bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating Braak stage from [18F]MK6240 PET scans
Authors: Whittington Alex , Porat Lily , Christian Bradley T. , Devanand Devanand P. , Hostetler Eric D. , Johnson Keith A. , Johnson Sterling C , Klunk William E , Lao Patrick J. , Rowe Christopher C , Devanarayan Viswanath , Reilhac Anthonin , Reyderman Larisa , Irizarry Michael C. , Charil Arnaud , Gunn Roger N 
Published: December 2023

AbstractBackground[18F]MK6240 is a second‐generation radiotracer for imaging tau pathology in vivo. Regional thresholds that allow for an assessment of Braak stage have yet to be established and importantly may vary between regions. In this work we use a Z‐score approach to define regional thresholds and estimate Braak stage in Alzheimer’s Disease.MethodAll static MK6240 images used were downloaded from the Lantheus/Cerveau database, spatially normalised into MNI space using DARTEL and SUVR images were computed using an inferior cerebellum reference region. Three Braak meta‐ROIS, Braak I/II, Braak III/IV and Braak V/VI (Figure 1), were applied to 275 amyloid negative healthy control images to define regional thresholds for positivity in each ROI at the level of mean SUVR + 2 SD. These thresholds were then applied to 232 scans from subjects across the AD spectrum with associated MMSE data (88 healthy control, 68 MCI and 76 AD: 131 Aβ+ / 101 Aβ‐).Result[18F]MK6240 showed similar mean values and low variability across all ROIs in the amyloid negative healthy controls (Figure 1). The regional SUVR cut‐off values were estimated as: Braak I/II = 1.29, Braak III/IV = 1.15 and Braak V/VI = 1.15. When these cut‐offs were applied to subjects across the AD spectrum with MMSE data (Figure 2), 118 out of 232 were negative for Braak pathology. These subjects were predominantly healthy controls and their mean MMSE was 27.3. For subjects that demonstrated Braak positivity in at least one region, 104 subjects demonstrated an ordering consistent with Braak staging whilst 10 subjects had an atypical ordering consistent with hippocampal sparing. 64 subjects were positive in all Braak regions with a mean MMSE of 23.4 and all but one of these subjects was either MCI or AD.ConclusionAnalysis of [18F]MK6240 images with thresholds that allow for the determination of Braak stage status provides data that are consistent with clinical status and MMSE score. This approach may be useful in natural history studies and clinical trials.
Childhood self‐reported socioeconomic status modifies the genetic risk of Alzheimer’s on mid‐ and late‐life cognitive decline in a population‐based study
Authors: Xu Yuexuan , Engelman Corinne D. 
Published: December 2023

AbstractBackgroundChildhood socioeconomic status (c‐SES) and genetic risk of Alzheimer’s disease (AD) contribute to an individual’s risk of developing AD in later life. A better understanding of the interactions between these risk factors can help design policy interventions to eliminate AD disparities at the earliest possible stage in life. In this study, we investigated whether global and domain‐specific c‐SES index modified the effect of genetic predisposition to AD on mid‐to‐late life cognitive decline.MethodsWe evaluated longitudinal associations of cognitive aging with validated global and domain‐specific c‐SES index, including childhood financial, human, and social capital domains. In the Health and Retirement Study, we separately tested interactions between the global and domain‐specific c‐SES index and a non‐APOE polygenic risk score (PRS) and APOE. We fitted all analyses using a linear mixed effects model and adjusted for within‐individual and within‐family correlation. Inverse probability weighting is used to adjust for selection mortality in the genetic sample.ResultsSelf‐reported overall and domain‐specific c‐SES index can significantly modify the age‐related effect of non‐APOE PRS on longitudinal global cognition, particularly among APOE ε4 carriers. After FDR correction, model parameters predicted that statistically significant PRS‐related differences in simple slopes between people with high (1 SD+ from population mean) and low (1 SD‐ from population mean) global and domain‐specific c‐SES index started showing after people reached age ∼77, with individuals who have low c‐SES bearing greater detrimental effect from the currently known combined effect of non‐APOE common variants as they age, and greatest among people who are also APOE ε4 carriers.ConclusionSelf‐reported childhood SES can modify the association between non‐APOE PRS and longitudinal cognition decline.
Depression amplifies the association between age and amyloid burden in an at‐risk cohort
Authors: Nelson Alexis R , Edmunds Kyle J , Brach Talia L. , Planalp Elizabeth M. , Christian Bradley T. , Betthauser Tobey J , Johnson Sterling C , Asthana Sanjay , Okonkwo Ozioma 
Published: December 2023

AbstractBackgroundOlder age is associated with increased risk for Alzheimer’s disease (AD), as well as amyloid‐beta (Aβ) deposition in key cortical regions associated with age‐related cognitive decline. Depression—especially late‐life onset—may influence the association of age on cortical amyloidosis. However, evidence is mixed in literature, making this association unclear. This study assesses whether depressive symptoms exacerbate the relationship between age and Aβ burden in an older cohort at‐risk for AD.MethodClinical Core participants (n = 238, mean ± SD age 68 ± 8.4 years, 63.9% females, 85.3% White, 8.8% Black or African American, 5.9% American Indian or Alaska Native, and 40% APOE‐ε4 carriers) from the Wisconsin Alzheimer’s Disease Research Center (WADRC) were included in this study. Aβ accumulation was quantified using Pittsburgh compound B positron emission tomography (PiB‐PET) DVR maps with a cerebellum gray matter reference region. Mean DVR values were extracted from the left and right precuneus. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). Cross‐sectional linear regression models were assembled in a moderation framework to test the interaction between age and GDS scores. Variables in the models included GDS scores, age at GDS data collection, sex, APOE‐ε4 carriage, and the difference between age at GDS data collection and age at PiB‐PET exam. An age x GDS interaction test was followed up with simple main effects analyses, testing the within‐group associations of age and PiB‐PET Aβ load at increasing levels of GDS scores.ResultGDS scores were largely normal (M = 1.29, SD = 1.61). Older age was associated with higher PiB‐PET binding (β = 0.01, p<0.01). The age x GDS interaction was significant (β = 0.003, p = 0.03). Conditional effects of the moderator were assessed at ±1SD from the mean GDS score, revealing progressively stronger associations between age and PiB‐PET binding across GDS groups (‐1SD GDS: β = 0.012, p<0.01; Mean GDS: β = 0.016, p<0.01; +1SD GDS: β = 0.021, p<0.01).ConclusionOur results suggest that greater depressive symptoms significantly amplify the association of age with Aβ deposition. Given AD’s increasing prevalence, it appears crucial to enhance treatment of late‐life depression, as that might lead to higher resilience against Aβ burden and subsequent dementia.
Single Molecule Detecting Amyloid Beta Oligomers In Human Cerebrospinal Fluid With Buoyant‐Antigen‐Magnetic Assay
Authors: karimpourkalou zahra , wang chuanlie , Viola Kirsten L. , Klein William L. , Anker jeffrey N 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease is a progressive neurodegenerative disorder that lacks a definitive treatment and affects an estimated 6.5 million Americans. Several lines of evidence suggest that Amyloid Beta Oligomers (ABOs) in cerebrospinal fluid (CSF) may be a cause of Alzheimer’s Disease and could be a biomarker for disease diagnosis/prognosis, and effectiveness of ABO modulating therapies. ABOs have been shown to target neuronal synapses, affect memory in cell and animal studies, and can be reversed in animal studies using antibodiesThere is also evidence that CSF ABO concentration is higher in Alzheimer’s patients, but these are reportedly found at very low levels.MethodWe are developing a single molecule counting assay using buoyant and magnetic beads that are functionalized with monoclonal antibodies specific to ABOs. A buoyant‐antigen‐magnetic (BAM) sandwich complex is formed when buoyant and magnetic particles both bind with ABOs. Unlabeled magnetic particles and buoyant beads are initially collected using magnetic force, while unlabeled buoyant particles separate and rise to the top. Removal of the magnet frees BAM complexes to rise away from the non‐labelled magnetic particles, where they can be observed and counted based on their intense scattering for light from a flashlight. The recorded video of BAMs movement is analyzed to determine the number of BAMs rising, which is correlated to the concentration of ABOs in the sample (McNaughton BH 2017).ResultThe procedure uses 20 microliter of CSF and takes 40 minutes and could be speeded up in future if needed. Rapid mixing via buoyancy bead motion provides a higher capture efficiency. The orthogonal forces from magnetophoretic and buoyancy separation ensure complete separation. Preliminary results show its capability to identify spiked synthetic ABOs at 20 fM in both cerebrospinal fluid and plasma samples (n = 20), although work is ongoing.ConclusionOverall, BAM assays provide a simple and elegant approach for isolating, detecting, and studying ABOs in CSF and plasma.
Characterization of data‐driven cognitive and amyloid‐beta phenotypes in older Veterans
Authors: Thomas Kelsey R. , Clark Alexandra L , Weigand Alexandra J. , Durazo Alin Alshaheri , Membreno Rachel , Luu Britney , Rantins Peter , Ly Monica T. , Rotblatt Lindsay J , Bangen Katherine J. 
Published: December 2023

AbstractBackgroundWithin older Veterans, multiple factors may contribute to cognitive difficulties. Beyond Alzheimer’s disease (AD), military‐related exposures leading to vascular disease (e.g., agent orange), posttraumatic stress disorder (PTSD), and traumatic brain injury (TBI) may also impact cognition. This study aimed to derive groups based on objective cognition, subjective cognition, and amyloid burden, and then compare groups on demographic, clinical, and biomarker characteristics.MethodA hierarchical cluster analysis was conducted on 233 Vietnam‐Era Veterans without dementia from the Department of Defense‐Alzheimer’s Disease Neuroimaging Initiative. Variables entered in the cluster analysis included: immediate and delayed memory, language, and attention/executive functioning domain scores; subjective cognitive decline (SCD) severity; and cortical amyloid PET SUVR. A discriminate function analysis (DFA) tested the extent to which the individual variables predicted cluster‐group membership. ANOVAs and chi‐squared tests examined demographic, clinical, and biomarker characteristics by group.ResultCluster analysis identified 4 groups: Group 1 with high cognition, low SCD, and average amyloid (n = 41); Group 2 with average cognition, average SCD, and low amyloid (n = 121); Group 3 with low attention/executive functioning, average SCD, and high amyloid (n = 28); and Group 4 with low memory/language, high SCD, and average amyloid (n = 43; Figure 1). The DFA correctly classified 88.8% of participants. Group 3 had the greatest proportion of APOE ε4 carriers and individuals with TBI, highest tau burden, and lowest hippocampal volume. Group 4 had the fewest years of education, highest proportion of Hispanic/Latino participants, PTSD, and worst sleep quality. Groups did not differ on age, depressive symptoms, hypertension, or substance use (Table 1).ConclusionWithin Vietnam‐Era Veterans, there were high and average cognition groups (Groups 1 and 2), both with low amyloid burden. Group 3 was most consistent with biological AD, yet attention/executive function was the lowest score. The complexity of older Veterans’ co‐morbid conditions may interact with AD pathology to show attention/executive dysfunction (rather than memory) as a prominent early symptom. Group 4 had the worst cognitive scores and highest SCD despite low amyloid; education, PTSD symptoms, sleep quality, and perhaps sociocultural factors may be contributing to this profile. Future work will investigate longitudinal cognitive and functional declines by group.
Volume of contrast‐based Substantia Nigra segmentation is decreased in dementia patients compared to healthy controls
Authors: Krohn Friedrich , Teipel Stefan , Spottke Annika , Düzel Emrah , Jessen Frank , Ziegler Gabriel , Betts Matthew 
Published: December 2023

AbstractBackgroundThe substantia nigra (SN) is susceptible to neurodegeneration in Alzheimer’s disease. Automatic segmentation of the SN using MRI permits in vivo morphological assessment of the SN in cohort studies. Here we evaluate the multi‐brain segmentation (MB, Brudfors, 2020) to learn a probabilistic tissue prior of the SN using neuromelanin‐sensitive MRI while systematically studying effects of (A) SN tissue contrast; and (B) volumetric differences between healthy subjects and memory patients.MethodWe studied 50 3T single‐site T1w FLASH MRI from cognitively healthy older adults from the DZNEDELCODE cohort and a second ageing cohort in Magdeburg and 25 multi‐site diagnosed memory patients (MCI or AD). We quantified local SN signal contrast and image noise as a quality metric (obtained from CAT/SPM toolbox). We learnt tissue priors for each 10, 20, 30 and 50 older adults with the highest SN tissue contrast. For each tissue prior, we obtained model‐based SN tissue segments and calculated (integrated) SN volume. We compared SN volume between tissue prior segmentations and correlated it to age and quality. We coregistered all patients to the N = 50 tissue prior and compared volumetric differences between healthy adults and patients using voxel‐based morphometry (VBM).ResultThe template‐space N = 50 SN prior (in red) was visually larger than all other priors (Fig 1A). Patients visually had a lower SN volume than healthy from N = 50 (Fig 1B). The N = 50 native space SN tissue prior volume was significantly higher than all other tissue prior volumes (p>0.01, Fig 2A). SN volume correlated with quality for N = 50 (p = 0.02, Fig 2B). The N = 50 sample SN contrast (Fig 2C) did not differ between patients and healthy adults. Patients had a decreased volume in a cluster overlapping with the SN (N = 268, pFDR corrected = 0.02 (Fig 2D).ConclusionHere we demonstrate that model‐based learning of a probabilistic SN tissue prior using intensity‐based generative approach to segmentation is feasable in a heterogenous cohort. Additionally, using this prior, we showed that while there is no difference of the SN contrast, there is a significant decrease in SN volume consistent with previous analyses (Krohn et al 2022).
Plasma ADRD Biomarkers are Altered in COVID‐19 ICU Survivors
Authors: Risacher Shannon L , Khan Babar A. , Dage Jeff L. , Clauss Matthias , Twigg Homer , Russ Kristen A. , Leary Erika L , Saykin Andrew J. , Wang Sophia 
Published: December 2023

AbstractBackgroundLong Covid, which features cognitive symptoms in some people, affects an estimated 23.3 million Americans. Older adult survivors of COVID‐19‐associated critical illness are more likely to experience the cognitive symptoms of Long Covid, including deficits in attention, memory, and executive functioning. We sought to evaluate Alzheimer’s disease and related dementia (ADRD) plasma biomarkers in pilot study of older ICU survivors of COVID‐19‐related critical illness and non‐COVID critical illness.Method17 ICU survivors (13 COVID‐19, 4 non‐COVID) underwent clinical and cognitive testing, a blood sample, and a structural MRI approximately 2 months after ICU discharge. Plasma from the blood sample was extracted, and SIMOA assays were used to measure Aβ42, Aβ40, glial fibrillar acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau (pTau181). Structural MRI scans were processed using Freesurfer version 6 to measure brain atrophy (mean global cortical thickness). Plasma analyte values over three standard deviations outside the mean of the whole group were excluded (1 NfL and 1 pTau). Two‐sample t‐tests were used to compare plasma analytes between ICU groups. Pearson or Spearman correlation models were used to evaluate the relationship of target analytes with brain volumes. Covariates were tested but did not change the results.ResultSignificantly lower Aβ42/40 ratio and Aβ42 levels were observed in COVID‐19 ICU survivors relative to non‐COVID ICU survivors (Figure 1). Across all participants Aβ42/40 ratio was not associated with mean global cortical thickness, while NfL and GFAP levels were negatively associated with cortical thickness (Figure 2). However, when limited to only the COVID‐19 ICU survivors, a more ADRD‐like pattern was observed, with a trend for a positive association of Aβ42/40 ratio with cortical thickness and negative association of GFAP and NfL with cortical thickness (Figure 3).ConclusionCognitive impairment in COVID‐19 critical illness may be related to ADRD pathophysiology. Future studies in larger samples of COVID‐19 ICU survivors, as well as those with Long Covid symptoms with a history of mild to moderate COVID‐19 infection are needed to better understand these relationships.
Circadian sleep regulation and brain tissue microstructure in cognitively unimpaired older adults
Authors: Deantoni Michele , Reyt Mathilde , Dourte Marine , De Haan Stella , Lesoinne Alexia , Vincenzo Muto , Hammad Grégory , Christina Schmidt , Baillet Marion 
Published: December 2023

AbstractBackgroundCircadian dysfunction increases with age, leading to changes in the circadian regulation of physiological and biological rhythms, including sleep. Actigraphy studies demonstrated that altered 24‐h rest‐activity patterns, an estimate of circadian sleep‐wake regulation, is related to cognitive decline and tightly linked to Alzheimer’s disease progression. Here, we assessed whether circadian sleep regulation, measured during a multiple naps protocol, is related to brain microstructural integrity in a group of cognitively unimpaired older adults.MethodEighty‐six retired older individuals (mean age [SD] = 69.9 ± 5.2 y.o., 32 females, Table 1) with no major sleep disorders or medical condition, underwent an in‐lab 40‐h multiple naps protocol and brain structural magnetic resonance imaging. As rapid eye movement (REM) sleep is under strong circadian control, circadian REM sleep amplitude was computed by fitting a Gaussian curve on REM sleep duration (% of total sleep time) measured for each nap opportunity. The multiparametric mapping protocol was used to derive indices of brain tissue microstructure using magnetization transfer saturation (MTsat), R1 and R2* maps (hMRI toolbox v0.2.2). Statistical models were adjusted for age, sex, education, and for additional covariates related to sleep architecture and its circadian modulation, including mean REM% and sleep efficiency (SE), the accumulation of REM sleep and sleep need (slope of a fitted first‐order polynomial curve), and circadian SE amplitude.ResultsWhole‐brain voxel‐based quantification analysis revealed that low circadian REM amplitude was related to low MTsat, R1 and R2* values in several white matter regions mostly located around the lateral ventricles (Figure 1A). In addition, a significant association was observed between low circadian REM amplitude and low R1 values in two grey matter clusters encompassing the hippocampus, entorhinal cortex, thalamus and hypothalamus (Figure 1B).ConclusionOur findings provide first evidence that changes in circadian sleep regulation is associated with microstructural changes in key brain regions sensitive to the aging process and involved in sleep‐wake regulation. These results further emphasize the relevance of monitoring circadian sleep regulation for the early detection of individuals at risk for neurodegeneration and cognitive decline.
Errors and repetitions on tests of language, verbal learning, and memory in cognitively unimpaired adults at increased risk for Alzheimer’s disease
Authors: Mueller Kimberly D , Basche Kristin E , Bruno Davide , Frost Casey Michelle , Christian Bradley T. , Betthauser Tobey J , Johnson Sterling C , Hermann Bruce P , Langhough Rebecca E 
Published: December 2023

AbstractBackgroundErrors and repetitions on verbal fluency and list learning tasks have been found to predict progression to MCI and differentiate between healthy aging, MCI, and dementia. This study examined whether errors and/or repetitions on verbal measures were cross‐sectionally associated with amyloid pathology in baseline cognitively unimpaired (CU) adults, and provided additional information beyond traditional total score measures.MethodWe included 437 participants from the Wisconsin Registry for Alzheimer’s Prevention who completed comprehensive neuropsychological testing and amyloid (Ab) positron emission tomography (PET) scans using Pittsburgh Compound‐B (PiB). Ab(+/‐) status was determined using an established threshold average distribution volume ratio(DVR) >1.19 across several brain regions. From the most recent testing visit, we extracted the total number of errors and repetitions from the Rey Auditory Verbal‐Learning Test (AVLT), animal fluency, and letter fluency; these were summed to form error and repetitions composites. We ran ANCOVAs with Ab(+/‐) as predictor; age, sex, and WRAT‐3 reading were covariates. Cohen’s D effect sizes characterized strength of relationships, where higher errors = negative effect sizes, and higher total scores = positive effect sizes. Sensitivity analyses examined errors and total scores from individual tests, and removal of participants who progressed to MCI.ResultSample characteristics are presented in Table1. Relationships between error, repetition and total score variables are shown in Figure1. Ab(+/‐) was a significant predictor of the error composite (p = .001) but not the repetition composite. Ab(+/‐) was significantly associated with AVLT learning total (p = .01), but not with animal or letter fluency totals. Secondary analyses revealed that AVLT errors alone were associated with Ab(+/‐) (p<.0001); effect sizes were greatest for AVLT errors (d = ‐.46) than for the error composite (d = ‐.39) or for AVLT total score (d = .39) (Figure 2). Removal of impaired participants yielded similar effect sizes.ConclusionFindings from this CU sample suggest that AVLT errors may be more sensitive to early AD pathology than traditional total score measures. Errors on list‐learning may represent other cognitive and/or sensory processes (e.g., auditory processing, hearing, attention, inhibition) that are sensitive to AD but are not represented in total scores. Future research includes examining longitudinal and additional error composites’ relationships with AD pathology to develop more sensitive cognitive measures.