bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial Pattern of Medial Temporal Lobe Cross‐Sectional and Longitudinal Structural Change in Cognitively Normal Individuals
Authors: Xie Long , Das Sandhitsu R. , Li Yue , Wisse Laura E.M. , McGrew Emily , Lyu Xueying , DiCalogero Michael , Shah Ujashi , Ilesanmi Ademola , Denning Amanda E , Brown Christopher D. , Cohen Jesse S , Sreepada Lasya P , Dong Mengjin , Sadeghpour Niyousha , Khandelwal Pulkit , Ittyerah Ranjit , Ravikumar Sadhana , Sadaghiani Shokufeh , Hrybouski Stanislau , de Flores Robin , Gibson Eli , Yushkevich Paul A. , Wolk David A 
Published: January 2025

AbstractBackgroundThe medial temporal lobe's (MTL) early involvement in tau pathology makes it a key focus in the development of preclinical Alzheimer’s disease (AD) biomarkers. ROI analyses in prior studies reported significant MTL structural differences in cognitively normal individuals with and without ß‐amyloid (A+/‐CN). Pointwise analysis, offering spatial information of early neurodegeneration, has potential to pinpoint “signature regions” of pathological change, but has been underexplored in the MTL. This study employs a specialized pointwise analysis pipeline to examine the spatial pattern of MTL structural change in subgroups dichotomized by both ß‐amyloid and tau status in a large cohort of CN individuals.MethodsA dataset of 3036 CN (A‐/A+: 1270/1558, Table 1) individuals from ADNI, HABS, A4 and ABC were analyzed. We extracted MTL regional thickness maps from MRI using tailored pipelines, ASHS‐T1 and CRASHS. For participants with prospective longitudinal MRI (five years follow‐up), regional maps of longitudinal atrophy rate were extracted using SkelDBM. Subjects with cross‐sectional tau PET available (N=563) were further divided into A and T subgroups by tracer uptake. General linear modeling was performed on each surface point to investigate cross‐sectional and longitudinal MTL structural group differences (detailed in Figure 1) and their correlation with MTL tau burden in All/A+/A‐ CN. Age and sex were covariates and cluster‐level multiple comparison correction was performed.ResultsA+CN demonstrated a significantly faster atrophy rate than A‐CN across the whole MTL, primarily driven by A+T+CN individuals (Figure 1‐b). Notably, A‐T+CN showed significantly faster atrophy rate in the entorhinal cortex (ERC) and Brodmann area 35 (BA35), the earliest sites of tau pathology (Figure 1‐b, second column). Figure 2‐b displays an MTL‐wise significant correlation between atrophy rate and tau in All/A+/A‐ CN. In both analyses, cross‐sectional effects are consistently weaker than longitudinal ones, but have some significant clusters in ERC and BA35.ConclusionsPointwise analysis revealed extensive tau‐associated accelerated neurodegeneration in the MTL in preclinical AD. Furthermore, accelerated atrophy was observed in early Braak regions in A‐CN with evidence of tau pathology, potentially driven by primary age‐related tauopathy (PART). These pointwise longitudinal MTL measures provide sensitive measures that may allow for disease monitoring in preclinical AD.
Among older African Americans, high‐risk ABCA7‐80 allele carriers have lower medial temporal lobe dynamic network flexibility than APOE‐ε4 allele carriers
Authors: Budak Miray , Fausto Bernadette A. , Piaszczynska Wiktoria , White Payton G. , Gluck Mark A. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles which cause neurodegeneration and cognitive decline1. APOE‐ε4 is identified as the first common genetic risk factor with high penetrance in the early onset of AD3. ABCA7 (rs115550680) (ABCA7‐80) is associated with the development of late‐onset AD among African Americans2. The medial temporal lobe (MTL) is the first region that displays atrophy and neurofibrillary tangle involvement during AD4. However, the comparative influence of APOE‐ε4 and ABCA7‐80 on neural functions among African Americans is not yet known. The present study investigated the effect of APOE‐ε4 and ABCA7‐80 high‐risk alleles on the MTL dynamic network flexibility among cognitively unimpaired older African Americans.Method175 older, cognitively unimpaired African Americans drawn from the ongoing longitudinal study, Pathways to Healthy Aging in African Americans completed saliva collection for genotyping and underwent an MRI scan in a Siemens 3T Prisma scanner. AFNI and ANTs were used for dynamic functional MRI processing and analysis for MTL dynamic network flexibility. Gender, age, and education were used as covariates for analysis.ResultThe analysis revealed trend‐level differences in MTL Dynamic network flexibility between high‐risk and non‐risk allele carriers for ABCA7‐80 (F = 3.531, η² = 0.025, p = 0.062) and for APOE‐ε4 allele (F = 2.421, η² = 0.017, p = 0.122). Individuals with the ABCA7‐80 high‐risk allele exhibited significantly lower MTL dynamic network flexibility compared to those with the APOE‐ε4 allele (F = 4.577, η² = 0.067, p = 0.036).ConclusionABCA7‐80 high‐risk allele may better capture the dynamic neural dysfunction in the MTL network rather than APOE‐ε4 among cognitively unimpaired older African Americans.
Differential association of moderate alcohol use with neurodegeneration, cerebrovascular disease, and cognition by racial, ethnic and sex/gender groups in middle age
Authors: Guzmán Diana S. , Rentería Miguel Arce , Avila Justina F , Turney Indira C. , Johnson Aubrey S. , Smith Anna C. , Okafor Amarachukwu , Houlihan Hannah M. , Heuer Lauren B. , Alshikho Mohamad J. , Morales Clarissa , Mazen Jessica , Gu Yian , Manly Jennifer J. , Brickman Adam M. , Lao Patrick J. 
Published: January 2025

AbstractBackgroundModerate alcohol use may be associated with brain and cognitive benefits compared to heavy alcohol use. However, results have varied. We hypothesized that the relationship between alcohol use and cognition is mediated by neurodegenerative and cerebrovascular measures in a diverse middle‐aged sample of non‐alcohol dependent community‐dwelling adults in Northern Manhattan.MethodParticipants (N = 451; age = 53±10 years; 36 Black Men (BM), 68 Black Women (BW), 95 Latinx Men (LM), 198 Latinx Women (LW), 17 White Men (WM), 37 White Women (WW)) from the Offspring study of Racial and Ethnic Disparities in Alzheimer’s Disease underwent structural and vascular MRI (total brain volume (TBV), cortical thickness in AD signature regions, hippocampal volume, white matter hyperintensities (WMH)). Moderate alcohol use was assessed by the Alcohol Use Disorder Identification Test–Concise (AUDIT‐C = 9). Mediation models tested whether the association of alcohol use on cognition (SRT total and delayed; Animal and letter fluency; Digit Span Backwards) is mediated by brain measures, stratified in sex/gender by racial and ethnic groups.ResultGreater moderate alcohol use was associated with lower cortical thickness and hippocampal volume LM (cortical thickness: ‐0.005 mm [‐0.008, 0.001], p = 0.005; hippocampal volume: ‐25.0 mm3 [‐45.0, ‐4.7], p = 0.02), greater vascular burden in BM (temporal WMH: 0.07 cm3 [0.001, 0.121], p = 0.05), and lower TBV in WM (‐24.0 cm3 [‐27.5, ‐20.4], p = 0.01), but not associated with brain measures in women. Greater moderate alcohol use was associated with lower animal fluency for LM (ADE: ‐0.25 to ‐0.21, p = 0.04), but higher letter fluency for LW (ADE: 0.24 to 0.25, p = 0.04) and BW (ADE: 0.43 to 0.43, p = 0.05), accounting for brain to cognition associations. However, mediation pathways (ACME) were not significant.ConclusionMen had lower cortical thickness and brain volume, greater WMH volume, and lower cognitive measures, while women had higher cognitive measures with greater moderate alcohol use in midlife. Neurodegenerative and vascular associations with moderate alcohol use differed by race and ethnicity in men, while the directionality of associations between moderate alcohol use and fluency differed by sex/gender. Future work should explore alcohol use factors (e.g., context of use, duration of use), and the relationship to brain and cognitive changes over the life course.
Characterizing White Matter Hyperintensity (WMH) Patterns with Texture‐Based Analysis
Authors: Alshikho Mohamad J. , Morales Clarissa , Pyne Jeffrey D. , Amarante Erica , Lao Patrick J. , Turney Indira C. , Edwards Natalie C. , Gu Yian , Manly Jennifer J. , Mayeux Richard , Brickman Adam M. 
Published: January 2025

AbstractBackgroundWhite matter hyperintensities (WMHs) are areas of increased signal on T2‐weighted MRI scans. They vary in size, location, and intensity, suggesting different underlying conditions like small vessel disease and inflammation. This variation potentially links WMH to outcomes ranging from normal aging to severe neurological disorders. We used a texture analytic approach, Gray‐Level Co‐occurrence Matrix (GLCM), to characterize the intensity heterogeneity of WMHs. This method classifies WMHs into distinct zones based on homogeneity scores that represent uniformity in signal intensity. We explored associations among white matter microstructure, cerebral blood flow, and WMH volume within these zones.MethodOne hundred sixty‐one participants from the Washington Heights‐Inwood Columbia Aging Project (WHICAP) were included. White matter hyperintensities were labeled using in‐house software, which also created normalized homogeneity maps through GLCM. These maps were used to define three WMH zones based on their degree of homogeneity (i.e., homogeneous, intermediate, and heterogeneous) (Figure 1). We examined the relationship among fractional anisotropy (FA), cerebral blood flow (CBF), and WMH volume within these WMH zones and compared CBF and FA values across the zones.ResultIn homogeneous and intermediate WMH zones, there was no association between FA and CBF (rhomo. = 0.022, phomo. = 0.787; rinter. = ‐0.12, pinter. = 0.132). However, both FA and CBF negatively correlated with WMH volume in these zones (rFA‐homo. = ‐0.348, pFA‐homo.< 0.0001; rFA‐inter. = ‐0.538, pFA‐inter.< 0.0001; rCBF‐homo. = ‐0.36, pCBF‐homo.< 0.0001; rCBF‐inter. = ‐0.40, pCBF‐inter.< 0.0001). In the heterogeneous zone (Figure 2), FA and CBF were negatively correlated (rhetero. = ‐0.422, phetero.< 0.0001). CBF, but not FA, was associated with WMH volume (rCBF‐hetero. = ‐0.471, pCBF‐hetero.< 0.0001; rFA‐hetero. = 0.085, pFA‐hetero. = 0.300) In homogenous WMH regions, both [FARatio (0.776±0.009) and CBFRatio (0.96±0.014)] values were lower than in intermediate [FARatio (0.84±0.009) and CBFRatio (0.97±0.014)] and heterogeneous zones [FARatio: (1.029±0.009), CBFRatio: (1.002±0.014)].(Figure 3)ConclusionDistinct correlation patterns exist between CBF and FA in WMH clusters defined by intensity heterogeneity. Homogeneous zones, likely reflect older lesions, show low microstructural integrity and minimal relationship with CBF, suggesting high gliosis. Heterogeneous zones, possibly reflecting recent white matter damage, show associations between CBF and microstructure, potentially indicating active inflammatory processes contributing to vascular injury.
In vivo data‐driven patterns of Amyloid‐ and Tau accumulation associated with AD progression using 18F‐MK6240 and 18F‐NAV4694 PET
Authors: Fonov Vladimir S , Rosa‐Neto Pedro , Collins D Louis 
Published: January 2025

AbstractBackgroundAlzheimer’s disease is a neurodegenerative disease associated with the accumulation of Amyloid‐ß and Tau neurofibrillary tangles following a pattern known as Thal and Braak stages, respectively (Thal 2002; Braak 1995,2011). Recent research (Pascoal 2020) showed the possibility of recapitulating Braak’s histopathological stages in vivo using PET tracer [18F]‐MK‐6240 with manually defined regions of interest. This study analyzes the joint patterns of Amyloid‐ß and Tau accumulation associated with AD in a completely data‐driven fashion.MethodWe used T1w MRI, [18F]‐NAV4694, and [18F]MK6240 PET scans from 36 young individuals (47 scans), 192 healthy elderly individuals (280 scans) in the community or outpatients at the McGill University Research Centre for Studies in Aging (97 individuals with mild cognitive impairment (140 scans) and 75 patients with AD (98 scans). T1w MRIs were pre‐processed (non‐uniformity correction, intensity normalization, stereotaxic registration, brain masking, tissue classification) and non‐linearly registered to the ADNI template using ANTs (Avants et al 2011). PET scans were linearly registered to the T1w MRI, and voxel‐wise standardized uptake value ratios (SUVR) were calculated using whole cerebellum grey matter as the reference, and then non‐linearly warped into the space of the ADNI template and downsampled to 2mm3 resolution. All PET scans were concatenated to create a matrix 518×345846. This matrix was factorized into two low‐rank components (Krichene 2018) with the constraint that all matrix elements should be positive, spatial loadings constrained to be between 0 and 1, latent vectors ordered monotonously to capture the additive nature of disease progression, and the loadings aligned with MOCA scores, by minimizing cosine distance. We used spatial components to create pseudo‐probabilistic ROIs associated with the different stages of disease progression.ResultOur method revealed regional patterns of joint tau and amyloid accumulation associated with AD progression, shown in Figure 1. Associated weighted SUVR average values are shown on Figure 2. The first two components, as visible on Figure 2, have almost no relationship with MOCA score and are most likely associated with off‐target bindings for both tracers.ConclusionThis work is a stepping stone towards creation of the Tau & Amyloid AD disease staging system.
Alzheimer's disease staging with [18F]MK6240 and [18F]Flortaucipir ‐ the HEAD study
Authors: Soares Carolina , Povala Guilherme , Bauer‐Negrini Guilherme , Lussier Firoza Z , Ferreira Pamela C.L. , Bellaver Bruna , Amaral Livia , Zalzale Hussein , Madeiros Marina Scop , Cehula Juli , Bloomquist Madeleine , Oliveira Markley , Felix Cynthia , Rodrigues Matheus Scarpatto , Ruppert Emma Patrice , Abbas Sarah , Zimmer Eduardo R. , Pascual Belen , Gordon Brian A. , Lowe Val J. , Oh Hwamee , Soleimani‐Meigooni David N. , Rosa‐Neto Pedro , Tudorascu Dana , Jagust William J. , Klunk William E , Baker Suzanne L. , Pascoal Tharick A. 
Published: January 2025

AbstractBackgroundUtilizing PET amyloid‐beta (Aß) and tau for staging Alzheimer’s Disease (AD) has demonstrated potential in identifying individuals with varying degrees of disease severity, applicable to both clinical trials and practice. However, the diverse binding characteristics of tau tracers pose challenges to the application of this staging across different ligands. In this study, we evaluate a novel staging framework proposed by the AA working group, employing Aß PET and either [18F]MK6240 or [18F]Flortaucipir in individuals participating in a head‐to‐head study of tau PET tracers. This will provide insights into the robustness of this framework when applied across different tau ligands.MethodWe evaluated 154 people (89 CU and 65 CI), with MK6240, Flortaucipir, Aß‐PET, MRI. SUVRs used inferior cerebellar gray as reference. Participants were categorized in Aß positivity(A), using visual read, and tau positivity (T) in medial temporal lobe(MTL) and neocortex(NEO). Tau MTL(TMTL) and NEO positivity were defined as average +3 SD of youngs. NEO moderate(TMOD) and high(THIGH) was defined as below and above median SUVR of NEO‐positive individuals. Individuals were grouped as: A‐T‐, A+T‐, A+TMTL+(early), A+TMOD+(intermediary), and A+THIGH+(advanced).ResultsWe found that the distribution of the number of individuals across the five AD stages was comparable when using both MK6240 and Flortaucipir tracers (Figure 1). However, upon examining the concordance within each group, we found a low concordance of 30% (3/10) between tracers in the early tau stage (A+TMTL+). Concordance increased in the intermediary stage A+TMOD+, with a rate of 65% (9/14), and further increased to 79% (11/14) in the advanced stage (A+THIGH+). The A+T‐ group exhibited the highest concordance between tracer results, at 95% (21/22).ConclusionOur findings indicate that the application of this framework across different populations using different tau tracers can lead to a compatible distribution among groups. However, in a direct comparison, we noted that this did not necessarily result in high concordance between groups, as group shifts were observed that depended on the cutoffs used (data not shown). These results emphasize the necessity for harmonization of tau PET tracers prior to their utilization for stage determination.
Theta‐ and alpha‐band functional connectivity are associated with longitudinal tau accumulation in asymptomatic individuals expressing Aβ pathology
Authors: Rudolf Jonathan Gallego , Wiesman Alex I , Baillet Sylvain , Villeneuve Sylvia 
Published: January 2025

AbstractBackgroundRecent studies suggest that tau pathology spreads between functionally connected (FC) brain regions. The accumulation of amyloid‐beta (Aß) promotes neural hyper‐activity in asymptomatic older adults, which might enhance tau spreading. We assessed the relationship between band‐specific neurophysiological FC and the rate of tau accumulation over time and tested whether this association is dependent on the presence of Aß pathology.MethodWe measured cortical Aß deposition using positron emission tomography (PET) and resting‐state neurophysiological activity using magnetoencephalography (MEG) at baseline, as well as longitudinal cortical tau PET deposition (mean time between scans = 4.3 years), in a group of cognitively unimpaired older adults with family history of Alzheimer’s Disease (PREVENT‐AD cohort; N = 84). Region‐specific measures (i.e. Aß, tau, MEG timeseries) were extracted from 68 cortical parcels of the Desikan‐Killiany atlas. Neurophysiological FC between cortical regions was estimated across delta, theta, alpha and beta frequency bands using the corrected amplitude envelope correlation (AEC‐c). A global Aß standardized uptake value ratio (SUVR) was calculated by taking the average across a set of early Aß accumulating regions. Individual‐specific tau epicenters were defined as the six cortical regions with the highest levels of baseline tau‐PET binding. The annual rate of change in tau SUVR between the first and second scan was calculated for each cortical region (Figure 1). Linear mixed‐effects models were designed to test if the neurophysiological FC connectivity of each cortical parcel with tau epicenters was related to increased longitudinal tau accumulation in that region, and whether this association was dependent on baseline levels of Aß pathology.ResultTau epicenters identified across individuals were mainly localized in temporal and medial posterior brain regions. Regional increases in theta‐ and alpha‐band FC with tau epicenters at baseline related to greater longitudinal tau accumulation in individuals expressing higher levels of global Aß pathology (Figure 2).ConclusionOur results suggest that tau spreads across cortical regions that are functionally connected in the theta‐ and alpha‐bands, but only in individuals with high levels of cortical Aß. This finding supports the notion that Aß‐related neural hyper‐activity promotes tau spreading across the cortex following individual‐specific patterns of FC in asymptomatic older adults.
Brain Functional Flexibility and its Relationship to the Preclinical Stage of Alzheimer’s Disease
Authors: Javanray Mohammadali , St‐Onge Frederic , Bellec Pierre , Misic Bratislav , Soucy Jean‐Paul , Villeneuve Sylvia 
Published: January 2025

AbstractBackgroundCharacterizing pathological and functional features of the preclinical stage of Alzheimer’s Disease (AD) is essential as Amyloid beta (Aß) and tau, the pathological hallmarks of AD, start to accumulate years prior to the onset of clinical symptoms. Whether Aß and/or tau are related to the brain’s ability to functionally reconfigure in time (functional flexibility) remains unclear despite its important role in behavior and cognition.MethodWe included 233 cognitively unimpaired individuals with family history of AD from the PREVENT‐AD cohort who underwent both Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI). We computed the element‐wise product of the BOLD fMRI timeseries of the 400 Schaefer atlas nodes as co‐fluctuation matrices for the scan duration (all TRs). We then calculated the variabilities of the obtained co‐fluctuations at the whole brain and network level (DMN and limbic as early susceptible networks in AD) and used these measures of variability as a proxy of functional flexibility. We also computed the average of the obtained co‐fluctuation matrices, which mathematically corresponds to the Pearson correlation of the nodal timeseries pairs and used this as our marker of static functional connectivity (sFC). We then assessed the relationship between functional flexibility and sFC with the level of Aß (global index) and tau (temporal meta‐ROIs), using those, both as continuous and dichotomized variables (Figure.1). Two thresholds were used for Aß, one associated with low Aß accumulation (centiloid of 18) and the other with significant Aß burden (centiloid of 40).ResultNo association was found between AD pathology and functional flexibility or sFC using AD pathology as continuous or dichotomized variables (Figure 2 and 3). However, the maximum range of functional flexibility values in individuals with significant Aß burden and high tau was about half the one found in individuals with low or no pathology, a result that was particularly striking with tau.ConclusionThe absence of group difference suggests that functional flexibility cannot be used as a proxy of AD. While individuals with AD pathology have a low range of functional flexibility values, low values are also frequent in individuals with no pathology.