bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of NLRP3 and NLRP1 inflammasome pathways in patients with Alzheimer’s disease: a clinicopathological study
Authors: Toscano Eliana Cristina de Brito , Justo Alberto Fernando Oliveira , Grossi Laura Barbosa , de Paula Michelle Claudia Alves , Farias Daniela Souza , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Grinberg Lea T. , Teixeira Antonio L , Suemoto Claudia Kimie 
Published: December 2023

AbstractBackgroundA growing body of evidence has suggested a detrimental role of NLRP1 and NLRP3 inflammasome in experimental AD. However, the characterization of these pathways in AD human brains is still missing. We aimed to characterize the hippocampal expression of the NLRP1 and NLRP3 inflammasomes in individuals with AD neuropathological change (ADNC) compared to age‐ and sex‐matched controls. We also sought to investigate the association of the expression of these proteins with cognitive abilities and AD‐pathology.MethodThe expression of NLRP1, NLRP3, caspase‐1, ASC, and hyperphosphorylated tau (p‐tau) was evaluated in the cornu ammonis (CA), dentate gyrus (DG), and subiculum (SUB) of individuals with pure AD and controls (n = 28 per group), using immunohistochemistry. The percentage of the immunostained area (IA) and the optical density (OD) of the staining were quantified through semiautomatic morphometry. Cognitive abilities were evaluated using the Clinical Dementia Rating – sum of boxes (CDR‐SB) and the AD‐pathology was based on Braak staging and the Consortium to Establish a Registry for AD (CERAD) criteria. We applied the Mann‐Whitney test to compare control with ADNC hippocampi, linear regression to examine the association of inflammasome proteins with cognition and AD‐pathology, and Spearman coefficient to examine the correlation of these proteins with p‐tau.ResultSociodemographic and clinical variables were similar between the groups (Table 1). NLRP1 and caspase‐1 expression was predominant in neurons, while ASC was detected in glial cells. NLRP3 was expressed in neurons and glia. NLRP1 and NLRP3 deposits were observed in neuritic plaques. Except for NLRP1, all the inflammasome proteins were overexpressed in CA and SUB of individuals with ADNC compared to controls (p<0.05) (Figure 1). CDR‐SB and CERAD criteria were associated with increased IA for NLRP3, caspase‐1, and ASC; the Braak stage was associated with higher expression of caspase‐1 and ASC (p<0.05, Table 2). Interestingly, NLRP3 (r = ‐0.52, p = 0.009) and ASC expression (r = ‐0.43, p = 0.004) correlated negatively with OD of p‐tau immunostaining in the CA of individuals with ADNCConclusionNLRP3 inflammasome pathway is up‐regulated in the ADNC hippocampi and was associated with AD‐pathology. Our results suggest that NLRP3 inflammasome contributes to cognitive impairment in AD.
Apolipoprotein E Status Mediates Pericyte Recruitment Mechanisms in the Presence of Excess Cholesterol
Authors: Laing Krystal K. , McQuaid Conor , Lao Patrick J. , Chagnot Audrey , Stefancova Dorota , Garcia Daniela Jaime , Fialova Nela , Brickman Adam M. , Wardlaw Joanna M , Montagne Axel 
Published: December 2023

AbstractBackgroundApolipoprotein E (APOE) is a multifunctional lipid transporter, involved in lipoprotein metabolism and mediation of cholesterol homeostasis. The E4 variant of APOE is a primary genetic risk factor for Alzheimer’s disease and has been associated with vascular conditions such as hyperlipidemia, hypercholesterolemia, atherosclerosis and coronary artery disease (CAD). The mechanisms underlying APOE involvement in blood‐brain barrier breakdown (BBB‐B) are not well understood. In vivo, in vitro and clinical models of E4 have all demonstrated distinct profiling of molecular factors involved in ECM remodelling ‐ such as upregulation of PDGF‐BB in plasma and downregulation of VEGF in CSF. Associations between PDGF‐BB and white matter disease burden have also been reported. Investigating how APOE contributes to BBB‐B, through its function as a lipid transporter, could be imperative to understanding the pathophysiology behind vascular contributions to dementia.MethodUsing data from the Alzheimer’s Disease Neuroimaging Institute (ADNI), we analyzed plasma concentrations PDGF‐BB, VEGF and serum‐derived lipoprotein cholesterol (measured as LDL.C/HDL.C) for 521 patients with differing APOE status (E3/E3: n = 216, E3/E4: n = 195, E4/E4: n = 60). The LDL.C/HDL.C ratio has been used to assess the prevalence lipoprotein particles in cardiovascular diseases, such as CAD and is a studied marker of lipoprotein expression.ResultOur findings revealed that APOE‐dependent upregulation of PDGF‐BB was predicted by blood derived measures of VEGF, LDL.C/HDL.C and an interaction effect of both. Interestingly, results of this model for the E3/E4 subgroup were non‐significant, instead we found that PDGF‐BB and VLDL.C/HDL.C predicted white matter hyperintensity burden on MRI. To further explore this relationship, biofluidic protein quantification and immunohistochemical staining of humanized APOE knock‐in mice (APOEε3/ε3, APOEε3/ε4
and APOEε4/ε4
) are being conducted to characterize differences of peripheral vascular protein expression and brain‐specific PDGFRβ upregulation. In vitro modelling of pericyte‐endothelial cells is also being conducted to further investigate interactions of APOE‐dependent glio‐vascular signaling.ConclusionThis study provides additional support to previous reports that APOE4 contributes to impaired cerebrovascular function through mechanisms related to pericyte recruitment, vascular destabilization, and cognitive impairment. It may also provide additional insights for concepts which focus on APOE‐dependent cholesterol trafficking and lipid metabolism contribution to BBB destabilization.
Heterogenous factors modulate social cognition across diverse settings in brain health and disease
Authors: Fittipaldi Sol , Legaz Agustina , Maito Marcelo Adrian , Hernandez Hernan , Altschuler Florencia , Canziani Veronica , Moguilner Sebastian , Castillo Josefina , Lillo Patricia , Slachevsky Andrea , Henriquez Fernando , Fraile‐Vazquez Matias , Santamaria‐Garcia Hernando , Campo Cecilia Gonzalez , Bertoux Maxime , Ibanez Agustin 
Published: December 2023

AbstractBackgroundSocial cognition dysfunction in neurodegenerative diseases such as the behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s Disease (AD) is typically ascribed to the underlying pathophysiological processes spanning specific atrophy and connectivity alterations. However, social cognition performance might be modulated by a set of more heterogenous, non‐specific factors, including demographics (sex, age, education, socioeconomic status), general cognitive and executive abilities, and behavior inside the scanner (i.e., movements), but their relative contribution is poorly understood. Here, we develop a machine learning approach to characterize multimodal factors that explain the inter‐individual heterogeneity of social cognition in a diverse multicentric sample.MethodA total of 998 individuals > 50 years from international research networks in high‐ and middle‐income countries participated in this study: 102 with bvFTD, 339 with AD, 96 with mild cognitive impairment (MCI), and 461 with preserved cognition (with and without cognitive complaints). Social cognition was assessed with the Mini Social Cognition and Emotional Assessment (MiniSEA) battery, which includes tests of facial emotion recognition and theory of mind. After data harmonization, we implemented support vector regressions combined with bootstrapping to predict social cognition outcomes from multimodal features, including diagnosis, demographics, cognitive and executive functions, grey matter volume, fMRI resting‐state network connectivity, and movement artifacts, and assessed their relative contribution to performance (Figure 1). Models were assessed with the coefficient of determination R², Fisher’s F test, Cohen’s F², 95% confidence intervals, and p‐values.ResultGeneral cognitive and executive functions and years of education consistently emerged among the top predictive features of social cognition performance and explained more variance than diagnosis. Other features making significant contributions were: sex, the gray matter volume of relevant regions, and in‐scanner movements. Age and resting‐state network connectivity did not make any significant contribution to performance heterogeneity (Figure 2).ConclusionSocial cognition performance was more strongly predicted by a set of heterogenous individual differences than by neurodegenerative diagnoses and associated brain signatures. Diagnoses might relate to complex profiles. Results highlight a critical modulator role of heterogeneity on social cognition, with implications for the neuropsychological assessment in brain health and disease across diverse, multi‐setting populations.
Medial Temporal Lobe White Matter Integrity is Related to Memory and Amyloid‐Beta Pathology in Aging
Authors: Parker Dana M , Adams Jenna N. , Taylor Lisa M. , Keator David B. , Sathishkumar Mithra , Harris Alyssa L. , McMillan Liv , Yassa Michael A. 
Published: December 2023

AbstractBackgroundDamage to white matter (WM) within the medial temporal lobe (MTL) may underlie memory decline in aging and Alzheimer’s disease (AD). We measured MTL WM tract integrity through diffusion tensor imaging and Neurite Orientation Dispersion and Density Imaging (NODDI). We tested WM integrity associations with memory performance and amyloid‐β pathology in cognitively normal older adults.Method105 cognitively normal older adults (70.8 years old, 65% female) with diffusion MRI were processed with MRtrix3. Standard diffusion metrics of fractional anisotropy (FA) and mean diffusivity (MD) were calculated. NODDI MDT was used to generate the neurite density index (NDI), representing number of voxels with unhindered diffusion, and the orientation dispersion index (ODI), representing the variability of neurite orientation. We calculated these measures for MTL tracts from the JHU WM Atlas: cingulum‐hippocampus, fornix column/body, and fornix/stria terminalis. Participants received 18F‐florbetapir (FBP) to measure Aβ pathology (n = 94), and global FBP SUVR was calculated. Memory was measured with the Rey Auditory Verbal Learning Test delayed recall score (RAVLT, n = 81). Analyses covaried for age and/or education.ResultBetter memory was associated with lower ODI in the fornix column/body (r = ‐0.27, p = 0.018), with trends for higher FA (r = 0.021, p = 0.06) and lower NDI (r = ‐0.19, p = 0.09). Better memory was also associated with higher MD in the cingulum‐hippocampus (right: r = 0.23, p = 0.04; left: r = 0.25, p = 0.03), with trends for lower ODI (right: r = ‐.20, p = 0.08; left: r = ‐0.20, p = 0.09). Higher FBP SUVR was associated with increased FA in the fornix column/body (r = 0.31, p = 0.003) and a trend in the left cingulum hippocampus (r = 0.20, p = 0.054). Memory or FBP SUVR was not significantly related to integrity of the fornix/stria terminalis.ConclusionIntegrity of fornix column/body and cingulum‐hippocampus were related to both memory performance and Aβ pathology. Our results suggest that using a combination of NODDI as well as diffusion tensor metrics provided a more robust understanding of memory impacts in aging.
Multiple Chronic Conditions and Midlife Cognitive Function in Black and White Adults: The Bogalusa Heart Study
Authors: Moukaled Shirine , De Anda‐Duran Ileana , Potts Kaitlin S , Fernandez‐Alonso Camilo , Libon David J , Bazzano Lydia 
Published: December 2023

AbstractBackgroundIn late‐life, multiple chronic conditions (MCCs) has been associated with cognitive decline and Alzheimer’s Disease and related dementias. However, this relationship has not been investigated in a middle‐aged population, a time when MCCs first begin to develop, or in rural and low socioeconomic settings, where individuals are at a higher risk of MCCs. We examined the relationship between MCCs and midlife cognitive function among Black and White men and women from a rural, community‐based cohort in Bogalusa, Louisiana.MethodsThis cross‐sectional study includes 1,223 Black (33%) and White (67%) individuals (mean age 48.10 ± 5.26; 59% female) from the Bogalusa Heart Study with a complete neuropsychological (NP) assessment, and no history of stroke. Six chronic conditions were selected from the CMS (Centers for Medicare & Medicaid Services) Data Warehouse, and defined using self‐reported data, medication use, and physiological/laboratory measures (Table 1). MCCs was defined as the coexistence of ≥2 conditions. NP performance was measured by global cognitive z‐scores (GCS) and by domain specific z‐scores for attention and processing, episodic memory, and executive function. All z‐scores were standardized for age, sex, and race. Regression models assessed the association between MCCs and cognitive outcomes, adjusting for alcohol consumption, smoking status, and education.ResultsA total of 66% participants had MCCs; 44.4% (n = 543) had 2 CCs, 17.8% (n = 218) had 3 CCs, and 3.8% (n = 46) had 4+ CCs. Compared to no chronic conditions, having 2,3, and ≥4 CCs was significantly associated with poorer executive function z‐scores after adjusting for covariates (all p’s < 0.05). Having three MCCs had the worst impact on executive function z‐scores (‐0.88(.20), p <0.001) (Table 2). The most prevalent conditions in this group were hypertension, dyslipidemia, and diabetes which co‐occurred in 87.7% (n = 165) of participants with three CCs.ConclusionThis study suggests that the presence of MCCs is associated with lower executive function performance as early as midlife. Hypertension and dyslipidemia commonly occur together and are particularly prevalent in midlife. These findings highlight the importance of addressing chronic conditions earlier in life, a less studied and critical time window for potential prevention of adverse cognitive outcomes in late life.
Characterizing plasma biomarkers of Alzheimer’s Disease in aging marmosets and genetically engineered PSEN1 mutation carriers.
Authors: Rizzo Stacey J Sukoff , Schultz Laura , Mongeau Lauren , Huhe Hasi , Schaeffer David J , Schaeffer Lauren K Hayryren , Carter Gregory W , Park Jung Eun , Homanics Gregg E , Strick Peter L , Silva Afonso C 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is a progressive disease that presents as a continuum evolution from preclinical AD to mild cognitive impairment and, ultimately, dementia. The phenotypic characterization of AD was unified under a biological construct research framework supported by the National Institutes on Aging and Alzheimer’s Association (NIA‐AA). This framework, referred to as ATN, is based on the presence of biomarkers for amyloid (Aβ, A), pathologic tau (T), and neurodegeneration (N). The present studies aimed to establish normative values of these biomarkers in our colony of outbred marmosets from infancy through aged individuals and compare them to the values from our population of marmosets genetically engineered with early onset familial mutations in the PSEN1 gene.MethodPlasma (EDTA) and fibroblast media from skin biopsies were evaluated using MesoScale Discovery (MSD) Aβ peptide panel 4G8 ELISA and Human Neurofilament L (NfL) per the manufacturer’s protocols for each kit.ResultThere was a significant increase in the plasma Aβ42:40 ratio in PSEN1 mutation carriers relative to age‐ and sex‐matched wild‐type (WT) controls, which was also observed in culture media generated from fibroblasts of the same individuals. Longitudinal analysis of plasma Aβ revealed consistent levels in WT controls across multiple samplings with persistent increases in PSEN1 carriers. An increase in Nfl was observed in aging WT marmosets relative to young subjects.ConclusionWe have optimized the detection of plasma biomarkers for amyloid and NfL in marmosets and established normative values within our colony. Importantly, these results demonstrate the sensitivity and validity of these reagents for tracking plasma Aβ longitudinally across the marmoset lifespan. Other clinically utilized commercially available reagents are in the process of being optimized and validated to enable an analogous marmoset ATN. Pilot studies are ongoing evaluating the potential of pTau plasma biomarkers as part of the longitudinal assessments. The application of the NIA‐AA Research Framework to marmosets will attain a more accurate characterization and understanding of the etiological sequence of events that lead to AD development, in line with the currently used framework in AD patients.
Neurofilament Light and mean Free Water as prognostic enrichment biomarkers for cognitive worsening and small vessel disease progression
Authors: Maillard Pauline , Beiser Alexa S. , Habes Mohamad , Tracy Russell P. , Kautz Tiffany F , Saklad Amy R. , Kivisäkk Pia , Lu Hanzhang , Arfanakis Konstantinos , Gold Brian T. , Kramer Joel H. , Wang Danny J.J. , Rosenberg Gary A. , Singh Herpreet , Schwab Kristin , Helmer Karl G. , Greenberg Steven M. , Arvind Caprihan , Seshadri Sudha , Decarli Charles , Satizabal Claudia L. 
Published: December 2023

AbstractBackgroundPlasma neurofilament light (NfL) and free water (FW), a DTI‐derived measure, are considered, individually, sensitive markers of axonal damage that relate to cognition. A significant remaining challenge for clinical trials resides in identifying biomarkers able to detect, simultaneously, early SVD abnormalities and baseline cognitive impairment, particularly in non‐demented participants, who are also at risk of cognitive worsening and SVD progression during the trial.MethodThis study includes 200 non‐demented individuals from the MarkVCID‐UH3 cohort who had baseline NfL and baseline and follow‐up (1.3±0.5 years) cognitive assessment and MRI (Table 1). We used a composite measure of global cognitive function (GCF) using scores from the NACC‐UDS. WMH volumes were log‐transformed and corrected for intracranial volume. Annual change (Δ) in GCF and WMH was computed using baseline and follow‐up measures. A threshold, determined from 3 independent cohorts, was applied to FW measures to group individuals (low: <0.22 and high > = 0.22). Low and high NfL levels were defined using age‐based NfL z‐scores (low←0.5SD and high> = ‐0.5SD). We finally grouped individuals with both high NfL and FW levels (MULTIBIO+) vs. individuals with at least one biomarker with low level (MULTIBIO‐). We used linear regressions with either baseline GCF, baseline WMH, ΔGCF or ΔWMH as the dependent variable and, separately, baseline FW, NfL and MULTIBIO as the independent variable. Analyses were adjusted for relevant confounding variables.ResultsWe found that, as compared with MULTIBIO‐, MULTIBIO+ group had significantly lower baseline GCF and higher baseline WMH (p = 0.033 and p<0.001), as well as accelerated ΔGCF and larger ΔWMH (pvalues<0.01, Table 2, Figure 1). Individually, although FW was associated with baseline WMH and accelerated ΔGCF, neither FW nor NfL levels simultaneously explained baseline cognition and SVD burden, or simultaneous ΔGCF and ΔWMH (Table 2).ConclusionThese findings emphasize the potential of combining NfL and FW measures as a prognostic enrichment biomarker panel for identifying individuals with both early SVD abnormalities and cognitive impairment and who are also at risk of cognitive worsening and substantial SVD burden progression during clinical trials.Data collection and sharing for this project was funded by NINDS/NIA as part of the MarkVCID Consortium (U24NS100591, UH2NS100599, UH2NS100605, UH2NS100588, UH2NS100608, UH2NS100606, UH2NS100598, UH2NS100614)
Discovering correlates of off‐target 18F‐MK6240 signal in community‐dwelling adults
Authors: Johnson Aubrey S. , Zou James , Smith Anna C. , Okafor Amarachukwu , Guzm Diana S. , Kreisl William Charles , Brickman Adam M. , Luchsinger José A. , Lao Patrick J. 
Published: December 2023

AbstractBackground18F‐MK6240 binds hyperphosphorylated tau protein in neurofibrillary tangles, a hallmark of Alzheimer’s disease(AD); however, the tracer may also bind to other similarly structured molecules, known as off‐target binding. Off‐target binding is inconsistent across individuals and can lead to biased quantitative assessment, making it difficult to accurately identify neurofibrillary tangle pathology. We examined variable off‐target binding by performing a correlation analysis with demographic factors, vascular risk, lifestyle factors, and co‐morbidities.MethodsNinety‐five participants (65±3yrs; 67% women; 42/58% White/Black; 66% Hispanic; 12±4yrs education) in the Northern Manhattan Study of Metabolism and Mind(NOMEM) underwent 18F‐MK6240(90‐110min) and 18F‐Florbetaben(90‐110min) PET imaging and completed surveys, including age, sex, education, exercise levels, and medical history. Only visually‐determined amyloid‐negative participants were included to increase the likelihood that elevated tau PET signal was off‐target. Tau SUVR (cerebellar gray matter reference region) was calculated for composite Braak stages (I/II, III/IV, V/VI) and two known off‐target regions, the choroid plexus and the extra‐cerebral space around the brain. The extra‐cerebral mask was generated by dilating the gray/CSF boundary of the ANTs probability map and then subtracting the brain. Percent of variance explained (r2) from general linear models are reported between off‐target regions and factors of interest.ResultsDescriptively, 18F‐MK6240 off‐target binding in choroid plexus was positively correlated with SUVR in Braak stage regions I/II (r2 = 0.37;p<0.001) and III/IV (r2 = 0.44;p<0.001) to a larger extent than V/VI (r2 = 0.21;p<0.001), while off‐target binding in the extra‐cerebral space was positively correlated with Braak stages I/II (r2 = 0.07;p<0.001) to a lesser extent than III/IV (r2 = 0.13;p<0.001) and V/VI (r2 = 0.18;p<0.001), suggesting that proximity of key AD regions to off‐target regions increases the likelihood of confounded signal. Off‐target binding in the choroid plexus was elevated amongst self‐identified Hispanic participants (r2 = 0.19;p<0.001). Extra‐cerebral off‐target binding was negatively associated with participant weight (r2 = 0.12;p<0.001).ConclusionExtra‐cerebral off‐target binding of 18F‐MK6240 may confound signal in key AD regions in amyloid‐negative participants. Off‐target binding should be accounted for regionally and methods for capturing extra‐cerebral signal are critical. Understanding the role of factors related to tracer distribution, including weight, and sociodemographic factors will enhance the quantification of 18F‐MK6240 for the early detection of neurofibrillary tangle pathology.