bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regional patterns of pathological tau accumulation in sporadic early‐onset Alzheimer’s disease: Longitudinal tau‐PET in the LEADS Cohort
Authors: Schonhaut Daniel R , Mundada Nidhi S. , Insel Philip S. , soleimani‐Meigooni David N. , Zeltzer Ehud , Windon Charles , Tanner Jeremy A. , Heath Courtney Lawh , Shankar Ranjani , Amuiri Alinda , Aisen Paul S. S , Eloyan Ani , Koeppe Robert A. , Carrillo Maria C. , Dickerson Brad C. , Apostolova Liana G. , Rabinovici Gil D. , La Joie Renaud 
Published: December 2023

AbstractBackgroundThe longitudinal progression of tau pathology in sporadic early‐onset Alzheimer’s disease (EOAD, age‐at‐onset<65) has not been well established and may be key to its understanding and treatment. We utilized in vivo PET imaging to characterize regional patterns of pathological tau accumulation in the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS), an ongoing, large‐sample, multi‐site cohort.Method[18F]Flortaucipir tau‐PET was acquired 75‐105min post‐injection in 277 amyloid‐PET‐positive patients with sporadic EOAD and 90 healthy controls (Table 1). Patients had mild cognitive impairment (CDR‐SB = 0.5‐4, n = 206) or mild dementia (CDR‐SB = 4.5‐8, n = 71) at baseline. Longitudinal tau‐PET was collected in 126 patients (2‐4 scans/subject, 1.3 ± 0.4 years apart). Tau‐PET SUVRs were calculated in 72 FreeSurfer‐defined regions referenced against inferior cerebellar gray matter, and SUVRs were W‐scored within‐region to adjust for age and sex associations in controls (control W‐score mean = 0, SD = 1). Baseline tau‐PET W‐score differences between patients and controls were assessed using linear regression. Linear mixed‐effects models were used to calculate tau‐PET W‐score change rates among EOAD patients.ResultTau‐PET was significantly elevated in EOAD patients at baseline in every region examined (p<0.05, FDR‐corrected), with highest tau‐PET signal in lateral prefrontal, parietal, and posterior cingulate cortices bilaterally, and relative sparing of primary cortices (Figure 1a). In longitudinal analyses, tau‐PET increased significantly in 69/72 regions (p<0.05, FDR‐corrected; Figure 1b), and regions with higher tau‐PET at baseline had faster prospective accumulation rates on average (r = 0.47, p<0.0001; Figure 2). Exceptions were noted in posterior cingulate and parietal association regions, which had high tau‐PET at baseline but comparatively slow accumulation; and in anterior prefrontal and occipital regions with low‐to‐moderate tau‐PET at baseline yet rapid accumulation.ConclusionTau pathology is present throughout cortex by the mild dementia stage in EOAD and is still accumulating globally, especially in anterior prefrontal and occipital cortices. Parietal association regions have high baseline tau but slower‐than‐expected prospective accumulation, suggesting these regions are early pathological foci that plateau early in the clinical disease stage.
An automated pipeline for Centiloid quantification of amyloid‐β using multiple 11C‐PiB‐PET and 18F‐PET tracers
Authors: Gordon Elizabeth , Borrot Mathilde , Gueddou Ayoub , Jubault Thomas , Guizard Nicolas 
Published: December 2023

AbstractBackgroundQuantitative measures of amyloid‐β (Aβ) pathology using positron emission tomography (PET) imaging are sensitive to identify pathological changes early in Alzheimer’s disease (AD). The Centiloid scale aims to standardize these in vivo amyloid quantifications to a 100‐point scale, where an average value of zero signifies high certainty of amyloid negativity and 100 identifies average typical AD Aβ‐pathology load (Klunk et al., 2015). The current study developed and validated a single and fully automated Centiloid quantification pipeline for multiple amyloid PET compounds.MethodQyScore’s® fully automated pipeline was validated on 11C‐PiB‐PET and 18F‐PET images from the Centiloid project (https://www.gaain.org/centiloid‐project): 34 young controls [age = 31.5 ± 6.3 years] and 47 AD patients [age = 67.5 ± 10.5 years; CDR = 0.5–1]. 18F tracers included Florbetapir (FBP, N = 46), Forbetaben (FBB, N = 35), Flutemetamol (FTM, N = 74) and NAV4694 (NAV, N = 55). PET/MR image pairs were both co‐registered and normalized in the MNI template space. The fully automated segmentation from QyScore®, a CE‐marked and FDA‐cleared neuroimaging medical device, parcellated the masks of the grey matter tissue (target) and of the cerebellum (reference) region (Figure 1). The standardized uptake value ratio (SUVr) was computed as the ratio of the mean signal in both regions. Correlations of 11C‐PiB‐PET and 18F‐PET SUVr values with published SUVr data were computed. Further, correlations between 18F‐PET SUVr and paired 11C‐PiB‐PET SUVr were computed. Correlation coefficients (R2) > 0.7 were required to consider the Centiloid calibration valid.ResultQyScore’s® fully automated quantitative pipeline produced SUVr values well within the bounds defined by the Centiloid method (SUVr_AD‐100 = 2.08 +/‐ 0.2; SUVr_YC‐0 = 1.01+/‐ 0.05; R2 = 0.99; slope = 1.00; intercept = ‐0.44). 11C‐PiB SUVr correlation coefficients with published values were above 0.99 (Figure 2). Correlation coefficients of 18F‐PET SUVr with 11C‐PiB‐PET SUVr were respectively 0.91, 0.95, 0.96, 0.99 (Figure 3).Equations for converting to Centiloid were respectively
o Centiloid = 177.79 FBP_SUVr ‐ 183.56
o Centiloid = 153.08 FBB_SUVr – 152.93
o Centiloid = 122.39 FTM_SUVr – 120.97
o Centiloid = 90.20 NAV_SUVr – 91.61ConclusionWe demonstrate the feasibility and reliability of a fully automated amyloid PET pipeline for multiple amyloid‐PET compounds (11C‐PiB and 18F) suitable for implementation in clinical trials.
Comparison of diffusion metrics in dementia
Authors: Beaumont Helen 
Published: December 2023

AbstractBackgroundThe recent FDA approval of a disease‐modifying drug for Alzheimer’s disease has stressed the need for a test which can be used at scale to detect neurodegeneration. MRI diffusion shows great promise (Douaud et al., 2013), and recently a multiplicity of analysis methods have been developed. We look at which diffusion analysis method might be most sensitive.MethodWe worked with data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Weber et al., 2021). Participants with Alzheimer’s disease (AD) and a group of age‐matched healthy controls (HC) were identified. T1 images were processed with FreeSurfer v7 (Fischl, 2012), providing tissue segmentations and cortical parcellations, as well as regional volumes. Diffusion images were preprocessed using the PreQual pipeline in native space (including FSL’s Topup and Eddy) (Cai et al, 2021), and analysed with Diffusion Tensor Imaging (DTI), Neurite Orientation Dispersion and Density Imaging (NODDI) (Zhang, Schneider, et al, 2012), Apparent Measures Using Reduced Acquisitions (AMURA) (Aja‐Fernández et al, 2022), Diffusion Orientation Complexity (DOC) (Haroon et al, 2009) and Probabilistic Index of Connectivity (PICo) (Parker et al, 2003). Regional values were extracted in FreeSurfer regions (grey and white matter).Pairwise Mann‐Whitney U‐tests were carried out between AD and HC regional measures. Regions with the most statistically significant volume differences were selected; diffusion‐based metrics for these regions were calculated using weighted values and compared. The 10 metrics with the smallest p‐values were used to find the most significant regions, and these were compared with volumes.ResultParticipants: 100 AD (38 female, age 74.5±7.9 years) and 207 HC (132 female, age 72.0±7.4 years).We selected the 25 most significant regions from the volumetric analyses. From these regions, the most effective diffusion metrics were DTI‐derived mean, axial and radial diffusivities, and 5 of the AMURA metrics.Given the 10 most significant metrics, of the 15 most significant volumes, 8 were also in the top diffusion regions.ConclusionThis study demonstrates that DTI metrics are most sensitive at differentiating HC from AD. If confirmed this has clinical significance, as these scans are widely available.
Associations between 5‐lipoxygenase activating protein (FLAP) genetic variation rs9551963 and Alzheimer’s disease phenotypes
Authors: Noor Shiropa , Mori‐Fegan Daniel K , Wong Yuen Yan , Wu Che‐Yuan , Swardfager Walter ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2023

AbstractBackgroundLeukotrienes are inflammatory mediators, synthesized by 5‐lipoxygenase and its activating protein (FLAP), and their activity may play a role in Alzheimer’s disease (AD). In AD mouse models, inhibition of FLAP improved memory and reduced amyloid (Aβ) deposition. Single nucleotide polymorphisms (SNPs) of ALOX5AP, which encodes FLAP, have been implicated in ischemic stroke in humans. However, there is limited research on the relationship between ALOX5AP and AD. This longitudinal study investigated associations between the ALOX5AP SNP rs9551963 A/C and various AD phenotypes.MethodParticipants from the Alzheimer’s Disease Neuroimaging Initiative (phases GO, 2, and 3) diagnosed with AD, mild cognitive impairment (MCI), or clinically normal cognition (CN) were categorized as minor allele carriers (AC, CC) or non‐carriers (AA) of rs9551963. Mini Mental State Exam (MMSE) and Rey Auditory Verbal Learning Test (RAVLT) % forgetting were selected to assess cognition. Cerebrospinal fluid biomarkers and MRI brain volumetric data were also considered. Interactions between rs9551963 genotype and time (baseline, month 24, and month 48) were measured in mixed models. All models controlled for age, sex, and APOE e4 status; education and baseline intracranial volume were additional controls in cognitive and volumetric analyses respectively.ResultMinor allele carriers in the AD‐MCI Aβ‐positive group had worse decline on the MMSE (F1,297 = 5.33, p = 0.022, n = 521), and smaller volumes of whole brain (F1,146 = 7.13, p = 0.008, n = 408) and hippocampus (F1,132 = 6.38, p = 0.013, n = 377) over time that were not seen in other subgroups. In the AD subgroup, Aβ‐positive carriers had greater increases in RAVLT % forgetting scores (F1,135.5 = 6.19, p = 0.014, n = 158) and greater whole brain volume loss (F1,27.6 = 5.67, p = 0.024, n = 132), over time. These associations were not seen in Aβ‐negative participants.ConclusionMinor allele carriers of the ALOX5AP SNP rs9551963 who were Aβ‐positive showed greater loss of cognitive status and memory, and more hippocampal and whole brain atrophy, over time. These findings suggest a possible effect of leukotriene synthesis in the progression of AD.
Mechanisms of reduced Apolipoprotein E4 lipidation in iPSC‐derived astrocytes
Authors: Kerman Bilal Ersen , Makhlouf Maria E , Bantugan Mikaila Ann , Lee Joon , Meuret Cristiana Joy , Wang Shaowei , Cai Zhiheng , Tuck Tony , TCW Julia , Yassine Hussein N. 
Published: December 2023

AbstractBackgroundCarrying the apolipoprotein E ε4 (APOE4) allele is the highest known genetic risk factor for late‐onset Alzheimer’s disease (LOAD). Although how APOE4 leads to LOAD is not known, dysregulated endo‐lysosomal trafficking and lipid metabolism are key defects associated with APOE4. Cholesterol accumulation in glia instigates intracellular trafficking defects, increases cellular stress, and disrupts secretion. Additionally, enlarged endosomes were observed in the frontal lobes of APOE4‐carrying individuals, decades before the appearance of Aβ fibrilization. Therefore, we asked if cholesterol and endo‐lysosomal trafficking dysregulation in APOE4 carriers were due to differential lipidation of APOE3 and APOE4.MethodLocalization of ATP Binding Cassette Subfamily A Member 1 (ABCA1) in early, late, and recycling endosomal compartments were analyzed in human isogenic induced pluripotent stem cell (iPSC)‐derived neural cells and in cell lines treated with recombinant APOE in microscopic images. Membrane and cytoplasmic ABCA1 were compared using Western blots. Secreted high‐density lipoprotein (HDL) particles containing fluorescently tagged APOE3 or APOE4 were analyzed using ion‐mobility spectrometry. CS‐6253, an ABCA1 agonist peptide, was used to increase APOE lipidation.ResultThe protein levels of ABCA1, which mediates cholesterol and phospholipid efflux to the nascent apolipoprotein particles, were lower in APOE4/4 iPSC‐derived astrocytes compared to astrocytes derived from isogenic APOE3/3 iPSCs. Advanced image analysis revealed lower ABCA1 protein levels in Rab11+ recycling endosomes and less colocalization between ABCA1 and Rab7, a late endosome marker, in APOE4/4 astrocytes than APOE3/3 astrocytes. Consequently, less ABCA1 was detected at the cell membrane. Combined with previous data, these findings suggest APOE4 lipidation was reduced due to reduced ABCA1 activity. Additionally, BHK cells treated with recombinant APOE3 or APOE4 showed differences in ABCA1 localization that were altered by increasing APOE lipidation by activating ABCA1 via CS‐6253. Finally, fluorescently tagged APOE3 and APOE4 were incorporated in HDL particles and were secreted whose sizes were altered after CS‐6253 treatment, suggesting differences in lipidation levels.ConclusionWe demonstrated that diminished APOE4 lipidation is, at least in part, due to dysregulation of endo‐lysosomal trafficking of ABCA1 and that increasing APOE4 lipidation could alleviate cellular defects.
Two‐year longitudinal outcomes of subjective cognitive decline in Hispanics compared to non‐Hispanic Whites
Authors: Boza Carolina , Zhang Yian , Shao Yongzhao , Masurkar Arjun V. 
Published: December 2023

AbstractBackgroundHispanics are at higher risk for Alzheimer disease (AD) than non‐Hispanic Whites (NHW), motivating further study of differences and risk factors at the preclinical level. Subjective cognitive decline (SCD) is considered a preclinical AD stage, but its features and outcomes in Hispanics are less studied. We investigated the differences in longitudinal change in SCD phenotype, cognition, and function among Hispanics compared to NHW.MethodLongitudinal analyses were performed on consecutive participants with SCD who were evaluated at the NYU Alzheimer’s Disease Research Center. Inclusion criteria were self‐identification as Hispanic (n = 23) or NWH (n = 165) and a 2‐year follow‐up visit. Demographics, conversion rate to mild cognitive impairment (MCI), SCD characteristics, and psychometric performance were analyzed by t‐test, multiple linear regression models, or Cox models as appropriate. Models were adjusted for age, sex, education, depression, and baseline values.ResultHispanics were at higher risk for conversion to MCI (HR: 6.57, 95% CI 1.25‐34.47, p = 0.02596). Hispanic ethnicity was associated with increased SCD severity in time as measured via the total Brief Cognitive Rating Scale (BCRS) score (OR: 4.28, 95% CI 1.42‐12.83, p = 0.0094), and in specific BCRS domains: mood and behavior (OR: 0.18, 95% CI 0.03‐0.89, p = 0.0355) and calculation (OR: 29.68, 95% CI 4.02‐219.18, p = 0.0009). Global cognitive function by Mini‐Mental State Examination had a higher risk of declining in time in Hispanics (HR: 2.83, CI 1.09‐7.35, p = 0.0320). Likelihood of decline in domain‐specific tests associated with Hispanic ethnicity for Trails A (HR: 4.05, 95% CI 1.93‐8.47, p = 0.0002), Trails B (HR: 3.16, 95% CI 1.62‐6.14, p = 0.0007), and delayed paragraph recall (HR: 2.08, 95% CI 1.01‐4.24, p = 0.0444).ConclusionHispanics present a higher risk of conversion from SCD to MCI than NHW. Apart from stage conversion, subjective and objective measure of cognition worsen more in Hispanics, but in a domain‐specific manner. These findings suggests that Hispanics not only decline at a faster rate, but that this decline is expressed with a different phenotype. This should be considered when studying this population in preclinical investigations.
Mitochondrial Genome‐Wide Association Study Investigating Indices of Mitochondrial Dysfunction in Mexican Americans Compared to non‐Hispanic Whites
Authors: Reid Danielle M , Rowe Megan , Housini Mohammad , Subasinghe Kumudu , Garlotte Isabelle , Barber Robert , Jones Harlan P , Thorpe Roland J. , Sun Jie , Zhou Zhengyang , Phillips Nicole 
Published: December 2023

AbstractBackgroundMexican Americans (MAs) endure racial/ethnic disparities in Alzheimer’s Disease (AD) risk, such as late‐stage diagnosis, earlier onset, and more severe forms of cognitive impairment (CI) compared to non‐Hispanic Whites (NHWs), despite low propensity for the genetic predisposition (e.g., APOE e4 has limited effect on MA AD risk). These complexities have challenged our understanding of AD etiology in this population. MAs are the fastest growing subpopulation within the Hispanic/Latinx population, and as they age, AD will disproportionately affect MAs. Common risk factors for developing CI in MAs include stroke, diabetes, obesity, and depression; however, the reason for the association remains unknown. Diabetes is three times more prevalent among MAs relative to NHWs, and mitochondrial dysfunction is implicated in both AD and diabetes. As a result, mtDNA can accumulate reactive oxygen species damage and elicit pro‐inflammatory processes upon release. Previously, we determined MAs exhibited elevated oxidative mtDNA damage and associated with AD, sex, tobacco abuse, and education compared to NHWs. Here, we hypothesize that mtSNPs will be associated with indices of mitochondrial dysfunction (e.g., mtDNA copy number [mtDNA CN] and 8oxoG variants) in MAs, particularly those with AD and/or diabetes, compared to NHWs.MethodWhole mtDNA was amplified from extracted buffy coat PBMCs and plasma from 559 TARCC participants using REPLI‐g® Human Mitochondrial DNA Kit and sequenced via Illumina NextSeq. We performed a mitochondrial genome‐wide association study to identify variants associated with 8oxoG mutational load and altered mtDNA CN in MAs compared to NHWs. Analyses control for covariates like age, sex, education, diabetes, tobacco abuse, and depression.ResultWe will report haplogroup effects and determine if specific variants are associated with elevated oxidative burden and/or altered mtDNA CN to better understand population‐specific risks for mitochondrial dysfunction in connection to complex age‐related disease.ConclusionThis study will establish if mtDNA‐based genetics is relevant to mitochondrial dysfunction (i.e., oxidative damage and/or altered mtDNA CN), which we have shown to be associated with cognitive decline. These results will be evaluated for population‐ and sex‐specific effects taking into consideration key comorbidities (e.g., diabetes). This data could help identify targets for precise approaches to help assess and reduce disease risk.
Characterization of an African ancestry‐specific protective allele of the APOE ε4 allele for Alzheimer’s disease risk
Authors: Wang Liyong , Vasquez Marina Lipkin , Nuytemans Karen , Rajabli Farid , Whitehead Patrice , Gearing Marla , Bennett David A. A , Flanagan Margaret E , Weintraub Sandra , Geula Changiz , Scott William K. , Schuck Theresa , Jin Fulai , Xu Wanying , Dykxhoorn Derek M. , Pericak‐Vance Margaret A. , Griswold Anthony J. , Young Juan I. , Vance Jeffery M. 
Published: December 2023

AbstractBackgroundWe recently identified a protective interaction between the APOE ε4 allele and an African ancestry‐specific allele (rs10423769_A) significantly reducing the odds ratio for Alzheimer’s disease by 75% in APOE ε4 homozygous carriers. rs10423769 is located approximately 2 mB upstream of APOE in a large area of segmental duplication, within a cluster of pregnancy specific beta‐1 glycoproteins (PSG) genes and a long noncoding RNA, lncRNA (ENSG00000282943). Hi‐C analysis in multiple brain cell types showed no direct chromatin interactions between APOE and the rs10423769 region. rs10423769 has been reported to be a splicing quantitative trait locus for the transmembrane protein 145 gene (TMEM145), which has the highest expression in cerebellum.MethodsSince this interaction region is enriched for segmental duplications, long‐read whole genome sequencing was performed on 16 individuals (nine heterozygous and seven homozygous rs10423769_A carriers) using the Oxford Nanopore PromethION24 to more precisely map this variant. Expression of PSG genes (2, 4, 5 and 11), ENSG00000282943, and TMEM145 isoforms were analyzed by qPCR in cerebellum and frontal cortex of carriers and non‐carriers of rs10423769_A. Hi‐C analysis was conducted in these brain samples as well.ResultsNanopore long‐read sequencing showed that rs10423769 is present as a single copy on chromosome 19. In the frontal cortex, preliminary Hi‐C results supported the presence of transcriptionally active chromatin over the PSG region in some individuals but not in others. Both PSG genes and the lncRNA had low expression in the frontal cortex and cerebellum. We observed higher TMEM145 expression in the cerebellum compared to frontal cortex and detected alternative splicing forms of TMEM145. There was a trend of increased expression of TMEM145 in rs10423769_A carriers, which was not statistically significant likely due to sample size.ConclusionWe established that only one copy of rs10423769 exists in the modifying region, which will facilitate future haplotype analysis. The Hi‐C analysis suggested inter‐individual variations on chromatin structure over PSG genes in frontal cortex, although no expression of these genes was detected. Further analysis of regulatory activity of the region is ongoing. This modifier locus appears to represent a novel protective mechanism for APOE ε4.