bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting Major Decline in Older Adults: The Role of Time Spent Out of Home
Authors: Au‐Yeung Wan‐Tai M. , Miller Lyndsey M. , Steele Joel S. , Mattek Nora , Beattie Zachary T , Silbert Lisa C , Kaye Jeffrey A 
Published: December 2022

AbstractBackgroundFor older adults in community settings, predicting undesired outcomes (needing higher levels of care or death) is important for advancing preventative care and achieving successful aging. We examined whether a combination of baseline characteristics (demographic, clinical) and a continuous digital measure of general mobility and socialization (time‐out‐of‐home) would be predictive of transitions of care and mortality.MethodLongitudinal data from community‐dwelling older adults in the Collaborative Aging Research using Technology (CART) Study was examined for occurrences of undesired life transitions: moving residences due to needing more assistance, receiving non‐temporary in‐home assistance, and death. In‐home sensor data (passive infrared motion and contact sensors) was used to create an algorithm for time when no one was home (TOH). For homes with a transition recorded, a 90‐day window preceding the transition was used to calculate average TOH per day; for homes that did not have transitions, a 90‐day window was randomly selected. Logistic regression was used to predict whether mean duration of TOH (hours), age, gender, Clinical Dementia Rating Scale Sum of Boxes (CDR‐SOB), and Cumulative Illness Rating Scale (CIRS) could predict undesired transitions in single‐resident and dual‐resident homes of older adults.Result177 participants residing in 123 homes were included in the analysis: 56.1% of the homes were single‐resident homes. Mean age in years was 72 (6.4), 52% of participants were women, mean CDR‐SOB = 0.30 (0.46), and mean CIRS = 22 (3.9). Transition to needing greater assistance or death was significantly associated with less TOH (OR 0.66 [95% CI 0.44‐0.98]) after controlling for known risk factors that included age, CIRS, CDR‐SOB and gender. Older age (OR=1.07 [CI 0.98‐1.16]), higher CDR‐SOB (OR=2.66 [CI 0.80‐8.87]), higher CIRS (OR=1.05 [CI 0.90‐1.21]), and being male (OR=0.55 [CI 0.19‐1.64]) were associated with a major transition or death with wide CI’s among these mediating factors.ConclusionLess duration of TOH (likely reflecting mobility and motivation) is predictive of major decline in older adults after controlling for known demographic and clinical risk factors. Digital behavioral biomarkers assessing older adults’ day‐to‐day behaviors may provide valuable information in addition to clinical assessments.
Mechanisms Mediating the Anti‐inflammatory Effects of Eicosapentaenoic Acid in the APPswePS1dE9 Alzheimer's Mouse Model
Authors: Yavari Mahsa , Ramalingam Latha , Harris Breanna N. , Kahathuduwa Chanaka , Zu Yujiao , Chavira Angela , Biltz Caroline , Alers Kaylee , Mounce Philip , Moustaid‐Moussa Naima 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a progressive, neurodegenerative disorder characterized by amyloid‐beta (Aβ) plaques, which may be exacerbated by obesity. We previously reported anti‐obesity and anti‐inflammatory effects of eicosapentaenoic acid (EPA), in diet‐induced obese mice. Therefore, the objective of this research is to determine whether EPA also protects against AD‐associated Aβ deposition.MethodMale and female AD mouse model APPswePS1E9 transgenic (TG) and non‐TG wild type littermates (WT) were fed with low fat (LF), high fat (HF), or HF supplemented with 36g/kg EPA (EPA) for 8 months. Mice were metabolically phenotyped during the intervention and blood and tissues were collected at the end of the study. Cortex RNA was isolated, and changes in genes related to AD, obesity, and inflammation were measured. Data were analyzed by 3‐way ANOVA using GraphPad Prism.ResultHF groups weighed significantly more than LF groups (p < 0.001), but other groups were comparable regardless of diet or genotype but overall, males weighed more than females. TG mice had higher serum Aβ‐40 levels than WT mice (p= 0.004), paralleled with higher cortex human APP mRNA levels in TG mice (p = 0.0204). Compared to HF, EPA decreased serum Aβ‐40 in WT male mice (p = 0.0182) as well as APP gene expression in the cortex of male and female TG mice (p = 0.0168 and 0.0030). Moreover, TG mice expressed higher level of MCP1 and IL1β (p = 0.0158 and 0.0142, respectively) mRNA levels compared to WT. Females in both genotypes expressed higher level of MCP1, IL1β and NLRP3 than males (p = 0.0025, 0.0038, and < 0.0001 respectively). In addition, EPA exhibited anti‐inflammatory effects in both sexes of TG mice as indicated by downregulation of mRNAs levels for MCP1 (p = 0.0226 and 0.0108) NLRP3 (p = 0.0205 and < 0.0001) and for IL1β in TG females only (p= 0.0344).ConclusionOur data indicate protective effects of EPA in AD, in part, by reducing Aβ deposition, possibly through inflammatory/neuroinflammatory mechanisms. Given the popularity of fish oil supplements, our findings merit further investigation to dissect mechanisms of fish oil effects especially in AD patients with obesity.
Identifying Matrix‐ and Transporter‐Type Pericytes in Human Brain
Authors: Khan Sofia M , Bauman Allison J. , Elkadi Osama , Nelson Amy R. 
Published: December 2022

AbstractBackgroundPericytes are vascular mural cells that wrap around capillaries and are crucial for the formation and maintenance of the blood‐brain barrier (BBB). A recent RNAseq study discovered that the human brain has two novel and distinct pericyte subtypes (Yang et al., 2022). The first, termed transporter (T)‐type, are enriched with transporter genes. The second are matrix (M)‐type pericytes which have increased expression of extracellular matrix (ECM) genes. Notably, the authors found that a decrease in M‐type pericytes and not T‐type pericytes contributes to the formation of Alzheimer’s Disease (AD). The loss of M‐type pericytes is speculated to lead to perturbations of vascular ECM. Here, we aimed to determine which protein markers work best for the identification of M‐ and T‐type pericytes and their localization in human hippocampal and cortical post‐mortem brain tissues.MethodBased on the Yang et. al. paper, we selected COL4A1 and GAT1 to identify M‐pericytes and T‐pericytes, respectively. Next, we used immunofluorescence staining and microscopy to study the localization of these pericyte types in post‐mortem human brain tissue. Primary antibodies (mouse‐COL4A1 and goat‐GAT1) were incubated in blocking buffer on the tissue sections at room temperature overnight. The next day, the sections were washed in phosphate buffered saline (PBS) and incubated in secondary antibodies (anti‐mouse, anti‐goat, and UEA) for 90 minutes and subsequently washed with PBS. The sections were treated with an autofluorescence quenching treatment (5min) and then cover slipped and imaged.ResultWe successfully performed immunofluorescence staining to identify M‐ and T‐type pericytes in human hippocampus and cortex. We are currently working to quantify M‐ and T‐type pericyte number and coverage in human hippocampus and cortex.ConclusionKnowing how to identify these new pericyte types in human brain is essential to begin understanding their abundance, location, and possible functions. In the future, we will measure changes in M‐ and T‐type pericytes in AD vs. aged‐matched control post‐mortem brain tissues using our immunofluorescence protocol.
p75NTR modulation counteracts alterations in neuronal and glial activity‐dependent profiles of gene co‐expression networks in tauopathy mice
Authors: Latif‐Hernandez Amira , Moran‐Losada Patricia , Yang Tao , III Robert R. Butler , Tran Kevin C , Liu Harry , Massa Stephen M. , Wyss‐Coray Tony , Longo Frank M. 
Published: December 2022

AbstractBackgroundP75NTR is a key mediator in the regulation of neuronal plasticity, and modulation of its signaling prevents synaptic dysfunction in Tau.P301S mice, as measured by long‐term potentiation (LTP). Since LTP alters gene expression programs and results in transient post‐translational modifications at synapses, we asked whether tauopathy‐associated alterations in gene co‐expression, in response to stimulation, can be counteracted by p75NTR modulation.
MethodLM11A‐31 (C31), a small molecule p75NTR modulator, was orally administered to Wildtype (WT) and Tau.P301S mice for 3 months, at a time when tau pathology was fully developed. RNA sequencing with cell‐type enrichment analysis was performed on unstimulated and stimulated hippocampal slices that underwent theta burst stimulation (TBS) to induce late‐phase LTP and generate activity‐dependent profiles of gene co‐expression networks, using weighted analysis with a soft‐threshold power of 18 to achieve scale‐free topology R2>0.8 and module size 25.ResultThe most significantly expressed activity‐dependent transcriptional co‐expression modules related to synaptic function in WT mice, that were down‐regulated in Tau.P301S mice, showed an enrichment for genes in neurons and transcripts selectively expressed in CA1 pyramidal cells. The top significant gene pathways enriched in these modules were glutamatergic synapse, post‐synapse, pre‐synapse, post‐synaptic density, dendritic and neuron spine, with Cacna1h, Gabbr1, Kalrn, Shisa7, and Epha7. All of these were normalized to WT levels with C31 treatment. In addition, significantly up‐regulated co‐expression modules in Tau.P301S relative to WT mice associated with pathways such as complement binding, immune system process, myeloid leukocyte migration and neutrophil chemotaxis were enriched in genes found in microglia, such as Trem2, C1qa, C1qb, C1qc, Tyrobp. Notably, these expression profiles also reverted to WT levels with C31. Further, comparison of mouse and human modules demonstrated that those affected in treated mice have similar up‐ and down‐regulated patterns of expression as those found in human AD.ConclusionModulation of p75NTR with C31 normalized tauopathy‐related neuronal and glial transcriptional profiles. These transcriptional alterations are in part concordant with alterations found in human AD‐relevant gene co‐expression networks.
Rater perspectives on Applied Training of cognitive Clinical Outcome Assessment (COA) scales delivered by neuropsychology experts
Authors: Wacker Svenja Mirjam , Barbone Jordan Mark 
Published: December 2022

AbstractBackgroundCognitive assessments are critical in understanding the effects of investigational therapies, but their use can be vulnerable to variability test administration and scoring. Careful training of raters on proper test administration cognitive tests is crucial to ensure optimal reliability and validity of clinical outcome data (Targum, 2006) and (Jeglic, 2007). Trainee feedback is important in ensuring a training program is comprehensive, well‐delivered and well‐received.MethodPerceived effectiveness of live training videoconferences, with expert neuropsychologists as clinical coaches (referred to as Local Expert Advisors “LEADs”), was evaluated via optional, online “Rater Training Survey” deployed to raters to report on their training experience, trainer, and preparedness for live assessments with study participants.ResultOf 261 survey invitations, 48 (18.4%) raters submitted responses on training sessions with 6 different expert trainers, questions on LEAD Knowledge, LEAD Feedback, and Rater Equipped received 100% positive responses. Additional comments lauded the trainers’ engaging and constructive approach to training delivery with effective preparation for assessments with study subjects.ConclusionThis survey format proved to be a low‐burden approach to quality control of clinical coaches. Raters, trained through this rater training program, reported an overwhelmingly positive training experience with the program overall and with the Applied Training session, specifically. The “personal touch” of live training modalities with expert coaches appears to be an effective training approach for raters’ skill mastery and feeling of preparedness.
Impact of Phospholipase C Gamma 2 Alzheimer's Disease Variants on Microglial Biology and Disease Pathogenesis
Authors: Tsai Andy Po‐Yi , Lin Peter Bor‐Chian , Dong Chuanpeng , Prisco Gonzalo Viana Di , Wang Nian , Bissel Stephanie J , Oblak Adrian L , Moutinho Miguel , Liu Yunlong , Atwood Brady , Nho Kwangsik , Lamb Bruce T , Landreth Gary E 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) and other neurodegenerative diseases are typified by a robust microglial‐mediated immune response. Phospholipase C gamma 2 (PLCG2), whose variants confer altered risk for AD, is a critical signaling element for various immune receptors and is a key regulatory hub gene for immune signaling. A functional hypermorphic P522R variant (rs72824905) of PLCG2 has been identified to be protective against AD (OR= 0.68, p=5.83‐10). Significantly, we identified a novel SNP (rs617749044) associated with elevated AD risk (OR=1.164; p=0.047) encoding the PLCG2 M28L variant.MethodTo investigate the impact of PLCG2 AD risk variants on microglial biology and disease pathogenesis, we have generated mice bearing either the M28L risk or the P522R protective PLCG2 variant, all crossed onto the 5XFAD amyloidogenic murine model of AD.ResultHere, we provide comprehensive analysis of PLCG2 action in mouse models of AD. We demonstrate that PLCG2 variants regulate protein‐protein interaction, alter microglial phenotypes in 5XFAD mice, regulate cytokine levels, drive distinct transcriptional phenotypes of microglia, and affect plaque pathology. Our data demonstrate that the M28L variant results in accelerated and exacerbated disease‐related pathology, and conversely, the P522R variant appeared to attenuate disease severity and progression.ConclusionTogether, our finding provides evidence that PLCG2 play an important role in AD pathophysiology, indicating PLCG2 as a potential new therapeutic target for AD.
Association of Cerebrovascular Reactivity and Cognitive Performance in a Racially Diverse Cohort
Authors: Kulshreshtha Ambar , Henley Brandon , Okafor Maureen , Rogers Steven , Thomas Tiffany , Goldstein Felicia C , Hajjar Ihab 
Published: December 2022

AbstractBackgroundCerebrovascular reactivity (CVR) to increased carbon dioxide (CO2) reflects cerebral microvascular function and is impaired in hypertension and stroke. Limited studies have looked at its relationship with cognitive performance in African Americans and Whites.MethodsWe used data from the Brain‐Stress Hypertension and Aging Program cohort (B‐SHARP) consisting of racially diverse individuals with normal cognition or mild cognitive impairment (MCI). CVR was measured using advanced signal modeling approach developed by BH/IH during blood oxygenation level dependent (BOLD) resting state ‐fMRI. Participants underwent cognitive assessment using global and domain‐specific tests such as Montreal Cognitive Assessment (MoCA), Boston Naming Test (BNT), Hopkins Verbal Learning Test‐Revised (HVLT‐R), and Trail Making Test. We used multivariate regression models to assess the relationship of CVR and cognitive domains and tested interaction of CVR with race.ResultsSuccessful CVR data were completed on 219 participants with mean age= 65.3 years (SD 7.8), 46% African American and 65% women. An increased resting whole brain CVR was associated with a higher MoCA score (β = 6.46, SE 2.43, p‐value 0.008), higher BNT score (β =2.15, SE 0.93 p‐value 0.02), and shorter time on Trail B‐A, (β= ‐113.4, SE 42.0, p‐value 0.007) after adjusting for mean arterial pressure. After adjusting for age, sex, and race, increased resting whole brain CVR was associated with higher MoCA (β =4.4, SE 2.26, p‐value 0.05), BNT score (β =1.46, SE 0.89, p‐value 0.1) and Trail B‐A score (β =‐86.7, SE 40.3, p‐value 0.03). There was no association with delayed memory based on HVLT‐R. The results were similar for individuals with normal cognition or MCI. There was a significant interaction by race (p<0.01) such that whole brain CVR was associated with better performance on all cognitive tests for African Americans but not for Whites.ConclusionsHigher CVR, reflected by resting state BOLD‐fMRI, was associated with higher overall cognitive status and specific domains including language and executive functioning in individuals with normal cognition or MCI. The differential effect in African Americans vs Whites could suggest a greater contribution of microvascular dysfunction for the higher prevalence of cognitive impairment in African Americans.
Dissecting the Neuropathological Contributors to Rapidly Progressive Dementia
Authors: Day Gregory S , Lazar Evelyn , Ghayal Nikhil B , Roemer Shanu F , Graff‐Radford Neill R. , Dickson Dennis W. 
Published: December 2022

AbstractBackgroundMost series exploring the causes of rapidly progressive dementia (RPD) rely on clinical diagnoses, with limited pathological confirmation. This approach may underestimate the contributions of Alzheimer disease and related dementias to RPD, recognizing challenges associated with extrapolating clinical phenotypes to neuropathological diagnoses. A clearer understanding of the neuropathological causes of RPD is needed to inform the diagnosis and treatment of patients. To meet this need, we determined the neuropathological causes of RPD within the Mayo Clinic neurodegenerative brain bank.MethodPatients with disease duration <4.0 years (symptom‐onset to death due to dementia) were identified within the Mayo Clinic neurodegenerative brain bank (1998‐2020). Available clinical records were reviewed, and details extracted including demographics, family history, dominant symptoms/signs at onset, and common comorbidities (depression, psychoses, sleep disturbance). Neuropathological diagnoses were assigned following standard protocols.Result310/8586 (3.6%) cases met RPD criteria. Relative to typically progressive cases, prion disease most commonly presented as RPD (74%, 32/43), followed by progressive supranuclear palsy/corticobasal degeneration (PSP/CBD: 7.5%, 142/1894), other frontotemporal lobar degeneration (FTLD: 5.7%, 32/561), Lewy body disease (LBD: 4.1%, 49/1202), and Alzheimer disease (AD: 1.8%, 48/2687). Average age‐at‐symptom onset was 69.5±10.4 years. Patients with rapidly progressive AD were older than others (p<0.01), except LBD. Patients with FTLD were younger than others (p<0.05), except prion disease. Average disease duration was 2.9±1.0 years: prion diseases had the most rapid disease course (1.6±1.3 years). Comorbid cerebrovascular disease (25.5%), and clinically symptomatic depression (41.3%), psychoses (37.1%) and sleep disturbances (39.4%) were common across groups. Only psychosis was associated with shorter disease duration (β=‐0.31 years, CI95% [‐0.53, ‐0.082]; controlling for age‐at‐symptom onset).ConclusionRapidly progressive neurodegenerative diseases accounted for 3.6% of cases in this neurodegenerative brain bank. Although prion disease commonly presented as RPD, atypical presentations of more prevalent neurodegenerative diseases accounted for most cases. Atypical (rapidly progressive) variants of typical neurodegenerative diseases warrant consideration in clinical practice.
Administration of Selective α2‐Adrenergic Receptor Agonist Dexmedetomidine During Spine Surgery is Associated with Reduced Postoperative Increase in Plasma p‐Tau181
Authors: Wilson Edward N. , Pinkert Vincent J , Navales Andres Tirado , Quinn Joseph F , Schenning Katie J 
Published: December 2022

AbstractBackgroundRecent studies have revealed that biomarkers of neuronal injury and Alzheimer's disease (AD) are increased in patients following major surgery. However, the contribution of specific anesthetic agents, such as inhalational or intravenous, remains unclear. In this study, we evaluated whether patients having a predominantly inhalational anesthetic (GAS) compared to patients having a predominantly intravenous anesthetic (IV) would have differences in plasma p‐tau181 levels from preoperative baseline to 3‐months postoperatively. We also examined whether there were differences in p‐tau181 in patients who were intraoperatively administered dexmedetomidine, a selective α2‐adrenergic receptor agonist with neuroprotective effects.MethodIn this prospective observational study of 70 patients (>= 65 years) having elective inpatient spine surgery under general anesthesia at a single academic center, we compared changes in plasma p‐tau181 levels from preoperative baseline to 3‐months postop in patients who received GAS (n=38) compared to IV (n=32). Plasma p‐tau181 levels were measured using the fully automated immunoassay analyzer (Lumipulse G1200, Fujirebio). T‐tests were used to compare 2 groups and 2‐way ANOVA with Tukey's multiple comparisons test was used for dexmedetomidine analyses.ResultOn average plasma p‐tau181 levels increased in the GAS group (n=38) and decreased in the IV group (n=32, mean ± SD; 0.64 ± 2.46 pg/mL vs. ‐1.06 ± 3.24 pg/mL; p=0.014) at 3‐months postop. This was despite the IV group having increased duration of surgery, blood loss, and hospital length of stay. A greater postop increase in plasma p‐tau181 was observed in patients not administered dexmedetomidine (p=0.002). Patients who were not administered dexmedetomidine had a greater increase in postop plasma p‐tau181 in both the GAS and IV groups (main effect of Dexmedetomidine, p=0.02).ConclusionChanges in plasma p‐tau181 levels from preoperative baseline to 3‐months postop were greater in older surgical patients who had GAS compared to IV maintenance of general anesthesia. Importantly, patients not receiving dexmedetomidine showed a greater increase in plasma p‐tau181 levels regardless of anesthesia type.
Case‐control co‐twin study on the associations of dementia risk factors with episodic memory in nonagenarians
Authors: Varjonen Anni , Schwarz Claudia , Kaprio Jaakko , Vuoksimaa Eero 
Published: December 2022

AbstractBackgroundSeveral risk and protective factors of dementia are known, but the importance of genetic and environmental influences and the antecedents of cognitive functioning in 90‐year‐olds are not well known. Genetic and environmental confounding can be controlled better by using family data compared to samples of unrelated individuals. We examined dementia risk factors in 90‐year‐olds by conducting a case‐control co‐twin study on the associations of physical and psychological well‐being with episodic memory (EM).MethodWe invited 90‐year‐old twins from a population‐based older Finnish Twin Cohort study to participate in the ongoing NONAGINTA –study that includes questionnaires (risk factors) and telephone interview (cognitive functioning). To date, eight full same‐sex pairs have cognitive data available (6 female, 6 monozygotic). We calculated a risk score for each twin and co‐twin, based on the following factors: depressive symptoms (measured with the Center for Epidemiological Studies – Depression, CES‐D), body mass index (BMI), physical activity (MET hours), life satisfaction, neuroticism, and years of education. Within each twin pair, co‐twins were assigned as having greater versus lower risk score. We ran a paired t‐test to compare EM performance (total number of recalled words in three trials of 10‐word list) in co‐twins with greater versus lower risk score. Associations of individual factors with EM were studied with exact McNemar test.ResultMean difference in EM within twin pairs was 3.38 (SD = 2.50). Pairwise correlation of EM was r = 0.75 and seven twin pairs were discordant for EM. Co‐twins with lower risk score remembered more words (M = 13.25, SD = 5.59) than their co‐twins with greater risk score (M = 12.88, SD = 5.82), but this difference was not significant (p = 0.82). Examining each risk factor individually, the strongest – non‐significant – association was that co‐twins with greater life satisfaction had better EM in 5/6 pairs (p = 0.10).ConclusionPreliminary data did not indicate any significant within‐twin pair associations of dementia risk and episodic memory. As expected, co‐twins were highly similar in EM. Ongoing data collection will result in more twin pairs and greater statistical power to see if the suggestive association of greater life satisfaction (or other factors) with better EM is evident in nonagenarians.