bluuebunny/crossref_metadata_2025_split huggingface dataset:
iNOS expression in the pyramid layer of the rat hippocampus in the modeling of chronic cerebral discirculatory disorder
Authors: Smirnov Alexey Vladimirovich , Mednikov Dmitry , Tyurenkov Ivan Nikolaevich 
Published: December 2023

AbstractBackgroundStudying of various forms of NO‐synthases is of great interest, since they are involved in many of the mechanisms of neuronal injury, aggravating the ischemic cascade and negatively affect the clinical status of cerebrovascular diseases. Impaired functioning of NO synthase plays an important role in the progressing of neurodegenerative diseases, since nitric oxide is a modulator of neuroplasticity.MethodChronic cerebrovascular disorder was modeled on rats by the method of overloading in the caudo‐cranial vector with a force 9 G for 5 minutes with an interval of 12 hours for 28 days. The level of iNOS expression was assessed by calculating the relative area of the immunoreactive material.ResultThe heterogeneity of the distribution of the immunoreactive material was expressed both in dust‐like cytoplasmic accumulation and in the presence of small‐lumpy deposits of iNOS‐positive material in the neurons of the pyramidal layer and in the neuropil, and in glial cells the intensity of expression was more pronounced, reaching a pronounced one. The relative area of iNOS‐positive material increased most significantly in CA3, by 8.3% (p<0.001), amounting to 12.1% [9.8;14.3]%. In CA1, the increase in the same indicator relative to the control was 3.9% (p<0.001), reaching 5.7 [4.5;6.1]%. In CA2 and CA4, respectively, the increase in the relative area of the IRM was 4.5% (p<0.05).ConclusionWe presume that the pronounced neuronal injury that is observed in the chronic cerebrovascular disorder modeling is a factor in the disruption of the hematoencephalic barrier, leading to edema, the subsequent acquisition of a pro‐inflammatory phenotype by astrocytic and microglia and the switch from the constitutive type of NO‐synthesis to the predominantly inducible type associated with activation of iNOS.
Peripheral and central markers of inflammation increased in frontotemporal dementia and related conditions
Authors: Malpetti Maura , Swann Peter , Chouliaras Leonidas , Tsvetanov Kamen A , Jones P Simon , Cope Thomas E , Bevan‐Jones W Richard , Savulich George , Street Duncan , Whiteside David J , Rittman Timothy , Murley Alexander G , Stockton Katherine , Hong Young T , Fryer Tim D , Aigbirhio Franklin I , O'Brien John T , Rowe James B. 
Published: December 2023

AbstractBackgroundNeuroinflammation is an important pathogenic mechanism in frontotemporal dementia (FTD) and related disorders. Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, and as proportionate to symptom severity and rate of progression. However, data on inflammation blood markers of inflammation and their relationship with central inflammation are limited. Here we assess inflammatory patterns of 41 serum cytokines from patients with FTD and related conditions, and their association with regional microglial activation (TSPO PET).MethodBlood samples were obtained from 29 healthy controls, and 214 patients with a clinical diagnosis of behavioural variant FTD (bvFTD = 52), primary progressive aphasia (PPA = 51), progressive supranuclear palsy (PSP = 58) and corticobasal syndrome (CBS = 53). Serum assays used the MesoScale Discovery V‐Plex‐Human Cytokine 36 plex panel plus five additional cytokine assays. A Principal Component Analysis (PCA) across all participants was used to reduce dimensionality of cytokine data. A sub‐group of patients (bvFTD = 10, PPA = 17, PSP = 17) underwent PET imaging with [11C]PK11195 PET, as index of microglial activation. Kruskal‐Wallis and pairwise t‐tests were performed on the resulting components to compare each patient cohort to controls. [11C]PK11195 non‐displaceable binding potential (BPND) was calculated in 83 regions of interest (ROIs) across the whole brain. Spearman correlations tested associations between cytokine components and regional [11C]PK11195 BPND.ResultSixteen cytokines were undetectable in >50% of participants and thus excluded. The first component identified by the PCA on the remaining 25 cytokines (explaining 19.7%) was strongly loaded by pro‐inflammatory cytokines (Figure 1, left). Kruskal–Wallis one‐way analyses of variance on detected significant differences across the groups (χ2(4) = 11.0, p = 0.027), and the pairwise t‐tests identified significant differences between each patient cohort and controls (Figure 1, right). Spearman correlations identified regional positive associations between individual cytokine‐component scores and microglial activation in frontal and brainstem regions across the whole group (R≥0.25), and syndrome‐specific regional patterns (Figure 2).ConclusionThis data‐driven approach identified a pro‐inflammatory profile across FTD and related conditions, which is positively associated with higher levels of microglial activation in syndrome‐related key brain regions. Blood‐based tests could greatly increase the scalability and access to neuroinflammatory assessment in dementia and experimental medicine studies.
Clinical and biomarker characteristics of amnestic MCI patients exhibiting a temporo‐limbic FDG‐PET pattern suggestive of LATE
Authors: Grothe Michel J. , Silva‐Rodríguez Jesús , Moscoso Alexis , Schöll Michael 
Published: December 2023

AbstractBackgroundWe have recently described a specific temporo‐limbic FDG‐PET signature that characterizes autopsy‐confirmed cases with limbic age‐related TDP‐43 encephalopathy (LATE), and have demonstrated its clinical utility for differential diagnosis of amnestic dementia patients. Here we assessed the utility of this pattern for patient stratification at a predementia disease stage, and further used tau‐PET data to study the degree to which this “LATE‐specific” FDG‐PET signature may correspond to a limbic‐predominant AD subtype.MethodIndividual FDG‐PET scans of 909 amnestic MCI (aMCI) patients from the ADNI cohort were screened for hypometabolic patterns being suggestive of LATE (sLATE) or typical AD (sAD) using automated pattern‐matching to autopsy‐confirmed pathology‐specific FDG‐PET signatures. sLATE and sAD patients were compared on clinical features, APOE4 genotype, and CSF biomarkers. Tau‐PET scans ([18F]Flortaucipir) were available in a smaller subsample (30%) and were analyzed for tau‐positivity using an FDA‐approved visual interpretation method as well as entorhinal SUVR (positivity‐threshold: SUVR≥2.1).Result734 aMCI patients showed evidence of significant regional hypometabolism, and of these 92 had a pronounced temporo‐limbic hypometabolic pattern classified as sLATE, whereas 68 had a classical temporo‐parietal pattern classified as sAD(Fig‐1). Compared to sAD, sLATE patients had similar MMSE and memory scores but more preserved executive function scores, and they showed generally slower cognitive decline over follow‐up (p<0.001)(Fig‐2). They were also significantly older (d = 0.83, p = 0.01), less often APOE4 carriers (39% vs 64%, p<0.001), and had less abnormal CSF Aβ42 (d = 0.60, p = 0.001) and p‐tau181 levels (d = ‐0.40, p = 0.01). With regards to tau‐PET, 9/30 sLATE (30%) and 9/10 sAD (90%) patients were visually positive and similar proportions were seen for entorhinal SUVR (40% vs 90%).ConclusionThe majority of amnestic MCI patients exhibiting a LATE‐typical temporo‐limbic FDG‐PET pattern show clinical and biomarker features that deviate from prodromal AD. A smaller subset of these patients shows elevated tau‐PET signal and could thus represent a limbic‐predominant AD subtype.
Imaging genetics based dementia risk prediction using deep survival neural network
Authors: Yu Jing , Vernooij Meike W , Ikram M. Arfan , Niessen Wiro J. , Roshchupkin Gennady V. 
Published: December 2023

AbstractBackgroundDementia has a large impact on people’s lives and is one of the leading causes of death. Therefore, accurate risk assessment is essential for improving early diagnostics and intervention. Previous studies have proposed various models for dementia risk prediction, based on imaging biomarkers and genetic factors. However, most of them have linear, unimodality or low‐dimensional nature due to model limitations and computational challenges of integrating such heterogeneous and high‐dimensional domains as images and genotype data. Recent development of Artificial Intelligence, specifically neural networks, enabled such integration, yet focused on classification problems, not risk prediction. We present a deep survival neural network to meet the purpose.MethodData were obtained from the Rotterdam Study. Individuals with complete data and available brain MRI before dementia diagnosis were included. MRI scans were pre‐processed using voxel‐based morphometry according to Good et al. into gray matter images. We included ApoE‐ε4 and 76 top‐risk SNPs based on most recently published GWAS (Bellenguez et al.). We developed the model combining Convolutional Neural Network and Survival Analysis, with the maximum‐likelihood estimator and C‐index of cox proportional hazard (Cox) model as the loss function and metric. To evaluate model performances, we used Cox model as comparisons: one baseline model with gender, age, genetic inputs and one extended model with additional extracted brain measurements. We performed 10 cross‐validation by stratified sampling to reveal the true differences.ResultTable1 shows little performance differences among the models, as expected age is already the strongest predictor. However, we see that raw gray matter and genetics inputs contribute to prediction additionally in all models. Furthermore, using the method from Tsang et al. we show strong interactions among image, age and genetic features (Fig.1). Fig.2 visualizes the most important brain regions for prediction on 3D image using GRAD‐CAM.ConclusionWe developed a deep survival model for dementia risk prediction which do not outperform classical model with brain measurements at present. However, our model is able to integrate high‐dimensional MRI and genetic data, detect and visualize the importance and interactions among input data, which may give additional insight for dementia prediction and etiologic research.
High‐salt diet enhances Helicobacter pylori infection and increases the prevalence of Alzheimer’s disease
Authors: Balendra Vyshnavy 
Published: December 2023

AbstractBackgroundThe American Heart Association recommends that adults consume less than 2,300 milligrams of salt (sodium chloride) daily; anything surpassing this limit is classified as a “high‐salt diet (HSD)” [1]. Research has shown that excessive salt intake stimulates the gastric mucosa, favoring Helicobacter pylori (Hp) colonization [2]. In this review, the relationship between HSD and the susceptibility to Hp infection will be discussed. It is proposed that increased salt consumption will cause neurodegeneration, i.e. Alzheimer’s disease (AD) by way of increased expression of Hp strains in the gastric mucosa.MethodsA complex and specific literature search was conducted across various scientific, international databases for English, peer‐reviewed articles and reviews published in the last decade using the following terms: Helicobacter pylori, amyloid‐β, high‐salt diet, and Alzheimer’s disease. Case reports were excluded. The main objectives were predominantly focused on animal‐based studies.ResultsExperimental data shows HSD enhances Hp growth in mice. The subsequent microglial activation containing H. pylori‐specific IgG, IL‐8 and TNF‐α in the cerebrospinal fluid, induces oxidative damage in neuronal cells. In addition, urease in Hp increases cytosolic [Ca2+] apoptosis and autophagy of neurons. Hp filtrate induces tau hyperphosphorylation at AD‐tau phosphorylation sites such as Thr231 and Ser404. Hp ‐infected mice show a significantly larger GFAP‐positive astrocyte area than non‐infected mice. Immunostaining reveals microglia and astrocytes to be found adjacent to amyloid‐β plaques in Hp‐infected AD model mice. Injection of Hp filtrate impairs the maturation of dendritic spines, increasing Aβ42 production in the hippocampus and cortex, and enhancing expression of PS‐2, resulting in delayed spatial learning and impaired memory in rats.ConclusionThis review provides comprehensive evidence of potential synergistic effects of HSD and Hp on the brain resulting in neurodegeneration and AD progression. Understanding the pathologic consequences of salt consumption on this infection may be key in the prevention of dementia and AD. Thus, further research is required for substantiation of causality, the role of antibiotics and to examine other novel therapeutics.
C9orf72 dipeptides trigger neuroinflammation via the NLRP3 inflammasome
Authors: Auty Jack , Hoyle Chris , Pointer Ayesha , Pickering‐Brown Stuart , Brough David , Ryan Sarah 
Published: December 2023

AbstractBackgroundThe most common cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a repeat expansion in C9orf72. The expansion is translated to produce five toxic dipeptides (DPRs), which aggregate in patient brain. Neuroinflammation is observed in patients, with increased microglial activation and elevated levels of pro‐inflammatory cytokines in CSF. However, the causes of this inflammation are unknown. Here, we investigated whether DPRs activate immune cells and contribute to neuroinflammation.MethodPrimary macrophages or microglia were treated with synthetic C9orf72 dipeptides and levels of pro‐inflammatory cytokines released into the culture media were analysed by ELISA and Western blot. Cytotoxicity was measured by LDH assay. Mouse organotypic hippocampal slice cultures were also treated with DPRs and cytokine release measured.ResultOne of the DPRs, GR, caused secretion of the pro‐inflammatory cytokine, interleukin (IL)‐1β, from macrophages, microglia and in hippocampal slice cultures. GR also caused significant toxicity. IL‐1β secretion was prevented by pre‐treatment with MCC950, a drug which inhibits the NLRP3 inflammasome. The inflammasome is a protein complex which forms in the cytosol of immune cells is response to “danger” stimuli, resulting in cleavage of caspase‐1 and subsequent release of IL‐1β. We confirmed that caspase‐1 was cleaved in macrophages following GR treatment. In addition, knockout of NLRP3 prevented IL‐1β secretion in response to GR. Finally, we showed that several drugs which are clinically approved for use in other conditions rescued GR‐induced NLRP3 activation.ConclusionHere, we demonstrate that C9orf72 dipeptides could directly contribute to neuroinflammation in FTD/ALS via the NLRP3 inflammasome. Furthermore, we demonstrate that this can be inhibited pharmacologically, highlighting NLRP3 as a potential therapeutic target in FTD/ALS.
Body Mass Index, but not Visceral Abdominal Obesity and Insulin Resistance, Negatively Impacts White Matter Microstructure in Midlife
Authors: Raji Cyrus A. , Dolatshahi Mahsa , Rahmani Farzaneh , Commean Paul K. , Nguyen Caitlyn , Ippolito Joseph , Benzinger Tammie L.S. 
Published: December 2023

AbstractBackgroundMidlife obesity, as evidenced by high body mass index (BMI), is increasingly understood as a risk factor for development of Alzheimer’s disease. Importantly, visceral fat, by producing adipokines, contributes to inflammation as well as insulin resistance, mechanisms involved in development of Alzheimer’s disease. Herein, we aimed to assess association of white matter microstructure, measured by Diffusion tensor imaging (DTI), with obesity and abdominal adipose tissue composition at midlife.MethodA total of 34 middle‐aged (age: 51.27 ± 6.12 years, BMI: 32.28 ± 6.39 kg/m2), cognitively normal participants, underwent bloodwork, brain and abdominal MRI. Insulin resistance status was assessed using Homeostatic Model Assessment for Insulin Resistance. Abdominal visceral and subcutaneous adipose tissue (VAT, SAT) were automatically segmented using VOXel Analysis Suite (Voxa) and VAT/SAT ratio was calculated. A diffusion spectrum imaging scheme with a total of 98 diffusion samplings and a voxel size of 2 mm was acquired. Using DSI studio (https://dsi‐studio.labsolver.org/), the diffusion data were reconstructed using generalized q‐sampling imaging and the tensor metrics were calculated. Fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, RD, respectively) for white matter tracts were compared across study groups using one‐way ANOVA. Multiple regression models with sex, age, and education as covariates were used to assess the association of BMI, VAT/SAT ratio, and HOMA‐IR with DTI metrics.ResultOur data showed that BMI was negatively associated with AD values in right inferior fronto‐occipital fasciculus, tapetum and forceps major of Corpus Callosum (CC), superior and middle cerebellar peduncle, and bilateral reticular tract. The negative association of BMI with AD values in tapetum of CC was significant only in women. Right reticular tract MD and superior cerebellar peduncle MD and RD values were also significantly associated with BMI. There were no significant associations between neither of diffusion metrics and VAT/SAT ratio or HOMA‐IR.ConclusionAssociation of midlife obesity with lower axonal diffusivity, reflective of lower white matter integrity, with differential patterns in men and women especially in CC, is in line with previous findings in healthy individuals. Reduced axonal diffusivity in reticular and brain stem pathways could be indicative of early dysregulations observed in Alzheimer’s disease.
Feasibility of cognitive assessments post‐emergency department (ED) discharge: A longitudinal pilot study of Medicare‐enrolled adults 65 +
Authors: Dawson Walter D , Spoden Natasha , Gothard Sarah , Kaye Jeffrey , Wright Kirsten M 
Published: December 2023

AbstractBackground50% of US adults living with Alzheimer’s disease and related dementias (ADRD) never receive a formal diagnosis. This compromises the wellbeing of persons living with ADRD and their care partners, increases health services utilization, and the costs‐of‐care. Wider screening and assessment for ADRD may increase access to supportive care that prevents or delays disease progression, ameliorates care partner burden, and alleviates costs.MethodA sample of Medicare‐enrolled individuals 65+ (n = 149) presenting to the Oregon Health & Sciences University (OHSU) emergency department (ED) in Portland, Oregon between May 2022 and January 2023 were recruited and administered the Telephone Interview for Cognitive Status (TICS) up to one‐month post‐discharge. Study participants were queried about their physical health via the modified cumulative illness rating scale (M‐CIRS), while their cognitive health was assessed via the PROMIS Cognitive Measure Questions on Mental Clarity. Care utilization patterns were measured via review of subjects’ electronic health records (EHR) for three years prior to study enrollment date focusing on total hospitalizations, ED visits, and primary care (PC) visits. These reviews measured health care utilization across three groups comparing individuals with (A) un‐diagnosed cognitive impairment with (B) cognitively healthy individuals, and (C) individuals with a formal ADRD diagnosis.ResultStudy enrollment rate was 25.8% (n = 149) of individuals meeting eligibility requirements. Enrollment was limited to patients with an OHSU PC affiliated provider excluding the majority (ineligible n = 1681, 74%) of Medicare‐enrolled ED patients (total ED users available for recruitment was n = 2,258). Of those contacted, 10% declined participation due to lack of interest and 4% declined due to cognitive or health restraints. Time to administer instrument suite ranged between 26‐33 minutes.ConclusionMedicare‐enrolled adults 65+ recently discharged from the ED appear to be an acceptable population to administer cognitive assessments. Findings during the recruitment process show success at enrolling this population to the study and administration times did not appear burdensome in duration for those enrolled. This study provides preliminary evidence supporting a focus on older ED patients to administer cognitive assessments, linking outcomes to the EHR, and ultimately providing a platform for future research on the impact of under‐diagnosed ADRD on health outcomes and utilization.
Neurovascular Coupling in Hypertensive COVID‐19 Survivors Medicated With Different Classes of RAS Inhibitors: A Pilot Study
Authors: Guthrie Sarah E , Jacoby John R , Mellen Sarah F , Valencia Emily M , Maina Katherine N , Michel Christa B , Yadav Shrikanth M , Howard Casey M , Salat David H , Sitnikova Tatiana A 
Published: December 2023

AbstractBackgroundHypertension poses an increased risk of Alzheimer’s disease (AD). Coronavirus disease 2019 (COVID‐19) may exacerbate this risk by affecting the Renin‐Angiotensin system (RAS), which contributes to the regulation of neurovascular coupling (NVC). NVC is a mechanism that optimizes cerebral blood flow (CBF) to meet the metabolic and waste‐removal needs of the brain. Disrupted NVC may predispose individuals to AD through hypoxia‐related protein changes and suboptimal protein‐waste removal from the brain. Several studies reported reduced CBF in long‐haul COVID‐19 patients. Among antihypertensive medicines that target the RAS, angiotensin receptor blockers (ARBs), but not angiotensin‐converting enzyme inhibitors (ACEIs), were previously found to regulate CBF. Therefore, we hypothesized that, if taken during and after a COVID‐19 episode, ARBs rather than ACEIs would be protective against long‐term CBF dysregulation.MethodWe quantified NVC through a novel analysis paradigm that takes advantage of simultaneous resting‐state electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). We obtained scans from older adult participants (aged 55‐80), including healthy controls and hypertensive COVID‐19 survivors medicated with ARBs or ACEIs during their COVID‐19 infection (occurring 3‐27 months before scanning). Hidden Markov modeling on source‐localized EEG was used to detect transient electrophysiological activity in distinct neural networks. A rapid event‐related fMRI analysis deconvolved the blood oxygenation level‐dependent (BOLD) changes evoked by the network‐specific electrophysiological activations. NVC was measured as the slope of vascular BOLD changes over the time‐locked electrophysiological neural changes.ResultIn this pilot study, the default mode network (DMN) showed differences in NVC between the hypertensive COVID‐19 survivors and the healthy control group. Crucially, the ARB‐medicated subgroup, like the control group, showed the BOLD response in the DMN regions time‐locked to the DMN electrophysiological activations; NVC differences between the ARB‐medicated and control groups did not reach significance. In contrast, the ACEI‐medicated subgroup showed a reduced NVC in the DMN relative to the control group.ConclusionThe DMN, which is linked to memory dysfunction in AD, may be vulnerable to NVC disruptions, given its high metabolic demands. Hypertension management with ARBs may reduce COVID‐19’s effects on cerebrovascular regulation, preventing ischemic stroke, vascular dementia, and AD. Results replication is warranted.