bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synaptic dysfunction in the presence of tau tangles is not a strong predictor of atrophy
Authors: Soares Carolina , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Aguzzoli Cristiano Schaffer , Rohden Francieli , Ferrari‐Souza João Pedro , Zalzale Hussein , Abbas Sarah , Lemaire Peter Charles , Leffa Douglas Teixeira , Cabrera Arlec , Therriault Joseph , Benedet Andrea Lessa , Tissot Cécile , Servaes Stijn , Macedo Arthur C. , Vermeiren Marie , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Cohen Annie , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Villemagne Victor L , Soucy Jean‐Paul , Gauthier Serge , Souza Diogo O. , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Zimmer Eduardo R , Pascoal Tharick A. 
Published: December 2023

AbstractBackgroundTau plays a prominent role in the synapse and has been shown to be closely related to neurodegeneration. Recent evidence show that cerebrospinal fluid (CSF) synaptic markers are related to CSF tau and degeneration. However, it is not clear whether synaptic dysfunction in combination with tau tangles is associated with neurodegeneration in the same brain regions. Our study aims to map in the brain the association of synaptic markers with tau and degeneration.MethodWe evaluated 147 individuals from the TRIAD cohort with CSF GAP43, SYT1, SNAP25, neurogranin (Ng), ptau217, neurofilament light protein (NfL) quantification, as well as tau positron emission tomography (PET), magnetic resonance imaging, and clinical assessments. One‐way ANOVA tested group differences on synaptic levels. Spearman correlation tested the association among synaptic proteins. Linear regressions tested the association between biomarkers. Voxel‐based morphometry (VBM) was considered as an index of neurodegeneration.ResultWe observed an increase in synaptic markers across age and the AD spectrum, reaching a plateau when cognition is affected (Figure 1A). Among the synaptic markers, SNAP25 showed the greatest magnitude of change, on average, between young, aged cognitively unimpaired, mild cognitive impaired, and AD individuals (mean 62.44%). (Figure 1B‐C). In addition, we found that all synaptic markers are significantly intercorrelated (Figure 1D). Moreover, CSF ptau217 correlated with all synaptic biomarkers, GAP43 (ß = ‐044), SYT1 (ß = ‐0.41), SNAP25 (ß = ‐0.59) and Ng (ß = ‐0.25). Conversely, CSF NfL was strongly but only correlated with GAP43 (ß = 0.62) (Figure 2). Voxel‐wise correlation revealed that tau tangles measured by [18F]‐MK6240 PET, was positively associated with SNAP25 in AD‐related regions, and VBM was associated with all synaptic markers, but more closely with GAP43. Furthermore, the interaction between synaptic markers and temporal meta‐ROI [18F]‐MK6240 on VBM was significant for Ng and GAP43 (Figure 3).ConclusionOur results support a heterogenous role of synaptic markers in the AD continuum and suggest that synaptic dysfunction in the presence of tau pathology may not be driving atrophy.
Altered cerebrovascular reactivity along functional networks in older adults with long COVID
Authors: Pommy Jessica , Cohen Alexander D , Patel Milan , Umfleet Laura Glass , Franczak Malgorzata , Brett Benjamin L , Obarski Shawn , Agarwal Mohit , Ristow Kelly , Swanson Sara J , Wang Yang 
Published: December 2023

AbstractBackgroundCerebrovascular reactivity (CVR), an indicator of neurovascular function associated with cognitive decline, relies on vascular and inflammatory processes, making it a potential mechanism of interest driving neurological changes in long COVID among older adults. Given the variability in symptoms associated with long COVID, distribution corrected z‐scores (DisCo‐Z), a subject‐specific abnormalities (SSA) approach more suited for heterogenous conditions, was employed to examine CVR and long COVID in older adults. Relationships between CVR, post‐COVID subjective cognitive decline (pcSCD), and cognitive function were examined.Method15 older adults with long COVID (M age = 63.9, 6 males) and 24 healthy older adults (M age = 66.7, 6 males) performed a breath‐holding task while in the MR scanner to examine CVR. DisCo‐Z was used to examine the presence and size of extreme clusters of increased or decreased CVR (>100 voxels) within the 7 Yeo functional networks. Non‐parametric tests were used to examine group differences in presence and mean size of extreme clusters. Finally, relationships between: 1) extent of pcSCD and extreme cluster values in long COVID, and 2) cognitive testing scores and global “burden” (cluster size mean and sum) were examined.ResultGroups did not differ significantly on gender (p = .323) or age (p = .324). Greater incidence of positive extreme clusters within Ventral Attention (p = .028) and Limbic (p = .049) networks were observed in long COVID (with minimal incidences of negative extreme clusters across networks). Group differences were observed for mean cluster size in the Ventral Attention network (p = .016), as well. Extent of pcSCD was positively correlated with DisCo‐Z values for the Ventral Attention network (p = .021) with a trending level of significance for the Limbic network (p = 0.053). Finally, within the full sample, global CVR burden was negatively correlated with memory test scores (p = 0.014).ConclusionUsing the SSA approach, group differences in CVR were observed in older adults experiencing long COVID. In particular, differences were observed within functional networks thought to drive attention, executive function, and emotional control, which was correlated with pcSCD. Finally, global CVR burden was negatively correlated with memory. These findings, though preliminary, suggest CVR may represent a potential neurobiological mechanism driving pcSCD in older adults.
The investigation of hippocampal free‐water as a biomarker for cognitive impairment and decline in older adults
Authors: Sathe Aditi , Shashikumar Niranjana , Moore Elizabeth E. , Pechman Kimberly R. , Landman Bennett A. , Gifford Katherine A. , Hohman Timothy J. , Jefferson Angela L. , Archer Derek B 
Published: December 2023

AbstractBackgroundWhile diffusion MRI derived free‐water (FW) metrics have shown promise in predicting cognitive impairment and decline in aging and Alzheimer’s disease (AD), it is unclear whether hippocampal FW metrics would be superior to traditional structural neuroimaging biomarkers (i.e., hippocampal volume, AD Schwarz Signature, AD McEvoy Signature). We examined the relationships between hippocampal FW metrics and traditional neuroimaging biomarkers with longitudinal memory and executive function.MethodVanderbilt Memory & Aging Project participants [n = 298, age at baseline: 73 ± 7 years, 40% mild cognitive impairment (MCI)] underwent longitudinal neuropsychological assessment and brain MRI over a 7 year follow‐up (mean: 3 ± 2 years) period. Structural MRI was used to quantify hippocampal volume in addition to Schwarz and McEvoy signatures. Diffusion MRI in conjunction with the FW elimination technique was used to quantify hippocampal FW and FW‐corrected fractional anisotropy (FAFWcorr). Linear regression was used to determine the association of each biomarker with baseline memory and executive function. A subsequent competitive model analysis was conducted to determine how much additional variance was provided by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein‐e4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. Additionally, linear mixed‐effects regression was used to determine the association between baseline biomarker values with longitudinal memory and executive function scores. All analyses were corrected for multiple comparisons using the FDR procedure.ResultAt baseline, all biomarkers (excluding hippocampal FAFWcorr) were significantly associated with cognitive performance (Table 1), with hippocampal FW exhibiting the most significant association for memory (pFDR = 3.92×10‐6) and executive function (pFDR = 5.35×10‐3). Competitive models revealed that hippocampal FW contributed the most unique variance beyond covariates for memory (ΔRadj2 = 3.87%) and executive function (ΔRadj2 = 1.59%). Longitudinal models (Table 2, Figure 1) largely mirrored cross‐sectional models by demonstrating that hippocampal FW was most significantly associated with longitudinal decline in memory (pFDR = 5.04×10‐13) and executive function (pFDR = 6.15×10‐5).ConclusionThis study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD.
White Matter Correlates of Speech in Cerebrovascular Disease
Authors: Broberg Dana N , Haddad Seyyed MH , Aveni Katharine , Havens Alexander , Orange Joseph B , McLaughlin Paula , Binns Malcolm , Roberts Angela C , Bartha Robert 
Published: December 2023

AbstractBackgroundAnalyses of spoken discourse (speech beyond single words or sentences) can detect cognitive impairment in cerebrovascular disease (CVD) [Roberts, et al. (2021). Top Lang Disord 41(1):73‐98]. However, the neurological basis for altered spoken discourse in CVD is poorly defined. This study examined the association between spoken discourse and visible white matter damage detected using structural magnetic resonance imaging (MRI) and potential early‐stage damage in normal‐appearing white matter (NAWM) detected using diffusion tensor imaging (DTI) to better define the link between CVD‐related neurodegeneration and altered speech.MethodSpoken discourse and 3T MRI data were obtained from the CVD cohort of the Ontario Neurodegenerative Disease Research Initiative (n = 127). Spoken discourse analyses were completed previously [Roberts et al., 2021]. White matter hyperintensities (WMH) and the NAWM portions of the inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus – parietal (SLFp) and temporal (SLFt) endings, and uncinate fasciculus (UNC) were segmented in each hemisphere (Figure 1). Mean values of fractional anisotropy (FA) and mean diffusivity (MD) within NAWM, and normalized WMH volume were calculated for each of the white matter tracts. Three canonical correlation analyses examined associations between 10 spoken discourse measures and the imaging metrics (WMH volume, FA, MD) in each tract.ResultCanonical correlations were significant for FA (rc = 0.51, p<0.05) and MD (rc = 0.56, p<0.05) but not WMH volume (rc = 0.42, p = 0.69). Among the white matter tracts, the strongest canonical loadings were seen for FA and MD in the left SLFp (FA: 0.80; MD: ‐0.61) and left SLFt (FA: 0.60; MD: ‐0.40) (Figure 2). Higher FA and lower MD in the left SLFp and left SLFt were associated with fluency, information content, and syntax performance.ConclusionSpoken discourse performance was associated with microstructural integrity of NAWM but not visible white matter damage. These results suggest that DTI metrics provide a more relevant assessment of white matter tract function in relation to speech than a volumetric measure of tract lesion load. Of the white matter tracts investigated in this study, spoken discourse performance in CVD was most strongly linked to white matter microstructure in the parietal and temporal endings of the left superior longitudinal fasciculus.
Increased CSF GAP‐43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease
Authors: Franzmeier Nicolai , Dehsarvi Amir , Steward Anna , Biel Davina , Dewenter Anna , Roemer Sebastian Niclas , Wanger Fabian , Brendel Matthias , Ewers Michael , Moscoso Alexis , Blennow Kaj , Zetterberg Henrik , Schöll Michael 
Published: December 2023

AbstractBackgroundAnimal and in vitro studies of Alzheimer’s disease (AD) found that tau spreads trans‐synaptically in an activity‐dependent manner, suggesting that synapses are key routes for tau spread. Importantly, amyloid‐beta (Ab) induces synaptic remodeling and aberrant synaptic activity, which may accelerate trans‐synaptic tau spread. In AD patients, we found previously that PET‐assessed tau spreads from circumscribed epicenters across functionally connected brain regions. Yet, it remains unclear whether connectivity‐associated spread of tau in AD is accelerated by Ab‐related synaptic changes. The presynaptic growth‐associated protein 43 (GAP‐43) is implicated in synaptic plasticity and is consistently increased in cerebrospinal fluid (CSF) in AD, suggesting that GAP‐43 captures deviations in synaptic integrity such as aberrant synaptic activity. We therefore tested whether higher GAP‐43 is associated with faster Ab‐related tau spread.MethodWe included longitudinal [18F]Flortaucipir tau‐PET (follow‐up∼3.21±1.48yrs), baseline [18F]Florbetapir amyloid‐PET and CSF GAP‐43 from 93 subjects (i.e., cognitively normal [CN] controls Ab‐, n = 54; CN/Mild Cognitive Impairment Ab+, n = 33/21). To model connectivity‐associated tau spread, we determined a connectivity template across 200 cortical regions (i.e., Schaefer atlas) using 3T multi‐band resting‐state fMRI in 42 age‐ and sex‐matched Ab‐/tau‐ controls. All statistical models were controlled for age, sex and diagnosis.ResultUsing linear regression, we found that higher CSF GAP‐43 levels were associated with faster Ab‐related tau‐PET increase in pre‐defined ROIs (centiloid x GAP‐43 interaction, global/temporal‐meta‐ROI: b = 0.0019/0.0028; p = 0.009/0.007, Fig.1) as well as in the personalized Q1 ROI (b = 0.0024; p = 0.004) that summarizes regions most closely connected to subject‐specific tau epicenters with highest baseline tau‐PET (Fig.2A). Importantly, this centiloid x GAP‐43 interaction decreased across regions less strongly connected to tau epicenters (Q2/Q3/Q4: b = 0.0017/0.0008/0.0002; p = 0.009/0.080/0.344, Fig.2B‐D, 3A). Further, we quantified subject‐specific connectivity‐associated tau spread (i.e., the regression‐derived association between epicenter connectivity and tau‐PET increase in remaining brain regions). Here, higher CSF GAP‐43 was associated with a stronger association between Ab and connectivity‐associated tau spread (centiloid x GAP‐43 interaction, b = ‐0.0031; p = 0.037, Fig.3B).ConclusionHigher CSF GAP‐43 is associated with faster Ab‐related tau spread across interconnected brain regions in AD, suggesting that AD‐related synaptic abnormalities are associated with accelerated tau spread rendering synaptic changes a potential treatment target to attenuate tau spreading.
Tau deposition patterns within the medial temporal lobe follow the connectivity of the entorhinal cortex – a combined post‐mortem and 7T fMRI study
Authors: Franzmeier Nicolai , Berron David , Binette Alexa Pichet , Grande Xenia , Hansson Oskar , Ossenkoppele Rik 
Published: December 2023

AbstractBackgroundIn aging, tau pathology develops in the medial temporal lobe (MTL), but spreads extensively to the cortex in the presence of amyloid‐beta, driving neurodegeneration and Alzheimer’s disease (AD) dementia development. This suggests that earliest age‐related MTL tau is a pre‐requisite for cortical tau spreading and the development of AD. Using tau‐PET in AD, we found previously that functional connectivity routes the cortical expansion of tau, supporting the concept of trans‐neuronal tau spreading. However, it is unclear whether MTL tau accumulation follows within‐MTL connections, in particular those of the entorhinal (EC) and transentorhinal cortex (A35), i.e. the earliest sites of tau accumulation. To address this, we combined post‐mortem histopathological MTL tau assessments with high‐resolution 7T functional MRI to determine MTL subregional connectivity.MethodWe included 3D post‐mortem quantitative histopathological tau assessments of 14 MTL subregions (Fig.1A) in 18 participants with overall low AD neuropathological change to capture earliest tau (Fig.1B), and 7T resting‐state fMRI from young and healthy controls (n = 29) to characterize MTL functional connectivity. Using post‐mortem data, we assessed the covariance of AT8‐stained tau among MTL subregions (Fig.1C) and assessed the correlation with functional connectivity among the same regions (Fig.1D). Further, we determined seed‐based connectivity to determine which MTL subregions connectivity pattern was the best predictor of MTL‐wide tau patterns.ResultPost‐mortem tau levels were highest in the amygdala, followed by A35 and the EC (Fig.2A). As hypothesized, we found an association between MTL connectivity and covariance in MTL tau (r = 0.42, p<0.001, Fig.2B), where closely connected regions showed correlated tau. When assessing seed‐based connectivity as a predictor of MTL tau patterns, EC connectivity was the best predictor for MTL tau deposition patterns (Fig.2C).ConclusionClosely connected MTL subregions show correlated histopathologically‐assessed tau load, suggesting connectivity to route earliest within MTL tau spreading. Despite highest tau in the amygdala, EC connectivity was the best predictor of MTL tau patterns, suggesting that the EC is a key source for within MTL tau spreading. This can be critical to assess EC connectivity as a potential treatment target to prevent cortical tau spreading and thus neurodegeneration and cognitive decline in AD.
Age‐ and Sex‐Related Morphological Changes in Cerebral Blood Vessels: a 7T TOF MRA Study
Authors: Li Jiatai , Stetten George D , Schweitzer Noah , Shi Zonghua , Ibrahim Tamer , Yang Shaolin , Iordanova Bistra , Aizenstein Howard J , Wu Minjie 
Published: December 2023

AbstractBackgroundIn this study we evaluated age‐ and sex‐associated morphological changes of cerebral blood vessels using 7T Time‐of‐flight (TOF) magnetic resonance angiography (MRA).MethodOur study consisted of 25 cognitively normal older adults (20 female, mean age 68.2 years). Whole‐Brain TOF MRA images were collected on a 7T Siemens scanner at the University of Pittsburgh (slice number = 354, voxel size = 0.38*0.38*0.38 mm, 12 mins). An iterative vessel segmentation algorithm, VesselMapper, was used to segment blood vessels on TOF MRA images (Li et al., 2023). For each subject, vessels are further divided into large and small vessels by median split based on vessel diameters. Mean tortuosity of large vessels, small vessels and overall vessels was computed. Linear regression analyses were performed to evaluate the main effects of age and sex, and the age*sex interaction on vessel tortuosity and diameter.ResultAs shown in Figure 1, we found age‐related increase in mean vessel tortuosity (greater age is associated with greater tortuosity, p<0.02). This age‐related difference is driven by small vessels (p = 0.002) rather than large vessels (p = 0.7). We also found that age is positively associated with mean voxel tortuosity (p<0.001, black line in Figure 2). Furthermore, women showed greater age‐related increase in mean arterial tortuosity, compared to men (age*sex interaction p = 0.04, Figure 2).ConclusionOur findings validated that morphological markers of cerebral blood vessels are sensitive to aging. Small vessels in the brain are particularly vulnerable. Further, compared to men, older women are at a higher risk for cerebral small vessel disease, which may contribute to elevated SVD‐related AD risk in women. Limitation: The study has an unbalanced sample (more women than men) and a relatively modest sample size (N = 25). A cross‐sectional instead of longitudinal design was used in this analysis. Future study with a large balanced sample and a longitudinal design are required to confirm our findings. Reference: Li, Jiatai, et al. “VesselMapper ‐ A Robust Vessel Segmentation Algorithm for 3D Images.” Annual Meeting of the Organization for Human Brain Mapping. 2023
Astrocyte reactivity is associated with synaptic dysfunction across the aging and Alzheimer’s disease spectrum, whereas microglial reactivity is specifically associated with synaptic dysfunction related to cognitive impairment
Authors: Rohden Francieli , Ferreira Pamela C.L. , Bellaver Bruna , Aguzzoli Cristiano Schaffer , Soares Carolina , Povala Guilherme , Ferrari‐Souza João Pedro , Lussier Firoza Z , Zalzale Hussein , Abbas Sarah , Lemaire Peter Charles , Leffa Douglas Teixeira , Cabrera Arlec , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Benedet Andrea Lessa , Cohen Annie , Lopez Oscar L. , Ashton Nicholas J. , Karikari Thomas K , Zetterberg Henrik , Blennow Kaj , Souza Diogo O. , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick A. 
Published: December 2023

AbstractBackgroundHealthy synapses are the key to proper brain function, ensuring communication between neurons. Recent studies have associated synaptic dysfunction with Alzheimer’s disease (AD) proteins, however, little is known about the role of glial reactivity, another pathology closely linked to AD, in brain synaptic dysfunction (Figure 1).MethodWe evaluated 123 individuals (67 cognitively unimpaired (CU) and 56 cognitively impaired (CI)) who had available Aß‐ and Tau‐PET as well as cerebrospinal fluid measures of glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), synaptic markers (growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptotagmin 1 (SYT1), and presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25)). ANCOVA adjusted for clinical diagnosis, age, and sex was used to compare levels of CSF biomarkers; whereas linear regressions adjusted for age, sex, clinical diagnosis, and Aß/tau‐PET were used to test the associations between glial reactivity and synaptic markers.ResultDemographic information is shown in Table 1. Increased levels of GAP‐43, SNAP‐25, and Ng were observed in CI compared to CU individuals. CSF GFAP was highly associated with both presynaptic and postsynaptic biomarkers in CU and CI groups. CSF YKL‐40 was associated only with presynaptic biomarkers in both clinical groups. On the other hand, CSF sTREM2 showed an association with all synaptic markers but only in the CI group (Figure 2).ConclusionWe found a heterogeneous association between synaptic markers and glial activation. The presence of GFAP+ astrocytes was associated with dysfunction of presynaptic/postsynaptic markers, whereas YKL‐40+ astrocytes specifically reflected presynaptic dysfunction across aging and AD spectrums. On the other hand, microglial activation reflected synaptic dysfunction associated with dementia symptoms. Our results support recent experimental observations suggesting that clarifying the heterogeneity of different glial cell phenotypes is crucial to advancing our understanding of the role of immune cells in cognitive decline.