bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of clinical symptoms and diagnosis: The electronic Person‐Specific Outcome Measure (ePSOM) development programme
Authors: Saunders Stina , Muñiz‐Terrera Graciela , Sheehan Shane , Luz Saturnino , Ritchie Craig W.
Published: December 2021

Background

Regulatory bodies recommend that outcome measures used in Alzheimer’s disease (AD) clinical trials capture clinically meaningful changes for the trial participant. However, commonly used cognitive outcomes are limited in this regard. The aim of the electronic Person‐Specific Outcome Measure (ePSOM) programme is to better understand what outcomes matter to patients in early Alzheimer’s disease.

Method

As part of the ePSOM programme, we designed and ran an online study to understand what matters to individuals when developing new treatments for AD. The ePSOM survey ran Aug 2019 – Dec 2019 (UK) and collected primarily free text responses which were analysed using Natural Language Processing (NLP) techniques. Here, we focus on the responses from individuals diagnosed with Mild Cognitive Impairment (MCI); Alzheimer’s dementia or Other dementias. We compared each of these groups to the ‘no‐diagnosis’ group by undertaking chi‐squared tests for key demographic variables. Differences between the target and no‐diagnosis groups were looked for.

Result

The survey was completed by 5808 respondents, of whom 167 (2.9%) (women n=91, men n=69, other n=7) had received one of our three target diagnoses: [1] MCI n=61, 1.1% (mean age 69.42, SD=10.8); [2] Alzheimer’s Dementia n=57, 1.0% (mean age 71.24, SD=9.79; and [3] Other dementia n=49, 0.8% (mean age 69.67, SD=9.00). Respondents in the Alzheimer’s and Other dementia group were more likely to have lower educational level, whereas this effect was not found in the MCI group. Several thematic clusters were significantly more important for the target diagnostic groups in comparison with respondents who did not have a target diagnosis, e.g.,: “Expressing opinions” for the MCI group; “Playing Golf” for the Alzheimer’s dementia group; and “Maintaining Personal traits and social skills” for the Other dementia group.

Conclusion

The results of the ePSOM survey focusing on the individual’s views with a MCI or Dementia diagnosis provide evidence for what these groups consider important when developing treatments for AD. The numerous clusters which were significantly more likely to be important for those with a particular diagnosis indicate that priorities shift along the preclinical, prodromal and overt dementia continuum. This has important implications for the development of outcome measures.
Relationship between cortical neural synchronization at alpha resting‐state electroencephalographic rhythms and education attainment in normal elderly subjects and patients with amnestic mild cognitive impairment due to Alzheimer’s disease
Authors: Noce Giuseppe , Babiloni Claudio , Ferri Raffaele , Lizio Roberta , Lopez Susanna , Lorenzo Ivan , Tucci Federico , Soricelli Andrea , Nobili Flavio Mariano , Arnaldi Dario , Famà Francesco , Giubilei Franco , Marizzoni Moira , Güntekin Bahar , Yener Gorsev , Stocchi Fabrizio , Frisoni Giovanni , Percio Claudio Del
Published: December 2021

Background

In normal old (Nold) and Alzheimer’s disease (AD) persons, a high cognitive reserve makes them more resistant and resilient to brain neuropathology and neurodegeneration. Here we tested whether these effects may affect neurophysiological oscillatory mechanisms generating dominant resting state electroencephalographic (rsEEG) alpha rhythms in Nold and patients with mild cognitive impairment (MCI) due to AD (ADMCI).

Method

Data in 60 Nold and 70 ADMCI participants, stratified in higher (Edu+) and lower (Edu‐) educational attainment subgroups, were available in an Italian‐Turkish archive. The subgroups were matched for age, gender, and education. RsEEG cortical sources were estimated by eLORETA freeware.

Result

As compared to the Nold‐Edu‐ subgroup, the Nold‐Edu+ subgroup showed greater alpha source activations topographically widespread. On the contrary, in relation to the ADMCI‐Edu‐ subgroup, the ADMCI‐Edu+ subgroup displayed lower alpha source activations topographically widespread (Figure 1). Furthermore, the two ADMCI subgroups had matched cerebrospinal AD diagnostic biomarkers, brain gray‐white matter measures, and neuropsychological scores.

Conclusion

The current findings suggest that a high cognitive reserve may be related to changes in rsEEG alpha rhythms in Nold and ADMCI persons. These changes may underlie neuroprotective effects in Nold seniors and subtend functional compensatory mechanisms unrelated to brain structure alterations in ADMCI patients.
Reliability and participant acceptance of remotely administered RBANS in an MCI and Alzheimer’s disease cohort
Authors: Hunter Matthew B , Saunders Stina , Russ Tom C , Ritchie Craig W. , Muñiz‐Terrera Graciela
Published: December 2021

Background

In light of the COVID‐19 pandemic, it is increasingly likely that researchers will adopt home‐based remote administration of cognitive tests for the continuation of clinical studies. Yet, there are limited data on the reliability of remotely administered cognitive assessments compared to in‐person. Specifically, cross‐modal reliability of the RBANS has not been assessed under naturalistic home conditions in older persons with MCI and Alzheimer’s Dementia (MCI/AD). As this population has difficulties with communication and technology, an evaluation of participant acceptability of remote administration is warranted to gauge future engagement. The aim of this study was to provide cross‐modal test‐retest reliability estimates for the RBANS in a cohort of people with MCI/AD, obtain participant attitudes toward remote assessment, and explore the relationship between attitudes and test scores.

Method

MCI/AD participants were recruited from NHS Scotland clinical services onto an ongoing community‐based longitudinal cohort study. Participants received multiple at‐home RBANS assessments, followed by an at‐home remote assessment ‐ due to local changes in travel restrictions following the COVID‐19 pandemic. Remote administration was conducted via telephone or videoconference, depending on participant preference. Following adjustment for multiple in‐person data points, intraclass correlations, means, and variance tests were selected to statistically analyse cross modal reliability. A locally developed 13 item Likert scale acceptability questionnaire was administered to assess call quality, and participant attitudes toward remote assessment.

Result

At time of submission, N=46 MCI/AD participants completed both in‐person and remote (N=29 videoconference, N=17 telephone) RBANS assessments. Data collection is ongoing and up‐to‐date findings would be presented at the AAIC. Test‐retest reliability data will be presented at the item and index level for telephone and videoconference administrations, providing a comprehensive reliability analysis. Questionnaire data will be presented quantitatively and will portray attitudes toward remote assessment in comparison to in‐person assessment, controlling for call quality and test performance.

Conclusion

This study will provide ecologically valid RBANS reliability data in an MCI/AD population. The results of the acceptability questionnaire will provide evidence for individuals’ willingness to engage in future remote assessment.
Regression based machine learning model for dementia diagnosis in a community setting
Authors: Salem Fatima Abu , Chaaya Monique , Ghannam Hiyam , Al Feel Roaa E , El Asmar Khalil
Published: December 2021

Background

As the world’s population ages, the prevalence of cognitive decline, dementia and Alzheimer’s disease is on the increasing trend. From a public health perspective and the absence of a cure, the early identification of individuals at risk of dementia becomes of paramount importance for proper early prevention. We developed a ML application for dementia diagnosis that is based on the 10/66 one stage dementia diagnostic algorithm.

Method

Training and testing data belonged to three community based surveys conducted in Lebanon as part of a larger dementia cohort study. Our training sample was 802, our testing sample 200, with the dataset showing imbalance (20% positive, 80% negative). In our supervised approach, we explore techniques for imbalanced learning beginning with artificially oversampling the minority class and undersampling the majority class, in order to decrease the bias of any model to be trained on the dataset. Additionally, we incorporate cost‐sensitive techniques to over‐penalise the models when misclassifying an instance in the minority class. We explore both models that produce a probability that a person has dementia, as well as models that produce a crisp class label (dementia or not).

Result

The best model hyperparameters including the cost to be incorporated and the percentage of oversampling/undersampling are tuned via three times repeated, 10‐fold stratified cross validation. The balanced random forest was considered as our most robust probabilistic model ‐ using only 20 features/variables‐ with a F2 score=0.82 and G‐Mean= 0.88 and ROC AUC=0.88. The Calibrated Weighted SVM for the same number of features was our best classification model with F2‐score=0.74 and a ROC AUC=0.80

Conclusion

Compared to the regular 10/66 one stage dementia diagnostic algorithm, our proposed models show very promising results and high level of accuracy by using only a 20 variables predictive model. With additional data, such models can gain in accuracy, precision and efficiency. Machine learning based models would serve as a valuable community dementia screening and diagnostic tools.
Does targeted medication therapy management increase cognitive reserve? Results from the INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimer’s Symptomatic Expression (INCREASE) study
Authors: Moga Daniela C , Abner Erin L , Schmitt Frederick A , Eckmann Lynne , Huffmyer Mark , Martinez Ashley I , Beech Brooke F , George Rosmy , Khouli Riham H El , Ali Doaa , Jicha Gregory A
Published: December 2021

Background

The INCREASE study is based on the hypothesis that targeted reductions in inappropriate medication use will bolster cognitive reserve (CR) in individuals at risk for Alzheimer’s Disease (AD), delaying the onset of clinical symptoms, and reducing the prevalence and duration of symptomatic disease.

Method

We conducted a 12‐month, randomized controlled trial to: (1) evaluate the impact of a medication therapy management (MTM) intervention in reducing unnecessary and inappropriate medication use in community‐dwelling, non‐demented older adults, (2) determine the impact of preclinical amyloid burden on CR deficits and decline to evaluate efficacy of delaying symptomatic disease progression in preclinical AD (pAD). Primary outcome measures included pre‐ to post‐intervention measures of: (1) medication use ( Medication Appropriateness Index, MAI); 2) CR Change Score (CRCS) defined as the difference in the scopolamine‐challenged vs unchallenged neurocognitive scores (Trail Making Tests A and B; California Verbal Learning Test, CVLT) . For the second aim, we used baseline determination of total brain relative standardized uptake values for amyloid β‐ positron emission tomography to examine the relative impact of pAD pathology on CRCS at baseline and over time in the placebo group, as well as the interplay of pAD pathology with inappropriate medication use at baseline and optimization of medication use after one year.

Result

We randomized 90 community‐dwelling participants (N=104 screened for eligibility). Mean (SD) age at enrollment was 73.9 (6.0), with N=57 (63%) female, and N=10 (10%) non‐white participants. At baseline, participants reported using a mean (SD) of 12.72 (4.87) medications, with 2.37 (1.29) potentially inappropriate (Beers 2015 criteria). In preliminary analyses, participants with pAD (N=29) had lower baseline CR for tests of executive function (mean (SD) change score ‐0.17 (1.37) and ‐0.13 (1.10) [p=0.90] for pAD and non‐pAD respectively) and total learning (‐0.85 (0.84) and ‐0.29 (0.83) [p=0.01]). At the time of abstract submission, we anticipate that data collection will be finalized by March 31, 2021 and we are planning to present main study results during AAIC 2021.

Conclusion

The results of the INCREASE study will provide insights on the impact of optimizing medication use to bolster CR, as well as the interaction with preclinical amyloid burden.
Brain health actions: Evidence from the electronic Person‐Specific Outcome Measure (ePSOM) development programme
Authors: Ritchie Craig W. , Saunders Stina , Sheehan Shane , Luz Saturnino , Muñiz‐Terrera Graciela
Published: December 2021

Background

As Alzheimer’s disease (AD) clinical trials move to an earlier phase in the neurodegenerative disease process, any outcome measures used to assess an intervention’s efficacy would need to be appropriate for the earlier pre‐clinical or prodromal study population. Evidence suggests that 40% of dementia cases could be prevented by targeting modifiable risk factors. Our study explores attitudes towards looking after one’s brain health and by proxy, actions individuals take to prevent dementia.

Method

As part of the electronic Person Specific Outcome Measure (ePSOM) online study focusing on what outcomes matter to individuals, we collected data on specific actions individuals take to maintain their brain health. The question on brain health offered pre‐defined answers as well as an option for free text answers. Here, we report both the results from the pre‐defined answers as well as the analysis of the large free text answers data set. We used Natural Language Processing (NLP) techniques based on pretrained GloVe vectors to cluster the free text responses. The survey received ethical approval and ran August – November 2019 (UK).

Result

5808 people completed the ePSOM survey. Most were female (76.9%), married (63.4%) and living in an urban area (61.8%). The mean age in women was 57.35 (SD=13.8) and 62.88 (SD=13.08) in men. The most common activities undertaken to maintain brain health from the pre‐defined answers were “trying to keep brain active” (86.6%) followed by “trying to keep physically active” (70.8%). However, the NLP analysis of the 621 individual free text answers revealed 45 clusters which were not included in the pre‐defined categories. Some of the largest clusters were around mindfulness; learning new words/languages and preventing mood swings. These results will be presented in further detail by key demographic groups.

Conclusion

The ePSOM study has generated evidence on what activities individuals purposefully undertake to maintain brain health. The results of our study provide evidence for public health campaigns on which modifiable risk factors are more or less commonly known to prevent dementia.
Correlation of a mobile‐based cognitive test app with traditional neuropsychological tests in a community‐based cohort
Authors: Au Rhoda , Devine Sherral , Young Katie , McManus Chelsea , Lin Honghuang
Published: December 2021

Background

Over the past decade, a number of digital health devices and mobile apps have been developed to monitor cognitive health. These digital technologies provide the potential as a convenient and cost‐effective solution for cognitive health. However, many of them were tested only in a controlled environment with limited samples, whereas their validity for longitudinal cognitive health monitoring is largely unknown.

Method

The study included participants from the Framingham Heart Study (FHS) who previously completed traditional neuropsychological (NP) tests in the FHS research center. Participants were asked to complete additional cognitive tests using Defense Automated Neurobehavioral Assessment (DANA), which is the first FDA cleared mobile app with 9 different cognitive tests, including Code Substitution, Go No Go, Insomnia Severity Index, Match to Sample, Memory Search, Patient Health Questionnaire, Procedural Reaction Time, Simple Reaction Time, and Spatial Processing. Participants were asked to complete at least three tests at the baseline, and every three months. The correlation between DANA tests and 18 traditional NP tests were assessed by the Pearson correlation coefficient test.

Result

One hundred and twenty one participants were included in the current study (mean age 71±8, 64.5% women). These participants completed an average of 2.9 repetitive tests during a median of seven month follow‐up period. All DANA tests were correlated with at least one NP test with nominal significance (P<0.05). Three NP tests were correlated with Procedural Reaction Time and two NP tests were correlated with Code Substitution after Bonferroni correction for multiple testing (P<3.1x10‐4). The most significant correlation was observed between Procedural Reaction Time from DANA and the Trails B test that was conducted in the FHS research center, with correlation coefficient of 0.44 (P=6.8x10‐7). The correlation remained significant during follow‐up DANA tests (correlation coefficient=0.44, 0.34, and 0.41 for the 2nd, 3rd and 4th DANA exams, respectively).

Conclusion

Our study suggests that traditional NP tests were highly correlated with some DANA tests, which might be used as an alternative approach for habitual cognitive health monitoring in a person’s natural environment.
Transgender adults report greater cognitive and related functional challenges: Findings from the 2015‐2019 Behavioral Risk Factor Surveillance System
Authors: Cicero Ethan , Flatt Jason D , Wharton Whitney
Published: December 2021

Background

There is limited research investigating cognitive impairment and Alzheimer’s disease and related dementia (ADRD) among transgender adults. Transgender adults experience more health disparities and psychosocial stressors, including high rates of depression, discrimination, and chronic health conditions, compared to cisgender adults. The inequities endured by transgender adults are linked to an increased risk of cognitive impairment in other marginalized groups. Subjective cognitive decline (SCD), a self‐reported experience of worsening memory or thinking, is one of the first clinical manifestations of ADRD.

Method

Combined data from the 2015‐2019 Behavioral Risk Factor Surveillance System (BRFSS) surveys, representing 33 states that used the SCD and gender identity modules, were analyzed to examine SCD and associated functional limitations among transgender and cisgender adults. BRFSS, an annual cross‐sectional telephone survey, collects data on the health and health behaviors of non‐institutionalized adults aged >18 living in the US. The sample included 386,529 adults aged >45 (transgender, N=1,302; cisgender, N=385,227). Logistic regression methods were used to determine the SCD and SCD‐associated functional limitations prevalences and test for differences in prevalence, demographic characteristics, and chronic health conditions among transgender and cisgender adults.

Result

Transgender adults were 1.73x more likely to report SCD (17.06% vs 10.64%, 95% CL: 1.44‐2.08, P<0.001) and 2.30x more likely to report SCD‐related functional limitations (64.71% vs 44.37%, 95% CL: 1.62‐3.27, P=<0.0001) when compared to cisgender adults. Among those reporting SCD, transgender adults were younger (mean 61.89 vs 65.15 years, P=0.0005), more likely to be a racial/ethnic minority (37.31% vs 19.53%, P<0.0001), a high school graduate or less (59.56% vs 43.42%, P=0.0003), uninsured (17.04% vs 5.53%, P=0.0007), have a depressive disorder (58.82% vs 45.74%, P=0.0028).

Conclusion

Additional studies are needed to further understand correlates and modifiable risk factors of cognitive impairment among transgender adults. This understanding is necessary for identifying and targeting of preventive intervention strategies for transgender adults who are at higher risk of cognitive impairment and ADRD, developing culturally relevant screenings, and shape policies to improve the health and well‐being of transgender adults.
Characteristics of chemokines and pro‐inflammatory cytokines in elderly with major depressive disorder
Authors: Nie Jing , Li Xia , Qiu Qi
Published: December 2021

Background

Research evidence has shown that late life depression (LLD) and amnestic mild cognitive impairment (aMCI) are both related to Alzheimer's disease (AD) and usually accompanied by inflammatory dysregulation, but few studies have compared the levels of chemokines and cytokines between these two disorders.

Method

Sixty‐nine study subjects were age‐ and gender‐matched outpatients with LLD or aMCI without dementia (based on DSM‐IV criteria) and normal controls (NC) in community. All individuals were administered Chinese versions of MoCA, Chinese version of neuropsychological test battery and Geriatric Depression Scale. Chemokines and pro‐inflammatory cytokines, including C‐X‐C chemokine ligand(CXCL5, CXCL6, CXCL8, CXCL9, CXCL11,CXCL16),C‐C chemokine ligand (CCL1,CCL7,CCL3, CCL8,CCL19,CCL20,CCL24,CCL11,CCL23,CCL27, CCL2, CCL13, CCL15, CCL17, CCL25), high sensitive C‐reactive protein (hsCRP), Interleukin 1‐beta (IL‐1β), macrophage inflammatory protein (MIP)‐2, Interferon‐γ‐inducing factor(IFN‐γ), vascular cell adhesion molecule‐1(VCAM‐1), interleukin‐2(IL‐2),interleukin‐4(IL‐4), tumor necrosis factor‐alpha (TNF‐α) and interleukin‐6 (IL‐6) were assessed in all subjects by Luminex assays.

Result

Elderly with major depressive disorder had less education, lower rate of having habits in taking regular exercise or drinking tea and even lower scores on cognitive tests than aMCI patients and healthy controls. LLD group showed higher level of IL‐6( P < 0.05 ) than the control or mild cognitive impairment subjects. However, They exhibited a significantly lower levels of CXCL5,CXCL6,CXCL16, and CCL5 (all p < 0.05) than the NC groups. Furthermore, The results also showed that LLD group had lower levels of CCL2,CCL17,CCL15,CXCL11 and CCL13 than the aMCI group. The multiple regression analysis showed that CCL25,CXCL6 was significantly related to cognitive scores in female.

Conclusion

We are the first to report that LLD show different characteristics in inflammatory dysfunction from amnestic mild cognitive impairment patients and normal controls. Low levels of CCL2, CCL5,CCL13, CCL15,CCL17, CXCL5,CXCL6,CXCL11and CXCL16 were found in LLD than in aMCI. These results may suggest a quite different inflammatory dysregulation in LLD from aMCI though elderly with depression also show deficits in cognition. Future longitudinal studies should further explore the heterogeneity of LLD and whether these cytokines could be early markers to predict dementia.
Accelerated long‐term forgetting: Prognostic utility in familial Alzheimer’s disease
Authors: Alston Duncan , O'Connor Antoinette , Weston Philip SJ , Lu Kirsty , Pavisic Ivanna M , Rice Helen , Street Rebecca E , Bowman Erinna , Crutch Sebastian J , Fox Nick C
Published: December 2021

Background

In Alzheimer’s disease (AD), temporal lobe pathology begins years before onset of clinical symptoms1. Early detection of temporal lobe dysfunction would be valuable for trials. Accelerated long‐term forgetting (ALF) – failure to recall learnt material when the interval of testing is extended to days as opposed to the traditional interval of minutes – has been shown to be a sensitive measure of early cognitive change in AD. However, it is not clear if ALF can predict future progression. Here we investigate the prognostic utility of ALF by assessing whether baseline performance is associated with subsequent cognitive and clinical decline.

Method

Thirty‐five at‐risk participants were recruited from UCL’s Longitudinal Cohort Study of Familial Alzheimer’s Disease (FAD). At baseline ALF was assessed by comparing recall performance at 7 days to performance after a 30‐minute interval. Visual (figure) and verbal (list and story) measures were used. Annual follow‐up visits included a detailed neuropsychological battery, mini‐mental state examination, Clinical Dementia Rating scale (CDR), measures of anxiety and depression and subjective memory decline. We tested for an association between baseline performance in ALF and rates of change in cognitive and clinical measures.

Results

At baseline, mean time to estimated symptom onset (based on parental age at onset) for mutation carriers was 7.2 years (SD 4.5 years). Four mutation carriers became symptomatic (CDR>0); baseline performance in these cases was in the 5th‐23rd percentiles for verbal measures of ALF. We will present the value of accelerated long‐term forgetting in predicting cognitive decline in this cohort.

Conclusion

ALF is a feature of presymptomatic AD with potential utility in stratification and prognostication. References: 1. Bateman, R.J. et al. N. Engl. J. Med.
367, 795–804 (2012). 2. O’Connor, A. et al. Alzheimer’s Res. Ther.
12, 1–9 (2020).
Multifunctional edaravone‐N‐benzyl pyridinium derivatives: AChE inhibition kinetics, in vitro neuroprotective activities and BBB permeability studies
Authors: Zondagh Luke Shand , Joubert Jacques , Omoruyi Sylvester , Mentor Shireen , Malan Sarel F , Ekpo Okobi E , Fisher David
Published: December 2021

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is mainly prevalent in the older population. Approximately fifty million people are diagnosed with dementia, with AD accounting for 60–70% of these cases. Amyloid beta (Aβ) is considered a pathological hallmark of AD. The shorter Aβ 25 – 35 peptide fragments, formed from the amyloidogenic Aβ 1–40 peptide, plays a crucial role in the peptide’s neurotoxic activity (Pike et al., 2002). Acetylcholinesterase (AChE) as well as oxidative stress have shown to trigger Aβ formation and aggregation (Belluti et al., 2011; Cheignon et al., 2018). Previously, we synthesized multifunctional edaravone‐N‐benzyl pyridinium compounds that exhibited potent AChE inhibition and antioxidant activity as well as predicted to cross the blood‐brain barrier (BBB) using in silico models (Zondagh et al., 2020).

Method

Selected compounds were chosen to further investigate their AChE inhibitory kinetics, Aβ 25 – 35 and MPP+ attenuating ability, cytotoxicity and in vitro BBB permeability. The AChE inhibitory kinetics were determined using a modified Ellman’s method. The data was analyzed, and a double‐reciprocal Lineweaver‐Burk plot was drawn. Mode of inhibition was determined from the Lineweaver‐Burk plot. The compounds in vitro Aβ 25 – 35 and MPP+ attenuating activity and cytotoxicity at concentrations of 10 – 100 µM was assessed on the SH‐SY5Y cell line. The in vitro BBB permeability of the compounds were assessed on the b.End5 cell line.

Result

All of the compounds exhibited mixed non‐competitive – uncompetitive mode of AChE inhibition which correlate with previous molecular docking studies. Four of the five compounds exhibited no cytotoxic effects to the SH‐SY5Y cell line, with some exhibiting proliferating effects. Compound 5a, 5e and 5j caused greater cell proliferation compared to the control at 10 μM. Most of the compounds exhibited significant activity at attenuating MPP+ and Aβ 25 – 35. Compounds 5a, 5b and 5e exhibited the most promising attenuating affects over all concentrations. Compound 5e caused greater cell proliferation when compared to the control.

Conclusion

These multifunctional compounds exhibited significant neuroprotective effects against neurotoxins, especially against Aβ 25 – 35. The compounds have shown promising activity as potential anti‐Alzheimer’s agents.
Integrative ‐omics for discovery of network‐level disease biomarkers for Alzheimer’s disease
Authors: Xie Linhui , He Bing , Varathan Pradeep , Nho Kwangsik , Risacher Shannon L. , Saykin Andrew J. , Salama Paul , Yan Jingwen
Published: December 2021

Background

A large number of genetic variations have been identified to be associated with Alzheimer’s disease (AD) and related traits. But the downstream biology through which they exert effect on the development of AD remains unknown. Leveraging genomic, transcriptomic and proteomic data, and various biological networks, we proposed a modularity‐constrained logistic regression model (M‐logistic) to identify a set of functionally connected SNPs, genes and proteins related to AD.

Method

The GWAS genotype data, RNA‐Seq gene expression data and Protein expression data were obtained from the ROS/MAP Project. Detailed data processing steps can be found in AMP‐AD (https://www.synapse.org). In total, 179 subjects with full set of data were included (Table. 1). Using peptides as seed, we prefiltered the data and included 186 peptides, 743 unique genes and 822 Single‐nucleotide polymorphisms (SNPs) from upstream of their connected genes (Fig. 1). Functional interactions from REACTOME database [1] and the SNP‐gene mapping relationship were used to construct the prior network. These functional connected ‐omics features were used to classify AD patients from non‐symptomatic group, including cognitive normal and mild cognitive impairment.

Result

Across 10‐fold cross‐validation, we observed that M‐logistic largely outperforms other state‐of‐the‐art models (Table. 2). For feature selection, the proposed model identified 305 features predictive of disease status, which appeared in more than 6 folds. When mapped back to the prior network, these features formed three big sub‐networks with > 10 nodes (Fig. 2). For 20 genes in the largest sub‐network, their brain‐wide expression profile in the Allen Human Brain Atlas were found to be mostly correlated with the activation map of brain function term “vision” in Neurosynth [2] (Fig. 3).

Conclusion

M‐Logistic identified a set of SNPs, genes and proteins that are not only predictive of AD but also densely connected in the prior network. The trans‐omic paths in the selected sub‐networks indicates a potential pathway underlying the development of AD from SNPs to gene expression, protein expression and ultimately brain functional and structural changes. Future efforts are warranted to enable integrative analysis of multi‐omics data from decoupled subjects. [1] Fabregat et al., Nucleic acids research, 2018. [2] Yarkoni et al., Nature Method, 2011.
Dementia with Lewy bodies (DLB) with amyloid co‐pathology has a distinct CSF proteomics profile compared to pure DLB and Alzheimer disease
Authors: Vermunt Lisa , Doelkahar Brian S. , Peeters Carel F.W. , van de Beek Marleen , Visser Pieter Jelle , Tijms Betty M. , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Irwin David J. , Chen‐Plotkin Alice , Lemstra Afina W. , Del Campo Marta , Teunissen Charlotte E.
Published: December 2021

Background

In dementia with Lewy bodies (DLB), amyloid co‐pathology is common and associated with an unfavorable prognosis. For targeted treatment development for DLB, we need to establish 1) whether the presence of amyloid marks co‐occurring Alzheimer disease (AD), and 2) how DLB with amyloid differs from DLB without amyloid. We employ proteomics in cerebrospinal fluid (CSF), an established method to assess biological dysregulation in vivo, for characterization of DLB with amyloid pathology.

Method

We selected individuals from the ADC and UPENN cohorts, with DLB diagnosis with abnormal amyloid based on CSF (n=65), DLB with normal amyloid (n=45), AD dementia (n=235), and cognitively healthy controls with normal amyloid (n=252, Table 1). CSF protein levels (n=810) were measured using the Olink proximity extension assay. We compared protein levels between groups using ANCOVA’s adjusted for age and sex, and FDR‐controlled p‐values. To aid identification of proteins that contribute to disease processes, we developed a neural network model prototype. We trained the model to learn simultaneously a low dimensional representation of the data and a dementia classifier. The assumption is that biologically important proteins show the strongest influence on the low network dimension, because these proteins contribute to classification and/or share information with multiple proteins.

Result

The DLB‐amyloid group showed mostly decreased CSF protein levels, in particular compared to AD dementia (68%, Table 2). Compared to DLB‐pure, DLB‐amyloid has 132 decreased and 3 increased protein levels, which were most significantly enriched for KEGG pathways: cytokine‐cytokine receptor interaction and axon guidance; and for GO‐biological terms related to positive regulation of neurogenesis, axonogenesis, and neuronal differentiation. In DLB‐amyloid, most AD‐related proteins were normal or decreased, and multiple additional proteins were specifically decreased (Figure 1) These DLB‐amyloid associated proteins were enriched for GO‐biological terms related to chemotaxis and VEGF‐A induced cell proliferation.

Conclusion

The CSF proteome in DLB with amyloid pathology differed from AD dementia and DLB pure, and the changes may be linked to disturbed axonal maintenance and growth. This data indicate that amyloid pathology in DLB is not an independent co‐pathology. Complementary to pathology studies, we have started to disentangle mechanisms of mixed pathology in vivo.
Structural correlates of moral emotions in patients with behavioral variant frontotemporal dementia
Authors: Chonchol Andrea Slachevsky , Trujillo Catalina , Forno Gonzalo , Bleier Cristina , Lillo Patricia , de Souza Leonardo Cruz , Baez Sandra
Published: December 2021

Background

Social cognition impairments have been extensively described in patients with behavioral variant frontotemporal dementia (bvFTD). Moral emotions have recently emerged as a potentially sensitive domain to characterize and discriminate bvFTD patients from other types of dementia. Here, we examined the usefulness of moral emotions measures to characterize and discriminate bvFTD from Alzheimer’s disease (AD) patients, and their structural brain correlates in both groups.

Method

In this multicenter (Chile‐Colombia) study, 31 bvFTD, 30 AD patients, and 37 healthy controls –matched by age, sex, and educational level– completed an adapted version of the Moral Sentiments Association Task (MSAT) consisting of 29 text‐based scenarios evoking moral (guilt, pity, embarrassment, and indignation) and basic (fear and disgust) emotions. After reading each scenario, participants selected the emotion they would feel in that situation and rated their elicited intensity and disturbance levels. General cognitive (MoCA/ACE‐III) and executive (IFS) measures were also included. Additionally, we performed VBM analysis in a subsample (15 bvFTD, 20 AD, 17 controls) to study the association between grey matter volumes and moral emotions processing

Result

After controlling for cognitive and executive skills, bvFTD patients exhibited lower accuracy on identifying moral emotions –pity, embarrassment, and indignation– than AD patients, despite null differences in basic emotions. Subsequent discriminant analysis revealed that this differential pattern classified patient groups more accurately (74%: 65% bvFTD and 83% AD) than individual cognitive (59%) and executive (51%) measures. Crucially, between‐group classification substantially improved when combining the three measures mentioned above (79%: 68% bvFTD, 90% AD). In both groups, pity, embarrassment, and indignation identification correlated with reduced grey matter volumes in regions subserving social cognition and emotion processing, including the Rolandic operculum, the inferior and middle temporal gyri, and the postcentral gyrus (exclusive to bvFTD).

Conclusion

These results suggest that bvFTD patients exhibit moral emotion impairments as compared with AD patients. Particularly, pity, embarrassment, and indignation emerged as useful measures to patients' classification. Such findings contribute to a better understanding of the structural correlates of moral emotional deficits in bvFTD patients while highlighting the potential benefits of integrating this domain into the standard cognitive and executive assessment for a more accurate differential diagnosis.
Acute peripheral inflammation does not change cerebral glucose metabolism
Authors: Machado Luiza Santos , dos Santos Camila N. , da Rocha Andreia Silva , Fontana Igor C. , Bellaver Bruna , Leonardi Bianca F. , Venturin Gianina Teribele , Greggio Samuel , da Costa Jaderson Costa , Zimmer Aline R. , Zimmer Eduardo R.
Published: December 2021

Background

Neuroinflammation is a phenomenon already described in the brain of Alzheimer's disease (AD) individuals, with sustained neuroinflammatory response being detrimental. The effect of peripheral inflammation in AD is less understood. In fact, central nervous system (CNS) is protected from peripheral inflammation by the blood‐brain barrier. However, we recently demonstrated that severe sepsis causes acute brain metabolic disturbances, evidencing the CNS invasion of inflammatory mediators may affect brain function. Nevertheless, whether mild acute peripheral inflammation affects brain metabolism remains unclear. Objective: Here, we aimed at investigating the impact of mild acute peritonitis on brain energetic metabolism. Hypothesis: We hypothesized that mild peripheral inflammation will cause widespread brain glucose hypometabolism.

Method

Adult male Wistar rats were randomly separated into carrageenan group, a model of mild acute peripheral inflammation (n=6), and control group (n=6). Peritonitis was induced by the administration of 500 µg of intraperitoneal (i.p.) carrageenan, while the control group was i.p. injected with 500 µl of saline. In vivo cerebral glucose metabolism was assessed using (18F)FDG‐microPET 4 h after inflammatory induction, which represents the first peak of inflammation. The peripheral inflammatory process was evaluated by analyzing the peritoneal lavage in a Flow Cytometer 48 h after the scanning i.p. injections, the second of peak of inflammation,

Result

The animals treated with carrageenan presented a 5‐fold increase in macrophages numbers (p<0,05) and a 2‐fold increase in monocytes numbers (p>0,05). However, our data showed that carrageenan‐induced peripheral inflammation did not cause acute changes in the whole brain glucose metabolism (p>0,05). Further regional analysis, in frontal and temporoparietal cortices, striatum, hippocampus, cerebellum, thalamus and hypothalamus, did not identify any difference between groups.

Conclusion

Mild acute peripheral inflammation does not change brain glucose metabolism. Further evaluation aiming to investigate long‐term consequences of sustained mild inflammation are needed.
From research to realization: How a Texas health plan implemented an academic model of care for Alzheimer's disease
Authors: Stringer Cody , Smithroat Noemi , Samus Quincy M , Johnston Deirdre
Published: December 2021

MIND at Home is a comprehensive, home‐based care coordination intervention for people with Alzheimer’s disease or related dementias (A/D) who live in the community and for their family caregivers. Developed by researchers at Johns Hopkins University (JHU), the model has been shown to extend the time a person with A/D remains at home for almost two years, as well as improved quality of life and quality of care and reduced caregiver burden. The MIND at Home pilot at Superior HealthPlan is a collaboration between Centene Corporation, JHU, and Superior HealthPlan (Superior). The goal of the MIND at Home pilot is to adapt, implement, and evaluate the impact of MIND at Home within Superior’s Medicaid population. The pilot is structured as an interventional study of the MIND at Home program versus a propensity score‐matched (PSM) comparison group receiving standard‐of‐care. The duration of the pilot is approximately 12 months, with longitudinal follow‐up at 18 and 24 months. The pilot population includes Superior HealthPlan Medicaid members (receiving Long‐Term Services & Supports) who are community‐residing and have a confirmed diagnosis of A/D. The study has enrolled approximately 300 participants who have received the intervention. An analysis of claims data for participants receiving the MIND at Home intervention indicates the program increased primary care utilization (+10.0%) while reducing emergency department (ED) utilization (‐15.8%), polypharmacy (‐5.0%), and total spend (‐1.35%). Consumer survey results indicate high levels of satisfaction among both pilot participants and their family caregivers and case studies anecdotally illustrate the significant impacts the MIND at Home program has had on participant and caregiver quality of life. Preliminary outcomes of the pilot indicate the MIND at Home program reduces high cost healthcare utilization – particularly ED and polypharmacy – and overall participant costs. Additional outcomes illustrate participants are highly satisfied with the MIND at Home program and have experienced dramatic increases in quality of life. This pilot showcases the value of operationalizing this evidence‐based academic care model for A/D in a Medicaid population and that collaboration across academic research, industry, and government‐sponsored healthcare programs can result in improved outcomes for individuals with A/D.
Dementia‐related agitation in Portuguese public hospitals: A retrospective analysis of 6,586 hospitalization episodes
Authors: Ferreira Ana Rita , Gonçalves‐Pinho Manuel , Simões Mário Rodrigues , Freitas Alberto , Fernandes Lia
Published: December 2021

Background

Dementia‐related agitation (DRA) is highly prevalent, disruptive and distressing, being a key cost‐driver of dementia care due to the high risk of emergency hospital admissions and prolonged hospitalizations. These events often prove harmful for dementia patients, resulting in multiple adverse outcomes that heighten the dementia burden. Although emerging studies support the societal and economic toll agitation places on patients, families and healthcare systems, more population‐based studies are needed on how DRA affects healthcare utilization. Thus, this study aimed to describe the hospitalizations with DRA held in mainland Portuguese public hospitals from 2010‐2015.

Method

A retrospective observational design was used to analyze a nationwide database officially provided by the Portuguese Administração Central do Sistema de Saúde, IP (ACSS). This database comprises routinely collected healthcare data originally obtained for administrative purposes in all mainland Portuguese public hospitals, including International Classification of Diseases Ninth Revision Clinical Modification (ICD‐9‐CM) diagnostic codes. All inpatient episodes with age ≥65 years and a proxy DRA code of dementia with behavioral disturbance (ICD‐9‐CM 294.11, 294.21), were identified. Descriptive statistics were used to summarize the data.

Result

Overall, 6 586 DRA inpatient episodes were analyzed. Most of these were associated with female patients (58.1%), with a mean age of 81±7 years, who have been admitted due to delirium, dementia, amnestic and other cognitive disorders (22.0%), pneumonia (15.0%), urinary tract infections (8.4%), acute bronchitis (5.3%), and acute cerebrovascular disease (4.1%). The median length of stay was 9 days (Q1‐Q3: 5‐17), and a total of 831 patients (12.6%) died during hospitalization. The mean estimated charges per episode were 2 916.5€, representing a total of 19 208 069€ during the study time‐frame.

Conclusion

Results corroborate the clinical and economic DRA impact. Nevertheless, data also suggest that a great share of admissions was due to preventable causes, which could have been managed with ambulatory treatment, thereby preventing harmful hospitalizations. To our knowledge, this is the first attempt to characterize how Portuguese patients with DRA use healthcare services, providing useful information to project future healthcare needs. Support: FCT [PD/BD/114555/2016], ERDF through operation POCI‐01‐0145‐FEDER‐007746 funded by COMPETE2020, National Funds through FCT within CINTESIS (UID/IC/4255/2013; UIDB/4255/2020).
No effect of exercise on AD‐related cognition in older African Americans: Program for African American Cognition and Exercise (PAACE)
Authors: Carmichael Owen T , Gwizdala Kathryn L. , Brouillette Robert , Beyl Robbie , Johnson William , Hebert Callie , Carter Leah , Harris Melissa , Newton Robert L
Published: December 2021

Background

Lower levels of physical activity (PA) are associated with greater risk of cognitive decline and AD, and some studies suggest that interventions that increase PA engagement lower risk of cognitive decline and AD. However, interventions to date have largely not included substantial representation of African Americans.

Method

The Program for African American Cognition and Exercise (PAACE) randomized 56 sedentary African American adults in the Baton Rouge, Louisiana area (mean age ± s.d.: 69.2 ± 3.4 years) to a physical activity group (PAG) or successful aging group (SAG). The PAG aimed to increase moderate to vigorous PA to national guideline levels over 12 weeks by providing supervised PA 2 days per week (90‐120 minutes/week) at local YMCAs along with 30‐60 minutes/week of home‐based PA. The SAG completed one 60‐minute educational session on successful aging per week for 12 weeks. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was assessed before and after the intervention. ANOVA models assessed pre‐ to post‐intervention RBANS total scale and sub‐scale score changes, as well as differences between PA and control arms in these changes.

Result

Groups were well matched by age, sex, BMI, employment, education, and income. The SAG increased scores on the RBANS overall scale and scales of visuospatial function, immediate memory, and delayed memory, along with the story memory, figure copying, coding, and figure recall sub‐scales (all p<.05). The PAG increased scores on only the list learning sub‐scale (p=.047). Scores on the overall scale (p=.034) and story memory sub‐scale (p=.0008) increased significantly more in the SAG than in the PAG. No RBANS scores increased significantly more in the PAG compared to the SAG.

Conclusion

A 12‐week PA promotion program among community‐dwelling older African American adults provided significant cognitive benefits to an educational control group, and minimal benefits to those engaged in PA. Possible contributors to these results include inadequate PA stimulus in the PAG, and beneficial health behavior changes or cognitive stimulation in the SAG. Future research is needed to fully understand cognitive effects of PA interventions among older African Americans.