinen Timo , Mäntynen Ville , Hotta Jaakko , Koivisto Anne M , Liljeström Mia , Renvall Hanna
Published: December 2023

Background

In mild cognitive impairment (MCI), the first neurodegenerative changes may occur years before they can be effectively detected with current clinical tools. Early pathology has been linked to synaptic dysfunction causing brain network disturbances that may be observed with electroencephalography (EEG) and magnetoencephalography (MEG). These methods are still not widely utilized in dementia risk assessment, and the stability of suggested EEG and MEG features and their correlation has not been thoroughly addressed in this patient group.

Method

In a 5‐year EU Horizon2020 project ‘AI‐Mind’, we collect EEG and simultaneous MEG data from MCI subjects, to be compiled with cognitive, genetic and plasma biomarker measures and techniques based on artificial intelligence (AI) for predicting the overall dementia risk. Here, we analyzed a subset of 31 Finnish MCI participants (20 females, age 68 ± 5; mean ± SD) from the AI‐Mind dataset to assess the stability of prominent signal features from resting‐state EEG and MEG recordings. We determined within‐session test‐retest reliability for spectral peak frequencies and relative peak power over occipital brain regions in the 8‐13 Hz range, by utilizing intraclass correlation (ICC) for subsequent 5‐min runs of EEG and MEG data in both eyes‐closed (EC) and eyes‐open (EO) conditions. In addition, we determined the consistency of the features across methods (EEG/MEG).

Result

The results indicate good (ICC>0.6) test‐retest reliability across runs for EEG (peak frequency: 0.72 (EC); relative power: 0.86 (EC) and 0.66 (EO); p<0.001) and excellent test‐retest reliability (ICC>0.75) for MEG (peak frequency: 0.83 (EC); relative power: 0.96 (EC) and 0.85 (EO); p<0.001). Consistency across EEG and MEG was excellent (peak frequency: 0.86 (EC); relative power 0.89 (EC) and 0.84 (EO); p<0.001).

Conclusion

Electrophysiological recordings of brain networks are emerging as a diagnostic tool for early detection of dementia. Good stability of the measured signal features is a prerequisite for a clinically feasible tool. Here, we demonstrate good or excellent stability for prominent spectral features both within and across EEG and MEG recordings.
Comparing approaches based on the global functional organization of the brain versus local connectivity to predict tau‐PET across the Alzheimer’s disease phenotypic spectrum
Authors: Corriveau‐Lecavalier Nick , Botha Hugo , Schumacher Julia , Dicks Ellen , Barnard Leland R , Lee Jeyeon , Sintini Irene , Gunter Jeffrey L. , Kamykowski Michael G. , Graff‐Radford Jonathan , Ramanan Vijay K , Fields Julie A. , Machulda Mary M. , Boeve Brad F. , Lowe Val J. , Kantarci Kejal , Knopman David S. , Whitwell Jennifer L , Josephs Keith A , Petersen Ronald C. , Jack Clifford R. , Jones David T.
Published: December 2023

Background

Predictive models of tau‐PET accumulation have largely relied on the functional connectome to estimate its spatial patterns in Alzheimer’s disease (AD). Patterns of global functional organization represent a promising avenue as they encapsulate many biological properties relevant to neurodevelopment, cognition and degeneration. We compared approaches based on local connectivity (from task‐free fMRI) and global organization (from FDG‐PET) to predict regional tau‐PET across AD phenotypes.

Method

We included 430 cognitively unimpaired (CU) individuals (214 A+T‐, 216 A+T+) and 62 amnestic mild cognitive impairment (aMCI), 64 amnestic AD, 21 dysexecutive AD (dAD), 41 logopenic progressive aphasia (LPA) and 49 posterior cortical atrophy (PCA) patients (all A+T+) from the Alzheimer’s Disease Research Center, Mayo Clinic Study of Aging, and Neurodegenerative Research Groups (referred to as “Mayo cohort”). The connectivity approach consisted of assessing the relationship between a region’s tau level and its functional connectivity to the region of highest tau (epicenter). The global organization approach consisted of 1) performing a principal component analysis on 3000 FDG‐PET images that did not overlap with the Mayo cohort, 2) projecting FDG‐PET images of the Mayo cohort onto the low‐dimensional space generated in Step 1 and extracting corresponding weighted values across the first 100 components, 3) using these weighted values as predictors of regional tau‐PET in a linear model and determining optimal parameters based on predicted R2 values, and 4) using the parameters from the model built in Step 3 to predict tau‐PET in the ADNI cohort (n = 86) (Fig.2).

Result

The connectivity‐based approach yielded adjusted R2 values ranging from 0.19‐0.45 across diagnostic groups (Fig.1). The global organization approach yielded averaged adjusted R2 and predicted R2 values of 0.71 and 0.63, respectively, in the Mayo cohort. Out‐of‐sample median R2 in the ADNI cohort was 0.41 (range 0.10‐0.60) (Fig.3).

Conclusion

An unbiased approach based on the global functional organization of the brain and using an imaging modality widely used in clinical settings outperformed a connectome‐based one to predict regional tau‐PET across the AD phenotypic spectrum. Patterns of tau accumulation may better relate to the large‐scale physiology of the brain underlying specific mental functions rather than local connectivity factors.
Cognitive decline and longitudinal atrophy in successful and typical aging
Authors: Pezzoli Stefania , Giorgio Joseph , Chen Xi , Harrison Theresa M. , Jagust William J.
Published: December 2023

Background

Greater hippocampal volume (HV) and thicker mid‐cingulate cortex (MCC) are features of successful agers (SA), defined as exceptional cognitive performers, compared to typical agers (TA). This study aimed at examining whether SA experience different longitudinal change in cognition and atrophy from TA, and how baseline ß‐amyloid (Aß) affects these relationships.

Method

190 cognitively normal older adults (70+ years old) underwent 11C‐Pittsburgh compound B (PiB)‐PET to derive baseline Aß positivity, and longitudinal structural MRI and cognitive testing. A machine learning cognitive‐age model was used to predict participants’ cognitive‐age from cognitive testing. Cognitive‐age gap (CAG = cognitive‐age – chronological age) was computed to represent individual variability in cognitive aging, wherein negative values indicate better cognitive performance than expected for age; SA were below the 20th percentile (n = 39). Linear mixed‐effects models were used to investigate the relationship between longitudinal changes in 1) Preclinical Alzheimer’s Cognitive Composite (PACC), 2) HV, and 3) MCC, with baseline CAG or SA‐status, as well as Aß‐status as predictors.

Result

We found a significant main effect on PACC for CAG (p<0.001), but not Aß‐status (p = 0.9), and significant CAG x time (p = 0.002) and Aß‐status x time (p = 0.02) interactions (Figure 1). Results were similar when participants were dichotomized into SA and TA. In addition, baseline CAG showed significant main effects on 1) HV (p<0.001) and 2) MCC (p = 0.02), but the CAG x time interactions were not significant (HV: p = 0.6; MCC: p = 0.7) (Figure 2). Finally, when CAG, Aß‐status, and HV were included in the same model to predict PACC change, we found a significant main effect for CAG (p<0.001), significant CAG x time (p = 0.01) and Aß‐status x time (p = 0.02) interactions, and a marginally significant HV x time interaction (p = 0.06) (Figure 3).

Conclusion

Lower baseline CAG scores, indicating younger cognitive‐age, were related to greater HV and thicker MCC cross‐sectionally, but not longitudinal atrophy differences, suggesting that better cortical integrity in SA may reflect longstanding differences from TA. Lower baseline CAG and Aß negativity were independently associated with slower cognitive decline. These findings suggest that factors underlying SA include separate contributions of both brain maintenance and reserve.
Voxel‐by‐Voxel regression analysis identifies association between postmortem TDP‐43 and antemortem fractional anisotropy within white matter fibers connected to the hippocampus
Authors: Heywood Ashley , Stocks Jane K , Schneider Julie A , Bennett David A. A , Arfanakis Konstantinos , Beg Mirza Faisal , Wang Lei
Published: December 2023

Background

TAR DNA‐binding protein 43 (TDP‐43), has been shown to be involved in various neurodegenerative disorders involving axonal damage including ALS, FTLD, and LATE. Studying the relationships between postmortem TDP‐43 and antemortem white matter (WM) structural integrity can allow for a better understanding of the disease, rather than exploring clinical presentations alone.

Method

In‐vivo diffusion‐weighted images were gathered on a 1.5T scanner from subjects from the Religious Orders Study and the Rush Memory and Aging Project. Images were processed using TORTOISE to calculate fractional anisotropy (FA). We utilized the IIT probabilistic WM atlas to identify voxels containing fibers that originate or terminate in the hippocampus. A semi‐quantitative rating of TDP‐43 severity was assessed in 5 brain regions. We utilized regression models to relate postmortem disease and antemortem FA within each voxel. Coexisting disease including ß‐amyloid plaques, tau tangles, and cerebrovascular disease were used as covariates, along with demographic variables.

Result

The 58 subjects were 91.10 (SD = 6.37) years old at death with a median interval from MRI to death of 2.8 years (SD = 1.19). Results revealed a significant negative relationship (p<0.05) between postmortem TDP‐43 and FA within fibers connecting the hippocampus to the parahippocampal and entorhinal cortices, fornix, and lingual gyrus. Preliminary results did not survive multiple comparisons correction.

Conclusion

Our findings indicate that greater TDP‐43 disease burden is associated with lower white matter integrity within regions of the limbic system. These findings suggest the TDP‐43 disease process may contribute to reduced structural connectivity between the hippocampus and related regions, which may impact larger brain networks.
Biological sex and vessel specific relationships between cerebral pulsatility and white matter hyperintensities: a 4D flow MRI study
Authors: Moir M. Erin , Fico Brandon G. , Loggie Nicole A. , Gaynor‐Metzinger Sarean H.A. , Norby Alexander M. , Howery Anna J. , Rivera‐Rivera Leonardo A. , Eisenmenger Laura B. , Wieben Oliver , Johnson Sterling C , Barnes Jill N.
Published: December 2023

Background

Brain vascular dysfunction is a contributing factor to the increased risk of Alzheimer’s disease with advancing age. Cerebral pulsatility represents a marker of vascular function that quantifies fluctuations in blood flow within each cardiac cycle in the cerebral arteries. Increases in cerebral pulsatility may contribute to structural damage in the brain such as white matter hyperintensities (WMH). Additionally, biological sex differences are apparent in brain vascular function and Alzheimer’s disease risk. As such, this research aimed to determine associations between cerebral pulsatility and WMH and evaluate the influence of sex. This research tested the hypothesis that elevated cerebral pulsatility is associated with higher WMH, and that the associations are sex‐specific.

Method

407 cognitively healthy middle‐aged and older adults (45‐87 years of age; 271 females) completed magnetic resonance imaging (MRI) performed on a 3T MRI scanner. WMH volumes were evaluated from T2 fluid‐attenuated inversion retention (FLAIR) images, while cerebral pulsatility index (PI) was evaluated in multiple intracranial arteries from 4D flow MRI. WMH fraction was calculated as the cubic root of WMH volume relative to intracranial volume.

Result

PI in the vertebral arteries (VA) and basilar artery was positively associated with WMH fraction in females only (all female P = 0.01, all male P = 0.20). In contrast, PI in the internal carotid arteries (ICA) and middle cerebral arteries (MCA) was positively associated with WMH fraction in both sexes (all P = 0.01). However, the relationship between WMH fraction and PI in the MCA differed by sex such that the slope of the relationship was stronger in males than females (all P = 0.03). For example, higher right MCA PI was associated with greater WMH fraction in males (ß = 0.39±0.09 a.u., R2 = 0.13) compared with females (ß = 0.18±0.05 a.u., R2 = 0.05).

Conclusion

These data suggest that, among cognitively healthy middle‐aged and older adults, elevated cerebral pulsatility is linked to greater WMH. However, the associations are sex‐ and vessel‐specific which may contribute to sex‐specific trajectories in Alzheimer’s disease with advancing age. The present results support the idea that elevated cerebral pulsatility contributes to structural alterations in the brain and thus reducing cerebral pulsatility may represent a promising target for mitigating cognitive decline.
Association between lifestyle at different life periods and brain integrity in older adults
Authors: TURPIN Anne‐Laure , Felisatti Francesca , Ourry Valentin , Mézenge Florence , Landeau Brigitte , Vivien Denis , la Sayette Vincent De , Chetelat Gael , Gonneaud Julie
Published: December 2023

Background

Increasing evidence suggests that lifestyle factors are related to cerebral markers of aging and Alzheimer’s disease (AD) in older individuals. However, most studies addressed the association between current lifestyle and neuroimaging, providing little information on the relative effect of lifestyle at different life periods on older adults’ brain integrity. We proposed to determine the life period(s) at which lifestyle factors have the greatest influence on older adults’ brain health.

Method

We included baseline data of 135 cognitively unimpaired older adults (aged>65) from the Age‐Well study (NCT02977819). They underwent multimodal neuroimaging providing measures of Gray Matter volume (GMv), glucose metabolism, perfusion (early‐Florbetapir‐PET) and beta‐amyloid burden. The Lifestyle Experiences Questionnaires (LEQ) was used to assess complex mental activities during early‐ (13‐30y), mid‐ (30‐65y) and late‐life (>65y). To evidence the effect of activities at each life period controlling for the others, multiple regressions were conducted including the three LEQ sub‐scores to predict each neuroimaging modality, both 1) focusing on AD‐signature regions and 2) voxel‐wise. In the presence of significant associations, complementary analyses were realized to directly compare the effect of life periods between them. All analyses were controlled for age and sex.

Result

LEQ scores were not associated with AD‐signature regions. Voxel‐wise analyses revealed that higher LEQ score at midlife were positively associated with GMv, including the anterior cingulate cortex (Fig.1a), and negatively associated with amyloid burden, notably in the precuneus (Fig.1b). When compared with the other periods, these associations were statistically stronger for midlife. On the other hand, late‐life activities were positively associated with perfusion (Fig.2a) and glucose metabolism (Fig.2b), mainly in medial frontal regions, and these associations were stronger for late‐life than for any other life period.

Conclusion

Our study suggests that complex mental activities at midlife are more strongly associated with structural and molecular markers of brain integrity in older adults, while late‐life (i.e. current) activities are more strongly correlated with brain function. Interestingly, these associations were not found on AD‐signature regions but in brain regions relevant to reserve and aging. Lifestyle at different life periods might have an influence on distinct markers of brain health in late‐life.
Examining a telecognitive assessment‐derived Preclinical Alzheimer’s Cognitive Composite, the tPACC, for cognitive migration over one year in community‐dwelling older adults
Authors: Duran Tugce , Bateman James R. , Gaussoin Sarah A. , Rundle Melissa M. , Okonmah‐Obazee Stephanie E. , Espeland Mark A. , Williams Benjamin J. , Hughes Tim M. , Craft Suzanne , Lockhart Samuel N. , Sachs Bonnie C.
Published: December 2023

Background

ADRD clinical trials often target preclinical disease, where hope of averting the pathologic cascade and eventual cognitive decline remains highest. The preclinical Alzheimer’s cognitive composite (PACC5) was developed for in‐person administration to capture subtle cognitive decline. Early cognitive fluctuations may inform multidirectional disease progression, defined as cognitive migration. It is desirable to have a harmonized composite measurement derived from in‐person and remote assessments for detecting cognitive migration.

Method

We examined in‐person data from 417 adults (70.6±8.0y) from the Wake Forest ADRC Clinical Core, who received MRI, clinical evaluation and cognitive testing. The primary outcome was cognitive migration status determined by global CDR (0 and 0.5) increase/decrease between baseline (BL) and follow‐up (mean difference = 13.9 months): CDR‐0 Stable (51% maintained CDR‐0), CDR‐0.5 Stable (27% maintained CDR‐0.5), Reverter+ (13% migrated from CDR‐0.5 to CDR‐0) and Migrant‐ (9% migrated from CDR‐0 to CDR‐0.5). In‐person PACC5 was calculated (RAVLT Delayed Recall, Digit Symbol Coding [DSC], semantic fluency, Craft Story Delayed Verbatim, total MMSE) using BL participants with global CDR = 0 as reference. tPACC used measurements available at both in‐person and remote visits with minor modifications from PACC5: Montreal Cognitive Assessment (MoCA) replaced MMSE and DSC not included. We performed intraclass correlation coefficient (ICC) analysis and generated Bland‐Altman plots for BL tPACC and PACC5. We also evaluated associations between tPACC and neuroimaging.

Result

Participant characteristics and group differences in MRI markers are in Table 1. Bland‐Altman plots show differences and mean of tPACC and PACC5 (dashed line: ±1.96 SD, solid line: mean difference/bias). 92% of values lie within limit of agreement, indicating good agreement (overall ICC = .960, 95%CI = [.952, .967]), between tPACC and PACC5 in each group (Figure 1). At BL, there was a significant absolute agreement between in‐person tPACC and PACC5 in all groups (Figure 1). tPACC showed significant associations (Table 2) with Temporal Meta ROI thickness, hippocampal volume as % head size (ICV) and white matter hyperintensities (logWMH controlled for ICV) overall and in some cognitive migration groups.

Conclusion

There is generally good agreement between BL tPACC and PACC5 across cognitive migration groups. BL tPACC may predict BL neuroimaging based on cognitive migration status. Longitudinal tPACC examination is warranted.
Mediterranean diet protects against neuroinflammation and degeneration in female nonhuman primates
Authors: Shively Carol A. , Negrey Jacob D. , Frye Brett M. , Johnson Corbin S.C. , Kim Jeongchul , Barcus Richard A. , Lockhart Samuel N. , Whitlow Christopher T. , Chiou Kenneth L. , Snyder‐Mackler Noah , Montine Thomas J. , Craft Suzanne , Register Thomas C.
Published: December 2023

Background

Mediterranean diets may reduce Alzheimer’s disease (AD) risk and preserve cognitive function relative to Western diets in part by protecting against neuroinflammation. In middle‐aged humans that subsequently develop AD, increased cortical thickness precedes atrophy. It is hypothesized that the initial increase in brain volumes may be due to early neuroinflammation that precedes neurodegeneration (Pegueroles et al. Alzheimers Dement 2017). Long term impacts of diet patterns on health are difficult to quantify in human beings. Thus, we addressed this hypothesis in cynomolgus macaques (Macaca fascicularis), a nonhuman primate that undergoes age‐related changes in brain structure and function, and responds to Western diets, like humans.

Method

38 middle‐aged (mean = 12 years of age) female macaques were fed a Western or Mediterranean diet for 2.5 years in a randomized nonhuman primate trial. Changes from baseline in volumes of total brain, gray, cortical gray, and white matter, cerebrospinal fluid and (CSF), were determined by structural MRI. We also generated thickness‐based AD temporoparietal meta‐ROIs based on the AD clinical literature as previously described (Frye et al., 2021 Alzheimers Dement. 2021;17:733). Transcriptional profiles in the temporal cortex were determined at the end of the study by RNAseq.

Result

Western diet led to increases in temporoparietal cortical thicknesses, total brain and gray matter volumes, and diminished cerebrospinal fluid and white matter volumes. Diet significantly altered expression of seven genes (FDR<0.05). The Mediterranean group had lower expression of CDK14, a proinflammatory regulator, and higher expression of BTN2A1, KATNB1, LFNG, MRC2, SLCA32, and TMEM268, many of which have anti‐inflammatory associations. Several differentially expressed genes were correlated with AD‐relevant brain volumes. CDK14 was positively correlated with total brain, total gray, and cortical gray matter volumes and temporoparietal cortical thickness (Figure, Mediterranean = yellow), and negatively correlated with total white matter and CSF volumes. LFNG, MRC2, and SLCA32 were negatively correlated with total brain, total gray, and cortical gray matter volume, as well as temporoparietal cortical thickness, and positively correlated with CSF volume (all p’s<0.05).

Conclusion

These results suggest that the Mediterranean diet protects against, whereas the Western diet promotes, AD‐relevant neuroinflammation associated with early increases in gray matter volumes.
Blood‐brain barrier permeability measured with arterial spin labeling as potential cerebrovascular biomarker over the lifespan
Authors: Padrela Beatriz E. , Tee Mervin , Markus Sneve H , Geier Oliver , Mahroo Amnah , Grydeland Håkon , Fladby Tormod , Eickel Klaus , Günther Matthias , Barkhof Frederik , Hilal Saima , Mutsaerts Henk‐Jan , Petr Jan
Published: December 2023

Background

Blood‐brain barrier (BBB) dysfunction is considered a hallmark of Alzheimer’s disease (AD), making non‐invasive imaging of BBB with arterial spin labeling (ASL) MRI a potential imaging biomarker (BBB‐ASL). However, the normal BBB development over the lifespan is unknown. Here, we created population‐based BBB‐ASL permeability reference maps, and aimed to investigate associations between BBB‐ASL, chronological age, and biological cerebrovascular age – expressed as white matter hyperintensities (WMH) volume.

Method

Cognitively‐unimpaired (CU) participants were included from Center for Lifespan Changes in Brain and Cognition (LCBC) (n = 28, age 58.9±16.1y) and University of Singapore (n = 30, age 55.8±6.1y). The Singapore cohort is known to be vascularly compromised and thus expected to have early cerebrovascular pathology in the form of WMH. Multi‐echo, multi‐post‐labeling‐delay pseudo‐continuous ASL images were acquired at two identical Siemens 3T scanners and analyzed with ExploreASL. Gray matter (GM) BBB water time‐of‐exchange (Tex) was quantified with and without partial‐volume correction (PVC). For Singapore data, WMH were segmented on 3D FLAIR. Linear regression models were used to investigate associations of Tex with age and WMH volume, with and without covarying for sex and site.

Result

Both site population‐averages (Figure 1) show similar Tex patterns, with slightly higher posterior variability in the Singapore data. GM Tex was negatively associated with age (Figure 2A) irrespective of PVC, and after covarying for sex and site (Table 1). GM Tex was also negatively associated with WMH volume (ß = ‐0.005, p = 0.012), although the association became non‐significant if both PVC and sex and site corrections were applied (ß = ‐0.005, p = 0.068).

Conclusion

Our findings support the hypothesis of increased BBB permeability with aging and there are signs of association with increased cerebrovascular age assessed with WMH volume. We aim to further increase our sample size and also investigate associations with other AD biomarkers.
Brain‐age prediction and its associations with glial and synaptic CSF markers
Authors: Cumplido‐Mayoral Irene , Milà‐Alomà Marta , Falcon Carles , Cacciaglia Raffaele , Minguillon Carolina , Fauria Karine , Molinuevo Jose Luis , Kollmorgen Gwendlyn , Suridjan Ivonne , Wild Norbert , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Vilaplana Verónica , Gispert Juan Domingo
Published: December 2023

Background

MRI‐derived brain‐age prediction is a promising biomarker of biological brain aging. Accelerated brain aging has been found in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, no previous studies have investigated the relationship between specific pathophysiological pathways in AD and biological brain aging. Here, we studied whether glial activation and synaptic dysfunction are associated with biological brain aging in the earliest stages of the Alzheimer’s continuum.

Method

We included 418 cognitively unimpaired individuals (CU) from the ALFA+ study with available structural MRI, and CSF biomarkers of amyloid‐ß (Aß42/40) and tau pathology (p‐tau181), synaptic dysfunction (neurogranin, GAP43, SYT1, SNAP25), glial activation (sTREM2, YKL40, GFAP, interleukin‐6 and S100b) and a‐synuclein (Table 1). Aß42/40, neurogranin and the glial activation biomarkers were measured using the Roche NeuroToolKit. We computed brain‐age delta as the difference between chronological and predicted brain‐age. The latter was estimated using a previously pretrained machine learning algorithm on cerebral morphological measurements on individuals from the UKBioBank cohort (N = 22.000). General linear modeling was used to test the associations between CSF biomarkers and brain‐age delta, adjusting by p‐tau, age, APOE status and sex. For the biomarkers whose associations were significant, we evaluated the interaction term “biomarker” × AT status while adjusting by age, APOE status and sex. AT staging was performed using pre‐established cut‐off values. We then used hippocampal volume as a marker of AD‐related neurodegeneration and repeated the same association studies with CSF biomarkers, adjusting by p‐tau, age, APOE status, sex and TIV.

Result

Brain‐age delta was negatively associated with CSF sTREM2 (Padjusted<0.001), meaning that younger‐appearing brains showed higher levels of this biomarker (Table 1). None of the other biomarkers survived multiple comparisons. Hippocampal volume was not significantly associated with any of the CSF biomarkers (Table 2). There was no significant interaction between AT status and CSF sTREM2 for brain‐age delta, nor for hippocampal volume.

Conclusion

These results showed that higher levels of CSF sTREM2 were associated with younger‐appearing brains in CU individuals independently of AT status, which might indicate a protective effect of this microglial phenotype in brain aging. This effect might not be AD‐related.
Altered Resting‐state fMRI BOLD Signal Fluctuations in the Spectrum of Alzheimer’s Dementia and in Patients with White Matter Hyperintensities
Authors: Behrenbruch Niklas , Incesoy Enise I , Bernal Jose , Menze Inga , Vockert Niklas , Kleineidam Luca , Buerger Katharina , Wolfsgruber Steffen , Spottke Annika , Fließbach Klaus , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schneider Anja , Heneka Michael T. , Wagner Michael , Teipel Stefan , Wiltfang Jens , Speck Oliver , Perosa Valentina , Yakupov Renat , Jessen Frank , Düzel Emrah , Mattern Hendrik , Schreiber Stefanie , Ziegler Gabriel , Maass Anne
Published: December 2023

Background

Altered fluctuations in blood oxygen level dependent (BOLD) signal during resting‐state functional magnetic resonance imaging (rs‐fMRI) have been considered indicative of decreased cerebrovascular health. Previous studies reported changes in BOLD fluctuations associated with Alzheimer’s dementia (AD) and white matter hyperintensities (WMH). However, to date, there has been no large‐scale study involving patients with AD, mild cognitive impairment (MCI), subjective cognitive decline (SCD), and control subjects (CON) that has explored local AD‐ and WMH‐related effects in BOLD fluctuations.

Method

We calculated the voxel‐based coefficient of variation (CV: standard deviation divided by the mean) and the relative CV (rCV: CV divided by the mean CV of the whole‐brain) of the rs‐fMRI BOLD signal in the large multicentric DZNE DELCODE cohort. After spatial preprocessing, regression of movement parameters, movement spikes, and scanner drift, low‐pass filtering and exclusion of subjects with high motion, CV and rCV maps were obtained and compared with respect to (A) clinical diagnosis (AD: n = 79; MCI: n = 113; SCD: n = 314; CON: n = 192) and cerebrospinal fluid Aß42/40 (AD: n = 41; MCI: n = 64; SCD: n = 139; CON: n = 77); and (B) effects of vascular‐related lesions, here WMH.

Result

The CV and rCV of the precuneus and middle cingulum indicated increasingly reduced BOLD fluctuation across the clinical groups towards AD. Interestingly, we observed increases in rCV in the basal ganglia and frontal white matter in AD compared with CON. Of note, lower CSF Aß42/40 (more pathological) was associated to reduced CV and rCV in the precuneus and with lower rCV in the right angular gyrus. Subjects with higher WMH volume showed widespread reductions of CV in white matter near the left angular gyrus and reduced rCV in large portions of white matter and subcortical gray matter.

Conclusion

The AD spectrum exhibits altered BOLD fluctuations that are at least partially tied to actual amyloid differences. Larger WMH are associated with reduced BOLD signal fluctuations consistent with widespread white matter pathology ‐ beyond the effects of diagnosis. We argue that rCV is a useful complement to CV to detect these changes that might reflect cerebrovascular impairment.
Comparison of Expert Reads vs. Local Clinical Reads of Amyloid PET Scans in IDEAS
Authors: Windon Charles , Zeltzer Ehud , Hanna Lucy , Carrillo Maria C. , Iaccarino Leonardo , La Joie Renaud , March Andrew , Mejía Jhony Alejadro , Mundada Nidhi , Arora Anupa , Bullich Santiago , Sherwin Paul , Siegel Barry A , Gatsonis Constantine , Rabinovici Gil D.
Published: December 2023

Background

Amyloid‐directed therapies will increase the clinical use of amyloid PET. IDEAS captured >17,000 clinical scan interpretations from local radiologists and nuclear medicine physicians. This study aimed to establish accuracy of these interpretations by comparison to expert readers across identical scans.

Method

Randomly selected amyloid PET/CT scans performed using one of three FDA‐approved agents [18F‐Florbetaben (FBB), 18F‐Florbetapir (FBP), 18F‐Flutemetamol (FMM)] and previously interpreted by local readers from the Imaging Dementia ‐ Evidence for Amyloid Scanning (IDEAS) study were assigned to vendor‐selected panels of 3 expert readers for interpretation; 500 scans per agent and 1 panel per agent. Scans were stratified to match frequencies observed in the overall study by 1) participant age; 2) MCI vs dementia; 3) positive/negative interpretation; and 4) type of PET facility. Respective vendors performed quality control on attenuation‐corrected PET/CT images. Visual interpretations (positive or negative for Aß cortical deposition) were performed according to agent‐specific validated interpretation criteria. Expert panel readers were blinded to clinical and demographic data. Cohen’s kappa statistic with two‐sided 95% confidence interval estimates examined agreement between local reader and majority expert panel visual interpretation.

Result

Expert panel readers’ visual interpretations totaled 4489. Median age for scanned participants was 75 (range 65‐96), 51.4% were female and 60.5% had MCI. Local readers interpreted 60.9% of scans positive and 39.1% negative (Table 1). Across all radiotracers, agreement between majority expert read and local readers was excellent (k coefficient 0.76; 95% CI 0.73 – 0.80, p<.0001) with 86.6% (791/913) agreement for positive scans and 90.9% (532/585) agreement for negative scans (Figure 1). Agreement by individual radiopharmaceuticals was good to excellent: k coefficient 0.78 (95% CI 0.72 – 0.83, p<.001) for FBB, k coefficient 0.72 (95% CI 0.66 – 0.78, p<.001) for FBP, and k coefficient 0.78 (95% CI 0.73 – 0.84) for FMM (Figure 1). Agreement levels between local readers and individual experts varied from good to excellent (Figure 2).

Conclusion

We found good to excellent agreement between local readers and majority assessment of three‐member expert panels for all combined scans and scans by individual agents. Visual interpretation of Aß PET can be performed in a clinical setting with high reliability.