bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal cortical atrophy in cases of AT concordance and discordance
Authors: Ioannou Konstantinos , Mohanty Rosaleena , Poulakis Konstantinos , Leuzy Antoine , Muehlboeck J‐Sebastian , Rodriguez‐Vieitez Elena , Westman Eric , Chiotis Konstantinos 
Published: January 2025

AbstractBackgroundAlthough ß‐amyloid and tau PET positivity (A+T+) has been related to neurodegeneration and cognitive decline in Alzheimer’s disease (AD), the driving force of neurodegeneration in discordant AT cases remains controversial. We investigated the impact of AT status on longitudinal rates of cortical atrophy and cognitive decline.MethodA subset of 349 individuals (cognitively unimpaired [CU; n = 230], cognitively impaired [CI; n = 119]) with ß‐amyloid and tau PET (a priori baseline), longitudinal MRI (interval; Mean = 4.5±3.3 years, scans/individual; Median = 3, IQR = [2, 8]), and a cognitive follow‐up = 2 years, was selected from the ADNI dataset. We classified the individuals based on their AT PET status (A+; global ß‐amyloid = 20 CL, T+; composite temporal region = 1.34 SUVR) and clustered them based on their annual rates of cognitive decline on the ADAS‐Cog13 (fast vs. slow decliners [FDs vs. SDs]). Baseline AD‐signature cortical thickness was compared across AT groups. We employed a linear mixed‐effects model to assess the interaction between AT status and longitudinal cortical thickness across all cortical regions.ResultsDemographic characteristics were similar across AT groups (A‐T‐; n = 192, A‐T+; n = 5, A+T‐; n = 106, A+T+; n = 46). Most A+T+ individuals (70%) were CI, whereas most A+T‐ (71%), A‐T+ (80%), and A‐T‐ (71%) individuals were CU. Similarly, most A+T+ individuals (85%) were characterized as FDs, whereas most A+T‐ (74%), A‐T+ (60%), and A‐T‐ (88%) individuals were characterized as SDs. A+T+ individuals showed significantly lower AD‐signature cortical thickness (MeanA+T+ = 2.78±0.19 mm) compared to A+T‐ (MeanA+T‐ = 2.89±0.15 mm; P = 0.0023) and A‐T‐ (MeanA‐T‐ = 2.89±0.15 mm; P<0.001) individuals, and the highest Aß burden (Mean = 85.3±30.6 CL; P<0.0001) at baseline. AT status significantly influenced longitudinal cortical thickness. A+T+ individuals showed significantly steeper cortical thinning rates compared to A‐T‐ individuals, primarily in temporoparietal areas. Despite similar group‐level cortical thinning rates with A‐T‐ individuals, A+T‐ individuals showed heterogeneous patterns of cortical atrophy at the individual level. These findings remained consistent even when conducting separate analyses for CU and CI individuals.ConclusionUnlike AT discordance, concordant AT positivity exhibited homogeneous cortical atrophy patterns consistent with AD. Considering the concurrent high prevalence of mixed pathologies in neuropathological AD, we further aim to explore the underlying neurodegenerative force in discordant AT cases.
Correlations of antemortem [18F]MK‐6240 PET with ROI‐matched postmortem biochemical assessment of total tau and tau phospho‐epitopes pThr181, pSer199, pThr231, and pSer396
Authors: Betthauser Tobey J. , Abrahamson Eric E , De Chavez Elena Ruiz , Teague Jordan P , McVea Andrew K , Deming Yuetiva , Schroeder Brooke E , Barger Madeleine R , Johnson Sterling C. , Asthana Sanjay , Villemagne Victor L , Christian Bradley T. , Salamat Shahriar , Ikonomovic Milos D 
Published: January 2025

AbstractBackground[18F]MK‐6240 was developed for PET imaging of AD tau pathology, but the exact molecular signature of specific binding remains unclear. This study quantified levels of four phospho‐tau forms and total tau in postmortem brain tissues from [18F]MK‐6240 imaged cases to investigate associations with antemortem [18F]MK‐6240 PET.MethodsThis study included four participants from the Wisconsin ADRC or WRAP with antemortem [18F]MK‐6240 and [11C]PiB PET imaging and postmortem brain tissue obtained on average 32‐months after imaging (Table 1). Parametric SUVR were generated using T1‐w MRI to delineate regions matched to equivalent ROIs on fresh frozen brain tissue slabs. Tissue ROI dissected from ten brain regions per case were homogenized and ELISA was used to quantify concentrations of guanidine‐extracted total tau and tau phosphorylated at epitopes pThr181, pSer199, pThr231, and pSer396.ResultsMatched PET‐autopsy ROI analysis showed significant correlations of higher [18F]MK‐6240 SUVR with higher levels of all measured p‐tau forms or their ratios to total tau across all regions and cases. Analyses of two A+T+ cases with clinical AD dementia and postmortem Thal Phase 5/Braak NFT Stage VI showed higher [18F]MK‐6240 SUVR correlated significantly with higher levels of pThr181, pSer199, pThr231, and pSer396 tau or their ratios to total tau in a 79‐yo APOE‐e4e4 case, and with higher levels of pThr231 and pSer396 tau in a 78‐yo APOE‐e3e3 case. In two T‐ cases, we observed weak correlations of [18F]MK‐6240 SUVR with pThr181 and pSer396 tau in an A‐T‐ cognitively unimpaired case (Thal Phase 2/Braak NFT Stage II; 70‐yo; APOE‐e3e3), but no correlations in A+T‐ early‐onset AD dementia case with Thal Phase 4/Braak NFT Stage V (63‐yo; APOE‐e4e4). This latter case also had high [18F]MK‐6240 uptake outside the brain and a low tangle density outside the MTL.ConclusionsHigher [18F]MK‐6240 PET binding reflects high brain concentrations of pThr181, pSer199, pThr231, and pSer396 tau in AD dementia cases with high AD neuropathological change. Lack of associations between PET and p‐tau biochemistry in the T‐, Braak V early‐onset dementia case suggests that the T‐ PET status is more closely associated with p‐tau biochemistry than postmortem neuropathological staging, likely due to low tangle density.
Diabetes and brain MRI measures: results from SOL‐INCA MRI study
Authors: Gonzalez Kevin A , Tarraf Wassim , Banks Sarah , Bangen Katherine J. , Pa Judy , Gallo Linda C , Stickel Ariana M , Filigrana Paola , Isasi Carmen R , Daviglus Martha L , Testai Fernando Daniel , Decarli Charles , Gonzalez Hector M 
Published: January 2025

AbstractBackgroundHispanic/Latino communities in the US are rapidly growing and aging and are at two‐fold risk of Alzheimer’s Disease and Related Dementia’s (ADRD) compared to non‐Hispanic Whites. This additional risk could be, in part, due to increased risk of cardiovascular disease. Hispanics/Latinos also have higher rate of diabetes compared to non‐Hispanic Whites and nearly 2 out of 5 individuals with diabetes go undiagnosed. While diabetes has been linked to white matter hyperintensities (WMHs), less is known about the magnitude in diverse Hispanics/Latinos and even fewer studies have considered links to other neurobiological endpoints in this population. This work aims to clarify these associations in a deeply characterized diverse middle‐aged and older Latino cohort.MethodWe used data from the Study of Latinos‐Investigation of Neurocognitive Aging (SOL‐INCA) MRI study which is an ancillary study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The goal of SOL‐INCA MRI is to understand cerebrovascular pathology and ADRD etiology using MRI. A total of N = 2400 middle aged and older (50+ years) and N = 400 younger (35‐49 years) participants were recruited from the parent HCHS/SOL study. Diabetes was assessed using both continuous HbA1c % and recommended ADA cutoffs to assess prediabetes and diabetes status. Outcomes included structural (i.e., volumes; WMHs, total brain, regional and total gray matter volumes, lateral ventricles, hippocampus) and diffusion MRI (free water = FW, fractional anisotropy = FA). Survey weighted linear models (covariate adjusted by important confounders) were used to test the associations between our exposures and outcomes of interest.ResultCompared to no diabetes, diabetes was linked to smaller total brain and occipital volumes, larger WMHs, larger lateral ventricles, lower FA, and higher FW (Figure 1). Higher levels of HbA1c % (treated continuously) were additionally associated with smaller occipital and larger hippocampal volumes (Figure 2). These findings were consistent across men and women. We did not find significant differences with the pre‐diabetes group.ConclusionOur findings suggest that elevated HbA1c and diabetes status are linked to cerebrovascular pathology and brain atrophy. Findings with hippocampal volume could be due to maladaptive process or hypertrophy. Further research is needed to understand different neurobiological mechanisms in understudied communities.
Early Alterations of White Matter Neuroinflammation in Autosomal Dominant Alzheimer's Disease
Authors: Wang Qing , Jiang Meng , Cohen Kayle , Flores Shaney , Keefe Sarah J. , Patel Aakash , Chen Gengsheng , Millar Peter R , Schindler Suzanne E. , Cruchaga Carlos , Gordon Brian A. , Morris John C. , Bateman Randall J. , McDade Eric , Wang Yong , Benzinger Tammie L.S. 
Published: January 2025

AbstractBackgroundAutosomal Dominant Alzheimer's Disease (ADAD) is a rare and early‐onset form of Alzheimer's disease with a familial pattern of inheritance. While the pathological features of ADAD, such as amyloid plaques and neurofibrillary tangles, have been extensively studied, the involvement of white matter (WM) neuroinflammation is not well‐explored. In sporadic AD, the hindered ratio (HR) derived from diffusion basis spectrum imaging (DBSI) has been used to study neuroinflammation in WM. This study aims to investigate the potential role of WM neuroinflammation as an early driver in the progression of ADAD using DBSI.MethodThis study included 104 participants from the Dominantly Inherited Alzheimer Network (DIAN) Observational Study. 60 participants were identified as mutation carriers of pathologic variants in PSEN1, PSEN2, or APP. Estimated years until symptom onset (EYO) were calculated for each participant based on previous methods (1). Participants’ demographics are summarized in Table 1. Diffusion MRI was acquired using a multi‐b value scheme (bmax =2000 s/mm2 and 28 directions) (2). The DBSI‐HR was quantified and obtained from the JHU white matter tracts. Non‐parametric Kruskal‐Wallis and Chi‐square tests were employed to compare demographic variables. The DBSI‐HR on each WM tract as a function of EYO was explored using generalized additive mixed models. All statistical tests were conducted in R4.2.2 (R Core Team). Age, sex, education, and APOE e4 carrier status were adjusted as covariates.ResultDemographic data are summarized in Table 1. Mutation carriers had an elevated averaged DBSI‐HR for total WM tracts compared to non‐carriers (Fig. 1). Mutation carriers displayed divergent trends from non‐carriers prior to the expected symptom onset for the posterior thalamic radiation (‐5.87 EYO, Fig. 2), tapetum (‐2.9 EYO), and sagittal stratum (‐1.20 EYO).ConclusionDBSI‐HR measurements indicate increased WM neuroinflammation in the posterior thalamic radiation, tapetum, and sagittal stratum prior to symptom onset in ADAD. We have recently identified these three WM tracts as having the earliest change in DBSI‐HR in sporadic AD. Together, these findings suggest that WM neuroinflammation occurs prior to onset of AD symptoms.
Atrophy Network Mapping of Anxiety in Cognitively Unimpaired Older Adults in Preclinical AD
Authors: Lee Soyoung , Palm Stephan T , Drew William J , Zide Benjamin S , Donovan Nancy , Fox Michael D , Siddiqi Shan 
Published: January 2025

AbstractBackgroundAnxiety is prevalent among cognitively unimpaired older adults and is associated with accelerated amyloid‐ß‐related cognitive decline and incident cognitive impairment. Investigating these mechanisms is challenging due to low pathologic burden, high individual variability, and subsyndromal level of symptoms. Recently, brain networks involved in AD were successfully localized by mapping the brain connectivity of atrophy patterns associated with memory impairment and delusions. In this study, we investigated anxiety symptoms in older adults with elevated amyloid‐ß using the novel method of atrophy network mapping.MethodWe utilized baseline data from ∼1800 cognitively unimpaired older adults, aged 65‐85, from the Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) trial, including clinical assessment of anxiety measured by the 6‐item State‐Trait Anxiety Inventory as well as structural brain MRI and amyloid‐ß (18F‐florbetapir) PET acquisitions. We generated a vertex‐wise general linear model of cortical thickness to create individualized atrophy maps for each participant with elevated amyloid‐ß deposition, using data from older adults with low amyloid‐ß deposition as a control group. Then, we used a normative human connectome (n = 1000) to estimate the functional connectivity of each participant’s unique atrophy pattern. From the network connectivity maps, we identified atrophy‐based brain networks associated with higher anxiety. To validate this brain network, we performed a spatial correlation with a pre‐established anxiosomatic network derived from focal brain stimulation sites that selectively modify anxiety and assessed significance using permutation testing. We hypothesized that atrophy patterns associated with greater anxiety would correspond to this anxiosomatic network.ResultAnxiety symptoms localized to a distinct brain network based on individuals' atrophy patterns. The identified brain network was correlated to the anxiosomatic network (r = 0.65), and the correlation was stronger when controlled for depressive symptoms (r = 0.67). The network was more similar to the anxiosomatic network than expected by chance (p<0.05).ConclusionWe identified a brain network associated with anxiety symptoms in cognitively unimpaired older adults with elevated amyloid‐ß. These findings help elucidate a neuropathophysiology of anxiety in preclinical AD and, possibly, its role in disease progression. The brain network identified in this project could yield new neurostimulation targets for anxiety in older adults across the AD continuum.
Astrocyte reactivity associates with tau phosphorylation and neurodegeneration before detectable amyloid‐β pathology
Authors: Saha Pampa , Povala Guilherme , Ferreira Pamela C.L. , Amaral Livia , Abbas Sarah , Lussier Firoza Z , Rodrigues Matheus Scarpatto , Oliveira Markley , Rahmouni Nesrine , Tissot Cécile , Soares Carolina , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Hong Chang‐Hyung , Roh Hyun Woong , Karim Helmet T. , Benedet Andrea L. , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Karikari Thomas K , Kim Sang Joon , Bellaver Bruna , Pascoal Tharick Ali 
Published: January 2025

AbstractBackgroundAß plaques are the first detectable signs of AD pathology. Our group recently demonstrated that the astrocyte activation marker, glial fibrillary acidic protein (GFAP), has a pivotal role in the association between Aß burden and tau phosphorylation. However, the role of astrocyte activation in individuals that do not present detectable Aß pathology using biomarkers is still underexplored. Here we sought to understand the association between plasma GFAP with tau phosphorylation and neurodegeneration in Aß negative individuals.Method598 study participants [cognitively unimpaired, (CU)=200, and cognitively impaired, (CI)=398] from two cohorts (TRIAD, Canada and BICWALZ, South Korea) were assessed for Aß‐PET, plasma GFAP, p‐tau217, NfL, and hippocampal volume measures. Pearson correlations between plasma GFAP and plasma p‐tau217, plasma NfL along with hippocampal volume was performed in Aß‐PET negative individuals.ResultRemarkably, we found that plasma GFAP levels positively correlate with plasma p‐tau217 levels in Aß‐PET negative individuals in both cohorts [TRIAD cohort: r=0.23, p=0.01; BICWALZ cohort: r=0.21, p=0.0001; Figure: 1A, B]. Further, the correlation between plasma GFAP with plasma NfL has also been found to be positively correlated among the two cohorts [TRIAD cohort: r=0.45, p=0.0001; BICWALZ cohort: r=0.49, p=0.0001; Figure: 2A, B]. We also observed that hippocampal volume, as a neurodegeneration marker, reveals a significant negative Pearson correlation with plasma GFAP levels in Aß‐PET negative human individuals from both the cohorts [TRIAD cohort: r=‐0.27, p=0.0009; BICWALZ cohort: r=‐0.24, p=0.0001; Figure: 3A, B].ConclusionOur study provides evidence from research and clinical cohorts that astrocyte reactivity may be associated with very early tau phosphorylation and neurodegeneration in the absence of Aß pathology.
Poor sleep is adversely associated with MRI markers of AD‐specific neurodegeneration
Authors: Shi Hui , Archer Derek B. , Perry Arden , Pechman Kimberly R. , Shashikumar Niranjana , Landman Bennett A. , Hohman Timothy J. , Jefferson Angela L. , Full Kelsie M 
Published: January 2025

AbstractBackgroundPoor sleep has emerged as a potentially modifiable risk factor for Alzheimer’s disease (AD) and related dementias (ADRD). Few previous studies have incorporated objectively‐measured sleep and structural neuroimaging to understand if poor sleep relates to changes in brain structure. In a cohort of older adults, we investigated actigraphy‐measured sleep health and associations with well‐established magnetic resonance imaging (MRI) markers of AD‐specific neurodegeneration.MethodParticipants from the Vanderbilt Memory and Aging Project (n=390, Mean age: 69.5± 9.3 year; 47.4% women) wore ActiGraph GT9X accelerometers on their wrist daily for 10 days. Data were processed to estimate sleep regularity, wake after sleep onset (WASO), average awakening length, sleep fragmentation index, sleep timing, and sleep duration. 3T brain MRI was used to quantify hippocampal volume and to estimate the McEvoy AD signature (calculated according to published guidelines). We used cross‐sectional multivariate linear regression to assess the associations between individual sleep measures and neuroimaging markers. Models adjusted for age, sex, race, education, APOE‐e4 status, cognitive status, sleep medication use, body mass, index, physical activity, depressive symptoms, and cardiovascular risk. For sleep timing and duration, quadratic terms were added in regression models. Models examining the total hippocampal volume also adjusted for intracranial volume.ResultIn the fully adjusted models, we found abnormal sleep duration (ß = ‐2.35, 95% CI = ‐4.58, ‐0.11) and greater sleep irregularity (ß = ‐0.34, 95% CI = ‐0.62, ‐0.07) were associated with lower AD signature values. Additionally, greater sleep irregularity (ß = ‐262.36; 95% CI = ‐451.71, ‐73.00), greater WASO (ß = ‐2.76; 95% CI = ‐5.30, ‐0.21) and greater average awakening length (ß = ‐74.20; 95% CI = ‐128.47, ‐19.94) were associated with lower hippocampal volumes.ConclusionOur results suggest that several measures of poor sleep, including greater sleep irregularity, wake time, and sleep fragmentation, are cross‐sectionally linked to smaller hippocampal volume and smaller brain volumes in regions most affected by AD neuropathology. Longitudinal studies are needed to clarify if poor sleep contributes to brain atrophy over time.
Regional microglial activation differs across the cortex of patients in the Alzheimer's disease trajectory: a cross‐sectional study
Authors: Tuil Marie Emilie , Calsolaro Valeria , Crook Harry , Femminella Grazia Daniela , Pasqualetti Giuseppe , Buckley Christopher , Trigg William , Gentleman Steve , Brooks David J , Jogaudaite Simona , Abarrategui Javier Alegre , Hinz Rainer , Edison Paul 
Published: January 2025

AbstractBackgroundMicroglial reactivity and neuroinflammation are crucial pathological processes in Alzheimer’s Disease (AD). Several attempts to develop a treatment by supressing the immune response in AD have been made, yet these yielded very limited results. Recent studies suggest contrasting effects of microglial reactivity, indicating a biphasic response with both beneficial and deleterious effects at distinct stages of AD. We evaluated the regional differential influence of microglial reactivity on neuropathological processes across AD trajectory.Method48 patients were divided by diagnosis into control (11), Mild Cognitive Impairment (MCI, 14), and AD (23) groups. They underwent TSPO‐PET imaging, magnetic resonance imaging (MRI), and neuropsychological testing. The spectral analysis generated a TSPO‐PET impulse response function at 90 minutes (IRF90), reflecting its volume of distribution. Region of interest and voxel‐level analyses were performed, and grey matter (GM) volume was calculated using FreeSurfer and voxel‐based morphometric analysis. Additionally, post mortem brain tissue from 27 patients at Braak Stages IV‐VI was stained for CD32a and CD163, markers of pro and anti‐inflammatory activation respectively.ResultThe AD group showed increased microglial reactivity in the temporal, parietal, occipital, and medio‐temporal lobes, and the cingulate cortex compared to controls. Voxel‐wide analyses of AD and MCI patients yielded similar results across the cortex. The voxel‐wise analysis revealed both positive and negative clusters of association between tracer uptake and GM volume, with negative associations more often found in regions affected earlier in AD trajectory. This dual effect is further denoted by the presence of both CD32a‐positive and CD164‐positive microglia within the same regions in post mortem tissue.ConclusionThe contrasting effects of reactive microglia on different pathological processes show regional disparities, with deleterious effects more closely associated with regions affected in the early stages of AD. This suggests a diverging response driven by both anti‐ and pro‐inflammatory reactivity profiles. The former, neuroprotective, would emerge locally alongside early pathology, while the later, neurotoxic, would only appear with more advanced pathology. Consequently, potential treatments should promote anti‐inflammatory polarization and supress pro‐inflammatory activation in microglia for an effective therapeutic strategy.