bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amyloid and tau pathologies associate with distinct aspects of the inflammatory cascade
Authors: Bellaver Bruna , Leffa Douglas Teixeira , Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , De Bastiani Marco Antônio , Tissot Cécile , Lussier Firoza Z , Therriault Joseph , Benedet Andréa Lessa , Servaes Stijn , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Gauthier Serge , Schöll Michael , Ashton Nicholas J. , Zimmer Eduardo R , Zetterberg Henrik , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick A 
Published: December 2022

AbstractBackgroundInflammation has long been pointed out as a key feature in Alzheimer’s disease (AD). However, the heterogeneity of AD pathology might trigger different aspects of the immune response. Here, we aimed to study the association of the newly proposed concept of inflammatory composite indexes with Aβ and tau pathologies across the aging and AD spectra. We hypothesize that distinct inflammatory pathways are associated with the different hallmarks of AD.MethodA panel of 92 inflammation‐related markers was measured in the CSF of 60 individuals (35 cognitively unimpaired and 25 cognitively impaired) from the McGill TRIAD cohort. These 92 proteins were clustered by ontogenetic similarity and physical interaction using STRING. A z‐scored composite value representing each cluster was created for each individual. Individuals were classified as Aβ‐ and tau‐positive using global [18F]AZD4694 and temporal meta‐ROI [18F]MK6240 PET, respectively. Linear regressions (corrected by diagnosis, age, sex, and APOEɛ4 status) and receiver operating characteristic (ROC) analyses evaluated clusters’ performance.ResultOf the six clusters identified in our protein network analysis, three positively correlated with global Aβ‐PET (C4,C5, and C6) and three with meta‐ROI tau PET (C2,C4, and C5;Fig.1). However, controlling for Aβ PET, tau PET was only associated with C2, indicating that the association with the other two clusters (C4 and C5) was dependent of Aβ pathology. The cluster exclusively associated with tau (C2), represents tumor necrosis factor‐mediated signaling pathways. On the other hand, C6, related to the stimulation of interferon‐gamma production, and C5, related to glial cell‐derived neurotrophic receptor binding, are exclusively associated with Aβ. ROC analysis showed that all clusters presented a better performance predicting Aβ‐PET positivity than tau‐PET positivity (Fig.2A,B). Additionally, overall the clusters showed a better performance than sTREM2, a classical inflammatory biomarker.ConclusionOur novel clustering approach supports that Aβ and tau proteinopathies are associated with distinct aspects of the inflammatory cascade. Our results suggest that a composite of inflammatory proteins better identifies AD pathology than a single marker. Finally, this suggested cluster approach helps to understand the inflammatory response to Aβ and tau and can uncover inflammation‐related AD pathways.
Cognitive‐behavioral associations of amygdala subregional tau pathology in cognitively unimpaired Presenilin‐1 E280A mutation carriers
Authors: Langella Stephanie , Sanchez Justin S , Martinez Jairo E. , Rubinstein Zoe B. , Baena Ana Y. , Vila‐Castelar Clara , Ramirez‐Gomez Liliana A. , Aduen Paula , Jacobs Heidi I.L. , Sperling Reisa A. , Johnson Keith A. , Lopera Francisco , Gatchel Jennifer R , Quiroz Yakeel T. 
Published: December 2022

AbstractBackgroundCarriers of the Presenilin‐1 (PSEN1) E280A mutation are virtually determined to develop Alzheimer’s disease (AD) dementia by midlife. Tau pathology accumulates in the amygdala of PSEN1 carriers prior to clinical onset. Amygdala dysfunction, particularly in basolateral regions, may contribute to early neuropsychiatric symptoms in sporadic AD and other dementias. We aimed to examine the cognitive‐behavioral associations of subregional amygdala tau pathology in preclinical PSEN1 carriers, focusing on episodic memory and neuropsychiatric symptoms.MethodsParticipants included 25 unimpaired PSEN1 carriers and 37 non‐carriers from the Colombia‐Boston (COLBOS) Biomarker Study, matched in age, sex, and education (Table 1). In vivo regional tau pathology was measured using PET (Flortaucipir), with lateral and basal (aggregate region comprised of basal and accessory basal nuclei) amygdala as primary regions of interest (automatic segmentation using FreeSurfer v7). Memory was measured using the CERAD Word List Delayed Recall. Neuropsychiatric symptoms were measured using the Geriatric Anxiety Scale (GAI) and Geriatric Depression Scale (GDS). Associations with tau were tested using Spearman correlation. Group differences on cognitive‐behavioral measures were tested using independent samples t‐tests.ResultsCarriers and non‐carriers did not differ in overall depression or anxiety symptoms, but carriers had lower memory recall scores (Table 1). In carriers, lower recall was associated with greater tau accumulation in lateral (r = ‐.422, p = .036) but not basal (r = ‐.291, p = .158) amygdala. Higher depressive symptoms in carriers were associated with greater tau in both lateral (r = .530, p = .007) and basal (r = .467, p = .019) amygdala. Anxiety symptoms were not associated with amygdala tau in carriers (ps > .309). No significant associations were observed in non‐carriers.ConclusionsAmygdala tau pathology is associated with depressive symptoms and lower memory recall in cognitively unimpaired PSEN1 carriers, particularly in lateral amygdala. These results suggest that lateral amygdala tauopathy may be an early indicator of disease progression and may underlie cognitive and neuropsychiatric changes associated with early AD. Future longitudinal studies with larger samples and additional regional tau measures are needed to clarify the effects of subregional amygdala tau pathology on clinical onset and progression of AD.
Negative Correlation of Corpora Amylacea with pTau in the Hippocampus of People with AD
Authors: Dallmeier Julian , Vontell Regina T , Davis David A. , Gober Ryan , Barreda Ayled , Garamszergi Susanna , Sun Xiaoyan , Wander Connor , Cohen Todd J , Scott William K. 
Published: December 2022

AbstractBackgroundRecent studies suggest corpora amylacea (CA) activity may be involved in modulating AD pathology. Normally, CA function in the clearance of brain waste products by amassing cellular debris and extruding it into the cerebrospinal fluid. Disruption of this process may play a role in AD pathogenesis, and its effect might be influenced by degree of tau pathology and genetic risk. In this study, we determined if the abundance of CA was correlated with paired helical filament tau pathology in the CA1 region of the hippocampus in AD postmortem tissue samples. Tau pathology was assessed using both total pTau and total NFTs. Additionally, we investigated whether that correlation was influenced by APOE genotype.MethodPostmortem brain hippocampal tissue sections from 11 brain donors with pre‐mortem cognitive impairment and neuropathologically confirmed AD were double‐stained with Periodic‐acid Schiff (PAS) stain to identify CA and AT8 antibody to identify hyperphosphorylated Tau protein (pTau). Using the Motic slide scanner, stained sections were digitized at 40x. QuPath 0.3.2 was used to extract the CA1 hippocampal region and export to ImageJ for analysis. ImageJ 1.8 color thresholding was used to quantify the number and area of CA and pTau. Neurofibrillary tangle (NFT) pathology was classified by pTau aggregations larger than 150μm2. The percent area occupied (%AO) was calculated by dividing the sum of all positively stained objects by the area of the image, then multiplying by 100. Pearson correlations between CA %AO, pTau %AO, and NFT %AO were calculated in Python 3.7.ResultWhile not statistically significant, we found negative correlations of CA %AO with pTau %AO (‐0.14), and NFT %AO (‐0.28) in the CA1 of the hippocampus. These correlations (‐0.68 and ‐0.54 respectively) were stronger in the 4 individuals who did not carry the AD risk‐increasing APOE‐4 allele.ConclusionThese results suggest that as CA decline, pTau accumulates, which is consistent with prior studies that described a decline in CA from intermediate to advanced Braak Stages (III‐VI) in the dentate gyrus. These changes are consistent with our
Brain TSPO expression is associated with plasma pTau181 & pTau231 across the AD spectrum
Authors: Rahmouni Nesrine , Therriault Joseph , Tissot Cécile , Lussier Firoza Z , Stevenson Jenna , Stevenson Alyssa , Servaes Stijn , Ashton Nicholas J. , Arias Jaime Fernandez , Wang Yi‐Ting , Kang Min Su , Karikari Thomas K , Gauthier Serge , Pascoal Tharick A , Zetterberg Henrik , Blennow Kaj , Benedet Andréa Lessa , Rosa‐Neto Pedro 
Published: December 2022

AbstractBackgroundMicroglial activation is an important component of the immune response in the brain of AD patients and has been shown to follow a similar propagation pattern to tau tangle accumulation. However, it is unclear to what extent cerebral microglial activation is associated with biofluid concentrations of phosphorylated tau (pTau). The objective was to investigate whether concentrations of pTau181 and pTau231 are correlated with microglial activation indexed by [11C]PBR28 PET across the AD spectrum.MethodThe present study was conducted in a population of 130 individuals from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort: 20 young cognitively unimpaired, 65 cognitively unimpaired elderlies, 31 with mild cognitive impairment and 14 with AD dementia. Participants were evaluated with blood biomarkers and [11C]PBR28 PET. Plasma pTau181 and pTau231 concentrations were quantified using a Simoa assay. Microglial activation was assessed via [11C]PBR28 PET, standardized uptake value ratios (SUVRs) were calculated between 0 and 90 minutes post‐injection, using cerebellum grey matter as the reference region. Voxel‐based regression models evaluated the relationship between plasma pTau181 and pTau231 with neuroinflammation as assessed by PET, correcting for age and sex.ResultIn the present study, positive correlations were found between concentrations of both pTau181 and pTau231 and neuroinflammation indexed by PET‐imaging. Voxel‐level analyses indicated that these associations prenominated in regions of the default mode network including the precuneus, posterior cingulate cortex and medial prefrontal cortex. These regional associations survived corrections for multiple comparisons.ConclusionPeripheral phosphorylated tau is associated with neuroinflammation in brain regions associated with AD. Our findings highlight the importance of neuroinflammation in the pathogenesis of AD.
Association of Mid‐life Discrimination Stress and Coping on Brain Volumes
Authors: Kulshreshtha Ambar , Misiura Maria , Hu William T. , Verble Danielle D , Likos Kelly D. S. , Wharton Whitney 
Published: December 2022

AbstractBackgroundChronic stress is related with poor health outcomes including changes in brain structure and function. Stress‐related glucocorticoid and adrenergic receptors are richly expressed in hippocampus, prefrontal cortex, and amygdala, but it is unclear if all forms of stress impact these brain regions. Perceived discrimination is a form of stress, and there is limited research in how perceived discrimination can impact brain volumetrics. Our goal is to assess the association of perceived discrimination in brain regions prone to stress‐related affect.MethodsWe examined data from 35 cognitively normal, racially diverse, middle‐aged adults with a parental history of Alzheimer’s disease (AD). Participants provided medical history, demographic and discrimination survey data. Discrimination scales included the Expanded Everyday Discrimination Scale (EED), Major Experiences of Discrimination Scale (MED), Heightened Vigilance Scale (HVIGIL), and Coping with Discriminating scale (COPE). Participants underwent structural MRI with high resolution anatomical images of regions including the hippocampal, prefrontal cortex and amygdala. Multivariate linear regression was used to model the association between stress scales and brain volumes controlling for age and race. Volumes are adjusted for intracranial volume.ResultsParticipants were average 61.5 years, 60% women, 8.6% African American and 40% had a postgraduate education. 54.3% participants had hypertension, 74.3% had dyslipidemia. EED score was associated with an increase in left (p = 0.49) and right (p = 0.03) hippocampal volume. MED score was associated with an increase in left (p< 0.01) and right (p = 0.01) hippocampal volume. HVIGIL sum score was associated with an increase in left (p = 0.02) and right (p = 0.03) hippocampal volume. The COPE sum score was associated with increased in left p = 0.01) and right (p< 0.01) hippocampal volume. There was a positive association in the above stress scores with left and right amygdala and prefrontal cortex, but these were not statistically significant.ConclusionContrary to our hypothesis we found that perceived discrimination is associated with larger brain volumes particularly in the hippocampus region. Mid‐life discrimination when accompanied with better coping skills is related to larger brain volumes suggesting mechanisms that warrant further exploration. Mid‐life maybe an important phase for intervention efforts to mitigate long‐term effects of stress.
Gender differences in cognitive performance among health volunteers of SANSCOG cohort
Authors: Lingegodwa Abhishek Mensegere , Giridhar Varsha , TEJA KARRU VENKATA RAVI , Sundarakumar Jonas S. , Ravindranath Vijayalakshmi , Collaborators SANSCOG 
Published: December 2022

AbstractBackgroundWomen are at higher risk of AD probably due to longer life span. However, differences in cognitive performance across gender among normal aging individuals is inconclusive. Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) is a longitudinal study in healthy aging individuals in a town located near Bangalore, India.MethodOur objective was to compare cognitive performances at baseline assessment measured by COGNITO battery and HMSE between men and women participants of SANSCOG cohort who did not have dementia.ResultIn a sample of 2354 individuals, 1141 (48.5%) were women. Men were older and had more years of education when compared to women. Generalized linear models were constructed which used age and education as confounding variables revealed that males performed better than females on global cognition (β = ‐0.62, p < 0.001). When we examined individual domains, men achieved better scores in visuospatial domain and attention domain, however, women achieved better scores in memory domain. In the language domain, females scored more than males in semantic association test but males scored more in semantic fluency. There was no difference found in executive function domain.ConclusionWe have demonstrated that healthy rural Indian women perform poorly in global cognition and attention suggesting that they are at greater risk of developing dementia.
A longitudinal analysis of depressive symptoms in relation to repeated measurements of regional tau
Authors: Munro Catherine E , Buckley Rachel F. , Vannini Patrizia , Hanseeuw Bernard , Quiroz Yakeel T. , Farrell Michelle E. , Rentz Dorene M. , Blacker Deborah , Sperling Reisa A. , Johnson Keith A. , Amariglio Rebecca E. , Marshall Gad A , Gatchel Jennifer R 
Published: December 2022

AbstractBackgroundDepressive symptoms are commonly observed early in Alzheimer’s disease (AD), but their temporal association with progression along the AD continuum is less clear. We sought to determine if initial measurements of regional tau were predictive of increasing depressive symptoms, and if changes in depressive symptoms predicted later tau levels. We examined these relationships in a region of early tau accumulation (i.e., entorhinal cortex (EC)), and in regions of later neocortical tau spread commonly involved in affective regulation (amygdala and medial and lateral orbitofrontal cortex (mOFC, lOFC)).MethodParticipants (n = 257; mean age = 70.7; 61% female) came from the Harvard Aging Brain Study, a longitudinal observational cohort of cognitively unimpaired adults with no/low depression at baseline (mean years of follow‐up = 7.2). All participants completed the self‐reported 30‐item Geriatric Depression Scale (GDS) annually and tau PET imaging (Flortaucipir‐FTP) every 3 years. On average, initial tau PET scans occurred 2.3 years after enrollment and the latest available scan occurred 5.1 years after enrollment. Separate linear mixed effects models investigated relationships between longitudinal GDS and cross‐sectional regional tau (FTP PET SUVr), at initial scan and at the latest scan available, in the following regions of interest: EC, amygdala, mOFC, and lOFC. Covariates included age, sex, and education.ResultHigher initial FTP levels were associated with significant increases in GDS score over time in temporal cortex (amygdala: b = 0.29,p = 0.0002; EC: b = 0.21,p = 0.0006) and mOFC (b = 0.30,p = 0.004), with marginal significance in lOFC (b = 0.21,p = 0.07). However, the reverse temporal sequence was only observed between GDS scores over all time points and later measurement of amygdala FTP, such that increasing depressive symptoms over time preceded higher final amygdala tau levels (b = 0.15,p = 0.02).ConclusionHigher tau in EC, amygdala and OFC regions predicted increasing depressive symptoms over time in older adults. Only for the amygdala did we also observe the converse relationship: increasing depressive symptoms predicting higher final tau. These results suggest early tau proliferation in affective regions is associated with increased depressive symptoms, though the question of causality is still unclear. Further work is needed to dissect possible temporal relationships across whole brain voxels to better understand depressive symptoms in AD progression.
Factors associated with the Big 5 personality traits in Alzheimer’s disease and related dementias (ADRD)
Authors: Rhodes Emma , Massimo Lauren , Mechanic‐Hamilton Dawn , McMillan Corey T , Phillips Jeffrey S , Burke Sarah E , Hlava Quinn , Cook Philip , Gee James C. , Grossman Murray 
Published: December 2022

AbstractBackgroundInformant ratings of behavior and personality change are the gold standard of measurement in Alzheimer’s disease and related dementias (ADRD) where insight is often impaired, but informant report can be biased by psychosocial factors such as caregiver burden. This study assessed the impact of caregiver burden on informant ratings of patient Big 5 personality traits (Extraversion, Agreeableness, Conscientiousness, Neuroticism, Openness) and associations between degree of discrepancy between informant and patient ratings with cortical volume in regions implicated in loss of insight.MethodA sample of 70 ADRD participants with heterogeneous neurodegenerative clinical phenotypes (Figure 1) and their informants completed the NEO Personality Inventory (NEO‐PI). Disease severity was measured using the Clinical Dementia Rating Scale (CDR). Caregiver burden was measured using the Zarit Burden Interview (ZBI). Discrepancy scores were computed for all NEO‐PI Big 5 scores and a global discrepancy score. Participants were classified as having high/low discrepancy using a median split for each NEO‐PI discrepancy score. T1‐weighted 3T MRI grey matter volumes were normalized to intracranial volume for all ROIs in the Schaefer100×17 parcellation, and linear regression analyses related global difference score to Bonferroni‐corrected atrophy regions.ResultHigher levels of caregiver burden were associated with higher informant ratings of patient Neuroticism (ß = 0.02, p = .013) and lower informant ratings of patient Agreeableness (ß = ‐0.02, p = .0004), Conscientiousness (ß = ‐0.02, p = .005), and Openness (ß = ‐0.01, p = .014) independent of disease severity. Patients with high global discrepancy scores showed reduced cortical volumes in left ventral PFC, right medial PFC, and right superior temporal gyrus. Patients with low discrepancy scores showed relatively preserved cortical volumes in bilateral somatomotor cortex, right posterior cingulate, and left supplementary motor, superior parietal lobule, and postcentral gyrus (all p‐values<.05, Figure 2). Reduced volumes in the high discrepancy group were driven by patients with bvFTD (Figure 3).ConclusionInformant ratings of Big 5 personality factors may be confounded by caregiver burden, highlighting the need for more objective measures of personality and behavior in ADRD. Additionally, high levels of discrepancy between informant and patient ratings of personality may reflect loss of insight secondary to cortical atrophy in frontal and temporal structures.
A Haptoglobin (HP) Exon Deletion Polymorphism Alters the Effect of APOE Alleles on Alzheimer’s Disease in European‐Descent People with APOEε4
Authors: Bai Haimeng , Naj Adam C. , Leung Yuk Yee , Wang Li‐San , Schellenberg Gerard D. , Mayeux Richard , Pericak‐Vance Margaret A. , Farrer Lindsay A. , Dumitrescu Logan , Hohman Timothy J. , Kunkle Brian W. , Martin Eden R. , Haines Jonathan L. , Bush William S. 
Published: December 2022

AbstractBackgroundHaptoglobin (HP) is an antioxidant of apolipoprotein E (APOE) – the strongest risk gene for sporadic Alzheimer’s disease (AD). The HP gene has two functional alleles, HP2 and HP1, which contains a two‐exon deletion that changes its protein structure conformation. We hypothesize that this structural variation is associated with AD.MethodTo investigate this, we imputed the HP genotypes for 12,403 cases and 11,699 normal controls from the Alzheimer’s Disease Genetics Consortium (ADGC), respectively within each cohort of 18 European‐descent cohorts, using a custom reference panel. We then evaluated the association between HP genotype and the AD status using logistic regression, adjusting for sex, age, and the first 3 principal components.ResultThe imputed HP1 frequency is 0.376. We found HP influences AD given an APOEε4 genetic context. In individuals with ≥1 APOEε4 allele (n=10,054), HP1 homozygotes attenuate the effect of the second APOE allele; both the protective effect of the ε2 allele and the risk effect of the ε4 allele are dramatically reduced (odds ratio, OR=0.92, p=0.415 of ε2 versus ε3, OR=1.09, p=0.415 of ε4 versus ε3). However, the HP2 allele accentuates the effect of the second APOE allele, both the protective effect of the ε2 allele and the risk effect of the ε4 allele (OR=0.80, p= 0.003 of ε2 versus ε3, OR=1.25, p=0.003 of ε4 versus ε3). This effect is even stronger in HP2 homozygotes (OR=0.64, p=0.003 of ε2 versus ε3, OR=1.55, p=0.003 of ε4 versus ε3). In addition, we analyzed time to AD diagnosis with a cox proportional hazard regression model within the more consistently examined National Alzheimer's Coordinating Center (NACC) cohorts (n=7,448). A cox model shows that HP2 alleles additively decrease the hazard of AD (hazard ratio=0.94, p=6.85e‐3).Conclusion
HP impacts AD risk in people with APOEε4. Furthermore, this risk is different in people with APOEε24, APOEε34, and APOEε44 genotypes. Though the mechanism still awaits investigation, based on the current knowledge of HP function our results suggest a possible differential anti‐oxidative ability of HP proteins for distinct APOE proteins. As such, the HP protein may be an imminently translatable therapeutic target for AD in APOEε4 carriers.