bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroinflammation co‐localizes highly with tau in amnestic mild cognitive impairment
Authors: Appleton Johanna , Funk Quentin , Bradbury Kathleen , Yu Meixiang , Faridar Alireza , Beers David , Appel Stanley H , Fujita Masahiro , Masdeu Joseph C. , Pascual Belen 
Published: December 2022

AbstractBackgroundNeuroinflammation, along with beta amyloid and tau brain deposition, is a potential diagnostic biomarker and therapeutic target in patients with Alzheimer’s disease (AD). The role of inflammation at various stages of the AD process needs to be clarified. TSPO PET is useful to image brain inflammation, but some tracers have low affinity for TSPO and “second generation” tracers, with higher affinity, cannot image subjects with a low‐binder TSPO rs6971 genotype. We overcame this problem by using 11C‐ER176, a high‐affinity tracer allowing for imaging of all participants and with a more favorable metabolite profile than other high affinity tracers (Fujita, 2017). Then, we correlated the localization of neuroinflammation tau and amyloid in a subset of the participants.MethodWe imaged 15 patients with amnestic MCI (mean age 63±5, 7 women) and 15 healthy controls (HC) (8/15 women, mean age 65 ±7) using 11C‐ER176 PET. TSPO affinity was similar (MCI/HC = 2/3 low, 8/7 mixed, 5/5 high). A full factorial analysis was performed on V
T values between groups at the regional level (Hammer’s atlas). Ten MCI patients had also amyloid PET (18F‐florbetaben or 18F‐florbetapir) and tau PET (18F‐flortaucipir). Standard uptake value ratios (SUVRs) were calculated for both tracers using the cerebellum as reference. Regional correlations among the three tracers were determined for each patient and an average calculated. All images were corrected for partial volume effect.ResultNeuroinflammation in MCI was bilaterally increased in precuneus and lateral temporo‐ parietal cortex, and right amygdala. There was a correlation between the localization of amyloid and tau in the brain (r=0.61). However, the correlation between neuroinflammation and tau was even higher (r=0.73); neuroinflammation also co‐localized with amyloid, but not as strongly (r=0.59).Conclusion
11C‐ER176 PET allowed for the identification in MCI of neuroinflammation in regions known to be involved in the AD process. Importantly, all subjects with any TSPO genotype could be studied. As expected, the localization of amyloid and tau in the brain was correlated, but the co‐localization of neuroinflammation with tau was even higher than between amyloid and tau. This finding highlights the importance of neuroinflammation as a biomarker of neurodegeneration and as a therapeutic target.
Assessing trust and research attitudes in Blacks/African Americans following a personalized vs less personalized community approach
Authors: Bouges Shenikqua , Noell Debra , Osman Fauzia , Benton Susan Flowers , Clipps Antwon D , Fischer Barbara L. , Gooding Diane C. , Anthony Ruben L , Carter Fabu P , Salazar Hector , Simó Carola A. Ferrer , Ennis Gilda E. , Van Hulle Carol A. , Zuelsdorff Megan , Wyman Mary F. , Johnson Adrienne L. , Lambrou Nickolas H. , James Taryn T. , Carlsson Cynthia M. , Asthana Sanjay 
Published: December 2022

AbstractBackgroundSeveral studies have shown the importance of establishing trust in supporting an individual’s willingness to participate in research; yet evidence is limited regarding systematic studies testing the effectiveness of various methods used to build trust. Our pilot study examined two methods of building trust in communities of color by measuring willingness to participate in research pre‐ and post‐intervention. We hypothesized that a more personalized intervention would be more effective than a non‐personalized one in changing attitudes about research participation.Methods97 non‐randomized African American participants, without self‐reported cognitive impairment, completed the research attitudes questionnaire (RAQ) before and after participating in two different community engagement (CE) activities: 1) personalized medication review (MR), n = 48; and/or 2) a less personalized public community talk (Talk), n = 49. Numeric comparisons were conducted using student t‐tests. We used chi‐square and Fisher’s exact test for categorical comparisons. Pre‐ and post‐Talk and MR outcomes were tested for significant changes using the paired Wilcoxon non‐parametric sign rank test.ResultsIn this predominantly female sample (80% female), mean age was 64 (standard deviation = 9.9). Study participant characteristics provided in Table 1. There were no significant differences in RAQ or trust questions in the pre‐ and post‐Talk session. However, during the MR session, significant changes were seen on the question “I have a positive view about medical research in general” (P = 0.007). During the pre‐MR, 16.7% strongly agreed with this statement, while 39.6% strongly agreed at the post‐MR. Similarly, agreement with the statements “Medical researchers treat people from my racial group as guinea pigs” (p = 0.004) and “Medical researchers work hard to keep participants’ information private and secure” (P = 0.01) were also significantly different following the intervention (see Figure 5).ConclusionsThese findings support our hypothesis that a more personalized community engagement approach would have a greater influence on participant’s research attitudes. Compared to individuals with ≤ 1 co‐morbidities at baseline, those with ≥2 co‐morbidities had positive responses prior to an intervention and felt less responsibility to volunteer post med review. Additional studies are needed to further investigate these findings and the role of trust in association with research attitudes.
Use of Cognitive Training in an Outpatient Memory Clinic
Authors: Anderson Allan A , Ashish Dev 
Published: December 2022

AbstractBackgroundPatients with MCI or mild AD often search out non‐pharmacologic treatments to improve their cognitive deficits or aid in managing them. At BAI Tucson we developed a multi‐component and multi‐domain cognitive training program with patients and care partners.MethodIndividual sessions of cognitive training are provided to select patients at our outpatient memory center.ResultPatients often benefit with improved productivity at work and in their personal lives. They also improve emotionally with increased self confidence in their day‐to‐day activities. Outcomes of post treatment interviews validate these benefits.ConclusionCognitive training can be a powerful tool for use in outpatient memory clinics offering an alternative to pharmacologic treatments. Data demonstrate improvements in quality of life measures including improved mastery of daily activities, improved self esteem, and reduced complaints of cognitive dysfunction.
Plasma p‐tau181 concentration accurately predicts clinically diagnosed Alzheimer’s Disease cases
Authors: Kumar Pankaj , Vanbrabant Jeroen , Encarnacion Mary , Mousavi Ali , Mammel Anna , Aziz Tariq , Hsiung Ging‐Yuek Robin , Vanmechelen Eugeen , Stoops Erik , Frykman Hans 
Published: December 2022

AbstractBackgroundThe feasibility of detecting tau phosphorylated at threonine‐181(p‐tau181) in CSF makes it a valuable biomarker for diagnosis in the field of Alzheimer’s Disease (AD). Recently, the novel technologies accurately measuring biomarkers directly in blood offer a unique advantage for use in clinical testing and trials. This study describes the performance testing of a novel plasma p‐tau181 Simoa assay to predict clinical AD.MethodThe presented data were obtained after analysis of EDTA plasma from cases with clinical AD who had been referred to the UBC Hospital Clinic with complaint of cognitive impairment and were assessed for dementia and AD between 2008 – 2018.We also analysed serum of 50 random healthy donors and 50 aged ‐ matched controls with normal cognition. The samples were assayed using an ADx Neurosciences developed p‐tau181 specific Simoa assay. Analytical performance (precision, detection limit, parallelism) and analyte stability was evaluated using healthy‐donor samples. Finally, the p‐tau181 specificity was assessed using synthetic peptides.Result254 AD patients (female = 125) and 100 controls (female = 39) were included. The average of plasma p‐tau181 was 72.9 ±36.8 ng/L in AD cases and the average of serum p‐tau181 was 8.1± 10.5 ng/L in controls.The concentration of plasma p‐tau181 in patients with AD was significantly increased with at‐least 9‐fold versus controls (p=<0.001). ROC analysis demonstrated an AUC of 0.92 and a suitable clinical cut‐off of 34.3 ng/L. Analytical performance testing: 1 of the 254 AD samples tested were below the LLOQ of 1.38 ng/L. The intra‐ and inter‐ assay variability was 8.2% CV and 11.8 % CV, respectively. Sample dilution (df 2‐4‐5‐6) resulted in mean parallelism of 93.5 %. P‐tau181 levels were stable up to 5 Freeze/Thaw cycle (mean 98.9%) and up to 24h at 4°C or RT. The assay was found to be highly specific towards p‐tau181 and nonreactive to p‐tau175.ConclusionThe plasma p‐tau181 concentration in AD cases were significantly higher than controls with limited overlap and in line with published data. The specific measurement of plasma p‐tau181 shows good promise in offering a non‐biased measurement and help in the clinical assessment of AD patients and clinical trials.
Comparison of C2N Diagnostics’ Aβ40, 42, and 42/40 ratio in Plasma Stored in Micronic and Sarstedt Tubes
Authors: Edler Michael C. , Russ Kristen A , Mitchell Colleen M. , Holubasch Mary S. , Kirmess Kris , Meyer Matthew R. , Yarasheski Kevin E. , Foroud Tatiana M. , Dage Jeffrey L. 
Published: December 2022

AbstractBackgroundVariation in biospecimen collection, processing, and storage parameters can introduce pre‐analytical variables that may confound interpretation of biomarker results. Samples collected under different study protocols or over a long period of time may require different labware, such as storage tubes. Comparability of storage tubes is necessary to better interpretate data collected both longitudinally within studies and across studies that may utilize various labware. The focus of this experiment was to perform comparability studies between plasma biomarkers measured in two polypropylene tube types: Sarstedt tube (72.694.006) and an automation friendly Micronic tube (MP52755).MethodsBlood was collected from healthy controls (N=23) and Alzheimer’s Disease (AD) subjects (N=16) by the Indiana Biobank. Participants’ brain amyloid status was unknown. Plasma from the same subjects was aliquoted (0.5 mL) into both Micronic and Sarstedt polypropylene tubes following standard NCRAD protocols and then frozen and stored at ‐80 °C for <7 months prior to analysis. Blinded samples were thawed once and analyzed for ApoE proteotype, Aβ40 and Aβ42 using liquid chromatography‐high resolution tandem mass spectrometry (LC‐MS/MS; C2N Diagnostics, St. Louis, MO). Data was analyzed in JMP 16.0.0 with the method comparison add‐in and GraphPad PRISM 9.3.1 to determine comparability of the measurements made in the two sample tube types.ResultsComparability analysis found a high correlation of measured Aβ40, Aβ42 and the Aβ42/Aβ40 ratio in plasma stored in Micronic and Sarstedt tubes. Correlation analysis revealed slopes and intercepts within 95% confidence limits of 1 or 0 respectively. Bland Altman analysis showed low measurement bias (4‐7%) between the two tube types. ApoE isoform specific proteotypes were identical between tube types for all subjects.ConclusionResults of the tube type study were within the validated performance range of the measurements. Plasma stored in Micronic and Sarstedt tubes can be used interchangeably when detecting ApoE proteotype and quantifying Aβ40 and Aβ42 concentrations using C2N’s LC‐MS/MS analytical platform. These results support the efforts of large biorepositories, like NCRAD to transition the storage of biospecimens from the larger, less automation friendly Sarstedt tube to the more automation friendly, freezer‐space saving Micronic tube. Supported by U24 AG021886 and UL1TR002529.
Identification TDP‐43 fragments specific for frontotemporal lobar degeneration with TDP‐43 inclusions
Authors: Forgrave Lauren M , Li Yun , Moon Kyung‐Mee , Mackenzie Ian R , Foster Leonard J , DeMarco Mari L. 
Published: December 2022

AbstractBackgroundAnte‐mortem biomarkers specific for TDP‐43 pathology are highly desired given the challenge in distinguishing frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP) from phenotypically related disorders. TDP‐43 post‐translational modifications, like C‐terminal fragments, are regarded as disease‐specific TDP‐43 proteoforms; however, the exact structure of these proteoforms remains unclear. This lack of clarity is due in part to the use of instrumentation and techniques with low structural resolution and the study of small sample sizes. With this in mind, we performed high resolution mass spectrometry (HRMS) analysis of brain tissue from cases with and without TDP‐43 proteinopathy to identify TDP‐43 proteoforms unique to FTLD‐TDP.MethodHRMS was used to determine TDP‐43 proteoform composition in insoluble frontal lobe brain tissue from immunohistochemically‐confirmed FTLD‐TDP (n=13), related dementias (i.e., Alzheimer’s disease and FTLD‐tau without TDP‐43 deposits; n=10) and neuropathologically‐unaffected controls (n=3). Brain tissue was fractioned by gel electrophoresis, with HRMS analysis performed on molecular weight regions corresponding to <28 kDa (low molecular weight TDP; L‐TDP), 28‐38 kDa (mid molecular weight TDP; M‐TDP), and 38‐55 kDa (intact TDP; I‐TDP).ResultIn all samples tested, the greatest TDP‐43 sequence coverage was observed for I‐TDP, followed by L‐TDP and then M‐TDP. TDP‐43 peptides from L‐TDP were more frequently detected in the FTLD‐TDP cases compared to both sets of controls, whereas no frequency differences were observed for I‐TDP and M‐TDP. Quantitative analysis revealed peptide concentrations from M‐ and L‐TDP were significantly increased in FTLD‐TDP cases compared to controls. The L‐TDP peptides concentrations differentiated FTLD‐TDP cases from related dementias and unaffected controls with 78% sensitivity and 100% specificity. Further, three in vivo cleavage sites of TDP‐43 were identified, which were unique to FTLD‐TDP cases.ConclusionThis is the largest reported proteomics study to date of histology‐confirmed FTLD‐TDP. This is also the first study to include a large number and range of control tissues, and to provide supporting evidence for in vivo cleavage sites including corroboration of the proteolytic fragment recently found in TDP‐43 fibrils. Clarity and consensus on the sequence of TDP‐43 disease‐specific proteoforms will be helpful in advancing biomarker and drug discovery efforts for TDP‐43 proteopathies.
Examining Alzheimer’s Disease Blood‐Based Biomarkers and Cognition Among Non‐Hispanic White and Mexican Americans After Traumatic Brain Injury
Authors: Garcia Joshua M , Lopez Andrea P Ochoa , Medina Luis D 
Published: December 2022

AbstractBackgroundThere is limited evidence on the relationship of traumatic brain injury with loss of consciousness (TBI‐LOC) and Alzheimer’s disease (AD) blood‐based biomarkers in relation to cognition. This research has predominantly examined associations among non‐Hispanic White (NHW) male service members and veterans, which limits generalizability to ethnically diverse community‐dwelling individuals. This study evaluated cognition in relation to TBI‐LOC in a NHW and Mexican American (MA) sample from Dallas‐Fort Worth, Texas in the United States.MethodData were obtained from the Health and Aging Brain Study – Health Disparities. Excluding participants with failed performance validity testing, evidence of alcohol use disorder, severe anxiety/depression, and a history of stroke or seizures, we estimated a cognitive composite using principal component analysis of the cognitive test battery. The remaining sample (n = 899) enabled baseline comparison of those with and without TBI‐LOC, before examining cognition within the TBI‐LOC group (n = 134, mean age(range) = 66.69±7.10(50‐87), mean education = 12.96±4.74, 41% female, 24.6% MA Spanish‐speaking). Multiple regression model comparisons explained variance in cognition by sociodemographic factors (age, gender, education, ethnicity/language), AD blood‐based biomarkers (Aβ42/Aβ40, Tau, Neurofilament light), and TBI‐LOC variables. TBI‐LOC variables included TBIs with loss of consciousness >30 minutes, age at first TBI‐LOC, and longest period of unconsciousness after TBI, scored by the Ohio State University TBI Identification Method.ResultThe TBI‐LOC group did not differ from the non‐TBI‐LOC group across age, education, ethnicity/language, CDR status, or cognition (ps > 0.05); they did differ by gender where the TBI‐LOC group was 59% male compared to 42.4% in the non‐TBI‐LOC group (p <0.001). Within the TBI‐LOC group, sociodemographic factors explained 49.6% of variance in cognition, and the inclusion of AD biomarkers accounted for an additional 0.4% of variance (p = 0.241). The final model including the TBI‐LOC variables explained an additional 2.5% of variance (p = 0.038) in cognition.ConclusionCognitive differences between participants with and without history of TBI‐LOC were not demonstrated. Among those with TBI‐LOC, higher severity of injury was associated with lower cognition, while AD blood‐based biomarkers had non‐significant associations with cognition. Further investigation of alternative biomarkers and specific cognitive domains among ethnically diverse individuals with TBI is warranted.
Association between tau uptake and verbal fluency converge in language centers
Authors: Stevenson Alyssa , Rahmouni Nesrine , Therriault Joseph , Stevenson Jenna , Tissot Cécile , Lussier Firoza Z , Bezgin Gleb , Chamoun Mira , Pascoal Tharick A , Gauthier Serge , Benedet Andréa Lessa , Vitali Paolo , Rosa‐Neto Pedro 
Published: December 2022

AbstractBackgroundRecent studies have shown that pathological tau accumulation, a hallmark of Alzheimer’s disease (AD), is closely related to cognitive deficits in older populations. Semantic deficits, measured using tests of category verbal fluency, are among the features of early clinical stages of AD presentations. While the association between semantic decline and AD biomarkers have been evaluated, the use of a novel tau positron emission tomography (PET) tracer [18F]MK6240, remains relatively unexplored. The present study aims to evaluate whether tau accumulation is associated with participants’ performance on both category and letter fluency neuropsychological tests and whether category fluency performance is disproportionately impaired in AD in comparison to letter fluency.MethodThe study was conducted in a population of 298 individuals (188 cognitively unimpaired, 110 cognitively impaired). The D‐KEFS Category Fluency test was used to assess semantic knowledge while Letter Fluency was used to measure lexical speed access. Participants also underwent the Mini‐Mental State Examination (MMSE) to assess overall global cognitive functioning. Accumulation of tau was assessed with [18F]MK6240 PET and standardized uptake value ratio (SUVRs) were calculated between 90 to 110 min post‐injection, using cerebellum grey matter as the reference region. A voxel‐based regression model evaluated the relationship between the cognitive scoring and the PET marker [18F]MK6240, correcting for age, sex, education, diagnosis and RFT was used to account for multiple comparisons.ResultThis study found negative associations between Category and Letter Fluency scores and tau accumulation. Notably, stronger associations were found in the Category Fluency grouping. The associated regions are mainly in the left hemisphere in language related regions and the temporal lobe. Letter Fluency scores demonstrated the strongest association in the frontal regions. Comparatively, the MMSE scores were strongly associated with tau accumulation in both right and left hemispheres.ConclusionTau accumulation is associated with language dysfunction and is a major driver of domain‐specific cognitive impairment across the AD spectrum. Associations were more pronounced in the left hemisphere for both semantic knowledge and lexical speed. These results also suggest that tau accumulation is more strongly associated with semantic knowledge as indicated by uptake in language related areas.
Amyloid duration and entorhinal tau interact to influence cognition in preclinical Alzheimer’s disease
Authors: Cody Karly Alex , Koscik Rebecca Langhough , Jonaitis Erin M. , Hermann Bruce P , Chin Nathaniel A. , Asthana Sanjay , Christian Bradley T , Betthauser Tobey J , Johnson Sterling C. 
Published: December 2022

AbstractBackgroundThe degree of involvement of amyloid and tau on cognitive decline in the pre‐symptomatic phase of AD remains unresolved. This study examines whether duration of amyloid positivity and entorhinal tau individually contribute or interact to influence longitudinal cognitive decline in initially unimpaired older individuals.MethodData were from 358 initially unimpaired individuals from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center who underwent amyloid and tau PET imaging and longitudinal cognitive assessment (Baseline age: 59.7 ±6.7 years; 67% female; follow‐up years, Median(IQR)=8.0 (6.1‐9.8); Table 1). Amyloid burden was quantified from cortical 11C‐PiB DVR, and amyloid duration, quantified as years from PiB positivity (A+/‐; global PiB DVR1.16), was estimated using a sampled iterative local approximation algorithm. Tau burden was quantified using 18F‐MK‐6240 standard uptake value ratios (SUVRs; 70‐90min, inferior cerebellar grey matter reference region). Linear mixed effects (LME) models (random intercept and age‐related slope; unstructured covariance) investigated contributions of amyloid duration (at MK‐6240 scan) and entorhinal cortex (EC) MK‐6240 uptake to retrospective cognitive decline represented by a modified three‐test Preclinical Alzheimer’s Cognitive Composite (PACC‐3).ResultAmong initially unimpaired individuals, faster PACC‐3 decline was associated with both longer amyloid duration and higher EC tau. LME models showed significant linear and non‐linear interactions of amyloid duration and EC tau on cognitive decline, suggesting a synergistic effect whereby amyloid duration together with a higher tau burden increases the likelihood of cognitive decline beyond their separable effects (Table 2). To further characterize these interactions, we compared cognitive trajectories of groups based on amyloid duration and EC tau positivity (Figure 1A‐C). Post‐hoc analyses revealed significantly greater decline in the group with 10+ years of amyloid duration and high EC tau compared with all other groups over the study duration (Figure 1C).ConclusionThese results suggest that in this pre‐symptomatic sample, amyloid duration and EC tau were not redundant contributors to decline, but rather interacted to influence decline during the retrospective period of observation. Prospective follow‐up and mediation analyses will be essential to fully elucidate the influence of amyloid duration and early tau on cognitive decline in preclinical Alzheimer’s disease.