bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apnea‐associated hypoxemia is linked to greater tau deposition in women with Alzheimer’s disease risk
Authors: Lui Kitty K , Shepherd Alyx L , Wang Xin , Bernier Rachel A , Bosompra Nana , DeYoung Pamela N , Malhotra Atul , Sundermann Erin E. , Banks Sarah J 
Published: December 2022

AbstractBackgroundObstructive sleep apnea (OSA) is characterized by recurrent pharyngeal airway collapse and drops in blood oxygen levels that lead to intermittent hypoxemia. OSA has been associated with Alzheimer’s disease (AD) pathology, including tau. AD is more prevalent in women, and women tend to have higher levels of tau compared to men. OSA is underdiagnosed, particularly in postmenopausal women where OSA risk is similar to men. We conducted a pilot study examining the relationship between OSA and tau using positron emission tomography (PET) in older women at higher risk for AD who participated in the Women Inflammation and Tau Study (WITS).Method10 older women (aged 71±3.3 years) were recruited to WITS, which required elevated genetic risk of AD and a Montreal Cognitive Assessment score suggestive of mild cognitive impairment (range 13‐20). A home sleep test was completed to derive the apnea‐hypopnea index (AHI), nadir and mean oxygen saturation (Osat), and proportion of time in bed (TIB) with oxygen saturation ≤88% (Osat≤88%). Participants also underwent MK‐6240 PET to determine tau deposition. Standardized uptake value ratio (SUVR) was computed in temporal meta‐region of interest (ROI) Braak Stages I, III‐IV, and V‐VI. Spearman correlation was used to analyze the associations between OSA characteristics and tau PET SUVR in the respective ROIs.ResultIn this initial sample from WITS, 40% had mild OSA (AHI≥5/h and AHI<15/h) and 40% had moderate OSA (AHI≥15/h and AHI<30/h). Greater proportion of TIB with Osat≤88% was associated with higher tau SUVR in temporal meta‐ROI (rho=0.69, p=0.03), Braak III‐IV (rho=0.70, p=0.03), and Braak V‐VI (rho=0.69, p=0.03). No significant relationships were observed between AHI and tau PET SUVR in the respective ROIs (all p>0.40).ConclusionIn this small sample of women with elevated AD risk, OSA was evident in the majority. Additionally, we found positive relationships between proportion of TIB with Osat≤88% and tau deposition in temporal and neocortical regions. These findings suggests that OSA‐related intermittent hypoxemia could potentially contribute to the pathogenesis of tau; however, longitudinal studies are needed. Treatment of OSA may be a possible target to reduce or delay the impact of AD.
Peripheral inflammation and cognition in older adults with and without cognitive impairment
Authors: Wong Christina G. , Cross Chad L. , Kinney Jefferson W , Ritter Aaron , Caldwell Jessica ZK , Kramer Joel H. 
Published: December 2022

AbstractBackgroundUnderstanding how different inflammatory markers relate to cognition is important for the development of therapeutic targets in Alzheimer’s disease (AD). However, many studies have relied on a single, broad measure of inflammation or a select handful of markers that have been identified in the AD literature. We examined a large set of plasma inflammatory markers that were statistically grouped via principal component analysis (PCA). Associations between inflammation component scores and cognition were examined.MethodParticipants included 41 cognitively normal (CN) and 64 cognitively impaired (CI; 47 mild cognitive impairment and 17 AD) older adults from the Center for Neurodegeneration and Translational Neuroscience. Composite scores for memory, executive functioning, processing speed, and language were created by averaging age‐adjusted z scores for two tests per domain. Plasma levels of inflammatory cytokines were measured using the Luminex platform and Biorad 48‐plex cytokine assay. Five markers with null values were excluded, and the remaining markers were included in a PCA. Relationships between the inflammation component scores and cognition were examined using linear regression models with inflammatory marker as the predictor and each cognitive composite separately as the dependent variable, with adjustment for education, sex, and clinical diagnosis (CN vs CI).ResultThe PCA produced a 7‐component solution that accounted for 75% of the variance. In the final models, Components 2 (β = 0.260, p = 0.020) and 4 (β = 0.235, p = 0.036) were positively associated with memory, Components 2 (β = 0.231, p = 0.052), 4 (β = 0.260, p = 0.031), and 6 (β = 0.280, p = 0.016) were positively associated with executive functioning, and Components 2 (β = 0.221, p = 0.032) and 4 (β = 0.283, p = 0.007) were positively associated with processing speed. Inflammatory components were not significantly related to language.ConclusionHigher levels of peripheral inflammatory cytokines were associated with better memory, executive functioning, and processing speed in older adults, even when accounting for clinical diagnosis. Acute elevations of certain inflammatory markers may be associated with a protective role in cognitive aging. Longitudinal research examining stability of cytokine levels and association with cognition in AD trajectories is needed.
Regulation of T helper 17 to regulatory T cell (Th17/Treg) as mediator of stress‐induced psychological impairment and cognitive deterioration
Authors: Pasinetti Giulio Maria , Yang Eun‐Jeong 
Published: December 2022

AbstractBackgroundChronic stress disrupts immune homeostasis while gut microbiota‐derived metabolites attenuate inflammation, thus promoting resilience to stress‐induced immune and behavioral abnormalities. There are both peripheral and brain region‐specific maladaptations of the immune response to chronic stress that produce interrelated mechanistic considerations required for the design of novel therapeutic strategies for prevention of cognitive deterioration in a mouse model of Alzheimer’s disease (AD) type cognitive deteriorationMethodsChronic unpredictable stress was performed in wild‐type mice. Mice were treated with a combination of either prebiotics and probiotics (synbiotics) or vehicle. Mice were assessed for behavioral changes including mood and cognitive dysfunction. RNAseq was in performed in the gut and correlative analyses of behavior and inflammatory responses in the brain were conducted.ResultsUsing a model of chronic unpredictable stress, behavioral abnormalities were associated to strong immune cell activation and recruitment in the ileum while inflammasome pathways were implicated in the hippocampus. Chronic stress also upregulated the ratio of activated proinflammatory T helper 17 (Th17) to regulatory T cells (Treg) in the liver and ileum and it was predicted with ingenuity pathway analysis that the aryl hydrocarbon receptor (AHR) could be driving the synbiotic’s effect on the ileum’s inflammatory response to stress. Synbiotic treatment attenuated the stress‐induced immune and behavioral aberrations in both the ileum and the brain while in a gut‐immune co‐culture model, the synbiotic‐specific metabolites promoted anti‐inflammatory activity through the AHR. Overall, this study characterizes a novel synbiotic treatment for chronic‐stress induced behavioral impairments while defining a putative mechanism of gut‐microbiota host interaction for modulating cognitive functions through modulationof of the peripheral and brain immune systems.ConclusionThis study shows that a combination of probiotics and polyphenol‐rich prebiotics, a synbiotic, attenuates the chronic‐stress induced inflammatory responses in the ileum and cortical‐hippocampal regions promoting resilience to the consequent cognitive deterioration in male mice.
Consensus Automatic Speech Recognition (CASR) in Cognitive Testing
Authors: Herron Timothy J , Hall Kathleen , Sucich Gabriel , Blank Michael , Geraci Kristin , Baldo Juliana , Woods David L. 
Published: December 2022

AbstractBackgroundScoring verbal cognitive tests with automatic speech recognition (ASR) engines increases the efficiency of scoring and provides word timestamps that enable detailed temporal analyses of spoken responses. Here, we describe consensus ASR (CASR) procedures that incorporate multiple ASR engines to increase transcription and timing accuracy and generate CASR transcript confidence scores.MethodSeven ASR engines produced automatic transcriptions of both speech database samples (GMU Speech Accent Archive and NUS Auditory English Lexicon Project) and verbal test responses of 41 subjects from the California Cognitive Assessment Battery (CCAB). A novel Recognizer Output Voting Error Reduction (ROVER) algorithm was used to mutually align the transcripts, and a Bayesian weighted voting algorithm produced the best CASR transcript, mean word timestamps, and consensus scores. Word error rates (WER) gauged CASR accuracy against either predetermined or manually corrected transcripts.ResultDatabase sentence WERs from 1767 subjects ranged from a mean of 22% (Windows10 UWP) to 6% (Rev.ai) with CASR producing 5%, with no significant gender or age effects but better performance for native english speakers (Figure 1). In CCAB test responses, for limited word response tests CASR WERs ranged from 3% to less than 1% (Figure 2); for expansive word response tests CASR WERs ranged from 8% to 2% (Figure 3); and for discursive speech, CASR WERs ranged from 6% to 5%. Word start time ASR estimates for 594 database words in lists ranged in mean deviations from true times from 250ms std.dev. (Google) to 17ms std.dev. (Amazon) with CASR obtaining 14ms errors (Figure 4). Finally, consensus confidence scores from CCAB test responses, ranging from 0 to 1 (1 = complete agreement across ASR engines), show that CASR words with consensus scores above 0.8 and 0.9 are correct >99% and >99.8% of the time, respectively (Figure 5).ConclusionCASR produces transcripts for verbal test responses accurate enough for estimating scores in most limited word response tests. In large vocabulary response tests, CASR transcripts facilitate quick manual correction, and confidence values can identify transcript words needing manual correction. Patterns in CASR errors also indicate future substantial reductions to CASR WER on a per test basis.
Modeling retinal Alzheimer’s disease histopathology with human iPSC‐derived retinal organoids for mechanistic and DRUG DEVELOPMENT studies
Authors: Vergara M. Natalia , Vielle Anne , Li Helen T. , James Ethan , Johnson Noah R , Chial Heidi J , Potter Huntington 
Published: December 2022

AbstractBackgroundThe neuropathological features that characterize Alzheimer’s disease (AD), including the presence of beta‐amyloid (Aß) plaques and intracellular neurofibrillary tangles (NFTs) of abnormally phosphorylated Tau proteins (pTau), are manifested not only in the brain but also in the retina, an extension of the central nervous system. This is likely to contribute to the visual manifestations of AD that can pose additional challenges to this vulnerable population. Moreover, due to its accessibility and the availability of non‐invasive imaging technologies, the retina is being investigated as a potential biomarker of AD progression. In this context, hiPSC‐derived retinal organoids offer new opportunities for AD modeling that present advantages for DRUG DEVELOPMENT applications. Retinal organoids mimic the histoarchitecture of the native retina, have a consistent cellular composition, and are optically clear. Moreover, 3D automated reporter quantification (3D‐ARQ) technologies have been established to facilitate quantitative assay design in these models without loss of their 3D structure. Thus, we set out to develop and characterize an hiPSC‐derived retinal organoid model of AD that can be applied to the evaluation of pathophysiological mechanisms and to the validation of potential therapeutic drugs.MethodsHuman iPSC‐derived retinal organoids were generated from three healthy control (HC) and two familial AD (fAD) donors using the Zhong et al. (2014) protocol. Organoid structure, cellular composition and AD histopathology were assessed at three and six months of differentiation by immunoblotting and immunofluorescence staining, including retinal cell type‐specific markers as well as Aβ, pathological pTau forms, and NIAD‐4 staining for amyloid plaques. We also developed a NIAD‐4 fluorescence‐based assay for amyloid quantification in intact organoids using 3D‐ARQ technology.ResultsWe found similarities in the cellular composition of AD and HC retinal organoids, confirming the validity of the models. However, pathological Tau hyperphosphorylation and Aß deposits were significantly increased in AD retinal organoids compared to HCs. Finally, we developed proof of concept of a quantitative assay for amyloid plaque detection that is amenable to translational research applications.ConclusionsOur AD retinal organoid models mimic critical aspects of the histopathology of the human AD retina and constitute valuable tools for the screening and validation of candidate molecules with therapeutic potential.
CSF Biomarkers of Amyloid and Tau Pathologies in Participants Enrolled in the Stanford Alzheimer’s Disease Research Center
Authors: Ramos Benitez Javier A. , Wilson Edward N. , Swarovski Michelle S. , Shahid Marian , Corso Nicole , Channappa Divya , Belnap Malia , Tian Lu , Kerchner Geoffrey A. , Sha Sharon , Henderson Victor , Longo Frank M. , Wyss‐Coray Tony , Poston Kathleen L , Mormino Elizabeth C. , Andreasson Katrin I. 
Published: December 2022

AbstractBackgroundHeterogeneity in the clinical presentation of Alzheimer’s disease (AD) underscores the importance of biomarker‐defined diagnosis for use in medicine, research and clinical trials. Therefore, CSF measurement of amyloid and tau is an important tool in the diagnostic toolbox for inferring AD‐related brain pathologies. Because differences in preanalytical handling and in study population demographics render it difficult to apply a set of global concentration cut points for defining normal/abnormal for each analyte, it is critical that analyte cut points representing normal/abnormal be determined in a center‐specific manner.MethodThis is a cross‐sectional analysis of CSF collected from participants enrolled in the ongoing prospective cohort study of the Stanford Alzheimer’s Disease Research Center. Participants underwent lumbar puncture and cognitive evaluation to receive a diagnosis of cognitively unimpaired (CU), mild cognitive impairment (MCI) or AD. The current study included cognitively normal adults (n=78), individuals with MCI (n=36), and individuals with AD (n=26). Core CSF AD biomarkers p‐tau181, total tau, Aβ42 and Aβ40 were measured (Lumipulse G1200 platform, Fujirebio US, Inc). Cutpoints identifying normal/abnormal amyloid and tau were generated using the Youden method and Amyloid+ was defined as abnormally low CSF Aβ42/Aβ40 while Tau+ was defined as abnormally elevated CSF p‐tau181 and/or total tau.ResultClassification by amyloid and tau biomarkers revealed that in this population, 64.1% (n=50) CU were biomarker negative for tau or amyloid pathology. However, 28.2% (n=22) of the CU were Amyloid+, 5.1% (n=4) were Amyloid+ and Tau+, and 2.6% (n=2) were Tau+ alone. In the MCI diagnostic group, 33.3% (n=12) were Amyloid+ alone, while 30.6% (n=11) were both Amyloid+ and Tau+, and 5.6% (n=2) were Tau+ alone. 30.6% (n=11) were both Amyloid‐ and Tau‐. Within those receiving an AD diagnosis, 23.1% (n=6) had CSF biomarker evidence for being Amyloid+ only, 65.4% (n=17) were both Amyloid+ and Tau+, and 11.5% (n=3) participants had no biomarker evidence for Amyloid+ or Tau+.ConclusionThese results highlight the heterogeneity underlying amyloid and tau pathology in clinically defined diagnostic groups. Biomarker‐defined diagnosis using center‐specific cut points will support accurate diagnosis, treatment, clinical research and enrollment in clinical trials.
Associations Between Mild Behavioral Impairment (MBI‐C) Affective Domains and Alzheimer’s Disease Neuroimaging Biomarkers in Older Adults
Authors: Mayblyum Danielle V. , Quiroz Yakeel T. , Langella Stephanie , Udeogu Onyinye J. , Jacobs Heidi I.L. , Rubinstein Zoe B. , Sperling Reisa A. , Johnson Keith A. , Blacker Deborah , Marshall Gad A , Gatchel Jennifer R 
Published: December 2022

AbstractBackgroundPrevious work has shown that neuropsychiatric symptoms (NPS) such as depression in older adults are associated with cognitive decline and brain pathology related to Alzheimer’s disease (AD), but the constellation of NPS driving these associations is unclear. Traditionally, depressive symptoms have been assessed with the Geriatric Depression Scale (GDS), but newer NPS assessments, such as the Mild Behavioral Impairment‐Checklist (MBI‐C), have shown promise for identification of specific early features of symptomology. Here we examined the two affective domains of the MBI‐C in cognitively unimpaired older adults with moderate‐to‐severe depressive symptoms and non‐depressed older adults, and the association between these domains and neuroimaging biomarkers of AD.Method21 clinically normal (CN) older adults who met DSM5 criteria for major depression (MDD) (73.0±4.3 y.o., 62% female) and 25 non‐depressed older adults from related observational studies at our site (70.8±3.7 y.o., 64% female) underwent a clinical battery that included the GDS and MBI‐C self‐report domains focused on decreased interest‐motivation‐drive and increased dysphoria‐anhedonia‐anxiety (Range for each domain: 0–18). Participants completed neuroimaging consisting of MRI, amyloid‐(C11‐PiB)‐PET, and tau‐(F18‐FTP)‐PET. We focused analyses on neocortical amyloid and regional tau and atrophy in the amygdala and hippocampus. A Pearson correlation was used to assess the association between GDS total score and MBI‐C component scores. Linear regressions adjusted for age were used to investigate relationships between MBI‐C domains and ATN biomarkers.ResultGDS total score was correlated with both MBI‐C domains across all participants (Fig.1, p<0.01). In participants with MDD, the MBI‐C decreased interest‐motivation‐drive domain was associated with elevated FTP in the amygdala and hippocampus, while the increased dysphoria‐anhedonia‐anxiety domain was not significantly related to PET signal (Table 2, Fig.2). MBI‐C domains were not related to PET signal or atrophy in non‐depressed control participants.ConclusionPreliminary findings with the MBI‐C suggest that the decreased interest‐motivation‐drive domain may be associated with tau pathology in older adults with moderate‐to‐severe depression. Additional work needs to be done in a larger depressed cohort to further understand the associations between specific depressive phenotypes and AD pathology.
Midlife and current physical activity is associated with functional brain connectivity in older age
Authors: Ai Meishan , Morris Timothy Peter , Thovinakere Nagashree , de la Colina Adrián Noriega , Tremblay‐Mercier Jennifer , Villeneuve Sylvia , Kramer Arthur , Geddes Maiya R. ,   the PREVENT‐AD Research Group
Published: December 2022

AbstractBackgroundPrevious studies have shown a physically active lifestyle in both midlife and later life to benefit cognition and brain health in older age. However, exploring the influence of physical activity engagement on functional brain connectivity is needed to fully understand the neural mechanism underlying the effect of physical engagement. Additionally, in order to give lifestyle advice to different age groups, it is important to understand the unique contributions of physical activity at different life stages, which has rarely been examined.MethodThe current study investigated the effect of self‐reported midlife and current physical activity engagement on functional connectivity among 105 cognitively high functioning older adults (age = 66.6±4.1). Self‐reported midlife and current moderate‐to‐vigorous physical activity (MVPA) were recorded using the Lifetime Total Physical Activity Questionnaire. We included covariates in all analyses (i.e., age, sex, years of education, socioeconomic status, genetic risk of Alzheimer’s disease (i.e., APOE ε4 carrier status). Five regions of interest (ROIs) were selected based on previous literature on the relationship between exercise and brain health which included: prefrontal (i.e., bilateral superior frontal, middle frontal, and pars opercularis of the inferior frontal gyrus), and bilateral hippocampus.ResultResults showed that people who were active in midlife had greater functional connectivity between middle frontal gyrus and superior parietal region, postcentral gyrus (Voxel p<0.005, Cluster p<0.05 FDR corrected; figure 1a) than people who were relatively inactive in midlife. This effect stayed the same after controlling for current MVPA time. Secondly, the results showed that people who were active currently have greater functional connectivity between hippocampus and frontal pole (Voxel p<0.005, Cluster p<0.05 FDR corrected; figure 1b). Currently active participants also showed greater functional connectivity between pars triangularis of the inferior frontal gyrus, and bilateral middle temporal region, and frontal pole (Voxel p<0.001, Cluster p<0.05 FDR corrected; figure1c) compared to currently inactive participants, which stayed consistent after controlling for midlife MVPA time.ConclusionAs a conclusion, although midlife and current MVPA time were positively associated with each other, they both influence brain functional connectivity in later life independently. The results emphasize the importance of keeping a physically active lifestyle across midlife and into later life.
Associations between intergenerational transmission of AD, type 2 diabetes, and cognitive function among non‐Hispanic Black adults in midlife
Authors: Kraal A.Zarina , Palta Priya , Brickman Adam M. , Manly Jennifer J 
Published: December 2022

AbstractBackgroundType 2 diabetes (T2D) and parental history of Alzheimer’s disease (AD) are independent risk factors for late‐life cognitive impairment. The presence of T2D may strengthen the association of parental AD risk on cognition through pathways of vascular function, insulin signaling, and amyloid β/tau metabolism. Examining the independent and interactive association of parental AD risk and T2D on cognitive function, specifically in non‐Hispanic Black adults may advance our understanding of their contribution to the disproportionate rates of AD in this group. We hypothesize that parental AD risk and T2D would be independently associated with worse cognition and that the association between parental AD risk and cognition would be stronger in participants with T2D.MethodParticipants comprised non‐Hispanic Black adults (N = 331; 25.8% with T2D; Table 1) in the Offspring Study who are the adult children of participants in the Washington Heights Inwood Columbia Aging Project (WHICAP). AD risk was operationalized as parental memory performance residualized for age and education and assessed at their last WHICAP visit. Participant T2D was based on self‐reported physician diagnosis and cognition was assessed with measures of attention, language, and memory. Cognitive test scores were residualized for age and education (Table 1). Linear regression models quantified the independent associations and interaction of AD risk and T2D on offspring cognition.ResultT2D was associated with lower language (B = ‐0.13, 95% CI: [‐0.55, ‐0.08]) and memory (B = ‐0.45, 95% CI: [‐0.72, ‐0.17]) scores, but AD risk was not associated with cognition in any domain. However, AD risk was associated with lower language scores among participants without T2D, but not in participants with T2D (B = ‐0.36, 95% CI [‐0.71, ‐0.02]; Figure 1). No interaction was observed for AD risk and T2D with memory and attention (Figure 2).ConclusionOur results suggest that among middle‐aged non‐Hispanic Black adults, AD risk is associated with lower language performance in individuals without T2D. The association between AD risk and cognition may be masked by exposure to risk factors, such as T2D.