bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Sialylation in Alzheimer’s Disease Models
Authors: Fastenau Caitlyn , Solano Leigh , Wickline Jessica L , Smith Sabrina , Odfalk Kristian F , Bieniek Kevin F , Hopp Sarah C. 
Published: December 2022

AbstractBackgroundResearch shows evidence of increased sialylation localized to pathological protein aggregates in AD autopsied brains. Sialylation is a type of glycosylation with linkage bonds of sialic acid (SA) residues on glycoproteins and glycolipids. It is unclear how changes in SA distribution in AD contributes to disease. Microglia are partially regulated by sialylation. We hypothesize decreased removal of SA residues on microglia leads to increased sialylation near amyloid‐β (Aβ) plaques, reducing microglia mediated plaque clearance.MethodA plant‐derived lectin was used to recognize α2‐6 SA bonds. Aβ plaques, microglia, and α2‐6 SA were histologically labelled in cortical brain tissue from human AD cases and 5XFAD mouse model of Aβ pathology. Stained hemibrains were imaged with confocal microscopy and quantified. To investigate the effects of reducing SA cleavage, we treated a subset of our 5XFAD and wild‐type (WT) mice with oseltamivir (Tamiflu), an inhibitor of desialylation, for five days. On day 3 and immediately following treatment, we measured cognitive and non‐cognitive behaviors using open field and novel object recognition tests.ResultQualitatively, α2‐6 SA levels displayed similar microglial‐like phenotype in 5XFAD and human AD cortical brain tissue. Two‐way ANOVA of histologically labeled hemibrains revealed 5XFAD mice had significantly increased α2‐6 SA levels compared to WT mice (p = 0.0007). High magnification image analysis supported a significant increase of α2‐6 SA area in 5XFAD mice versus WT (p<0.0001), yet there was no effect of oseltamivir treatment. Behavioral data similarly demonstrated no effect of treatment. Post‐hoc analysis of open field revealed 5XFAD mice exhibited greater velocity compared to WT (p = 0.03) and 5XFAD mice lacked habituation behavior with no decrease in velocity compared to WT (p = 0.02). Investigation of Aβ pathology indicated no oseltamivir effect.ConclusionWe observed a significant increase in α2‐6 SA in 5XFAD mice similar to human AD, suggesting a plaque associated increase in sialylation. Next, we will closely examine localization of SA in the plaque microenvironment to understand the role of sialylation in microglial interactions with disease pathology. We postulate SA residues are localized to microglia interacting with Aβ plaques, potentially aggravating pathology.
Relationships between psychosocial stress, cerebrospinal fluid markers of Alzheimer’s disease, and cognitive function in middle‐aged and older adults
Authors: Zuelsdorff Megan , Van Hulle Carol A. , McLester‐Davis Lauren W. Y. , Chin Nathaniel A. , Livingston Sydnee , Logan Julianne , Carlsson Cynthia M. , Okonkwo Ozioma C. , Gleason Carey E. , Bendlin Barbara B. , Asthana Sanjay , Johnson Sterling C. , Betthauser Tobey J 
Published: December 2022

AbstractBackgroundExposure to psychosocial stress empirically associates with risk of cognitive impairment and dementia. Plausible mechanisms include (I) direct influence on AD pathology, and (II) indirect influence through cognitive reserve processes. Current evidence for modifiable determinants of amyloid and tau deposition is mixed, and stress has rarely been studied in this context. In richly characterized cognitive aging samples, we explored preliminary associations between (i) stress measures and amyloid (A), tau (T) and neurodegeneration (N) biomarkers in cerebrospinal fluid (CSF), and (ii) synergistic effects of stress and ATN in cognition.MethodParticipants were enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) or Wisconsin Alzheimer’s Disease Research Center (ADRC), were cognitively intact, had stress and cognition data from at least one timepoint, and had available CSF data assayed using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd). Predictors included Perceived Stress T‐scores from the NIH Toolbox Emotion Battery, and self‐reported recent (past‐year) stressors. ATN outcomes included CSF measures of amyloid positivity, tau positivity, and neurofilament light protein (NfL). Cognitive outcomes included performance in domains of (a) processing speed and mental flexibility and (b) episodic memory. Multivariable regression models assessed cross‐sectional predictor‐outcome relationships.ResultCharacteristics of the predominantly white, middle‐aged and older samples are in Table 1. Stress scores associated with poorer performance on tests of speed and mental flexibility but not memory. There were no significant associations between measures of stress and any AD biomarker (Table 2). Estimate precision was limited by sample sizes, but there were observable interactions between stress measures and tau positivity and NfL, specifically in domains of speed and flexibility (Table 3; eg Figure 1); higher stress predicted poorer performance in the presence of accumulated pathology.ConclusionThere was no evidence for direct relationships between stress exposure and ATN pathology. However, the presence of elevated AD biomarkers exacerbated cognitive detriment associated with psychosocial stress, particularly in a key domain of executive function. Our findings must be replicated in a larger and more diverse sample. However, this study provides preliminary evidence suggesting high stress may act on dementia risk indirectly, through reduced resilience to pathological changes in the brain.
Mouse Adapted SARS‐CoV‐2 induces ‘long‐COVID’ neuropathology in BALB/c mice
Authors: Gressett Timothy E , Ismael Saifudeen , Narayanappa Amruta , Biose Ifechukwude Joachim , Leist Sarah R , Baric Ralph S , Bix Gregory J 
Published: December 2022

AbstractBackgroundCOVID‐19 survivors develop neuro‐psychological symptoms as post‐COVID 19 syndromes, although the pathophysiology remains elusive. SARS‐CoV‐2 MA10 (MA10) is a model of mouse‐adapted SARS‐CoV‐2 that recapitulates acute respiratory distress syndrome observed in humans. However, the consequence of MA10 infection on brain pathology is not yet evaluated. The study aimed to evaluate the long‐term consequence of MA10 infection on blood‐brain barrier (BBB) integrity and neuroinflammationMethod10‐week and 12‐months old female BALB/c/cAnNHsd mice were infected intranasally with 104 PFU and 103 PFU SARS‐CoV‐2 MA 10 respectively. The brain was isolated 60‐ and 120‐days post‐infection (60 and 120 dpi) and subjected to histological analysis and mRNA expression by qPCR array.ResultImmunohistochemical analysis showed that MA 10 infection caused increased GFAP immunoreactivity in young mice. Histopathological analysis showed that MA10 infection induced significant neuropathology. Ongoing quantification on microglial activation and BBB integrity elucidated a possible correlation between infection and neuropathology.ConclusionOur data shows the first time that MA10 infection induces neuropathological outcomes several weeks after infection. These observations can help to develop novel therapeutic strategies to ameliorate neuroinflammation and restore brain function
Evaluating the Utility of Existing Plasma Biomarkers in a Clinical Patient Cohort
Authors: Dubois Kelly N. , Grabinski Tessa , Morgan Dave , Kanaan Nicholas M 
Published: December 2022

AbstractBackgroundBiomarker assessments will become an instrumental component of effective clinical management and trial coordination for Alzheimer’s Disease (AD) and related dementias and will enable precision medicine approaches to diagnosis and treatment. Plasma offers an inexpensive non‐invasive peripheral biofluid for biomarker assessments that can easily be collected longitudinally. The development of ultrasensitive single molecule array (SIMOA) assays has enabled plasma measurements for AD‐related blood biomarkers. Indeed, several plasma biomarkers were recently identified as potentially useful for AD and related dementias. However, their utility in additional clinical cohorts requires further investigation.MethodsPlasma samples were collected from participants clinically diagnosed as cognitively unimpaired (CU; n=30), mild cognitive impairment (MCI; n=60) or probable AD (AD; n=34) from the Michigan ADRC. Levels of total Tau, phospho‐tau 181 (pT181), amyloid β40 (Aβ40), and amyloid β42 (Aβ42) were measured using SIMOA. Ongoing studies will include additional samples and measure plasma neurofilament light chain, glial fibrillary acidic protein, placental growth factor, vascular endothelial growth factor, and phospho‐tau 231. Biomarker levels were compared across diagnostic groups and correlated with cognitive and demographic variables.ResultsAmong the biomarkers assessed, interim results indicated significantly elevated pTau181 in AD compared to CU and receiver operating characteristic (ROC) analysis showed an AUC of 0.81 for CU versus AD. This analyte correlated significantly with CDR sum of boxes (p=0.01). There was a nonsignificant reduction (8%) in the Aβ42:Aβ40 ratio and an AUC of 0.65 for CU versus AD. Aβ40 and the Aβ42:Aβ40 ratio were significantly correlated with age. No sex differences were detected. Except for pTau181, no significant correlations with CDR sum of boxes or CDR global were found. Biomarker levels showed no correlation with body mass index (BMI) within diagnostic groups.ConclusionsGenerally, our results align fairly well with other studies using clinical patient cohorts with extensive additional biomarkers (e.g. PET tracer measurements and CSF biomarkers). The AD‐associated increase in plasma pT181 levels support the potential utility of this form of phospho‐tau as a useful plasma biomarker. The lack of significant effects with the other biomarkers used here suggests additional novel biomarkers are necessary.
early noninvasive diagnosis of neurodegeneration
Authors: Sidenkova Alena Petrovna 
Published: December 2022

AbstractBackgroundAlzheimer's disease (AD) is a neurodegenerative pathology that develops mainly in elderly and senile people. The aim of the study was a comparative analysis of the results of neuropsychological tests with the indicators of the study of oral fluid and buccal epithelium cytograms in patients with Alzheimer's disease.Methodlaboratory, neuropsychologicalResultIn the main group of 12 patients with Alzheimer's disease, m=76.25±4.89. There were 12 cognitively healthy people in the control group. The average MMSE score among the observations of the main group was 13.42±3.63. The ADAS‐COG scale was used to detail the impaired cognitive functions. The concomitant pathology is compensated. The content of BDNF, TNF‐α, IL1RA, IL‐6, and IL‐8 was determined in the oral fluid and in the blood serum. The concentration of salivary and serum biomarkers was determined by multiparametric fluorescence analysis with magnetic microspheres. Micronuclei, karyopycnosis, karyorexis, and karyolysis were determined in the cellular structures of the buccal epithelium. The material for cytological examination was collected from the inner surface of the cheek.When analyzing buccal cytograms, attention was drawn to a pronounced increase in the number of cells with micronuclei in patients with AD to 1.8%; in the control group, the median was 0.1% (p<0.05). A direct correlation was established between the number of binuclear cells and the level of BDNF in the blood serum (r=0.646; p=0.03) in patients with AD. It is also important to note that the level of serum BDNF had a significant direct correlation with immediate memory, and the concentration of salivary BDNF correlates with the parameter of naming objects.ConclusionCorrelations between amnesia, speech disorders, praxis, gnosis and pathology of the oral fluid and buccal epithelium, especially with the severity of karyopycnosis and karyorexis, have been established, indicating a direct correlation between the neurodegenerative process pathogenetically associated with Alzheimer's disease and the processes of systemic inflammation and degeneration of the buccal epithelium.
The effect of COVID‐19 restrictions on sleep in individuals with cognitive impairment and their carers
Authors: Blackman Jonathan , Carrigan Neil , Wearn Alfie , Desai Bhavisha , Meky Saba , Selwood James , Piggins Hugh , Turner Nicholas , Greenwood Rosemary , Coulthard Elizabeth 
Published: December 2022

AbstractBackgroundCOVID‐19 restrictions have been associated with apathy, anxiety and depression in individuals with cognitive impairment1‐3 and increased stress in caregivers4. But despite links between these restrictions and sleep impairment in the general population5, effects on sleep in this cohort are not widely reported. Here we determine overall sleep quality in these populations during the first UK lockdown, how this changed over time and explanatory factors associated with longitudinal change.MethodCognitively impaired group (CIG), carer group (CG) and older healthy participants completed online self‐reported validated questionnaires (PSQI, GAD‐7, PHQ‐8 and DBAS) alongside bespoke questions comprising the ‘SleepQuest’ study at two comparable stringent lockdown periods within the UK [t1 – (29/4/20‐13/5/20) and t2 – (5/11/20‐2/12/20)]. Analysis utilised paired t‐tests with Bonferroni correction with 95% confidence intervals. Multivariable linear regression evaluated predictive factors.ResultWithin the CIG, baseline n = 79 [MCI, n = 33; AD, n = 19; Other, n = 27], mean age 68.7±9.7, with follow‐up data for n = 37. Within the CG, baseline n = 183, mean age 59.4±11.1, follow‐up n = 116. Overall sleep quality by PSQI Total was impaired at baseline (CIG = 7.8±4.3; CG = 7.9±4.0) compared to 6.6±3.6 for older healthy participants (n = 2354). There was a trend towards sleep quality deterioration from t1‐t2 in both groups (CIG ‐ Mean diff = 0.84, CI[‐0.20,1.84], p = 0.111; CG ‐ Mean diff = 0.51, CI[‐0.01,1.02], p = 0.053). PSQI subcomponent analysis revealed increasing sleep medication use in both groups (CIG – Mean diff = 0.83, CI[0.36,1.32], pcorr = 0.007; CG – Mean diff = 0.99, CI[0.81,1.17], pcorr<0.001). However, levels of daytime dysfunction improved in both groups (CIG – Mean diff = ‐0.54, CI[‐0.87,‐0.21], pcorr = 0.014; CG – Mean diff = ‐0.46, CI[‐0.61,‐0.30], pcorr<0.001). Within the CIG, affective and behavioural factors at t1 did not predict sleep at t2. Within carers, increased anxiety (total GAD‐7) at t1 predicted worse sleep at t2 (Est[normalised PSQI total] = 0.22, SE = 0.10, p = 0.041).ConclusionOverall sleep quality for individuals with cognitive impairment and their carers was poor at baseline and trended towards further deterioration, although daytime function improved. Within this cohort, potential compensatory strategies included increased use of sleep medication (associated with adverse outcomes). Given impaired sleep may accelerate progression of dementia neuropathology6,7, it is important to understand and ameliorate the impact of prolonged socio‐political stressors on people with dementia and their carers.
Associations between ALOX5 and ALOX5AP Genetic Polymorphisms and Cognitive Performance in Patients with Alzheimer’s Dementia and Mild Cognitive Impairment
Authors: Noor Shiropa , Xiong Lisa Y. , Wong Yuen Yan , Wu Che‐Yuan , Swardfager Walter ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

AbstractBackgroundLeukotriene activity may contribute to cognitive deficits in Alzheimer’s disease (AD). Leukotrienes are synthesized by 5‐lipoxygenase (5‐LOX) and its activating protein (FLAP), encoded by ALOX5 and ALOX5AP, respectively. This cross‐sectional study investigated the associations of ALOX5 and ALOX5AP single nucleotide polymorphisms (SNPs) with cognitive performance in patients with AD or mild cognitive impairment (MCI).Method
ALOX5 SNP rs2029253 and ALOX5AP SNPs rs10507391, rs12429692, rs4147064, rs9551963, rs9579646 were selected based on previous associations to ischemic stroke. Participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) diagnosed with AD or MCI at baseline were separated by genotype for each SNP. Rey Auditory Verbal Learning Test (RAVLT), Mini Mental State Exam (MMSE), and Trail Making Part B (TRAB) tests were selected to measure memory, overall cognitive status, and executive function, respectively. Associations between SNPs and white matter hyperintensities (WMH) were also explored. Additive, dominant, and recessive models were tested for each SNP and outcome pair. Linear regressions were used to assess associations between genotypes and outcomes controlling for age, sex, and education.Resultrs12429692 TT homozygotes (MAF = 25.3%) had lower RAVLT learning (i.e. Trial 5 minus Trial 1) scores (F1,508 = 7.19, p = 0.008, n = 513, recessive model). rs4147064 TC heterozygotes (MAF = 46.5%) had higher MMSE scores than TT homozygotes (F2,508 = 3.34, p = 0.036, n = 514, additive model). rs9551963 CC homozygotes (MAF = 49.1%) had higher TRAB times (F1,481 = 6.06,
p = 0.014, n = 486, recessive model). Split by sex, rs12429692 was associated with TRAB times in males (F1,277 = 5.52,
p = 0.020, n = 281, dominant model) and rs9551963 was associated with RAVLT % forgetting scores in females (F1,212 = 4.98,
p = 0.027, n = 216, recessive model). The rs12429692 A/T SNP (MAF = 25.4%) trended towards an association with WMH (F1,507 = 3.33,
p = 0.069, n = 512, recessive model).ConclusionThree ALOX5AP SNPs were associated with aspects of cognitive performance. This preliminary clinical evidence suggests a possible effect of leukotriene synthesis on cognition in patients with AD or MCI.
Conserved cell‐type specific signature of resilience to Alzheimer’s disease nominates role for excitatory cortical neurons
Authors: Telpoukhovskaia Maria , Hadad Niran , Gurdon Brianna , Dai Miko , Ouellette Andrew R , Neuner Sarah , Dunn Amy R , Hansen Shania L , Wu Yiyang , Dumitrescu Logan , O'Connell Kristen MS , Dammer Eric B , Seyfried Nicholas T. , Muzumdar Sukalp , Gillis Jesse , Robson Paul , Zhang Jigang , Hohman Timothy J. , Philip Vivek M. , Menon Vilas , Kaczorowski Catherine C. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease‐modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD.MethodIn this study, we use single‐nuclear transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid.ResultOur cross‐species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GABRB1, PTK2, and ROCK2. Nominated resilience genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Additionally, we identified several potential mechanisms of resilience, including regulation of membrane potential, axonal and dendritic growth, and general increase of protein cycle, potentially of membrane proteins.ConclusionBecause our discovery of resilience‐associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre‐clinical studies in our human‐relevant AD‐BXD mouse panel.
Tau and memory performance in women: Advantages of visuospatial over standard verbal memory tests
Authors: Shepherd Alyx L , Wang Xin , Bernier Rachel A , Lui Kitty K , Deters Kacie D , Chowdhury Tasnuva , Edland Steven D. , Sundermann Erin E. , Banks Sarah J 
Published: December 2022

AbstractBackgroundThe accumulation of pathological tau in the medial temporal lobe is a hallmark of early Alzheimer’s disease (AD) that leads to memory decline. The majority of studies in AD use exclusively verbal memory tests to detect this memory loss, which is problematic because women have a lifelong advantage in verbal memory such that these tests may be less responsive to early AD. In our Women: Inflammation and Tau Study (WITS), we used both verbal and nonverbal memory tests, with the hypothesis that the nonverbal test would more accurately reflect tau in women.MethodWITS is a study of older women (aged 65+) with high risk for AD by way of the AD polygenic hazard score and mild cognitive deficits. Data are from 16 participants thus far. Tau PET imaging was completed using the MK6240 ligand. Two volume‐weighted composite of Braak III&IV regions and metatemporal regions were our regions of interest (ROIs). Memory tests were the Rey Auditory Verbal Learning Test (RAVLT) and Brief Visuospatial Memory Test‐Revised (BVMT). Both tests have multiple learning trials in addition to delayed recall. A series of linear regression models separately examined RAVLT and BVMT scores in relation to tau burden in each ROI. We used Akaike Information Criterion (AIC) to compare model fits.ResultPoorer performance in both RAVLT and BVMT delayed recall was significantly related to greater tau in each ROI (ps<.01); however, relationships were stronger with the BVMT. For the metatemporal ROI, RAVLT explained 14.6% of the variance in tau, while BVMT explained 44.6% (Figure 1). For the Braak III&IV ROI, RAVLT explained 10.1% of the variance and BVMT explained 29.8%. The AIC implied superiority of the models with BVMT over the models with RAVLT.ConclusionOur preliminary results show that tau burden in women is better reflected by visual memory performance than verbal memory. Reliance on verbal memory may not be ideal in studies of AD involving women. Upon replication, our results suggest that visual memory performance may be a more accurate clinical marker of early AD with better prognostic value in women that can lead to improved effect sizes and more efficient clinical trials.