bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visual Sensory Binding is Associated with CSF Neurogranin in Cognitively Healthy Older Adults
Authors: Jacobs Diane M. , Festa Elena K , Galasko Douglas R. , Salmon David P. , Smirnov Denis S. , Marangi Camille A. , Heindel William C 
Published: December 2022

AbstractBackgroundCognitive tasks that require conjunctive binding – i.e., the integration of distinct features into a coherent representation – are sensitive to AD even in the preclinical stage. To further explore the sensitivity and utility of conjunctive binding tasks, we examined the association of visual sensory binding with novel CSF biomarkers of neurodegeneration in cognitively healthy older adults.MethodTwo versions of a visual search paradigm were used to compare sensory conjunctive binding under conditions that differ in terms of the demands placed on cross‐cortical interactions. In these tasks, the binding of motion direction (up/down or left/right) must be integrated with either luminance contrast (black or white; within stream binding) or isoluminant color (red or green; across‐stream binding). We examined the association of cross‐cortical sensory binding efficiency (the difference in overall median response time between the color and luminance conditions) with CSF biomarkers of AD pathology (Aß42/Aß40 and p‐tau 181) and synapse function (neurogranin, NPTX2, and SNAP25) in N = 32 cognitively healthy older adults (mean age = 74.6, SD = 5.5; mean Dementia Rating Scale score (max score: 144) = 139.9, SD = 2.9).ResultBivariate correlations revealed that cross‐cortical sensory binding efficiency was significantly associated with neurogranin (r = .36; p<.05) but not with Aß42 (r = .08; p = .68), p‐tau 181 (r = .25; p = .17), NPTX2 (r = .04; p = .82), or SNAP25 (r = .16; p = .41). In multiple regression analyses, neurogranin remained significantly associated with binding efficiency (ß = .46; p = .02) after controlling for age (ß = .03; p = .87), sex/gender (ß = .17; p = .33), and Aß42/Aß40 (ß = .30; p = .14). The addition of p‐tau 181 (ß = .45; p = .12) to this model slightly attenuated the association between neurogranin and binding (ß = .27; p = .24).ConclusionIn cognitively healthy older adults, efficiency of cross‐cortical conjunctive binding on a visual search task was significantly associated with CSF neurogranin, a post‐synaptic protein that is abundant in dendritic spines. Increased CSF neurogranin signifies synaptic degeneration and is specific to AD. Results suggest that visual sensory binding is a cognitive marker that is sensitive to changes in synaptic function in older adults who perform normally on traditional neuropsychological measures. Follow‐up investigation will determine if visual sensory binding efficiency is predictive of cognitive decline and subsequent dementia.
Vascular health is associated with locus coeruleus‐related entorhinal tau deposition
Authors: Riphagen Joost M. , Chhatwal Jasmeer P. , Becker Alex , Kwong Kenneth , Engels Nina , Yau Wai‐Ying Wendy , Prokopiou Prokopis C. , Schneider Christoph , Koops Elouise A. , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. , Jacobs Heidi I.L. 
Published: December 2022

AbstractBackgroundAutopsy studies reported that the locus coeruleus (LC) is one of the first sites of tau accumulation. In addition, LC‐mediated norepinephrine (NE) signaling is thought to play a role in blood‐brain‐barrier maintenance and neurovascular coupling through its projections to the microvasculature, suggesting that the NE‐LC system interacts with cerebrovascular disease and Alzheimer’s disease (AD) pathology. Since vascular risk factors are prevalent in older individuals and contribute to vascular pathology, a common co‐pathology of AD, understanding interrelationships among vascular health, tau and LC integrity as early as possible, can guide prevention.MethodWe included 124 individuals (Table1) from the Harvard Aging Brain Study with MRI and 18F‐Flortaucipir and 11C‐Pittsburgh‐Compound‐B PET‐imaging within one year of each other. LC‐MRI signal intensity was extracted from 5 maximum‐intensity voxels and normalized to pontine tegmentum. White matter signal abnormalities (WMSA intracranial volume adjusted) were obtained from FreeSurfer6. PET measures were partial‐volume corrected. The Framingham‐Risk‐Score (FRS‐CVD, likelihood of a cardiovascular event in 10 years) was calculated. Structural Equation Models were used to test hypothetic models (1: WMSA mediate the relationship between FRS‐CVD and LC, leading to entorhinal (EC) tau; 2: FRS‐CVD is associated with WMSA and LC, and the LC influences WMSA, both leading to EC tau) against the null model (independent paths of LC and WMSA between FRS‐CVD and EC tau;Figure1). Models were bootstrapped (n = 2000). Model fit measures determined which model described the data best (CFI >0.90, RMSEA <0.08, SRMR <0.08). Age and sex were included as covariates.ResultModels null and 2 had poor fit. Model‐1 had an excellent fit, suggesting that a higher likelihood of a cardiovascular event in ten years is positively associated with WMSA, WMSA is associated with LC intensity, which in turn is associated with EC tau (Table2). Posthoc, global Aβ (DVR) was added as covariate in model‐1, this did not change the model‐fit or outcomes.ConclusionPrevious work demonstrated that LC‐intensity correlates strongly with entorhinal tau. Our findings now suggest that presence of increased cardiovascular risk is associated with lower LC‐intensity through its effects on white‐matter damage, emphasizing the importance of mitigating risk factors earlier in life.
Impact of reduced injected dose on semi‐quantification of in vivo amyloid‐β pathology using [18F]flutemetamol
Authors: Young Peter , Heeman Fiona , Lubberink Mark , Rieckmann Anna , Axelsson Jan , Sanaat Amirhossein , Frisoni Giovanni B , Zaidi Habib , Gispert Juan Domingo , Barkhof Frederik , Farrar Gill , Baker Suzanne L. , Garibotto Valentina , Schöll Michael 
Published: December 2022

AbstractBackgroundReduced injected doses in PET examinations result in lower radiation exposure, reduced acquisition times, reduced costs for institutions and ethically allow for additional scans within the same subject. Previous research has demonstrated that the injected dose of several different PET tracers can be reduced without substantial effects on quantitative outcome measures. Here, we studied the effect of reduced injected doses on signal‐to‐noise ratios (SNRs) and standardised uptake value ratios (SUVRs) for the FDA‐approved amyloid‐β (Aβ) PET tracer [18F]flutemetamol.MethodThirty [18F]flutemetamol PET scans from previously classified Aβ‐positive and Aβ‐negative individuals were included in this study (Table 1). Amyloid positivity was derived using a validated centiloid pipeline. Subsets of the PET data containing 70%, 50%, 40% 30% and 20% of the total events was extracted randomly from the list‐mode data to generate sinograms and reconstructed using e7 tool. SUVRs were computed for a whole brain region‐of‐interest from an intracranial volume mask using whole cerebellum as a reference region. Reference and target ROIs were derived in MNI space. Next, group separation between Aβ‐positive (A+) and Aβ‐negative (A‐) using mean SNRs was computed using formula 1. Additionally, the differences in SUVR and SNR for true and the respective reduced injected dose were calculated.Group Separation= (meanA+ ‐ meanA‐)/(0.5√((SDA+)2+(SDA‐)2) (1)ResultInitial results (Table 2) show an absolute change in group separation from 0.65 to 0.62 (4.8% change) for original injected dose and a reduction of injected dose to 20% respectively. Whole cortical SUVRs changed by a maximum of 0.01 (<1% change) in both Aβ‐positive and ‐negative individuals. Figure 1 shows scans of a representative Aβ‐positive individual derived from true and different simulated reduced injected doses.ConclusionPreliminary findings in our pilot sample suggest that lower injected tracer‐doses for [18F]flutemetamol yield robust SUVRs at injected doses as low as 20% of the original dose. We will report further validation in a larger dataset. In addition, a whole cortex region was used for SUVR derivation, and investigations of smaller ROIs will be added. The effect of scanner and reconstruction settings as well as the effect of reduced injected doses on separating Aβ‐positive from ‐negative individuals will be investigated.
Sex differences in the protective effects of APOE ε2 on longitudinal cognitive decline
Authors: Wood Madeline , Xiong Lisa Y. , Buckley Rachel F. , Swardfager Walter , Masellis Mario , Black Sandra E. , Rabin Jennifer S. 
Published: December 2022

AbstractBackgroundThe APOE ε2 allele confers protection against cognitive decline and Alzheimer’s disease. There is some suggestion that APOE ε2 may have sex‐specific effects on cognition. We investigated sex differences in associations between APOE ε2 and longitudinal cognitive trajectories in a large sample of older adults.MethodWe used data from the National Alzheimer’s Coordinating Centre (NACC) database. We included participants who were ≥ 50 years old, White, free from dementia at baseline, and completed at least one follow‐up cognitive assessment. We categorized participants as APOE ε2 carriers (combining heterozygous and homozygous ε2 carriers) or APOE ε3 homozygote carriers. APOE ε4 carriers (including ε2/ε4 carriers) were excluded. Cognition was assessed approximately annually. We computed composite scores for memory, language, attention, and executive function. We examined the interaction between APOE allele (ε2 vs ε3), sex, and time on longitudinal cognition in linear mixed models, adjusting for baseline age, baseline MMSE, education, number of follow‐up visits, NACC test version, and their interactions with time.ResultWe included 6,733 participants classified as cognitively normal at baseline (mean age=72.9±9.12 years, mean education=16.0±2.87 years, 62.5% female), and 1,932 participants classified as mild cognitive impairment (MCI) at baseline (mean age=75.2±8.91 years, mean education=15.6±3.28 years, 44% female). Among participants with normal cognition, we observed significant interactions between sex, genotype, and time on longitudinal memory (β=0.022, p=0.039) and language (β=0.015, p=0.038), but not attention (β=0.01, p=0.09) or executive function (β=0.006, p=0.30). In sex stratified analyses, relative to male APOE ε3 carriers, male APOE ε2 carriers showed slower rates of decline in domains of memory and language. This effect was not observed in females. No significant interactions between sex, genotype, and time were observed in participants with MCI (memory: β=‐0.04, p=0.1; language: β=‐0.02, p=0.4; attention: β=‐0.01, p=0.5; executive function: β=‐0.02, p=0.3).ConclusionAmong cognitively normal adults, APOE ε2 carriage protects males but not females against longitudinal memory and language decline. The sex‐specific effect of APOE ε2 may contribute to the lower incidence of Alzheimer’s disease in males compared to females. Future research is needed to elucidate the mechanisms behind the observed sex disparities in cognitive decline.
Treatment with C5aR1 antagonist attenuates short‐term hippocampal memory decline and prevents DAM signature in Arctic mice.
Authors: Schartz Nicole D , Carvalho Klebea , Liang Heidi Yahan , Chu Shu‐Hui , Mortazavi Ali , Tenner Andrea J 
Published: December 2022

AbstractBackgroundUpregulation of complement genes in Alzheimer’s disease (AD) mouse models is associated with inflammation and cognitive decline. Genetic ablation of C5aR1 reduces loss of neuronal complexity and cognition in the Arctic mouse model. Inhibition of C5aR1 with PMX205 has shown success in preclinical studies of AD, reducing recruitment of reactive glia and amyloid deposition in the Tg2576 AD model. However, the molecular and cellular mechanisms underlying this neuroprotection are unclear. Thus, we used single cell RNA‐seq to interrogate gene pathways involved in C5aR1‐mediated deficits in the Arctic mouse model.MethodWT and Arctic mice were treated with PMX205 or vehicle via drinking water (20 µg/mL, equivalent to ∼5 mg/kg/day, consistent with previous studies) from 7.5 to 10 months of age. Effects of PMX205 on long‐ and short‐term memory were tested with object location memory (OLM) with a 24hr inter‐trial interval (ITI) and y‐maze spatial reference memory test with a 1hr ITI, respectively. Hippocampi were dissected and immediately prepared for microglial isolation and fixation. The single cell whole transcriptome kit (Parse Biosciences) was used to prepare single cell microglia libraries for RNA‐seq. Libraries were sequenced using NextSeq 2000. Parse Bioscience split‐pipe v0.7.6 was used to demultiplex reads into single‐cells, Scrublets to remove doublets, and Seurat for quality control, normalization, and clustering.ResultPMX205 protected against short‐, but not long‐, term memory deficits. Arctic‐PMX205 mice spent more time in the novel arm (44%) than Arctic‐vehicle mice (30%) in Y‐maze. Microglial single cell RNA‐seq identified 7 microglial clusters. Within these clusters, we probed for genes previously described as homeostatic, DAM1, and DAM2. DAM1 (Tyrobp, Apoe, Trem2) and DAM2 (Cst7, Itgax) genes were enriched in Arctic‐vehicle mice compared to WT mice, and expression was downregulated with PMX205 treatment in Arctic mice, most notably in DAM1 genes.ConclusionPharmacological C5aR1 inhibition confers some protective function even when treatment is initiated months after amyloid pathology onset in this aggressive mouse model of AD, and alters microglial polarization, suppressing detrimental inflammation. These findings complement previous data from genetic ablation of C5aR1, and suggest that C5aR1 may be a viable therapeutic target for individuals with an AD diagnosis.
Perceived Stress and Loneliness During the COVID‐19 Pandemic in a Cognitive Aging Cohort
Authors: Bateman James R. , Waugh Christian E , Kershaw Kiarri N , Quillen Ellen E , Lockhart Samuel N. , Peavey Jeremy J. , Hughes Tim M. , Cole Steve W , Seeman Teresa E. , Craft Suzanne 
Published: December 2022

AbstractBackgroundThe COVID‐19 pandemic has had disproportionate effects on the health and well‐being of older adults. Little is known about the effects of isolation and social distancing measures on the mental health of older adults with cognitive impairment.Method194 participants from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort adjudicated as cognitively normal (CN, n = 129), and mild cognitive impairment (MCI, n = 65) were given questionnaires cross‐sectionally measuring loneliness, perceived stress, well‐being, and coping style. We created multivariable regression models (adjusted for age, sex, race, and education) to assess relationships among dependent variables, loneliness and perceived stress, and independent variables of interest, well‐being and coping style (Table 2).ResultOverall, the mean age was 72±8 years. Table 1 lists baseline demographic and study measures for CN and MCI groups. Table 2 shows associations between dependent variables (perceived stress, loneliness) and independent variables of interest. Participants with MCI had significantly higher levels of loneliness (B = 3.30; p = 0.03) than CN participants. Participants who reported lower eudaimonic and hedonic well‐being had higher levels of perceived stress and loneliness (p < 0.01), and those who endorsed using self‐blame and behavioral disengagement to cope with stress had higher perceived stress (B = 3.06, = < 0.01) and loneliness (B = 7.84, p < 0.01). There was no interaction by cognitive diagnosis.ConclusionParticipants with MCI had higher levels of loneliness, but not perceived stress, than those with normal cognition. We found that participants expressing high feelings of well‐being had significantly lower, and participants reporting a coping style with self‐blame and behavioral disengagement had significantly higher perceived stress and loneliness. Next steps involve exploring associations of neuroimaging and Alzheimer’s disease biomarkers with perceived stress and loneliness and evaluating transcriptional measures of stress measured concurrently.
Does cognitive reserve or brain maintenance explain heterogeneity in episodic memory trajectories in late middle age?
Authors: Schwarz Claudia , Franz Carol E , Lyons Michael J. , Kremen William S. , Vuoksimaa Eero 
Published: December 2022

AbstractBackgroundAging‐related episodic memory (EM) decline and Alzheimer’s disease (AD)‐related brain changes begin in late middle age around age 60. However, rate and severity of cognitive decline do not consistently correspond to the extent of neuropathological changes, suggesting a high degree of heterogeneity in EM trajectories. We tested if brain maintenance (BM; relative absence of changes in neural resources as a determinant of preserved cognition) and/or cognitive reserve (CR; a property of the brain that allows for sustained cognitive performance in the face of age‐related changes and brain insult or disease) explain individual differences and heterogeneity in EM in late middle age.MethodParticipants were 1604 men from the Vietnam Era Twin Study of Aging. A practice effect‐adjusted composite EM score based on six measures was calculated at three time points with mean ages of 56, 62, and 68. Young adult general cognitive ability (GCA) and lifetime years of education were used as proxy measures of CR. BM was assessed as relative change (from age 56 to 68) in cortical thickness and surface area in a bilateral cortical signature of AD regions‐of‐interest (N = 321). We used linear mixed effect modeling.ResultOn average, there was a significant decline in EM from age 56 to 68 (p<0.001). Education (p = 0.042) and young adult GCA (p<0.001) were positively related to EM, but there were no significant effects of education or GCA on the rate of EM change (all p’s≥0.316). Relative brain changes were not related to EM (all p’s≥0.067) and there were no significant interactions of CR proxies and brain changes on EM (all p’s≥0.379).ConclusionHigher education and higher young adult GCA were related to better EM performance across late middle age – with a stronger contribution of GCA compared to education – but EM change did not differ as a function of these proxy CR measures. Our results did not support effects of BM or CR on EM change in late middle age but rather reflected baseline differences in memory in those with low versus high education/cognitive ability. Whether differential change occurs at later ages or with increased AD pathology remains to be determined.
Towards a more representative Alzheimer’s disease clinical trial: Ethnic differences in underlying pathology call for demographic consideration in drug label development
Authors: Anderson Nicolas , Stanek Jessica , Swearingen Blake , Gabriel Hoda , Strittmatter Warren , Chamberlain Stan , Didsbury John 
Published: December 2022

AbstractBackgroundClinical trials have historically underrepresented racial and ethnic minority groups, often exhibiting sub‐par external validity and representing a population that is exceedingly White and not Hispanic or Latino (H/L). An understanding of the underlying pathology and safety profile of racial and ethnic minority groups is important to interpretation of clinical trial results and the development of accurate drug labels. T3D Therapeutics’ Phase 2 PIONEER Study (evaluating the safety and efficacy of lead candidate drug T3D‐959) provides a unique opportunity to examine safety data in an Alzheimer’s disease (AD) trial with a relatively high percentage of H/L subjects.MethodPIONEER is an ongoing randomized, double‐blind, placebo‐controlled, Phase 2 trial involving 256 mild to moderate AD patients dosed orally once‐a‐day for 24‐weeks. Exploratory analyses examine ethnic differences in medical data including screen fail reasons, medical history, and adverse events.ResultMedical history and screen fail reason data suggest differences in underlying pathology between H/L and non‐H/L subjects. For example, data show a higher rate of screen failure due to elevated HbA1c among H/L subjects vs. non‐H/L subjects. Conversely, H/L subjects show lower rates of surgical and medical procedures as well as other medical history events. Rates of reporting adverse events as well as types of adverse events reported are also significantly different between the two groups.ConclusionEthnic differences drive differential safety profiles across study subjects, challenging the applicability of non‐H/L clinical trial data to the H/L population. Our data suggest that more weight should be put on ethnicity and other demographic characteristics in developing drugs’ side effects listings. We stress that ethnic background should play a larger role in label development, and urge the clinical trial community to continue in the direction of enrolling underrepresented racial and ethnic minority groups.
Validating Frontal Memory‐related Neuromarkers for Mild Cognitive Impairment using Identical Protocols in Two Racial and Culturally Distinct Cohorts
Authors: Jiang Yang , Zhao Xiaofeng , Zheng Zhiwei , Latham Jeremy J , Wang Baoxi , Liu Ziming , Zhao Xiaopeng , Jicha Gregory A , Li Juan 
Published: December 2022

AbstractBackgroundStudies using standardized cognitive assessments across disparate populations are often confounded by sociocultural differences, leading to a lack of comparative standards to assess the degree of Mild cognitive impairment (MCI). Thus, testing in diverse populations is essential in validating biomarkers for MCI and avoiding race and cultural confounders. Applying an identical, cross‐culturally accepted, non‐invasive, electrophysiological protocol, we test the hypothesis that the frontal neuromarkers for MCI are consistent in two samples of older adults in the US and China.MethodUsing an identical, clinically friendly protocol with a wireless 14‐channel headset (eMotiv), we recorded EEG signals along with accuracy and reaction times during a visual object working memory task in two samples of older adults. The Kentucky sample includes 12 Normal Cognition NC; (Mean age 68); 7 MCI (age 81) while the Beijing sample includes 11 NC (age 64) and 16 MCI (age 65). Each participant also received assessments in NACC UDS 3.0. The 10‐min task asked each subject to remember two visual objects and then determine whether the subsequent object is a Match or Nonmatch to one of the two held in working memory.ResultWe found that left frontal sites showed significant mean amplitude differences between MCI and NC during target match retrievals. The persons with MCI showed reduced responses to memory targets at the F3 and F7 sites in Kentucky. The MCIs’ reduction patterns were significant in the left frontal F3 but not significant at F7 in Beijing sample. The Beijing participants were on average younger than KY participants, leading to a reduction in quantitative signal change, however, the effect remains robust and parallels those from Kentucky. The current results using a fast and two‐target memory task are consistent with previously reported results using 64‐channels and a longer version of the memory task with single‐target.ConclusionWe have validated frontal neuromarkers for MCI risk in two diverse samples. The current finding has significant implications for clinical practice which creates a path for the next step: large‐scale, low‐cost, and culturally‐accepted screening for risk of cognitive decline in individuals, irrespective of their socio‐cultural, geographical, or societal background.