bluuebunny/crossref_metadata_2025_split huggingface dataset:
Locus coeruleus metabolic changes as a predictor of tau accumulation and cognitive decline
Authors: Koops Elouise A. , Dutta Joyita , Becker Alex , Van Egroo Maxime , Riphagen Joost M. , Hanseeuw Bernard J , Sperling Reisa A. , Fakhri Georges El , Johnson Keith A. , Jacobs Heidi I.L. 
Published: December 2023

AbstractBackgroundThe locus coeruleus (LC), the primary noradrenergic nucleus in the brainstem, is among the earliest brain structures to accumulate tau pathology, one of the neuropathologic hallmarks of Alzheimer’s disease (AD). Tau pathology in the earlier stages and significant cell loss in the disease’s later stages can affect the metabolic turnover of the LC. In addition, alterations in the LC’s metabolic turnover have been associated with tau formation and propagation. We investigated differences in LC glucose metabolism across AD clinical diagnostic and biomarker groups and its association with longitudinal tau, beta‐amyloid, and cognitive measurements.MethodWe investigated LC FDG‐PET signal of 295 participants from the ADNI‐1 and ADNI‐2/GO cohorts, who were equally distributed across the CSF beta‐amyloid (A) and phosphorylated‐tau (T) biomarker groups (Table 1). An in‐house developed joint‐entropy‐penalized image deblurring algorithm was used to quantify Positron Emission Tomography (PET) signal within small brain regions (Figure 2A). ANCOVA was used to investigate diagnostic and biomarker‐based group differences in LC metabolism. Post‐hoc Tukey contrasts corrected for multiple comparisons in subsequent pairwise analyses. Linear mixed‐effects models investigated the predictive value of LC metabolism on the rate of change in CSF‐based p‐tau, beta‐amyloid and cognitive scores.ResultLow LC FDG‐PET signal was observed in the amyloid and tau‐positive group compared to the other groups (p<0.0001). Pair‐wise differences between the diagnostic groups did not survive correction for multiple comparisons. Combining biomarker and diagnostic status, we observed lower LC metabolism in A+T+ MCI and AD groups compared to CN and MCI A+T‐ and A‐T‐ groups (p<0.001; Figure 1B). Lower LC metabolism predicted accumulation of p‐tau (t(127) = ‐2.65, p = 0.009) and PACC decline (t(128) = 2.2, p = 0.029; Figure 2). LC metabolism did not significantly predict changes in beta‐amyloid levels or MMSE scores.ConclusionThis is the first study relating in‐vivo spatially specific measures of LC metabolism to AD‐related biomarker status. Low LC metabolism was most pronounced in those with evidence of underlying AD pathologic change and cognitive impairment. Furthermore, lower LC metabolism predicted greater CSF‐based p‐tau accumulation and declining cognition over time, providing an early marker of AD progression.
Bowel movement frequency, the gut microbiome, and cognitive function in women and men
Authors: Ma Chaoran , Mei Zhendong , Mehta Raaj S , Yuan Changzheng , Kang Jae Hee , Grodstein Francine , Ascherio Alberto , Willett Walter , Chan Andrew T , Huttenhower Curtis , Stampfer Meir J. , Wang Dong D. 
Published: December 2023

AbstractBackgroundBowel movement frequency and the gut microbiome may be associated with the risk of dementia.MethodWe examined the association between bowel movement frequency and cognitive function in 112,753 women and men from Nurses’ Health Study (NHS), Nurses’ Health Study II (NHSII), and Health Professionals Follow‐Up Study (HPFS) and explored the role of the gut microbiome in explaining these associations in a sub‐cohort of 515 NHSII and HPFS participants. We collected data on bowel movement frequency in 2012/13 and subjective cognitive function from 2014 to 2017 in all participants and objective cognitive function using a neuropsychological battery between 2014 and 2018 in 12,696 NHSII participants. We profiled the gut microbiome using shotgun metagenomics.ResultBowel movement frequency was associated with overall objective cognitive function and learning and working memory in an inverse J‐shape dose‐response manner (both Pnon‐linearity<0.05). Compared to those with once daily bowel movements, participants with bowel movement frequency of every 3+ days had significantly worse cognition, equivalent to 3.0 (95% confidence interval (CI),1.2, 4.7) years of additional aging. We observed similar J‐shape dose‐response relationships of bowel movement frequency with the odds of subjective cognitive decline and the likelihood of having more subjective cognitive complaints over time. Bowel movement frequencies of every 3+ days and ≥twice /day, compared to once daily bowel movement, were associated with odds ratios of subjective cognitive decline of 1.73 (95% CI, 1.60, 1.86) and 1.37 (95% CI, 1.33, 1.44), respectively. These relationships were generally consistent across three cohorts and subgroups. Bowel movement frequency and subjective cognition were significantly associated with the overall variation of the gut microbiome (both P <0.005) and specific microbial species. Butyrate producers were depleted in those with less frequent bowel movements and worse cognitive function, while a higher abundance of dysbiosis‐related, pro‐inflammatory species was associated with bowel movement frequency of ≥twice/day and worse cognitive function.ConclusionLess frequent bowel movements were associated with worse cognitive function. The gut microbiome may be a mechanistic link underlying the association between intestinal motility patterns and cognitive function.
The impact of modifiable risk factor reduction on future dementia burden: a microsimulation modeling study
Authors: Brück Chiara C. , Wolters Frank J. , Ikram M. Arfan , de Kok Inge M.C.M. 
Published: December 2023

AbstractBackgroundForty percent of dementia cases could potentially be prevented through modifiable risk factors. However, the effect of risk factor reductions might be partially offset by individuals living longer and developing dementia later. Using a microsimulation model, we determined the effect of reductions in smoking and hypertension prevalence on the future dementia burden.MethodThe microsimulation model ‘MISCAN‐Dementia’ was used to simulate life histories and dementia development of 10 million individuals. We modelled mid‐life (40‐59 years) hypertension and late‐life (65+ years) smoking as risk factors (Figure 1), simulating four risk groups: (1) neither risk factor, (2) smoking only, (3) hypertension only, and (4) both risk factors. Sex‐specific population data were used to determine risk factor prevalence. Based on prior literature, smoking and hypertension were each set to a 1.6‐fold increase in dementia risk, and a loss of life expectancy of 4 and 2 years, respectively. Reductions in risk factor prevalence of 100% (i.e. elimination), 50%, 25% and 10% were modeled and evaluated in terms of life years (LYs) without dementia gained, LYs with dementia averted and incident dementia cases averted.ResultCompared to no reduction, for the lifetime of 1000 individuals, elimination of hypertension results in 360 LYs without dementia gained, 40 LYs with dementia averted and 4 incident cases averted. Although smoking elimination results in 600 LYs without dementia gained, it also causes 75 more dementia LYs and 10 more incident cases. These additional LYs with dementia occur primarily at older ages, due to relatively high life expectancy gains compared to moderate reductions in dementia risk (Figure 2). Reductions of 50%, 25% and 10% result in similar findings at lower magnitudes.ConclusionReductions in prevalence of hypertension and smoking result in a gain in life years free of dementia. However, for smoking this coincides with a (smaller) increase in life years with dementia at older ages. These findings suggest that treatment or prevention of dementia risk factors will generally result in a larger number of cognitively healthy life years, but potentially at the cost of minor increases in years with dementia for risk factors with large effects on survival.
Men show increased brain aging with respect to women among Cognitively Normal Individuals
Authors: Casanova Ramon , Lu Lingyi , Hsu Fang‐Chi , Anderson Andrea , Barnard Ryan , Justice Jamie , Bateman James R. , Lockhart Samuel N. , Walker Keenan A. , Hughes Tim M. , Kritchevsky Stephen B , Espeland Mark A. , Craft Suzanne 
Published: December 2023

AbstractBackgroundThere is an increasing interest in using machine learning and artificial intelligence to estimate chronological age using neuroimaging data. The gap between chronological age and estimated brain age (brain age gap, BAG) is used as a measure of accelerated/resilient brain aging. Previously, BAG has been associated with cognitive status. However, whether the BAG varies across sex and cognitive status have been less explored. The present study examines these associations and validates a voxel‐based machine learning approach based on the elastic net regression (ENR) for BAG calculation.MethodUsing data from the Atherosclerosis Risk in Communities Study (ARIC) study, the Wake Forest School of Medicine Alzheimer’s Disease Research Center (WFSM‐ADRC) clinical cohort and Alzheimer’s Disease Neuroimaging Initiative (ADNI), we examined associations of BAG across cognitive status and sex. We used structural MRI scans from 1853 ARIC participants (ages 67‐90, 60% females), 508 from the WFSM‐ADRC (55‐95 yo., 66% females) and 584 ADNI cognitively normal (CN) participants (55‐90 yo., 57% females). All images were aligned into a common template and the derived gray matter (GM) probability maps from ADNI MRIs were used as input to train the machine learning algorithm. Once the model was fitted the ARIC and WFSM‐ADRC GM probability maps were provided as input to the algorithm to estimate the BAG values. Finally, an age bias correction was applied. Linear regression methods were used to investigate differences between groups. Age, race, education, sex, and cognitive status were included in the model.ResultWe found in both ARIC and WFSM‐ADRC participants that differences in BAG values between CN‐MCI and MCI‐Dementia participants were highly significant. In addition, when we examined differences in BAG values across sex per cognitive status, we found again in both cohorts that differences were only significant for CN individuals. See Table 1 for details.ConclusionOur analyses show that our approach to estimate chronological age using high‐dimensional ENR, produces BAG values which are strongly associated with cognitive status. The increased severity of cognitive impairment is related to accelerated brain aging. Differences in BAG between men and women were significant for CN individuals only.
Cell‐Based Genetic Subtypes Predict Neuroimaging Biomarkers and Clinical Conversion to Alzheimer’s Disease
Authors: Sahelijo Nathan , Rajagopalan Priya , Priyadarshi Dhawal , Goldstein Daniel , Nho Kwangsik , Shen Li , Huang Heng , Davatzikos Christos , Saykin Andrew J. , Thompson Paul M , Jun Gyungah R 
Published: December 2023

AbstractBackgroundThe complex etiology and slow progression of AD have complicated efforts to establish robust patient subtypes resulting in high attrition rates among late‐stage clinical trials. We developed a novel procedure to stratify at risk individuals to develop AD using network‐based polygenic risk scores from brain cell‐type specific transcriptome signatures.MethodWe previously computed cell‐based polygenic risk scores (cbPRSs) in the Alzheimer’s Disease Neuroimaging Initiative (Sahelijo et al. 2022). Recently, we computed cbPRSs in 8,481 Framingham Heart Study (FHS) participants using the same genetic markers used in ADNI. We defined low‐ and high‐risk genetic subtypes using the first and the fourth quartiles of the cbPRS distributions, respectively. We conducted association tests with domain specific cognitive tests and neuroimaging biomarkers using subtype risk status as a binary outcome in cognitively normal (CN), mild cognitive impairment (MCI), AD, and all subjects from ADNI. We compared conversion rates from CN and MCI to AD between subtypes using a Cox proportional hazard regression in ADNI and FHS. Using brain‐wide gray matter volume maps with voxel‐based morphometry we compared brain atrophy patterns between subtypes in ADNI corrected for multiple comparisons using Standard FDR at q = 0.05.ResultGenetic subtypes for astrocytes (Ast‐M2) and oligodendrocytes (Oli‐M45) showed significant association with memory and executive function impairment, decreased hippocampal volume, increased amyloid deposition, and decreased glucose metabolism using all subjects from ADNI (P<1.39E‐3). These associations for memory impairment, global amyloid deposition, and decreased glucose metabolism remained significant only in MCI subjects (best P<7.23E‐09). Conversion rates for Ast‐M2 and Oli‐M45 genetic subtypes were significantly different in both ADNI (P<8.67E‐5) and FHS (P<3.90E‐9). These differential conversion rates for Ast‐M2 and Oli‐M45 in FHS were not fully explained by presence of APOE ɛ4 allele (P<0.05 in ɛ4 non‐carriers). Voxel‐wise whole brain analysis identified significant atrophy in bilateral hippocampi, entorhinal cortex, and amygdala for Ast‐M2 (P = 0.0007) and Oli‐M45 (P = 0.001).ConclusionWe demonstrate that polygenic risk scores informed by cell type specific brain transcriptomic networks can stratify at risk subjects with AD related changes in imaging biomarkers and higher chance of progression to AD. These findings provide insight into early detection of cell‐type specific at‐risk individuals for AD.
T1w/T2w MRI ratio brain signature across degenerative syndromes and their cognitive impairment continuum and mixed presentations
Authors: Potvin Olivier , Duchesne Simon , Dieumegarde Louis 
Published: December 2023

AbstractBackgroundWe aimed to investigate the ratio’s signature in diverse clinically‐defined neurodegenerative syndromes and their cognitive impairment continuum. Our hypothesis was that higher cognitive impairment would be associated with lower cortical T1w/T2w ratio in all clinical subtypes.MethodWe used standardized MRI data obtained from participants in the COMPASS‐ND study of the Canadian Consortium on Neurodegeneration in Aging. T1w images were resampled down to T2w resolution; after co‐registration, intensities were standardized between 1‐100 and the ratio computed. Brain segmentation was then performed using FreeSurfer 6.0 on T1w images with the Desikan‐Killiany‐Tourville and default subcortical atlases. Participants included 109 cognitively intact elderly (CIE), 131 subjective cognitive decline (SCD), 252 mild cognitive impairment (MCI), 113 vascular‐MCI (V‐MCI), 55 mixed vascular‐Alzheimer’s dementia (V‐AD), 76 Alzheimer’s disease (AD), 21 Lewy‐body dementia (LBD), 33 fronto‐temporal‐dementia (FTD), 77 Parkinson’s disease (PD), 35 PD‐MCI and nine PD with dementia (PDD). Since the between‐vendor distributions differed (Fig1), Z scores were computed separately for each scanner vendor (GE, Philips, or Siemens) with CIE as a reference group. ANCOVA with age as covariate and FDR correction were conducted between each group and CIE.ResultNo significant effect of age was observed. Compared to CIE, significantly higher T1w/T2w ratios were observed in SCD for most of the brain (57/86 regions), in MCI for six frontal areas only, while decline was observed in AD throughout the brain (Fig1). V‐MCI showed lower ratios in subcortical areas only while V‐AD had pronounced lower ratios in subcortical areas as well as in 11 cortical areas. PD had marked lower ratios throughout the brain with the exception of an intact corpus callosum (Fig2). Contrariwise, FTD only displayed a lower ratio in the corpus callosum whereas PD‐MCI and LBD did not show any significant difference with CIE.ConclusionWe observed clear distinct patterns of T1w/T2w ratios for SCD, MCI, AD and PD groups. Since this ratio does not seem specific to a neural biological substrate, the meaning of these differences remains to be determined. Nevertheless, these results suggest that simple MRI measures such as the T1w/T2w ratio can highlight underlying mechanisms in various neurodegenerative processes.
The potential utility of genetic susceptibility to life course modifiable factors for dementia prevention
Authors: Jung Sang‐Hyuk , Lee Dong‐Gi , Shen Li , Kim Dokyoon 
Published: December 2023

AbstractBackgroundPotentially modifiable risk factors for dementia prevention, intervention, and care based on efforts to curb the increasing prevalence of dementia have been presented by the dementia committees. These risk factors for developing dementia need to be managed throughout the life cycle. However, the criteria for prioritizing risk management in subtype dementias caused by various factors are still uncertain in clinical practice. In this study, using a polygenic risk score (PRS) approach, we investigated the association of genetic susceptibility to life‐course modifiable factors in each subtype of dementia, including all‐cause dementia, and evaluated the utility of using it for predicting dementia.MethodWe utilized 5,974 all‐cause dementia cases and propensity‐matched healthy control data from UK Biobank. We generated APOE isoforms and Alzheimer’s disease (AD)‐PRS (excluding APOE regions) derived from the IGAP 2019 genome‐wide association study (GWAS) using genotyped data. Then, we performed a regression analysis to confirm the associations between AD‐PRS, APOE status, and each type of dementia. In addition, to investigate the genetic susceptibility of life‐course modifiable factors, we generated PRSs related to 18 life‐course factors for dementia prevention using independent GWAS summary statistics. Then, using each life‐course factor PRS, multivariate regression analysis was conducted to evaluate whether PRS is associated with each type of dementia independent of age, sex, genetic principal components, APOE status, and AD‐PRS.ResultThe APOE status and AD‐PRS showed significant associations with all‐cause dementia as well as AD dementia (ADD), vascular dementia (VD), and frontotemporal dementia (FTD) (Figure 1). In the multivariate regression analysis, hypertension, and body mass index PRSs showed significant associations with ADD and VD. In addition, vascular risk factors such as type 2 diabetes, high‐density lipoprotein, and systolic blood pressure PRSs showed significant associations with VD. In particular, in FTD, unlike other subtype dementias, only depression genetic susceptibility and relationship were found.ConclusionWe observed that genetically predicted life‐course modifiable factors were associated with risks of several types of dementia independently of the well‐known non‐modifiable risk factors (APOE status and AD‐PRS). Our findings suggest the potential utility of prioritizing candidate modifiable factors that should be primarily managed for dementia prevention in personalized medicine.
Partial inhibition of complex I improves bioenergetics via improved glucose uptake/utilization and mitochondrial function in a cellular model of Alzheimer’s disease
Authors: Nguyen Thi Kim Oanh , Trushin Sergey , Trushina Eugenia 
Published: December 2023

AbstractBackgroundAlzheimer Disease (AD) currently has no effective treatments. A consistent failure of recent clinical trials focused on Aβ or pTau necessitates the identification of novel therapeutic targets and strategies. Since abnormal brain energy homeostasis and mitochondria dysfunction underlie early stages of AD, the development of treatments to restore these defects could be beneficial. We synthesized small molecules that selectively and mildly inhibit mitochondrial complex I (MCI) which restored synaptic and cognitive function in APP/PS1 and 3xTgAD mice. One of the most important mechanisms improved by the treatment included restoration of glucose uptake/utilization that resulted in augmented cellular energetics in mouse brains. However, mechanistic relationship between MCI inhibition, glucose uptake/utilization and mitochondrial function remains to be determined.MethodNeuroblastoma SH‐SY5Y cells that express mutant human APP protein (APPswe) and WT cells were treated with MCI inhibitors in a time‐ and dose‐dependent manner. Flow cytometry was used to measure the translocation of glucose transporters to the cell surface. Changes in protein expression in response to treatment were assessed using Western blot analysis. Changes in mitochondrial morphology were monitored using electron microscopy. Cellular energetics was assessed using a Seahorse Extracellular Flux Analyzer. The non‐radioactive Glucose Uptake‐Glo™ assay was utilized for measuring glucose uptake in cells.ResultsTreatment of with SH‐SY5Y‐APPswe cells with MCI inhibitors within an hour increased surface translocation of GLUTs enhancing glucose uptake and utilization. The effect persisted for 48 hrs. The mechanism of enhanced glucose uptake was associated with AMPK‐dependent activation of NRF2 pathway but not AKT. Furthermore, the improvement in the bioenergetic parameters including Spare Respiratory Capacity, an indicator of the mitochondrial ability to produce energy under stress conditions, and ATP levels were found 24 hrs after the compound treatment. Treatment activated mitochondrial morphofunctional pathway (e.g., fission, fusion, biogenesis and turnover) consistent with the improved cellular bioenergetics. Similar mechanisms were confirmed in the brain tissue of 3xTgAD mice treated with one of the compounds.ConclusionsPartial MCI inhibition activates multiple mechanisms essential for improved energy homeostasis and mitochondrial function. These mechanisms could be consistently induced by our compounds in vivo and in human brain cells support translational potential of this therapeutic strategy.
Dysregulation of memory‐induced protein synthesis in tauopathies
Authors: Evans Harrison Tudor , Kalava Srinidhi V , Yu Astra , Adler Drew , Alapin Jessica , Oliveira Mauricio M , Klann Eric 
Published: December 2023

AbstractBackgroundProtein synthesis is a vital biological process, important for many neuronal and cognitive processes such as synaptic plasticity and the formation, updating, and extinction of long‐term memories. Recent studies have identified dysregulated translation as a molecular hallmark of many neurodegenerative diseases, including tauopathies such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and corticobasal degeneration (CBD) (Evans et al., EMBO J, 2019; Evans et al., Acta Neuropathoc Comms, 2021; Elder et al., Commun Biol. 2021). This dysregulation of protein synthesis is thought to be driven in part by pathogenic alterations to tau, a neuronally enriched microtubule binding protein.MethodHere, we have utilized a series of de novo proteomic analyses, including in vivo non‐canonical amino acid (NCAA) tagging, surface sensing of translation‐based ribosome speed of elongation (SunRiSE), and polysome profiling, to explore both in vitro and in vivo how mutant human tau alters translation in a variety of tauopathies models, including the PS19 mouse strain, human neurons from a FTD patient‐derived inducible pluripotent stem cells (iPSCs) line, as well as in transfected HEK293 cells.ResultUsing these techniques, we have found that both P301S and V337M mutant human tau can severely impair protein synthesis, even when protein degradation is inhibited. Our data also suggests that the dysregulated translation is caused, at least in part, by impaired elongation, with SunRiSE assays showing that P301S and V337M mutant human tau both slow elongation rates. We also have demonstrated that FTD‐mutant tau impairs protein synthesis in CA1 hippocampal neurons in PS19 mice and are determining whether learning‐induced increases in hippocampal protein synthesis following contextual fear conditioning are impaired in these mice.ConclusionTogether, our results demonstrate that FTD‐mutant tau can severely impact several important components of the cellular translational machinery. Furthermore, our results also contribute to the growing evidence that impairments in protein synthesis are a feature of neurodegenerative diseases. This work was supported by the Alzheimer’s Association (H.T.E), Leon Levy foundation (H.T.E.), the Rainwater foundation (H.T.E.) and NIH grant NS121786 (E.K.).