bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of sex‐specific genetic variants associated with tau‐PET
Authors: Wang Xin , Broce‐Diaz Iris , Deters Kacie D , Fan Chun Chieh , Banks Sarah J. 
Published: December 2022

AbstractBackgroundAbnormal tau deposition is an important pathological feature of AD. Important sex differences exist, with women showing greater tau deposition along the AD continuum compared to men. Our group has previously shown sex differences in the genetic risk associated with AD. However, whether specific genetic variants are associated with sex differences in tau aggregation remains unknown. This study aims to identify sex‐specific genetic variants associated with tau deposition.MethodWe included 493 subjects (women n = 246, men n = 247) from the ADNI‐3 study with genotyping data and [18F]Flortaucipir tau PET data. Genetic data underwent standard quality control procedures to remove single nucleotide polymorphisms (SNPs) with more than 5% missingness, failing the Hardy–Weinberg equilibrium test at p = 1 × 10−6 and minor allele frequency < 1%. Participants were all white and included irrespective of clinical diagnosis (CN, MCI and AD). We focused our analysis on genetic variants within 10 genes previously shown to have sex‐dependent effects in AD to reduce the burden of multiple comparisons: BIN1, MS4A6A, DNAJA2, FERMT2, APOC1, APOC1P1, FAM193B, C2orf47, TYW5, CR1. One‐way multivariate analysis of variance (MANOVA) was applied to identify genetic variants associated with tau PET data in three ROIs (composite regions of Braak1, Braak34 and Braak56 stages) in women and men separately. We controlled for age, scanner, amyloid status, APOE ε4 carriership, diagnosis (CN vs MCI vs AD), and the first 20 genetic principal components to adjust for population stratification. Bonferroni correction was applied within each gene based on the number of SNPs tested.ResultTable 1 shows the significant genetic variants associated with tau PET. We identified three novel genetic loci associated with tau deposition specifically in women: DNAJA2 rs79711283, FERMT2 rs113357081 and TYW5rs74614106. In men, three loci within CR1: rs115096248, rs113698814, rs78150633 were found significantly associated with tau burden.ConclusionOur findings discovered sex‐specific genetic variants associated with tau deposition independent of APOE ε4, amyloid and clinical diagnosis. These results provide potential gene targets for understanding the mechanism of sex‐specific tau aggregation and developing sex‐specific gene‐guided precision prevention or therapeutic interventions for AD.
Associations of Amyloid, White Matter Hyperintensities, and Hippocampal Volume with Cognitive Trajectories in the Oldest‐Old: The 90+ Study
Authors: Wang Jingxuan , Ackley Sarah F , Woodworth Davis C. , Sajjadi S. Ahmad , Fletcher Evan , DeCarli Charles S. , Glymour M. Maria , Kawas Claudia H. , Corrada Maria M. 
Published: December 2022

AbstractBackgroundAmyloid pathology, vascular disease pathology, and hippocampal atrophy are associated with cognitive trajectories in older adults. However, there is almost no prior evidence on how these pathologies influence cognition in the oldest‐old.MethodWe included 216 individuals from The 90+ Study, a longitudinal study of aging and dementia in people aged 90 years and older, who had 18F‐florbetapir PET and MRI imaging. We examined the association of amyloid, white matter hyperintensities (WMH) volume, and hippocampal volume (HV) with baseline cognition and longitudinal cognitive decline. Amyloid burden was measured using the standardized uptake value ratio (SUVR) in the precuneus/posterior cingulate with white matter mask as reference. WMH volume and HV were normalized by intracranial volume (IV) and normalized WMH were log‐transformed. SUVR and HV for each individual were Z‐scored using the sample mean and standard deviation. Global cognitive performance was measured by Mental State Examination (MMSE) and modified MMSE (3MS) tests, repeated every six months. We defined baseline (time=0) as the visit closest to the PET imaging and included all visits starting from one year before baseline (time=‐1). We used linear mixed‐effects models with a random intercept to estimate the effect of pathologies on cognitive trajectories. All models included baseline age, sex, education, APOE‐ε4, time, time squared, amyloid, WMH, HV, and interactions between linear time and pathology variables.ResultAt baseline, participants were 93.2 years old on average, 65.3% were females, 10.6% were APOE‐ε4 carriers, and 66.2% had normal cognition (Table 1). Higher HV was associated with higher MMSE and 3MS scores at baseline. Both lower amyloid burden and higher HV were associated with slower rate of cognitive decline longitudinally. WMH was not associated with baseline cognition or cognitive trajectory. Parameter estimates are shown in Table 2 and illustrative cognitive trajectories predicted for a 93.2‐year‐old female with APOE‐ε4 alleles and a college degree predicted at varying degrees of amyloid, HV, and WMH are shown in Figure 1.ConclusionAmyloid burden and HV are associated with longitudinal cognitive trajectories, highlighting the utility of amyloid and HV in predicting future cognitive decline for the oldest‐old.
Life’s Simple 7 cardiovascular risk score and rate of cognitive decline in preclinical dementia
Authors: Speh Andreja , Payton Nicola Maria , Kramberger Milica G. , Grande Giulia , Qiu Chengxuan , Winblad Bengt , Fratiglioni Laura , Bäckman Lars , Laukka Erika J 
Published: December 2022

AbstractBackgroundWe investigated whether vascular risk factors (VRFs), assessed with the Life’s Simple 7 (LS7) score, are associated with rate of cognitive decline in the preclinical dementia phase. We sought to test whether (1) poor LS7 further accelerates rate of cognitive decline in preclinical dementia or (2) the dementia process itself overshadows potential effects of LS7.MethodThis population‐based study included 1,449 participants aged ≥ 60 years (M = 69.99, SD = 9.25) from the Swedish National Study on Aging and Care‐Kungsholmen (SNAC‐K). Participants aged < 78 years at baseline (M = 65.03) were categorised into a young‐old group and those ≥ 78 years (M = 82.61) into an old‐old group. An extensive cognitive test battery (episodic memory, semantic memory, verbal fluency, and perceptual speed) was administered across 12 years. VRFs were assessed with the Life’s Simple 7 (LS7) score at baseline and included four behavioral (smoking, diet, physical activity, and body mass index) and three biological (plasma glucose, total serum cholesterol, and blood pressure) metrics. Participants were categorised into having poor or intermediate/optimal cardiovascular health. Preclinical dementia was defined as being dementia‐free at baseline and diagnosed with dementia (DSM‐IV criteria) at one of the follow‐up assessments. Level and change in cognitive performance as a function of LS7 categories and future dementia status were determined using linear mixed‐effects models.ResultParticipants in a preclinical dementia phase were more likely to have a poorer LS7 score initially compared to those who remained dementia‐free (p = 0.023). For young‐old individuals, poor diet was associated with an accelerated perceptual speed decline (β = ‐0.05, 95% CI ‐0.08 to ‐0.02) and a poor plasma glucose score was associated with faster rates of verbal fluency (β = ‐0.019, ‐0.09 to ‐0.01) and global cognitive (β = ‐0.028, ‐0.06 to 0.00) decline in preclinical dementia.ConclusionThe association between VRFs and cognitive decline was most pronounced in young‐old individuals in a preclinical phase of dementia and driven mostly by diet and plasma glucose. Poor cardiovascular health may be associated with further acceleration of cognitive decline in preclinical dementia.
Differential effects of age and sex on medial temporal lobe networks revealed by longitudinal analyses across the adult lifespan
Authors: Chauveau Léa , Landeau Brigitte , Dautricourt Sophie , la Sayette Vincent De , Chetelat Gael , de Flores Robin 
Published: December 2022

AbstractBackgroundThe medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks which are particularly affected in Alzheimer’s disease (AD): the anterior‐temporal (AT) and posterior‐medial (PM) systems. As the specific and respective effects of age and sex on the functional integrity of these networks are still largely unknown, we sought to fill this gap using longitudinal data spanning the entire adult life.MethodLongitudinal data from 215 cognitively unimpaired adults (aged 19‐85, including 113 females, followed‐up up to 47 months, 419 scans) were analysed. Seed‐based analyses were applied to resting‐state functional magnetic resonance imaging to generate connectivity maps (seeds: the perirhinal cortex for AT and the parahippocampal cortex for PM). The AT and PM networks were defined by comparing baseline maps from adults younger than 40 using a paired permutation t‐test with threshold‐free cluster enhancement (TFCE) and familywise error (FWE) correction (p<.05) (Figure 1). These masks were then used to extract the mean functional connectivity (FC) for each participant. The interaction effects between network, age and sex were investigated using linear mixed models.ResultThere was a significant interaction between age and networks (p<.001), with a decrease of FC with age in PM and an increase in AT (Figure 2). Sex differences were also observed within these two systems (p<.001), with males exhibiting higher FC than females in AT but lower FC in PM (Figure 3). Age‐related trajectories were not modulated by sex differences (p>.05) and were best described by a linear relationship according to model comparison testing different polynomials.ConclusionBy encompassing the entire adult lifespan and assessing longitudinal changes, our study provides strong support that the two MTL networks display differential alterations in the context of aging, as well as sex differences. Since MTL connectivity has been described as particularly affected in the early stages of AD, and age and sex are risk factors, these findings may be helpful to enhance the clinical utility of such biomarkers for the early detection of AD‐related changes.
Steps towards the implementation of amyloid‐PET in memory clinics: AMYPAD Diagnostic and Patient Management Study
Authors: Altomare Daniele , van Maurik Ingrid S. , Caprioglio Camilla , Barkhof Frederik , Collij Lyduine E. , Scheltens Philip , van Berckel Bart NM , Alves Isadora Lopes , Garibotto Valentina , Moro Christian , Delrieu Julien , Molinuevo Jose Luis , Grau‐Rivera Oriol , Gispert Juan Domingo , Drzezga Alexander , Jessen Frank , Nordberg Agneta K , Walker Zuzana , Demonet Jean‐François , Gismondi Rossella , Farrar Gill , Stephens Andrew W , Berkhof Johannes , Frisoni Giovanni B 
Published: December 2022

AbstractBackgroundAmyloid‐PET allows the assessment of amyloid deposition, one of the main hallmarks of Alzheimer’s disease. However, in most countries, this exam is not routinely used in clinical practice. Several studies have assessed physician‐centered outcomes, yet often without a randomized study design. In addition, the choice to reimburse amyloid‐PET depends also on its cost‐effectiveness and on the safety of the procedure of disclosure.MethodWe assessed physician‐centered outcomes, cost‐effectiveness, and amyloid‐PET result disclosure in the AMYPAD‐DPMS cohort. Participants were memory clinic patients with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI) or dementia from 8 European memory clinics. They were randomized into three study arms: ARM1, amyloid‐PET performed early in the diagnostic workup (within 1 month); ARM2, late in the diagnostic workup (after 8±2 months); or ARM3, if and when the managing physician chose to. To assess cost‐effectiveness, we collected information on participants’ use of healthcare resources (through patient diaries) and assessed health‐related outcomes (e.g. EQ‐5D‐5L, ICECAP‐O, Brief COPE, global cognition, anxiety, and depression) at different time points. Impact of disclosure in SCD+ was assessed through the collection of the Impact of Event Scale – Revised (IES‐R) questionnaire and the assessment of anxiety and depression (both before and after disclosure).Result88% of ARM3 participants underwent amyloid‐PET within 3 months, and the average time from baseline to prescribe amyloid‐PET was 46 (IQR=58) days. We observed that, after 3 months, a diagnosis with very high confidence (≥90%) was more frequent in participants who underwent an early amyloid‐PET (ARM1: 40%, 109/272) and in those for whom amyloid‐PET could be freely prescribed by the managing physicians (ARM3: 37%, 97/261) as compared to those who had not undergone amyloid‐PET yet (ARM2: 11%, 30/260; p<0.001). More than 2500 patient diaries and more than 100 IES‐R have been collected throughout the study. Preliminary results on health economics and impact of amyloid‐PET result disclosure in SCD+ will be presented.ConclusionOur results suggest that an early amyloid‐PET has a relevant clinical impact. Results on its cost‐effectiveness and the impact of disclosure of the result on cognitively unimpaired individuals might further contribute to its introduction into clinical practice.
Associations of Sensory and Motor Functions in Midlife with Longitudinal Blood‐Based Biomarker Levels of Alzheimer’s Disease and Neurodegeneration
Authors: Merten Natascha , Pinto Alex A , Paulsen Adam J , Schubert Carla R , Chappell Richard J. , Chen Yanjun , Hancock Laura M , Engelman Corinne D , Cruickshanks Karen J 
Published: December 2022

AbstractBackgroundDementia has a long preclinical phase and pathological fluid biomarker levels change decades before clinical symptoms. Thus, early detection of people at risk for neurodegenerative and pathological changes, especially in midlife, might improve future treatments and preventions. Sensory and motor changes are common in aging adults and may be early markers of neurodegeneration since they are associated with cognition and risk factors of neurodegeneration. However, their associations with blood‐based neurodegenerative and AD biomarkers are not yet known. We aimed to determine if midlife sensory and motor functions are associated with long‐term changes in blood‐based biomarkers of neurodegeneration and AD (neurofilament light chain(NfL), total tau(TT), and amyloid beta(Aβ)).MethodThis longitudinal study is based on n=1529 (54% women, mean age 49years) Beaver Dam Offspring Study (BOSS) participants. The BOSS started in 2005 and had 5‐year and 10‐year follow‐up exams. We assessed sensory (pure‐tone audiometry, contrast sensitivity, olfactory identification) and motor (Grooved Pegboard) function, plus multiple potential confounding risk factors at baseline. NfL, TT, Aβ42, and Aβ40 levels were analyzed in serum samples from all three waves (SIMOA, Quanterix). We used linear mixed‐effects models with baseline hearing, vision, olfaction, and motor function as determinant and repeated biomarker levels as outcome and adjusted for age, sex, education, random intercept, random slope (if model fit was improved), and other confounders. NfL and TT were log‐transformed. Due to sex interactions, Aβ42/Aβ40 models were sex‐stratified.ResultsOverall, NfL increased 3% and TT 1% per year. Aβ42/Aβ40 decreased 0.5/year in women and 0.24/year in men. Individuals with hearing and vision impairment showed faster NfL level increase over time (0.8%/year; CI 0.3,1.4;p=.004; 0.5%/year; CI ‐0.1,1;p=.09; respectively). Worse motor function was associated with faster NfL increase (0.4%/year per 20s test time; CI 0.2,0.7;p<.001). These effects compared to effects of 2‐3 months of aging. There were no significant associations with Aβ42/Aβ40 or TT.ConclusionWe found associations between midlife sensory and motor functions and long‐term changes in NfL levels, a non‐specific marker of neurodegeneration, while there were no associations with AD‐specific biomarkers. Future studies with longer follow‐up should determine if sensory and motor changes are more reflective of general neurodegenerative than AD‐specific pathology.
Medial temporal atrophy in posterior cortical atrophy and its relationship to the cingulate island sign
Authors: Josephs Kennedy A , Pham Nha Trang Thu , Graff‐Radford Jonathan , Machulda Mary M. , Lowe Val J. , Whitwell Jennifer L 
Published: December 2022

AbstractBackgroundPosterior cortical atrophy (PCA) is associated with hypometabolism on FDG‐PET and atrophy on MRI in the parietal and occipital lobes, and patients often show the cingulate island sign (CIS) whereby posterior cingulate metabolism is relatively spared compared to the precuneus and cuneus. It has been hypothesized that medial temporal sparing may be related to CIS in PCA. We aimed to assess the severity of medial temporal atrophy in PCA and determine whether the presence of a CIS is related to medial temporal sparing.MethodFifty‐five PCA patients underwent a 3T volumetric MRI and FDG‐PET. The degree and symmetry of medial temporal atrophy on MRI was visually assessed in both hemispheres using the five‐point Scheltens scale (0=normal; 1=mild; 2=moderate; 3=marked; 4=severe). Visual assessments of FDG‐PET coded the presence/absence of a CIS and whether the CIS was symmetric or asymmetric. Hippocampal volumes and a quantitative CIS were also measured. Associations between medial temporal atrophy scores and clinical measures were assessed using linear regression correcting for age.ResultMedial temporal atrophy was most commonly mild (38% on the right, 40% on the left), followed by moderate (35% on the right, 29% on the left), and then no atrophy (18% on right, 25% on left). Marked or severe atrophy was only observed in 9% of patients on the right and 5% of patients on the left. Atrophy was asymmetric in 55%, and when asymmetric was most commonly worse on the right (76%). Greater medial temporal atrophy was associated with older age (p<0.001) and worse verbal episodic memory (p=0.008). The CIS was observed in 44% of the PCA patients and was asymmetric in 50% of these. The patients with a CIS showed greater medial temporal asymmetry (p=0.016), but did not show lower medial temporal atrophy scores, compared to those without a CIS. Hippocampal volumes were not associated with quantitative CIS.ConclusionMild to moderate medial temporal atrophy is a common finding in PCA and is associated with worse memory impairment and older age. However, medial temporal sparing was not related to the presence of a CIS in PCA.
Development of an artificial intelligence approach that employs genomic and brain imaging features to improve the diagnosis of Alzheimer’s Disease (AD)
Authors: Zhuang Xiaowei , Young Richard , Tillett Richard , Cordes Dietmar , Oh Edwin 
Published: December 2022

AbstractBackgroundIn the past 20 years, genome wide association studies (GWAS) and brain imaging analyses have identified various genetic risk variants and structural brain differences between AD and cognitively normal (CN) subjects1–3. However, due to the relatively large and colinear feature space, it remains a challenge to use these variants and features to classify AD status at an individual level for personalized diagnosis, treatment, and prevention4. In this study, we applied a novel artificial intelligence‐based technique to transform both genomic and brain imaging features into 2D artificial images, and further utilized a deep convolutional neural network (CNN) to classify these artificial images5,6. Together, we show that the approach significantly improves the classification accuracy of AD subjects.MethodsParticipants were selected from the AD Neuroimaging Initiative. Table 1 details the samples and features for each classification analysis. Briefly, 808 subjects with 2451 single‐nucleotide‐variants (SNV) with p‐values<1e‐4 in previous AD‐GWAS1 were included in classification of AD using SNV features. For classification of AD using brain imaging features, 1625 structural magnetic resonance imaging (sMRI) images from 941 subjects were included as samples. Each T1‐weighted sMRI image was entered into the FreeSurfer pipeline7 to compute features of regional thicknesses, volumes, and surface areas. Next, every feature was normalized to a scale of 0‐255, and the entire feature set from every subject was transformed into a 2D artificial image5. A CNN classifier was then trained on 80% of the samples with internal validation and tested on the remaining 20% of the samples.ResultsSince our samples were significantly biased towards non‐AD subjects, both the area under the ROC curve (AUC) and the accuracy were reported in Table 2 to assess the performance of the classifier. As listed in Table 2, the artificial intelligence approach outperforms 10 other regular/popular classifiers in discriminating AD from non‐AD samples, with an accuracy and AUC of 70.99% and 0.64 for SNV features, 86.50% and 0.74 for sMRI features, and 91.60% and 0.85 for combined features.ConclusionTaken together, these results indicate that our approach can efficiently deal with large and colinear feature spaces to classify AD subjects more accurately at an individual level.
Longitudinal trajectories in clinical progression of Alzheimer’s disease tau positron emission tomography subtypes
Authors: Rauchmann Boris‐Stephan , Ersoezlue Ersin , Luedecke Dorothea , Perneczky Robert 
Published: December 2022

AbstractBackgroundRecent evidence suggests substantial heterogeneity in Alzheimer's disease (AD). Distinct subtypes have been identified using tau pet positron emissions tomography. There is only limited knowledge about the longitudinal cognitive and clinical trajectories of these subtypes.MethodThree hundred and twenty‐one participants were included with 155 amyloid‐β (Aβ) negative and cognitively normal healthy controls (HC, 74 years, 85 female) and 166 Aβ positive patients with mild cognitive impairment or AD dementia (Alzheimer’s disease spectrum, ADS, 75 years, 76 female). We identified distinct subtypes using an unbiased, data‐driven and similarity‐based Louvain clustering algorithm, modified using a consensus method. Longitudinal trajectories in cognitive domain scores and clinical severity were compared between tau subtypes using mixed effect models.ResultFour distinct tau PET imaging subtypes were identified, including a posterior, a limbic, a medio‐temoral lobe (MTL) sparing and a temporal subtype (Figure 1). In longitudinal analyses, the subtypes differed substantially in disease progression in the different cognitive domains, i.e. episodic memory, executive functioning, language and visual memory. The temporal subtype showed the steepest decline in visual memory and language, the medial temporal lobe sparing subtype showed only minor language degradation and the limbic subtype showed relatively preserved executive functioning but decline in all other cognitive domains. The MTLs was by far worst affected by clinical progression. The remaining subtypes showed only slight deterioration in clinical severity (Figure 2).ConclusionOur results suggest characteristic differences in longitudinal cognitive and clinical trajectories of the tau PET imaging subtypes. Analyzing the heterogeneity in AD using tau PET spatial distribution patterns, significantly improves our understanding of the biological underpinnings of individual differences in clinical presentation and progression. An in‐depth understanding of the subtype’s characteristics in the longitudinal trajectories contributes significantly to improved prevention strategies and individualized precision treatments.