bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi‐tissue proteomic profiling for genetically defined Alzheimer disease cases
Authors: Sung Yun J. , Yang Chengran , Suhy Adam J. , Rhinn Herve , Norton Joanne , Wang Fengxian , Bradley Joseph , Farias Fabiana H.G. , Benitez Bruno A. , Harari Oscar , Cruchaga Carlos ,   Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2021

AbstractBackgroundAlzheimer disease (AD) is a complex and heterogeneous disease. Most AD cases present sporadically, while 1‐2% of the cases have autosomal dominant AD (ADAD), carrying mutations in APP, PSEN1, and PSEN2. Among sporadic cases, several rare variants in TREM2, which is involved in immune response, are shown to increase AD risk. Most proteomic studies, while instrumental in identifying novel AD genes and pathways, focus on single tissues and mainly sporadic AD cases. Proteomic signatures for each genetically defined AD case will advance the understanding of the underlying biology of this heterogeneous disease and help us create prediction models for AD risk, onset, and progression.MethodWe generated deep proteomic profiles of brain (n=370), cerebrospinal fluid (CSF; n=699), and plasma (n=486) for sporadic AD, ADAD, and TREM2 risk‐variant carriers, from the Knight‐ADRC and DIAN cohorts. After stringent QC, 1079 proteins in brain, 713 in CSF, and 931 in plasma remained.ResultWe identified 150 proteins with differential levels between sporadic cases and controls, 371 for ADAD, and 134 for TREM2 carriers in at least one tissue (with Bonferroni‐corrected statistical significance). Of these, 36, 74 and 31 were replicated across tissue types for sporadic AD, ADAD, and TREM2 carriers, respectively. Using proteins that replicated across tissues, we created a prediction model for CSF and plasma with an AUC (AUC=0.79‐1.0) similar to (or better than) that of the well‐accepted CSF pTau/Aβ42 ratio. A model using 23 TREM2‐specific plasma proteins was able to discriminate between TREM2 carriers and controls (AUC=0.94) or sporadic AD cases (AUC=0.91) with high sensitivity and selectivity. Our pathway enrichment analysis validated pathways previously implicated in AD (such as APP, APOE, GSK3B, NOTCH3, PPP3R1 and PPP3CA) and identified novel pathways such as a Parkinson’s disease pathway (LRRK2 and α‐synuclein) and innate immune response pathways (MEK1, SHC1, and PDGF‐BB), including cytokine‐mediated signaling and a DAP12‐mediated pathway.ConclusionWith the first multi‐tissue proteomic study of genetically defined AD cases, we have uncovered multiple novel AD biomarker candidates. These findings not only help to elucidate specific pathways implicated in AD but ultimately support the clinical utility of predictive models based on proteomic signatures.
Impact of protocol design on between scale discrepancies in early AD clinical trials
Authors: Miller David S. , Kott Alan 
Published: December 2021

AbstractBackgroundWe previously presented the impact of protocol design on the MMSE changes observed in the screening period. Protocols requiring inclusion criteria be met at Screening alone had significantly more large MMSE changes between Screening and Baseline than did protocols where the criteria needed to be met at both Screening and Baseline. [Kott,2020]. In the current analysis we explore the impact of protocol design on the presence of between scale change discrepancies at Baseline and 6 months after randomization.MethodData were pulled from multi‐national clinical trials in early Alzheimer's Disease (AD) where MMSE and ADAS‐Cog and/or CDR were collected at Screening, Baseline and 6 months after baseline. Subjects were categorized into 2 groups depending on whether inclusion criteria were required at Screening alone or at Screening and Baseline. We defined discordance as occurring when at least 2 of the 3 instruments showed a clinically meaningful change from the prior visit but the changes were in opposite directions. Chi‐square test was used to compare the distribution of discordances between the protocols at Baseline and at month 6.ResultOur dataset consisted of 4,237 subjects with data available from Screening, Baseline and month 6. At Baseline, we saw significantly more instances of discordance from Screening in studies requiring criteria be met at Screening alone (5%) vs 2% when the requirement needed to be met at both Screen and Baseline (chi2 = 12.5, P < 0.001). At month 6, no difference between the protocol types was identified – (12.2% vs. 12.4%, chi2 = 0.01, p = 0.912).ConclusionOur analyses indicate a significant impact of protocol design on the presence of between scale change discrepancies. Protocols requiring criteria be met at Screening only had a significantly increased number of discordances at Baseline but this difference disappeared by month 6. Among the potential explanations for such between scale discordances, score manipulations to comply with inclusion criteria needs to be considered. These findings should be considered when designing protocol inclusion criteria. Further research is necessary to understand the impact of these discrepancies on drug‐placebo separation.
Prediction of amyloid‐positivity in individuals with subjective cognitive decline: Machine learning approaches to optimize number‐needed‐to‐screen
Authors: Sahin Derya , Brosseron Frederic , Buerger Katharina , Heneka Michael T. , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schneider Anja , Spottke Annika , Teipel Stefan J. , Wiltfang Jens , Wolfsgruber Steffen , Düzel Emrah , Wagner Michael , Jessen Frank , Kambeitz Joseph ,   DELCODE Study Group
Published: December 2021

AbstractBackgroundSubjective cognitive decline (SCD) is defined as the worsening of cognitive functions reported by the patient without any objective cognitive deficits nor any significant impairment of daily functioning. SCD constitutes a heterogeneous clinical condition regarding aetiology, clinical presentation and prognosis that can either progress to dementia, remain stable over time or remit [1, 2]. SCD‐individuals with pathological ß‐amyloid‐42(Aß‐42)‐levels in cerebrospinal fluid are in Alzheimer’s disease (AD) continuum, have an increased risk for conversion to dementia and are an important target for prevention studies in AD. However, the invasiveness of lumbar punctures and costs of positron emmission tomography (PET) limit assessment of amyloid positivity in SCD‐cohorts on large scale. Increasing the likelihood of amyloid positivity is an approach to lower the number needed to screen for amyloid in SCD for intervention trials.MethodsWe conducted a supervised machine learning (ML) analysis in 211 SCD‐individuals of the DELCODE study, of which 88 were amyloid positive [3]. Amyloid positivity (pathological ß‐amyloid‐1‐ 41/40‐ratio) in SCD‐individuals was predicted by different data modalities including clinical (n=42 features), neuropsychological (n=70 features) and neuroimaging (n=231 features) data. Repeated cross‐validation was implemented to tune ML hyperparameters and to obtain reliable model performance. Feature selection methods were employed to derive robust and parsimonious ML models that can be implemented with as little and easy‐to‐collect data as possible.ResultsThe preliminary analyses indicated that Aß‐42‐status could be predicted based on cognitive data with a balanced accuracy of 58% (specificity 65%, sensitivity 51%), based on clinical data with an accuracy of 67% (specificity 75%, sensitivity 59%) and based on neuroimaging data (FSL derived parameters of structural MRI) with an accuracy of 56% (specificity 62%, sensitivity 39%).ConclusionWe demonstrate the potential of ML algorithms to predict Aß‐42‐status in individuals with SCD based on non‐invasively measurable parameters. These results underline the potential of ML to conduct efficient biological risk‐stratification in SCD populations with potential applications in clinical intervention trials or biomarker studies.
Identification of the neuroprotective Shc target in Alzheimer's and validation of the neuroprotective benefit of a set of small‐molecule Shc blockers
Authors: Tomilov Alexey , Maezawa Izumi , Jin Lee‐Way , Garcia Chase , Montgomery Claire A , Cortopassi Gino A 
Published: December 2021

AbstractBackgroundIncreased Shc expression has recently been linked to human AD progression. The human Shc locus has recently been identified as extremely important in the conversion from Mild Cognitive Impairment (MCI) to full Alzheimer's Disease (AD) [1]. Shc is more highly expressed in Hippocampus of human AD cases vs. Controls [2], and A‐beta increases Shc activity and gene expression in cells, and Shc knockdown reduces A‐beta toxicity [3]. Mice with Shc reduction resist AD and age‐related cerebrovascular dysfunction. It has been demonstrated that there is a significant benefit to PSAPP mice when Shc is genetically reduced, they have improved memory and cognition relative to PSAPP mice, and survive longer. Furthermore this improvement is with the same amyloid burden–thus Shc underexpression appears to neuroprotect downstream of the toxic A‐beta signal[4]. Furthermore, Shc reduced mice resist age‐related cerebrovascular dysfunction [5]. Under MTA we have received small molecules from Buto Corp, to identify their relative efficacy in cell and animal models of disease.MethodWe tested the neuroprotective potency of Shc blockers challenged with A‐beta in 384‐well plates. We also tested the anti‐inflammatory potency of Shc blockers, by measuring post A‐beta or LPS challenge to human microglial cells the expression of multiple inflammatory genes, including IL‐6, IL‐10, and Nos. We also tested the impact of Shc Blockers on memory loss in the ApoE4 mouse model of ADResultWe observe significant protection of several Shc blockers from A‐beta neurotoxicity. We observe significant protection of multiple Shc blockers from A‐beta or LPS mediated microglial inflammation. We observe significant protection from memory loss in the ApoE4 mouse model of AD by a molecule observed to be neuroprotective in Results 1 and 2.ConclusionThe data above suggest that small‐molecule Shc blockers are a novel therapeutic strategy for AD.
Healthy lifestyle, brain pathology, and cognition in community‐dwelling older adults
Authors: Dhana Klodian , James Bryan D , Leurgans Sue E. , Rajan Kumar B , Aggarwal Neelum T , Barnes Lisa L , Bennett David A , Schneider Julie A 
Published: December 2021

AbstractBackgroundLifestyle interventions for primary prevention of Alzheimer’s dementia recruit people at advanced ages who are at high risk of cognitive decline in the timeline of the trial. Given that Alzheimer’s disease and other dementia‐causing pathologies may accumulate in the brain years or even decades before older adults begin to show cognitive deficits, it is important to determine the association of lifestyle factors, cognition, and the role of dementia‐related brain pathologies.MethodUtilizing data from the Rush Memory and Aging Project, a longitudinal clinical‐pathologic study, we studied 566 decedents with lifestyle, cognitive testing proximate to death, and complete autopsy data at the time of these analyses. A healthy lifestyle score included being a non‐smoker, ≥150 min/week moderate/vigorous‐intensity physical activity, light‐to‐moderate alcohol consumption, MIND diet score >7.5, and late‐life cognitive activity score >3.2. Brain pathology included measures of beta‐amyloid, neuronal neurofibrillary tangles, Lewy body disease, hippocampal sclerosis, TDP‐43, cerebral infarcts, cerebral amyloid angiopathy, and arteriolosclerosis and atherosclerotic disease. The global cognitive score was derived from a comprehensive battery of nineteen standardized tests.ResultA higher healthy lifestyle score was associated with better global cognitive functioning proximate to death (beta=0.149, SE=0.036, p<0.001) and slower annual cognitive decline (beta=0.014 units/year, SE=0.004, p<0.001). A higher healthy lifestyle score was associated with less beta‐amyloid accumulation (beta=‐0.087, SE=0.041, p=0.034), but not with tangles, other neurodegenerative pathology, or indices of vascular pathology. Pathway analysis using structural equation modeling examined whether beta‐amyloid mediated the relationships between healthy lifestyle score and global cognition. Lifestyle score had a significant positive direct effect (beta=0.130, SE=0.035, p<0.001) on global cognition. The indirect effect of lifestyle score on cognition through the pathway of beta‐amyloid load was also significant but had a relatively small effect size (beta=0.019, SE=0.009, p=0.045)ConclusionA healthy lifestyle was associated with better cognitive functioning even after accounting for dementia‐related brain pathologies, suggesting that lifestyle intervention may have cognitive benefits. Moreover, given that beta‐amyloid accumulates years to decades prior to the onset of cognitive decline, the indirect effect of lifestyle on cognition through beta‐amyloid may indicate that a healthy lifestyle could additionally provide primary prevention of Alzheimer’s disease and dementia.
Cerebrospinal fluid AΒ42, total tau, and phosphorylated tau in the evaluation of Alzheimer’s dementia: Experience from a commercial reference laboratory
Authors: Batish Sat Dev , Haji‐Sheikhi Farnoosh , Kare Amogh , Datta Vivekananda , Meservey Marc , Radcliff Jeff 
Published: December 2021

AbstractBackgroundAβ amyloid plaques and tau neurofibrillary tangles play an important role in Alzheimer’s disease (AD) pathophysiology, and the CSF biomarkers Aβ42, total tau (T‐tau), and phosphorylated tau181 (P‐tau) have been extensively used in diagnosing AD. Here we describe our experience with use of the Aβ42/T‐tau index (ATI) and P‐tau for classification of patients with suspected AD.MethodA convenience sample of results from CSF specimens submitted to a commercial reference laboratory for measurement of Aβ42, T‐tau, and P‐tau (presumably for diagnosis in patients with suspected AD) was selected for analysis. Each marker was measured using sandwich ELISA−based tests. The ATI was calculated as Aβ42/(240 + (1.18 × T‐tau)). AD classification was based a combination of ATI and P‐tau thresholds: not consistent with AD (not‐AD; P‐tau <54 pg/mL and ATI >1.2); borderline (P‐tau 54‐68 pg/mL and/or ATI 0.8‐1.2); AD (P‐tau >68 pg/mL or ATI <0.8); indeterminant—possible non‐AD dementia (NADD; ATI <0.8, P‐tau <54); and “other” (highly elevated ATI). Differences in age at testing among the classification groups were assessed using ANOVA with Tukey pairwise analysis.ResultResults from 42,030 specimens (49.1% women) were included. The most frequent classifications based on ATI and P‐tau values were AD (30.0%) and borderline (30.2%), followed by indeterminate‐NADD (21.7%), not‐AD (16.3%), and other (1.9%). Individuals with an AD classification were significantly older than those classified as not‐AD (mean [SD] age 66.8 [10.1] vs 62.5 [12.3] years; P<0.001), and a higher proportion were female (55.6% vs 42.8%). The ANOVA model indicated significant differences in age at testing among the classification groups (P<0.001). In post‐hoc pairwise comparisons, the not‐AD group was significantly younger than the AD group (Tukey multiple comparison test: difference= ‐4.3 years, Padj <0.001). This pattern was consistent in analyses stratified by sex (women: difference=‐4.8 years, Padj <0.001; men: difference= ‐4.4 years, Padj <0.001).ConclusionNearly 30% of specimens submitted for AD testing yielded results consistent with AD, underscoring the value of the ATI and P‐tau measurements in CSF in patients with suspected AD. The greater age among those classified with AD vs non‐AD likely reflects the higher pretest probability of AD in older individuals.
Does brain volume explain the difference in Alzheimer’s disease diagnosis risk between men and women? Results from analyses of four research cohorts
Authors: Stites Shana D. , Dedhia Mehek 
Published: December 2021

AbstractBackgroundWomen are more likely than men to be diagnosed Alzheimer’s disease (AD) despite recent biomarker studies demonstrating no significant difference in prevalence of AD pathology between men and women. Given that larger brain volume has been shown to be protective against progression of AD symptoms, we hypothesized that sex‐based differences in brain volume may modify the risk of AD dementia and thus explain the difference in AD diagnosis risk between males and females.MethodWe describe sex‐based differences in brain volume in a well‐characterized and socioculturally and clinically homogenous sample of older adults screening for a clinical trial. To test our hypotheses, we analyze cross‐sectional data from four distinct research cohorts: Rush Alzheimer’s Disease Research Center, Mayo Clinic Study of Aging, National Alzheimer’s Coordinating Center Uniform Data Set, Alzheimer’s Disease Neuroimaging Initiative. We use two‐stage general linear models with binomial family and log link to estimate risk of AD diagnosis attributable to self‐report sex and brain volume. In step two, an interaction‐term for sex and brain volume is entered to test how the main effect for self‐report sex changes. Multivariable models control for age and race.ResultsWe will characterize sex‐based differences in brain volume in older adults using visual summaries, descriptive statistics, and estimates of effect. This information will be compared to other published estimates of sex‐based differences in brain volume.We expect that both self‐report sex and brain volume will show independent associations with AD diagnosis risk. However, in interaction analyses, brain volume will remain statistically significant while self‐report sex no longer shows an independent association with AD diagnosis risk. We will report model estimates from these analyses.ConclusionThe study results will help elucidate brain volume’s role in contributing to sex‐based disparities in AD diagnosis. Results from analyses of four distinct data sources will lend strength to conclusions related to this novel hypothesis. They will also help advance knowledge about the character of sex‐based differences in cognitively typical older adults. Moreover, the results will help inform future research to elucidate AD mechanisms and discover drivers of sex‐based disparities in AD.
Does olfactory dysfunction have the same relationship with limbic system integrity in Alzheimer’s and Parkinson’s disease?
Authors: Pappadatos Zoe , Phillips Natalie 
Published: December 2021

AbstractBackgroundWe have demonstrated that olfactory dysfunction is common in Alzheimer’s disease (AD), and is associated with poorer episodic memory performance and medial temporal lobe (MTL) integrity in groups at risk for AD. Olfactory decline is also common in Parkinson’s disease (PD); however, the difference in pathology between these diseases remains poorly understood.MethodUsing data from the Comprehensive Assessment of Neurodegeneration in Aging (COMPASS‐ND) study, we compared older adults with subjective cognitive decline (SCD; N=55, Mage
=70.1, %female=78), mild cognitive impairment (MCI; N=100, Mage
=71.2, %female=45) and AD (N=47, Mage
=74.8, %female=31) with those at risk for (PD‐MCI; N=25, Mage
=71.4, %female=20) and with Parkinson’s disease (PD; N=34, Mage
=66.5, %female=44) on measures of olfaction (Brief Smell Identification Test), cognition (episodic, working and semantic memory), and structural MRI (volume and cortical thickness of the MTL and orbitofrontal cortex). All analyses controlled for age, sex, and education; MRI analyses also controlled for total intracranial volume.ResultOur analyses revealed that olfactory function was highest in SCD (M=10.33, SD=1.69), and declined in MCI (M=8.84, SD=2.98), and AD groups (M=6.06, SD=2.73) successively. The PD group (M=7.12, SD=2.78) did not differ from PD‐MCI group (M=5.28, SD=3.26), and was in line with the poor performance of the AD participants. These groups had poorer olfactory performance compared to the SCD and MCI groups.ConclusionOlfactory deficits are present in PD participants regardless of MCI. We will also report on whether olfactory function predicts MTL integrity in PD, as it does in individuals at risk for AD.
Implications of bilingualism for neuropsychological evaluation: Insights from a multicentric study from India
Authors: Arshad Faheem , Alladi Suvarna , Paplikar Avanthi , Sharma Meenakshi , Varghese Feba Anna ,   Indian Council of Medical Research Neurocognitive Toolbox Consortium
Published: December 2021

AbstractBackgroundIn the background of linguistic diversity and a large population of bilinguals in India, it is essential to develop standards of neuropsychological testing in the context of bilingualism. Since bilingualism is known to impact specific cognitive processes, there is also the possibility of the need for separate normative data for bilinguals and monolinguals. Towards addressing these gaps, in this large multicentric study from India, bilinguals and monolinguals were evaluated on a comprehensive neuropsychological test battery: the Indian Council of Medical Research‐Neuro Cognitive Tool Box (ICMR‐NCTB).MethodThe ICMR‐NCTB that was standardized across five Indian languages was administered to 530 participants: 267 monolingual and 263 bilinguals A systematic method of testing cognition in bilinguals was developed, to identify the appropriate language for testing, ensure language proficiency of examiner, and to interpret the bilingual responses. Additionally, the performance of bilinguals on the ICMR‐NCTB was compared with monolinguals matched for age, education, and gender.ResultLinguistic proficiency of both participants and examiners were determined using validated measures. Cognitive testing in the bilingual context was performed in the most proficient language of the participants, by examiners well versed with the language. Results from the language‐based tests suggested language interference i.e. a frequent occurrence of borrowed‐ and language‐mixed words in responses thereby requiring consideration while scoring. The reported bilingual effect on cognitive processes did not reflect as differences in the performance between bilinguals and monolinguals on any of the standard cognitive tests of attention, executive function, language and visuospatial functions.ConclusionObservations from the study provide robust recommendations for neuropsychological testing in the context of bilingualism. These recommendations are consistent with the practice of bilingualism in the Indian context and are more ecologically valid. Results also indicate that separate normative data may not be required for bilinguals and monolinguals, in the Indian context. The study will provide a reference framework for comparison to address similar issues in other bilingual societies.