bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognability: An ecological model of cognitive function and neighborhood design
Authors: Finlay Jessica M , Esposito Michael , Clarke Philippa
Published: December 2021

Background

Neighborhood environments are linked to multiple established risk factors for cognitive decline and dementia including physical inactivity, depression, obesity, hypertension, and diabetes. As an upstream influence on modifiable risk factors, neighborhood environments may help delay or prevent the onset of cognitive impairment. They may promote physical activity, social engagement, intellectual stimulation, and healthy eating; reduce exposure to air pollution; and limit stress levels related to environmental factors such as traffic and noise. Ecological theoretical models of cognitive health are needed to systematically investigate the environments in which people develop and navigate cognitive decline. This paper builds evidence for a new concept of ‘cognability’: an innovative theoretical approach to indicate how supportive a neighborhood is to cognitive health through community resources and neighborhood amenities that support socially, physically, and intellectually active aging in place.

Method

We conducted analyses in the Reasons for Geographic and Racial Differences in Stroke study, a national sample of aging Black and white Americans (n=21,151, mean age at assessment 67 years). We used a confirmatory factor analysis of five cognitive tests measuring verbal learning, memory, and executive function (Root Mean Square Error of Approximation=0.013; Comparative Fit Index=0.999), and output standardized scores for each participant. Contextual measures were created for urban‐dwelling participants using a kernel density method to capture proximity and availability of neighborhood amenities. Multilevel generalized additive models estimated associations between global cognitive function and access to neighborhood places for physical activity, socialization, and intellectual stimulation.

Result

Analyses identified statistically significant positive associations between cognitive function and access to civic and social organizations (p‐value=<0.001), senior centers (p‐value=0.004), coffee shops and fast‐food restaurants (p‐value=<0.001), parks (p‐value=<0.001), recreation amenities (p‐value=0.023), walkable destinations (p‐value=<0.001), and arts/cultural sites (p‐value=<0.001).

Conclusion

Living in neighborhoods with more opportunities for social interaction, physical activity, and intellectual stimulation may support cognitive function among older adults aging in place. Promoting ‘cognability’ via neighborhood intervention and urban planning may complement and enhance biomedical and individual lifestyle approaches.
Protective effects of eicosapentaenoic acid on metabolic features and cognitive function in the APPswePS1dE9 Alzheimer’s mouse model
Authors: Yavari Mahsa , Ramalingam Latha , Harris Breanna N , Kahathuduwa Chanaka , Chavira Angela , Biltz Caroline , Mounce Philip , Alers Kaylee Alers , Davis Mckenna , Zu Yujiao , Moustaid‐Moussa Naima
Published: December 2021

Background

Alzheimer’s disease (AD) is characterized by amyloid‐beta (Aβ) plaque deposition and may be exacerbated by aging‐induced neuroinflammation and obesity. We hypothesized that compared to high fat (HF) diets, FO with anti‐inflammatory and anti‐obesity properties, would reduce metabolic and cognitive dysfunctions in an AD amyloidogenic mouse model of obesity.

Method

Two‐month‐old, both sexes, APPswePS1E9 transgenic (TG) and non‐TG littermates were randomly assigned and fed low fat (LF), HF, or HF supplemented with FO for eight months (n=8‐10/group). Body weight and food intake were recorded weekly, and body composition was measured bi‐monthly. Glucose Tolerance Test (GTT) and Morris water maze (MWM) were measures at 5‐ and 9‐ months, respectively. At termination, blood and tissues were collected. Serum Aβ‐40 levels were measured by immune‐multiplexing. Missing data were imputed via multiple imputations. Outcomes were analyzed in three‐way ANOVA, modeling genotype interactions, sex and diet, and subsequent Tukey‐corrected pair‐wise comparisons using R (version 4.0.2).

Result

On average, fat mass (FM) of non‐TG mice did not differ from TG mice. However, TG mice ate more (p < 0.001), trended towards lower glucose clearance (p = 0.066) and had higher Aβ‐40 (p < 0.05) vs. non‐TG mice. On average, male were fatter (p < 0.001) and more glucose intolerant compared to female mice (p < 0.001), yet there were no sex differences for Aβ‐40 (p = 0.8718). On average, LF diet decreased final FM and improved GTT vs. HF and FO diets (p < 0.001); however, adiposity and GTT were not different between FO and HF fed mice. Interestingly, compared to HF, FO decreased serum Aβ‐40 in TG male mice (p = 0.0182), but not among TG female or non‐TG mice. This unique between‐group difference was not apparent for FM or GTT. In MWM test, HF non‐TG mice found the platform faster than TG mice (p = 0.037).

Conclusion

Overall, LF diets conferred metabolic improvements over HF diets, while long term supplementation of FO to HF diets had limited metabolic and cognitive benefits. Interestingly, FO reduction of serum Aβ‐40 in AD mice merits further investigation.
Correlations between neuropsychological performance and functional measures: Preliminary findings from the novel cognitive and functional measure for Alzheimer’s Disease prevention trials (NoMAD)
Authors: Bell Sophie A. , Kim Hyun , Cohen Hannah R. , Lee Seonjoo , Rivera Andres M. , Brickman Adam M. , Harvey Philip D. , Schneider Lon S. , Gordon Marc L. , Goldberg Terry E.
Published: December 2021

Background

Two novel measures of cognition and function, the No Practice Effects (NPE) cognitive battery and the Miami Computerized Functional Assessment Scale (CFAS), were designed to have robust psychometric properties and reduced practice and ceiling effects for use in preclinical and early‐stage Alzheimer’s disease clinical trials. In this preliminary analysis, we sought to identify different cognitive domains in the NPE and evaluate their relationships with the CFAS functional measures.

Method

Fifty‐one cognitively healthy older adults (mean age 69.44 ± 6.29, 65.30% female) with baseline cognitive and functional assessments were included. We conducted an exploratory factor analysis to identify different cognitive domains within the NPE. We then computed a composite score for each domain and conducted partial Spearman correlations with CFAS functional measures, controlling for age, education and gender, and intracranial volume.

Result

The factor analysis yielded three factors corresponding to 1) episodic memory, 2) non‐verbal executive processes and speed, and 3) verbal working memory (loadings > 0.5). Composite scores from these factors exhibited strong correlations with CFAS functional measures. In particular, a greater executive functioning and speed composite score was significantly associated with a faster completion time (rs’s ≥‐.44) and more efficient performance (rs’s ≥.37) on most CFAS functional measures (p’s<.05).

Conclusion

Multi‐domain factors were identified in our novel cognitive measures. These cognitive domains strongly correlated with everyday functioning measures. Our results suggest that cognitive measures, particularly processing speed and executive function measures, obtained in clinic may be related to everyday function in older adults.
A study of MCI drivers' perception and acceptability of safety support
Authors: Suzuki Mio
Published: December 2021

Background

In Japan, around 30% of the older adults have dementia or MCI, and many of them drive daily. They have encouraged to surrender their driving licenses, but that have not been effective. It's said that older adult drivers are not aware of the dangers of driving, and they're not willing to switch to safety support vehicles. Hence in this study, I examined the relationship between MCI drivers’ driving behavior and their awareness or acceptability of safety support.

Method

In this study, the 196 subjects including MCI or dementia drove in a driving school to induce dangerous driving. When their behavior was dangerous, the following safety support was provided, and the changes in driving behavior and awareness were recorded: 1) The instructor sitting in the passenger seat gave advice at that moment, 2) The instructor gave advice after the experiment, 3) A alert was sounded, 4) Their driving were evaluated by scoring. After a few months, it was checked whether the subjects remembered the behavior and advice. The driving behavior on public roads was also recorded, and the awareness was investigated when the advice given later.

Result

It was found that MCI drivers behaved dangerously when the driving load was increased by multitasking, whether in a driving school or on public roads. However, since they underestimated their own dangerous driving and did not recognize it as dangerous, the post‐experimental advice was found to be ineffective. On the other hand, it was also revealed that giving advice or sounding a warning sound at the moment of dangerous driving increased the mental load of MCI subjects and might have negative effects on their subsequent driving. In the case of MCI drivers, the advice induced risky driving because they became too attached to the advice and neglected other driving skills.

Conclusion

Although immediate and specific driving advice or warnings are generally considered effective, they have been found to have a negative effect on MCI drivers. On the other hand, it is necessary to develop safe driving support measures that are immediate but do not give too much information, because drivers forget about dangerous driving over time.
Blood markers of neuronal/axonal and glial injury for clinical progression in a predominately Hispanic cohort: The Texas Alzheimer’s Research and Care Consortium
Authors: Gonzales Mitzi M. , Wang Chen‐Pin , Short Meghan I. , MacCarthy Daniel , Kautz Tiffany , Satizabal Claudia L. , Zare Habil , O'Bryant Sid , Seshadri Sudha
Published: December 2021

Background

The clinical translation of biofluid markers for Alzheimer’s disease and related dementias (ADRDs) requires validation in diverse cohorts. The goal of the study was to evaluate if blood biomarkers of neuronal/axonal and glial injury predict cognitive decline and clinical disease progression in a predominately Hispanic cohort from the Texas Alzheimer’s Research and Care Consortium.

Method

Participants included 745 Hispanic and 274 non‐Hispanic white participants, aged 55‐89 years, who annually completed cognitive assessments, the Clinical Dementia Rating scale (CDR), and dementia consensus reviews. Serum from the baseline examination was assayed to quantify levels of total tau (t‐tau), neurofilament light (NFL), ubiquitin carboxyl‐terminal hydrolase LI (UCHLI), and glial fibrillary acidic protein (GFAP) using the Simoa Neurology 4‐Plex Kit (Quanterix), as well as soluble CD14 (sCD14) and chitinase‐3‐like protein 1 (YKL‐40) using commercial ELISAs (R&D Systems). Generalized estimating equations were used to evaluate the associations between serum biomarkers and longitudinal cognitive outcomes, as well as disease progression (CDR Sum of Boxes), adjusting for covariates of age, sex, ethnicity, education, body mass index, systolic blood pressure, diabetes, APOE ε4 status, and clinical diagnosis. Cox proportional hazard models were used to evaluate the associations between serum biomarkers and incident mild cognitive impairment (MCI) and dementia with adjustment for the covariates listed above.

Result

Across the average four‐year follow‐up period, 162 individuals developed MCI and 96 developed dementia (Table 1). As displayed in Table 2, serum GFAP levels predicted cognitive decline across most cognitive domains. Serum t‐tau levels were associated with declines in global cognition, learning, and memory. Serum GFAP (b=0.154, SE=0.028, p<0.001), NFL (b=0.069, SE=0.026, p=0.007), and t‐tau (b=0.065, SE=0.023, p=0.004) predicted clinical progression. Higher GFAP levels at baseline were associated with increased risk of incident dementia (HR=1.485, p=0.009). None of the biomarkers predicted incident MCI.

Conclusion

Serum GFAP levels were associated with multi‐domain cognitive decline, clinical progression, and incident dementia risk. The results suggest that reactive astrogliosis may be an important mechanism underlying a progressive neurodegenerative disease course in our predominately Hispanic sample. With further validation, serum GFAP may hold utility for predicting disease progression and monitoring the efficacy of newly emerging treatments.
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

Background

Alzheimer 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.

Method

We 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.

Result

We 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.

Conclusion

With 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

Background

We 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.

Method

Data 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.

Result

Our 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).

Conclusion

Our 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

Background

Subjective 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.

Methods

We 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.

Results

The 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%).

Conclusion

We 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

Background

Increased 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.

Method

We 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 AD

Result

We 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.

Conclusion

The 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

Background

Lifestyle 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.

Method

Utilizing 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.

Result

A 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)

Conclusion

A 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

Background

Aβ 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.

Method

A 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.

Result

Results 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).

Conclusion

Nearly 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

Background

Women 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.

Method

We 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.

Results

We 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.

Conclusion

The 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

Background

We 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.

Method

Using 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.

Result

Our 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.

Conclusion

Olfactory 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

Background

In 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).

Method

The 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.

Result

Linguistic 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.

Conclusion

Observations 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.
A Phase 2a study evaluating the safety, tolerability, pharmacokinetics, and central nervous system activity of CY6463 when administered to participants with Alzheimer’s disease with vascular pathology
Authors: Glasser Chad , Chickering Jennifer , Wilson Phebe , Florine Emily , Winrow Chris , Wright Chris
Published: December 2021

Background

The soluble guanylate cyclase (sGC) stimulator, CY6463, is being developed as a symptomatic and potentially disease‐modifying therapy for serious central nervous system (CNS) diseases, including Alzheimer’s disease (AD). Nitric oxide (NO)‐sGC‐cyclic guanosine monophosphate (cGMP) is a fundamental neurotransmitter system critical to neuronal function. Impaired signaling of this pathway is known to play a role in the pathogenesis of many neurodegenerative diseases. CY6463, a positive allosteric modulator of sGC, amplifies endogenous NO signaling to increase cGMP production. In preclinical models, CY6463 improved neuronal function, cerebral blood flow, neuroinflammation, and cellular bioenergetics.

CY6463 has been evaluated in two Phase 1 studies (110 healthy younger adult volunteers and 24 healthy elderly volunteers >65 years of age) assessing the safety, tolerability, pharmacokinetics (PK), and CNS activity of CY6463. Once‐daily CY6463 administration was well tolerated across dose levels, led to target CNS concentrations, achieved predictable/linear food‐independent PK, and had positive impacts on saccadic eye movements as well as brain neurophysiology as measured by electroencephalography (EEG).

Method

This 12‐week, randomized, placebo‐controlled study will evaluate safety, tolerability, PK, and CNS activity of CY6463 in approximately 40 patients with a combination of AD pathology, sub‐cortical vascular disease, and cardiovascular risk factors. This defined subset of the larger AD population, referred to as AD with vascular pathology (ADv), is hypothesized to be more likely to respond to CY6463 treatment due to CY6463’s expected impact on vascular and CNS biology. This study is funded in part by a Translational Research Award from the Alzheimer’s Association Part the Cloud‐Gates Partnership Grant Program.

Result

The primary objective, safety and tolerability, will be evaluated based on adverse event reporting. Exploratory evaluations assessed variously at baseline and weeks 2, 4, 8, and 12, will include plasma and CSF biomarkers of disease; PK; quantitative EEG and event related potentials as biomarkers of neurophysiology; functional magnetic resonance imaging measures of cerebral perfusion and brain connectivity; and cognitive performance tests of attention, executive function, and memory.

Conclusion

Results from this study in patients with ADv will inform the design of larger, longer studies evaluating the potential for CY6463 to improve cognition in this patient population.
Self‐rated daily language use, more than self‐rated bilingual language competency, moderates the effects of brain on cognition in a Hispanic cohort
Authors: Elliott Meghan R , Rentería Miguel Arce , Mungas Dan M. , Whitmer Rachel A. , DeCarli Charles S. , Fletcher Evan M
Published: December 2021

Background

Some studies suggest that bilingualism may be associated with better cognition but the impact of bilingualism versus language practice on cognition and brain integrity is not well understood. Here, bilingualism encodes the knowledge of one language or two while language use encodes daily language practice (predominantly English or Spanish, or daily use of both). In a Hispanic cohort, we the assess effects of language variables on cognitive outcomes of baseline and longitudinal executive function and episodic memory, incorporating brain measures, age, gender, and education, and also whether they moderate the relationships between cognition and the MRI markers of brain integrity.

Method

A baseline Hispanic cohort (N = 100) with a single MRI scan and a longitudinal subset (N = 73) with serial scans were sampled from the UC Davis Aging and Diversity cohort (Table 1). Linguistic measures were based on self‐reports. They were bilingualism, and among bilingual participants, daily language use. Baseline and longitudinal executive and memory were modeled by regressions incorporating age, education level, brain signature regions, and language variable ‐ first for bilingualism in the entire cohort and then for language use restricted to the bilinguals.

Result

Bilingualism was not a significant predictor of baseline outcomes and there were no moderations with brain variables (Table 2). Among bilinguals, English‐only speakers showed significantly increased association of gray matter (Table 3) to memory compared to those who daily spoke Spanish or both languages. Longitudinally, bilingualism had no direct or moderating effects on cognitive change (Table 4). Bilinguals speaking primarily English had significantly increased association of atrophy signatures with both cognitive changes compared to Spanish or speakers of both languages (Table 5).

Conclusion

Results suggest a complex pattern of moderation of brain atrophy effects on cognitive decline in self‐reported bilinguals depending on whether daily language use is predominantly English, Spanish, or both. Bilinguals who spoke predominantly English were more susceptible to brain atrophy effects in comparison with those who used both languages or predominantly Spanish. These results have important implications for understanding how bilingualism relates to cognitive reserve but require replication in larger and different samples.
The neutral sphingomyelinase 2 inhibitor PDDC reduces tau burden in Alzheimer’s disease mice
Authors: Tallon Carolyn , Bell Benjamin J , Malvankar Medhinee , Hollinger Kristen R , Thomas Ajit G , Yoo Seung Wan , Chaudhuri Amrita Datta , Wu Ying , Rais Rana , Haughey Norman J , Slusher Barbara S
Published: December 2021

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by worsening cognitive impairment with amyloid and tau deposition spreading throughout the brain in a “prion‐like” manner. Mounting evidence suggests extracellular vesicles (EVs) can act as vectors to propagate these pathogenic proteins along connectivity pathways. Several studies have demonstrated that inhibiting neutral sphingomyelinase 2 (nSMase2) reduces the level of tau and amyloid in the brain. Despite these promising findings, current nSMase2 inhibitors are not suitable for clinical development given their lack of potency, solubility, and/or limited brain penetration. We recently discovered phenyl (R)‐(1‐(3‐(3,4‐dimethoxyphenyl)‐2,6‐dimethylimidazo[1,2‐b] pyridazin‐8‐yl) pyrrolidin‐3‐yl) carbamate (PDDC), the first selective, potent nSMase2 inhibitor (IC50 = 300nM), with excellent oral bioavailability (%F = 88) and brain penetration (AUCbrain/AUCplasma = 0.60). We demonstrated that PDDC was able to inhibit EV release both in vitro and in vivo.

Method

To facilitate chronic oral efficacy studies, PDDC was incorporated into mouse chow which provided consistent brain exposure levels above its nSMase IC50 over a 24h time period. 4‐month old PS19 mice were fed either vehicle or PDDC chow for 5 months and their brains were collected for nSMase2 activity and tau protein level assessments.

Result

Vehicle treated PS19 mice had elevated nSMase2 activity levels compared to WT controls, which was completely normalized by PDDC treatment. Total tau and Thr181 phosphorylated tau were elevated in PS19 mice and significantly reduced in PDDC treated animals. Decreases in Thr217 and Ser202/Thr205 phosphorylated tau were also observed in PDDC‐treated mice, but the effect did not reach statistical significance. We are currently expanding these studies to evaluate PDDC in a rapid tau propagation model where AAV‐P301LhTau vectors are being unilaterally injected into the brains of WT mice and the propagation of phosphorylated tau to the contralateral side is bring quantified.

Conclusion

PDDC reduces the levels of total and pTau Thr181 in AD mice supporting its potential use as a novel therapeutic for the treatment of AD.
Efficacy of non‐invasive brain stimulation on global cognition in Alzheimer’s disease and mild cognitive impairment: A meta‐analysis
Authors: Bawa Kritleen Kaur , Teselink Johannes , Koo Grace KY , Sankhe Krushnaa , Liu Celina , Swardfager Walter , Herrmann Nathan , Lanctôt Krista L.
Published: December 2021

Background

Non‐invasive brain stimulation (NIBS) is a non‐pharmacological intervention that has shown some promise in improving cognition in people with Alzheimer’s disease (AD), but clinical trials involving NIBS have shown inconsistent results. This meta‐analysis investigated the efficacy of NIBS, particularly repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) compared to sham stimulation on global cognition in people with AD and its prodromal stage, mild cognitive impairment (MCI).

Method

Multi‐session randomized sham‐controlled clinical trials were identified though Medline, PsycInfo, and Embase until November 2020. Standardized mean differences (SMD) and 95% confidence intervals (CI) between the two groups were calculated using random‐effects meta‐analyses. Outcome measures for global cognition included scores on the Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS‐cog). Heterogeneity, from different NIBS techniques, disease populations, or tests used to assess global cognition, was measured using chi‐square and I2, and investigated using subgroup analyses.

Result

A total of 17 studies (Nactive=233, Nsham=218) were included. NIBS (rTMS [11 studies] + tDCS [6 studies]) significantly improved global cognition in patients with AD and MCI (SMD=1.11; 95% CI=0.42,1.80; p=0.002). Subgroup analyses showed that rTMS (SMD=1.08; CI=0.32,1.84; p=0.005) but not tDCS improved global cognition. Patients with AD [13 studies] (SMD=1.02; 95% CI=0.28,1.76; p=0.007) but not MCI [4 studies] showed significant improvement on global cognition following NIBS as compared to the sham group. Additionally, significant improvement on both the MMSE (SMD=0.67; 95% CI=0.13,1.22, p=0.016) and ADAS‐cog (SMD=1.34; 95% CI=0.30, 2.39; p=0.012) scores were seen in patients with AD following rTMS, when analyzed separately. There was substantial heterogeneity across all analyses (all I2 > 50%) that was not resolved by subgroup analyses. Egger’s test showed no evidence of a publication bias.

Conclusion

NIBS, particularly rTMS, improved global cognition in those with AD. Further studies with bigger sample sizes in MCI and those using tDCS will help to fully evaluate the specific NIBS techniques and population most likely to benefit on global cognitive measures.