bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibiting tyrosine kinase c‐KIT as a therapeutic strategy for Alzheimer’s Disease
Authors: Stevenson Max E , Hebron Michaeline , Liu Xiaoguang , Kavulu Balaraman , Wolf Christian , Moussa Charbel E‐H
Published: December 2022

Background

Impaired autophagy and neuroinflammation, two primary features of Alzheimer’s Disease, were examined as potential pharmacological targets for alleviating amyloid‐beta and tau burden using novel tyrosine kinase inhibitors.

Method

Transgenic APP mice were treated for 6 weeks with either one of two novel tyrosine kinase inhibitors or DMSO (n = 10) before having their behavior tested on the novel object recognition test, the Morris water maze, and the elevated plus maze. Brain samples were then extracted and probed for levels of amyloid‐beta, tau, and autophagic machinery, as well as numbers of mast cells and microglia using ELISA, immunohistochemistry, and flow cytometry.

Result

Mice treated with our novel tyrosine kinase inhibitors exhibited robust improvements on behavioral measures. These treated mice displayed concurrent decreases in levels of amyloid‐beta and tau, as well as increased levels of autophagic machinery and decreased numbers of microglia and mast cells.

Conclusion

Tyrosine kinase inhibition represents a valid mechanism for improving autophagic clearance of neurotoxic protein and mitigating mast cell and microglial‐mediated inflammation, identifying this method as a potential target for therapeutic intervention for treating Alzheimer’s Disease.
Camouflaged regions conceal critical regions in ATAC‐Seq and Hi‐C sequencing assays, hiding potential contributing factors in Alzheimer’s disease
Authors: Wadsworth Mark E , Page Madeline L , Heberle Bernardo Aguzzoli , Miller Justin B , Ebbert Mark T.W.
Published: December 2022

Background

For many regions of the genome, genetic variants are completely overlooked when using standard short‐read sequencing approaches because of either; (1) lack of coverage (i.e., ‘dark‐by‐depth'), or (2) reads aligning to multiple regions (i.e., ‘dark‐by‐MAPQ', a.k.a. ‘camouflaged’ genes). Multiple alignments occur because of genomic duplication events that contribute to molecular evolution, but present major analytical challenges for aligning short‐read sequencing data to the genome. We previously presented a method to identify and differentiate dark and camouflaged regions by analyzing the read depth and reads with multiple alignments. Here we present data demonstrating that not only do camouflaged regions conceal essential genetic variants, but they further conceal results from other short‐read sequencing assays, including ATAC‐Seq and Hi‐C. Our results have important implications for all disease research, including Alzheimer’s disease.

Methods

We identified and validated genome‐wide camouflaged regions using an updated version of our algorithm to identify camouflaged genomic regions, and then applied it to publicly available ATAC‐Seq and Hi‐C sequencing data sets.

Results

We identified 148,197 camouflaged regions of greater than 20 bases. Of these regions 23.23% overlap at least one Ensembl transcript. Additionally, we found that results for camouflaged regions, including CR1 (a top Alzheimer’s disease gene), are also non‐existent in ATAC‐Seq and Hi‐C data. As previously described, we can rescue variants that fall within these regions such as the frameshift we described in CR1. Thereby, we show that including a rescuing step in your alignment pipeline may provide important insights into disease etiology.

Conclusion

While short‐read sequencing has been a major boon to research, there are many systematic flaws to using short‐read sequencing, including camouflaged regions. Rescuing variants or peaks in these camouflaged regions could elucidate important findings related to Alzheimer’s Disease etiology that are missed by standard short‐read sequencing methods.
Applying novel EMBRACE technological solutions to measure and optimize brain response to exercise.
Authors: de Frutos Jaisalmer , Doval Sandra , Fernández Ricardo Bruña , Cabrera Jesús , de Fano Antonio , Fiedler Patrique , Tamburro Gabriella , Haueisen Jens , Zanow Frank , Ros Bruno , Pusil Sandra Angelica , Vaquero Lucia , Comani Silvia
Published: December 2022

Background

Extensive evidence supports the notion that physical activity (PA) promotes healthy aging and contributes to the prevention of brain damage and dementia. However, there are relevant differences in individual response to exercise that could mediate the extent of the PA‐induced benefits. Here, we propose the application of the novel technology that is currently being developed by the EMBRACE project researchers to the characterization of the individual physiological response to exercise in older adults.

Method

EMBRACE is an intersectoral and international consortium that brings together experts in biomedical engineering, material science, signal processing, neuroscience and social psychology from 3 academic and 3 industrial partners across 3 EU countries to develop: 1) a new mobile and wireless dry electrode EEG system suitable for monitoring brain activity during full body movements; 2) novel body network sensors and a multimodal alignment system for simultaneously recording of neural, physiological and kinematic signals from two interacting subjects; 3) novel analytical solutions for motion artefact removal and multi‐level analysis of multimodal data; and 4) a new research dyadic paradigm to exploit the technological advances.

Result

The novel technological solutions that are being currently developed by the EMBRACE consortium will enable the study of joint action at the neural, cognitive, behavioral and social levels while the participant engages in PA (individually or in social interaction), wearing a comfortable and long‐lasting acquisition system.

Conclusion

A detailed characterization of the individual response to exercise will help in the optimization of exercise routines with the aim to elicit the desired physiological response to enhance brain health and prevent dementia.
Effect of calcineurin inhibitors on cognition in a canine model of Alzheimer’s disease
Authors: Sordo Lorena , Ubele Margo F. , Boaz Kathy , Mefford Jennifer L. , Jones Erin Denhart , Smiley Jeffrey , Bresch Fred , Phelan Michael J. , Puskas Laszlo G. , Norris Christopher M. , Head Elizabeth
Published: December 2022

Background

Calcineurin (CN) is a Ca2+/calmodulin‐dependent phosphatase that regulates diverse cellular phenotypes through activation of NFAT transcription factor1. CN/NFAT signaling increases in Alzheimer’s disease (AD)2,3 and is associated with synaptic loss, neuron degeneration, neuroinflammation, amyloid‐β production, and cognitive decline4,5. Thus, calcineurin inhibitors (CNI) are attractive potential therapeutic to improve cognitive impairments associated with AD.

Tacrolimus is an FDA‐approved CNI commonly prescribed for the prophylaxis of solid organ transplant rejection6. In mouse models of AD, tacrolimus ameliorates cognitive deficits7. Moreover, epidemiological studies suggest that tacrolimus reduced the incidence of dementia in kidney transplant patients, when compared to age‐matched controls8.

Q134R, a hydroxyquinoline derivative with cytoprotective properties9, inhibits NFAT activity without suppressing CN activity. Q134R improves synapse function and reduce neuroinflammation in AD mouse models10.

We hypothesized that chronic low dose tacrolimus and Q134R treatment will prevent cognitive decline over time in middle‐aged beagles, a natural model of human brain aging, amyloid‐β accumulation, and amyloid‐related cognitive impairment.

Methods

Cognitive outcomes were evaluated in 37 middle‐aged dogs at baseline and during follow‐up (years 1, 2 and 3). Spatial learning and working memory were evaluated using the landmark‐discrimination (1, 2 and 4cm) task and a delayed non‐matching to position (20‐, 70‐, and 110‐second delays) test. Dogs were ranked for cognition at baseline and randomized into one of three treatment groups: Control (n = 12; placebo), Q134R (n = 12; 8mg/day PO), and tacrolimus (n = 13; 0.075mg/kg/day PO).

Results

Accuracy at each landmark‐discrimination distance declined significantly among controls faster per year than both treatment groups. Control dogs declined 20% faster than tacrolimus dogs at all distances, and 15% faster than Q134R dogs, at the most difficult distance (4cm).

Accuracy on the spatial working memory task declined in each year among controls faster than dogs in the active treatment groups. This effect tended to increase with treatment duration in tacrolimus dogs, whereas it attenuated in Q134R dogs.

Conclusion

Our findings suggest that both tacrolimus and Q134R have beneficial effects on cognitive outcomes in a canine model of AD, as dogs treated with these compounds showed improved learning, memory, attention, and working memory. Hence, inhibition of the CN pathway may reduce/delay cognitive impairment in AD.
Microglia with fatty acid‐binding protein 5 deficiency exhibit proinflammatory phenotype contributing to neuroinflammation
Authors: Kagawa Yoshiteru , Jin Liang , Sun Jiaqi , Nicolazzo Joseph , Owada Yuji , Pan Yijun
Published: December 2022

Background

Microglia are the resident immune cells in the brain, which show a broad spectrum of phenotypes ranging from the pro‐inflammatory, potentially cytotoxic to the anti‐inflammatory, scavenging, and regenerative. Fatty‐acid binding protein 5, an intracellular protein that are important for cellular metabolism, have been identified in human and mouse microglia; however, its role in microglia is yet to be defined. Studies from our laboratory and others have shown that FABP5 is downregulated in the brain of Alzheimer’s disease patients and APP/PS1 mice. This study is to explore the impact of FABP5‐deficiency on microglia phenotype.

Method

Total protein from FABP5‐knockout mouse brains (4‐5 months old) was extracted to assess cytokine levels (TNFα, IL‐1ß). Microglia abundance in the hippocampus of FABP5‐knockout mice and their wildtype control mice was quantified immunohistochemically. FABP5 in the immortalized mouse microglia BV2 was downregulated using siRNA, and the metabolism of the treated microglia was assessed via [3H]‐2‐deoxy‐D‐glucose (2dg) uptake and oleic acid oxidation assay.

Result

A significant increased levels of TNFα (1.4‐fold) and IL‐1ß (1.25‐fold) was detected in the brain homogenates of FABP5‐knockout mice (vs wildtype control mice). Interestingly, a higher abundance (8%) of microglia was observed in the hippocampus of the FABP5‐knockout mice. The downregulated FABP5 in BV2 using siRNA and achieved a 76.4% reduction in FABP5 protein expression. We subsequently observed a 1.5‐fold elevation of 3H‐2dg uptake in FABP5‐downregulated BV2 cells, suggesting a possible increase in glycolysis. This shift was in agreement with the metabolism requirement of the proinflammatory microglia.

Conclusion

Further studies need to be performed to confirm the role of FABP5 in microglia. Our data supports that FABP5 deficiency possibly leads to microglia proinflammatory activation and contribute to neuroinflammation in mice.
Investigating Distinct Alpha Synuclein Oligomer‐Mediated Cellular Toxicity
Authors: Moore Kenya
Published: December 2022

Background

Alpha Synuclein (ASyn), an amyloidogenic protein observed in Parkinson’s (PD) and Alzheimer’s (AD) disease, oligomers are toxic and polymorphic protein aggregates that with further investigation could be essential to improving potential neurodegenerative therapeutics.

Method

Using monoclonal antibodies (SynTCs) that bind toxic conformations of ASyn, we utilize cellular models such as primary cortical neurons and primary astrocytes isolated from C57/BL6 mice to investigate differences in the neurotoxic effects of ASyn oligomeric strains. These differences were evaluated by both immunocytochemistry and cell‐based assays. In addition, we analyzed the thermodynamic binding occurring between SynTCs and ASyn oligomeric strains.

Result

Utilizing isothermal titration calorimetry (ITC), we confirm the thermodynamic binding between SynTCs and ASyn oligomers in contrast to ASyn monomers and fibrils. Asyn oligomeric strains exhibit differential toxicity in both primary neuron and astrocyte cells. When immunodepleted by SynTCs, cytotoxicity and endogenous ASyn aggregation decreased.

Conclusion

Investigating mechanisms of neurotoxicity mediated by Asyn oligomeric strains is valuable in determining biological effects and the therapeutic potential of targeting and reducing toxic ASyn oligomers that contribute to the neurotoxicity observed in multiple neurodegenerative diseases.
A Systemic Review of depressive intervention for the older adults
Authors: Choi Junsu , Choi Sungjoo , Jung Minye
Published: December 2022

Background

This study systematically review and analyze the types and effects of depressive intervention for the older adults.

Method

In the last 10 years, a total of 4,478 documents were searched and reviewed using databases of Pubmed, CINAHL, EMBASE, MEDLINE, SCOPUS, and Web of Science, and 8 studies that met the selection criteria were derived. The selected studies were systematically organized using the Cochrane’s Risk of Bias [RoB] and then the interventions were aggregated to derive content.

Result

The age criteria of the eight selected papers were 1 over 50 years old, 1 over 55 years old, 3 over 60 years old, and 3 over 65 years old. The five types of occupational therapy depressive intervention, 3(37.5%) of the studies were conducted on Problem solving therapy, 2(25%) of the studies were conducted on Cognitive behavioral therapy, 1(12.5%) of the study was conducted Behavioral activation, 1(12.5%) of the study was conducted Yoga and 1(12.5%) of the study was conducted Story sharing. In intervention other than Story sharing, depression symptoms in intervention groups were significantly reduced compared to the control groups.

Conclusion

The study investigated the effects of depressive interventions for the older in preparation for problems caused by the aging population of mankind. As a result of this study, it is thought that research on how to manage depression in the older in the clinical sector will be necessary.
Behavioral reaction to amyloid beta status disclosure
Authors: Lesman‐Segev Orit H. , Golan Sapir , Zadok Maya , Kishenevsky Sarah , Ben‐Meir Mery , Bem‐Moshe Ariela , Heymann Anthony , Azuri Joseph , Ravona‐Springer Ramit , Hoffmann Chen , Domachevsky Liran , Beeri Michal Schnaider
Published: December 2022

Background

Limited information exist regarding the reaction of cognitively unimpaired research participants to amyloid status disclosure and even more so in observational studies. We aimed to assess the associations of amyloid status disclosure with reported subjective memory concern, motivation to change lifestyle, anxiety, and depression.

Method

Research participants that take part in two observational studies and two clinical trials that incorporate amyloid‐PET where included. Participants received information regarding amyloid‐PET testing, results, and interpretation. They then performed an interview prior to PET scan and four‐to‐six‐month following result disclosure assessing their subjective memory concern, motivation to change lifestyle, anxiety, and depression from the possibility of a positive amyloid‐PET result.

Result

130 cognitively normal adults completed both the pre‐PET and post‐PET questionnaires. Only 11 had a positive amyloid‐PET result and thus were excluded from the analyses. Of the 119 subjects with a negative PET scan, 70 (59%) were females, mean age = 62Y (rang 44‐88Y), mean education = 16Y (4‐25), mean MMSE = 29 (24‐30); most (64%) reported no memory concerns or mild memory concerns (1/2 on a scale of 5). This increased to 94% at 4‐6 month following amyloid‐PET disclosure (Figure 1). Most (84%) had high or very high motivation to change lifestyle (4/5 in a scale of 5) in the pre‐PET assessment. This decreased to 30% in the post‐PET assessment. High and very high (4/5 in a scale of 5) anxiety and depression from a positive amyloid scan rates decreased from 25% to 0% and from 10% to 0%, respectively following a negative PET result disclosure (Figure 1). Although most individuals reported favorable post‐PET changes, a few subjects experienced increase in memory decline (N = 8), anxiety (N = 6) or depression (N = 1) following disclosure (Figure 2).

Conclusion

In cognitively normal adults, the disclosure of a negative amyloid‐PET scan result was associated with a general “comforting” effect as reflected by less subjective memory concerns, anxiety, and depression, and lower motivation to perform lifestyle changes. By AAIC 2022, we anticipate more participants who are amyloid‐PET positive allowing to compare their behavioral changes after disclosure of amyloid results to the changes of those who are amyloid‐PET negative.
Design Requirements for Financial and Legal Planning Platforms to support Care Partners of People Living with Alzheimer’s Disease and Related Dementias
Authors: Jolliff Anna , Dudek Alex , Parks Reid , Linden Anna , Elliott Christian , Zuraw Matthew , Werner Nicole
Published: December 2022

Background

People living with Alzheimer’s Disease or related dementias (ADRD) and their care partners (e.g. family, friends) experience legal and financial planning challenges. Technology‐based interventions have the potential to mitigate these challenges. However, care partners have reported discontinuing use of currently available technology‐based interventions because they did not align with their needs, were not relevant, or were not available when needed. This persistent need for solutions personalized to care partner needs can be met through participatory design (PD), which engages end users in collaborative design exercises. Our objectives were to conduct PD with ADRD care partners to design a web‐based financial and legal planning prototype that meets care partner needs.

Method

We enrolled two groups of designers (n = 5/group). Participants were recruited nationally through community partners. We used phone screenings to confirm that participants were self‐identified current or former care partners of someone living with ADRD, had internet access, were 18 or older, and spoke English. Design teams will complete 5 co‐design sessions across 6 months, with at least 4 weeks between each design session. Sessions 1‐3 have focused on problem identification, generating solutions, and solution convergence. Sessions 4 and 5 will focus on prototyping and evaluating the final prototype. Team members individually reviewed design session recordings to extract key design requirements. Discrepancies were resolved through consensus discussion.

Result

Participants (n = 10) cared for a spouse (80%) and were from Wisconsin, Texas, and California. Sessions 1‐3 generated 8 key design requirements. Participants wanted a tool that would help them 1) Learn, including learning new information; 2) Organize, including organizing existing information; 3) Act, including executing to‐do lists; and 4) Connect, including gaining access to existing resources. Participants wanted a tool characterized by 5) Privacy, including keeping their information safe; 6) Flexibility, including addressing their unique needs; 7) Peace of mind, including feeling in control of their responsibilities; and 8) Sustainability, including tool helpfulness over time.

Conclusion

The results of the first three design sessions shed light on current unmet needs of ADRD caregivers, and can guide the development of financial and legal planning technologies for ADRD care partners.
Prediction of Dementia Subtypes by Machine Learning: Feasibility of Error Control
Authors: Tian Ye , Rusinek Henry , Feng Yang , Vedvyas Alok
Published: December 2022

Background

Accurate prediction of dementia subtypes is important in geriatric decision‐making and in designing clinical trials. We used machine learning and a novel error control algorithm to analyze longitudinal data collected by the National Alzheimer Coordinating Center (NACC) from June 2005 to November 2021. Our goals were (1) Predicting the conversion to several dementia subtypes in patients who were dementia‐free at baseline; (2) Finding important clinical metrics and risk factors that contribute to the prediction; (3) Controlling the prediction error rate on specific dementia subtypes to help design clinical trials.

Method

We studied the 13,243 NACC participants who had normal clinical etiologic diagnosis results at their first visit. Then, we fit different machine learning models to predict the diagnosis result of their last visit. Among 13,243 patients, 10,679 remained dementia‐free, 1,793 had Alzheimer’s disease (AD), 153 had Lewy body disease (LBD), and 290 had Vascular dementia (VD) as the primary diagnosis at their last exam. After removing predictors with over 10% missing values and imputing missing values on the remaining predictors, our models tested 249 predictors, which included clinical, family history, and behavioral features. Cases were randomly split the data into training (90%) and testing (10%) subsets for 500 rounds. Multinomial regression, penalized multinomial regression, and random forest models were analyzed. We further manipulated the penalized multinomial regression model by controlling the prediction error rate on a given dementia subtype.

Result

Multinomial regression model, penalized multinomial regression model and random forest led to the overall prediction error rate of 10.73%, 9.26%, and 9.38%, respectively. Significant predictors included the length of time from the initial visit to the most recent visit, the cognitive status of the patient in the visit, and metrics of memory deficits. Error control results (Figure 1) showed that relaxing the strict control on some dementia subtypes serves to improve the prediction performance of the other dementia subtypes.

Conclusion

Machine learning methods can help predict the progression to dementia using commonly available variables available in memory clinics even in the absence of imaging and fluid biomarkers. ML is helpful in identifying most important clinical features and key risk factors.
Investigating the molecular consequences of co‐morbidites in Alzheimer’s disease
Authors: MacBean Lachlan Ford , Smith Adam R. , Smith Rebecca G. , Lunnon Katie
Published: December 2022

Background

Due to the transient and highly sensitive nature of DNA methylation, it is important that Epigenome‐Wide Association Studies (EWAS) account for numerous variables that may influence the methylome as it is becoming increasingly clear that other diseases can influence the onset and severity of Alzheimer’s disease (AD).

Method

DNA was extracted from both AD (n = 119) and cognitively normal (n = 76) post‐mortem middle‐temporal gyrus brain tissue and DNA methylation quantified using Illumina methylation arrays. Combining the methylation beta values with detailed phenotypic data collected for each patient, including data on diabetes mellitus and TDP.43 proteinopathy, Principal Component Analysis was performed to determine co‐morbidities of AD that had a confounding effect on DNA methylation across the genome. Linear regression models were then designed to compare the methylomic consequences of TDP.43 proteinopathy in AD when co‐morbidities, such as DLB, are corrected for. Additionally, Analysis of Variance was used to conduct an EWAS evidencing the additional methylomic consequences of diabetes on AD‐diagnosed patients.

Results

An EWAS of AD and diabetes mellitus showed significant differential methylation at several sites across the genome, in particular within the gene BACE2, suppression of which promotes β‐cell survival. Further linear regression analysis of methylation data that had been corrected for co‐morbidities, including DLB, shows that much of the methylation changes seen in EWAS may be accounted for by these confounding diseases, while changes in genes associated with the pathology of interest retain their significance. In the study of TDP.43 proteinopathy and AD this can be observed at probes in the genes HAX1, CUX1, and CCDC88C.

Conclusion

The next step for this project is to obtain more samples with clinical information on common co‐morbidities of AD. EWAS focussed on the effects of TDP.43 proteinopathy and diabetes mellitus can then be performed with greater power and the specific pathways identified. Nonetheless, this pilot data emphasises the need for comprehensive clinical data when performing studies on methylomic data.
Human: cognitive enhancement; Training for enhancement of cognitive abilities, activations
Authors: Mayer Gabriele
Published: December 2022

Background

Through our life style, social systems our sensory organs are in minimized activities, can’t feed our human being’s brain with all the necessary information.The transmitters are building less, brain cells haven’t enough keys to open them. The brain cells go down, neurodegenerative diseases arise. To hinder this our cognitive enhancement has priority with training in biological, neurobiological, physiological, neurophysiological courses.

Method

Brain working systems: ‐1.first step is cognition. It is the basic in order to notice that any kind is there. ‐2.step:notice that anything is there. ‐3.step:putting into awareness that there is anything ‐4.step:recognition of form ‐ 5.of color of anything with information in neurophysiological, neurological combination of visual transmission from eyes. ‐6.step:brain inside world at work: recording of form and color. ‐7.step:categorized, classified in brain, inside work. ‐8.step:word finding with “individual, subjective, selective processes” through accumulation of codes which are firmly rooted in past experiences learned, storage in memory queried, retrieved, call up in the brain, inside work. ‐9.step:classified in subject, object, person through characteristic descriptions. It follows brain related: changes of different areas to activation motoric function in order to speak with voice, mouth, tongue or for writing with pen, or to type. Brain related pre‐preparation: movement impetus, ‐draft, call up of movement program motorsensoric cortex, movement implementation over pyramidal nerve course to motor neuron. Brain related: activation muscles nerves, tendons for active movements. It’s necessary to know body awareness, ‐feeling, ‐scheme, or to train it. Because the brain has to activate for verbalization different areas or it can be that automatic movements are triggered.

Result

Training: ‐the consciousness, in daily life activities, actions. ‐Relationship to real object/subject to develop the names. ‐and use real things when describing them. ‐training the words in memory storage to call up.

Conclusion

All sensory organs are in abilities, activities and feed human brain with necessary information. Transmitters, neurotransmitters are building themselves. The brain cells work. Training in every daily life actions, activities.

Result

the output is better in cognitive enhancement, stops Alzheimer’s, Dementia. I developed this training like biological, neurobiological, physiological, neurophysiological processes are.

“Rediscover Recovery Practical Reference Training”, researcher, therapist, G.Mayer
Organochlorine pesticides and late life cognitive function: does race/ethnicity and sex matter?
Authors: Chanti‐Ketterl Marianne , Aranda Maria P. , Plassman Brenda L
Published: December 2022

Background

Organochlorines (OCs) pesticides persist in the environment and body for extended periods. Little is known about their long‐term impact on cognition in later life. Some studies, have shown higher levels of selected OCs associated with lower cognitive function (CF). It remains unclear if the association differs among racial/ethnic groups or by sex.

Method

Using weighted linear generalized estimating equations, we explored whether the association between seven log‐transformed lipid‐adjusted OCs (ng/g) and CF is modified by race/ethnicity and sex in 985 adults, age 60+ from the National Health and Nutrition Examination Surveys (2011‐2014). Sample included: 57% females; 78.8% Non‐Hispanic (NH) White; 9.2% NH‐Black; 3.6% Mexican‐American; 4.1% Other‐Hispanic; 3.7% NH‐Asian; 0.5% Other Race/Ethnicity. A composite CF score was created using the mean of the z‐scores for word‐list memory test (CERAD W‐L) which included delayed recall and word list learning, animal fluency, and the Digit Symbol Substitution test (DSST). Covariates included age, education, marital status, sex, race/ethnicity. Sensitivity analysis included: BMI, Ratio of Income‐to‐Poverty (IPR) categorized in tertiles, and longest occupation held.

Result

Adjusting for covariates, lower composite‐CF was associated with higher levels of p,p’‐DDT (p = 0.040). This remained significant after adjusting for BMI (p = 0.045), but not when accounting for IPR (p = 0.117) or longest held occupation (p = 0.083). For specific CF tests, beta‐hexachlorocyclohexane, hexachlorobenzene, mirex, oxychlordane, p’p‐DDE, p’p‐DDT, and trans‐nonachlor were all associated with lower scores on DSST (p‐range = 0.03‐0.001). None of the associations differed by race/ethnicity. But a few differed by sex. After sex‐stratification, lower DSST scores were associated with higher levels of hexachlorobenzene in women (p = 0.032], but not men (p = 0.242). In sensitivity analyses, hexachlorobenzene lost all statistical significance after adjusting for each additional variable. The association between mirex and DSST disappeared after adjusting for longest occupation (p = 0.068). All other specific‐OC associations remained significant after BMI, IPR and occupation adjustment (p<0.05).

Conclusion

Higher blood levels of some OCs were associated with lower CF among older adults, some particularly affecting women, suggesting there may be long term negative effects of these chemicals. Future exposure studies should focus on sex‐differences. These associations did not differ between races; thus future analyses should consider examining within race/ethnic differences.
Preclinical development of a small molecule inhibitor of tau self‐association for Alzheimer’s disease and related dementias
Authors: Moe James , Cheesman Edward H. , Patel Dhruv R. , Greco Mindy , Sussman Chaya , Lopez Patricia , Davidowitz Eliot J.
Published: December 2022

Background

The approach for targeting toxic tau aggregates was to develop a small molecule inhibitor of tau self‐association that is agnostic to the types of aggregates formed. Pharmacodynamic studies of the lead compound in mouse models of tauopathy were performed. Therapeutic treatment of aged P301L tau JNPL3 mice showed reduced tau aggregation and improved motor behavior. Preventive treatment studies in young JNPL3 and htau mice with the lead also showed reduced tau aggregation. These results supported preclinical development of the lead to evaluate the potential of the compound for an Investigational New Drug Application (IND) submission to enable a first‐in‐human study.

Method

Process development and manufacturing of the compound was performed for the nonclinical safety studies (non‐GLP) and for drug substance (GLP) for clinical studies. To enable nonclinical studies, formulation work for oral administration of the compound was performed for pharmacokinetic studies to ensure sufficient oral bioavailibility for the toxicity studies. Dose range finding studies included a maximum tolerated dose (MTD) phase and a 14‐day repeat oral dosing phase in rat and dog (non‐GLP).

Result

Manufacture of the compound has been scaled to a 3 Kg batch size with 100% purity by HPLC (% area) as a single polymorph. Manufacture of capsule drug product for clinical studies was completed. Both the drug substance and drug product have shown good stability at room temperature storage. Oral bioavailibility was about 70% in rats and 40‐60% in dogs. Oral doses of 100, 300 and 1000 mg/kg/day in rats, and doses of 50 and 150 mg/kg/day in dogs for 14 days were well tolerated clinically, but the 500 mg/kg/day dose in dogs caused slight generalized tremors 1‐2 hours post‐dosing on multiple days. Hepatic effects were seen in both species, mostly at the higher doses in rats.

Conclusion

The results of the 14‐day studies enabled the selection of doses for the 28‐day rat and dog toxicity studies (GLP). The results of these studies in combination with the array of studies required for the IND application have been completed. The results of these studies were generally favorable, and the application is being prepared for submission.
Sovateltide (IRL‐1620) prevents oxidative damage, mitochondrial dysfunction, and memory loss in a transgenic mouse model of Alzheimer’s disease
Authors: Briyal Seema , Voshtina Ralf , Gulati Anil
Published: December 2022

Background

Alzheimer’s disease (AD) is the sixth leading cause of death in the United States and has no treatment or cure. New treatments are urgently needed. We have demonstrated cerebral endothelin B receptors (ETBR) as a potential target to treat AD. However, the mechanism of ETBR‐mediated neural regeneration and repair remains elusive. Therefore, we investigated the effect of sovateltide on progenitor cells mediated neural regeneration and its effect on cerebral tissue repair and functional recovery in transgenic AD mice.

Method

In this study, APP/PS1 transgenic mice and C57BL/6 control mice were divided into two groups (vehicle and sovateltide). Sovateltide (5 µg/kg) was intravenously injected three times at 2‐hour intervals on days 1, 3, and 6 every month until study endpoints (3‐, 6‐, and 12‐months age). Memory deficit was assessed using the Morris water maze test. Separate sets of mice were sacrificed at the end of 3, 6, and 12 months and beta‐amyloid plaque formation, oxidative stress, mitochondrial dysfunction, and cell survival parameters were assessed in the brain.

Result

APP/PS1 transgenic mice showed significant (p<0.001) impairment in spatial memory with elevated amounts of Aβ plaque. Treatment with sovateltide rescued learning and memory deficits and significantly (p<0.001) decreased Aβ plaque load compared to vehicle in 6 months and 12 months aged transgenic mice. Moreover, vehicle‐treated animals had high oxidative stress levels, as indicated by increased lipid peroxidation, MDA, and decreased antioxidants, SOD, and GSH compared to the vehicle group. These effects were reversed (p<0.001) in sovateltide treated animals indicating reduced oxidative stress. Higher neuronal progenitor cells (NPCs) differentiation and better mitochondrial morphology in the brain of sovateltide mice were also noted. There were no changes in the expression of any of these markers at three months.

Conclusion

Our data collectively demonstrate that sovateltide can improve memory deficits and neuronal damage and reduce oxidative stress and Aβ plaques in APP/PS1 mice. Our findings also strongly support the potential of sovateltide as a new multi‐target drug that can be used for treating Alzheimer’s disease.
Post COVID‐19 Cerebral Venous Thrombosis presenting as Acute Dementia
Authors: Dubey Shubham , Dubey Ayush
Published: December 2022

Background

Coronavirus disease (COVID‐19) is an infectious disease caused by SARS‐CoV‐2 virus which may lead to various neurological complications as reported in the literature. One important complication is CVT (Cerebral Venous Thrombosis) which classically presents as acute headache, seizures and focal neurological deficits. We report an interesting and rare case presentation of CVT here.

Method

A 32 year old female presented to ER with history of progressive forgetfulness since 4 days. She had difficulty in remembering recent activities and names of close associates. This was followed by holocranial headache after 2 days. She had history of COVID‐19 infection 20 days before the symptom onset. With the suspicion of acute vascular event, she was subjected to brain imaging.

Result

MRI brain with MR venogram showed left temporal venous infarct along with left transverse sinus and superior sagittal sinus thrombosis. She was treated with heparin and acenocoumarol subsequently along with supportive care with full relief in her symptoms.

Conclusion

CVT is now a known complication of COVID‐19 infection. It is generally an acute condition presenting with its classical features. However, it can also rarely present with other manifestations like acute cognitive decline or rapidly progressive dementia. Careful approach towards clinical presentation with appropriate diagnostic testing can quickly identify this condition for proper and timely treatment.
Novel HDAC11 Inhibitors for Alzheimer’s Disease Treatment in Preclinical Models
Authors: Wang Changning , Zhang Can
Published: December 2022

Background

HDAC activity and expression are implicated in cognitive function and animal research in Alzheimer’s disease (AD). This strongly suggests that HDAC inhibition is a promising lead toward developing improved treatment for cognitive decline. However, little is known about the role of HDAC11 in the etiopathogenesis of AD and whether HDAC11 can be a potential therapeutic target for AD, mainly due to lack of knowledge of HDAC11 in AD and absence of brain penetrant HDAC11 inhibitors.

Method

We synthesized and analyzed novel HDAC11‐selective and brain penetrant inhibitors and performed treatment using our novel HDAC11 inhibitors in the 5xFAD mice. The treatment outcomes are measured by PET imaging for target engagement, live animal optical imaging for amyloid neuropathology and behavioral tests for cognitive functions.

Result

Herein we report the development and characterization of PB94, a novel HDAC11 inhibitor. It exhibited potency and selectivity against HDAC11 with IC50 = 108 nM and >39‐fold selectivity over other HDAC isoforms, respectively. Pharmacokinetic/pharmacodynamic evaluation indicated PB94 possesses promising drug‐like properties. An array of in vitro assays was conducted to predict the safety, efficacy, and function of PB94. Additionally, PB94 was radiolabeled with carbon‐11 as [11C]PB94 for positron emission tomography (PET), which revealed significant brain uptake and metabolic properties suitable for DRUG DEVELOPMENT in live animals. Furthermore, we demonstrated that pharmacological inhibition of HDAC11 by PB94 can reduce abeta plaques and neuroinflammation by neuroimaging, in association with improved cognition in these animals.

Conclusion

Our findings show that HDAC11 may be a potential target for AD DRUG DEVELOPMENT. Our results set the stage for further development of PB94 as a potential therapeutic agent against AD.
Telomere attrition in induced pluripotent stem cell derived neurons from ALS/FTD related C9ORF72 repeat expansion carriers
Authors: Gonzalez Rodrigo Lopez
Published: December 2022

Background

The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dysregulated DNA damage response and the generation of reactive oxygen species (ROS) have been postulated as major drivers of toxicity in C9ORF72 pathogenesis. Telomeres are tandem‐repeated nucleotide sequences that are at the end of chromosomes and protect them from degradation.

Method

We analyzed telomere length in neurons and neural progenitor cells from several induced pluripotent stem cell (iPSC) lines from control subjects and C9ORF72 repeat expansion carriers. In addition, we analyzed RNA levels and protein levels of sheltering complex members.

Result

We found an age‐dependent decrease in telomere length in two‐month‐old iPSC‐derived motor neurons from C9ORF72 carriers as compared to control subjects. We also found a significant decrease in TRF1 and POT1 protein levels in 2 month old motor neurons.

Conclusion

We found an ae dependent decrease in telomere length and dysregulation of sheltering complex members in 2‐month old motor neurons from C9ORF72 carriers.
ENVISION: Increasing diversity of a large phase 3b/4 confirmatory trial of aducanumab to better understand the efficacy and safety among historically underrepresented participants of Alzheimer’s disease research and clinical trials.
Authors: Montenigro Philip H. , Cheng Wenting , O'Gorman John , Murphy Jennifer , Gillis Cai , Maserejian Nancy Nairi , Mascherino Liz , Butts Cherie , Ashraf Daanish , Racine Annie M , Aisen Paul , Castrillo‐Viguera Carmen , Haeberlein Samantha Budd
Published: December 2022

Background

While Black/African Americans and Latinx/Hispanics have nearly twice the risk of developing Alzheimer’s disease compared to Non‐Hispanic Whites, their involvement in clinical research and trials remains low. Due to the lack of data and underrepresentation in research, it is unknown if there are clinicopathological differences in Alzheimer’s disease or response to therapies. We have established specific recruitment goals for underrepresented groups in the aducanumab Phase 3b/4 confirmatory ENVISION study, which is a multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study of participants with mild cognitive impairment and mild dementia stages of Alzheimer’s disease (Stages 3 and 4; NCT05310071), designed to better understand the efficacy and safety of aducanumab treatment for these populations.

Method

Epidemiological and clinical data by race/ethnicity in the United States (US) were obtained from systematic literature reviews and Clinical trial data were then used to characterize the clinicopathological profile of Alzheimer’s disease among diverse groups. Data from underrepresented participants were pooled and analyzed contemporaneous Alzheimer’s disease clinical trials to identify potential differences (i.e., heterogeneity) in clinical and biomarker outcomes.

Result

Based on epidemiological analyses, the ENVISION has an enrollment target of 18% for patient populations historically underrepresented in clinical trials in the US. Limited pooled clinical trial data suggests there may be greater heterogeneity in clinical and biomarker endpoints in underrepresented groups.

Conclusion

Research and clinical trial data from diverse patient populations with Alzheimer’s disease are lacking. Inclusive research is essential to advancing the mission to develop treatments for this devastating disease. Data‐driven recruitment goals have been established and analyses planned to address the safety and efficacy of aducanumab in historically underrepresented populations in the ENVISION study. This could serve as a model for evaluating differences in treatment outcomes across racial/ethnic groups.
Using Community Engagement Studios to Increase Recruitment and Retention of Under‐Resourced Participants in Aging Research
Authors: Person Elisa , Orellana Minerva , Myers Peter , Foster Erin , Campbell Meghan , Mozersky Jessica , Denny Andrea , Clark Pechaz , Johnson Charis , Johnson Charis , Balls‐Berry Joyce E
Published: December 2022

Background

As the population ages in the United States, the prevalence of many diseases like Alzheimer disease, related dementias, and Parkinson disease disproportionately affect those already at greatest risk for premature morbidity and mortality. Aging research has an opportunity to engage and support patients, communities, and caregivers most impacted by these diseases. However, under‐resourced communities frequently lack representation in research, causing decreased generalizability of study results and health inequities among these communities.

Methods

Using a community and patient engaged framework, we conducted three community engagement studios (studios) with caregivers, patients, providers, researchers, and advocates from the St. Louis community. The studios provide community input and recommendations on project feasibility, design, and cultural appropriateness. Proposed projects were presented during each studio, followed by a facilitated discussion with a neutral facilitator. Themes were derived using traditional qualitative content analysis.

Results

Stakeholders included under‐resourced community members, LGBTQIA+ participants, and those without/inadequate health insurance. The main themes included participant commitment to health, culturally appropriate research design, and incentives. In addition, participants desired collaboration between researchers and the community, including connecting with local Alzheimer’s Disease Associations, faith‐based groups, and philanthropic organizations.

Conclusion

Our community stakeholders provided feedback on how we could modify the research design to increase community involvement, enhance participant recruitment and commitment, and reach populations currently underrepresented in aging research, especially Alzheimer’s disease. The early inclusion of stakeholders in research design and implementation constitutes a preliminary step to building trust within under‐resourced communities and increasing the recruitment and retention of diverse populations.
Perturbed astrocyte Ca2+ signaling in a diet‐based mouse model of small cerebral vessel disease
Authors: Norris Christopher M , Sompol Pradoldej M , Weiss Blaine E. , Gant Christopher C , Wilcock Donna M , Lin Ruei‐Lung , Thibault Olivier
Published: December 2022

Background

The hyperhomocysteinemia (HHcy) diet model of small cerebral vessel disease exhibits vascular inflammation, cerebral hypoperfusion, impaired neurovascular coupling, synapse dysfunction, and cognitive decline. Pathological changes in astrocyte structural features have also been noted, but functional astrocyte phenotypes have not been characterized. Here, we assessed Ca2+ signaling in individual astrocytes and astrocyte networks in barrel cortex of mice, pretreated with control or HHcy diet. Investigations were performed in fully awake mice to avoid confounding interactions between anesthetics, neural circuit activity, and vasoactive factors.

Method

Adult C57/BL6 mice were fed for 15 weeks with control chow, or chow deficient in vitamins B6/B12 and enriched in methionine (HHcy diet). At week 11‐12, mice were injected with AAV‐Gfa104‐lck‐GCaMP6f into barrel cortex, followed by craniotomies and installation of a glass cranial windows with headmounts. Three weeks later, fully awake mice were head‐mounted under a two photon microscope to assess GCaMP6/Ca2+ transient activity in barrel cortex astrocytes during a 10 minute baseline (spontaneous activity) and also before, during, and air puff stimulation of contralateral whiskers (10Hz, 10 sec) . Mean Ca2+ transient amplitudes, transient rise/decay times, and number of transients per region of interest (ROI) were measured and averaged across the field of view (FOV). Functional relationships between multiple ROIs within the FOV were assessed to evaluate astrocyte network activity

Result

Spontaneous Ca2+ transients were comparable in amplitude and rise/decay kinetics across diet conditions. However, the number of transients per ROI was reduced in HHcy diet mice. Whisker stimulation evoked a primary Ca2+ elevation per ROI followed 10‐15 seconds later by a smaller amplitude Ca2+‐“aftershock”. Evoked Ca2+ signals were highly coordinated across ROIs within the FOV. However, the number of active ROIs and the functional connectivity between ROIs were significantly reduced in HHcy vs. control diet mice. Despite these network deficits, evoked Ca2+ transient amplitudes and aftershocks in individual ROIs were significantly larger with faster activation/decay kinetics in HHcy mice.

Conclusion

The results suggest that altered astrocyte Ca2+ signaling, as a result of vascular pathology, may play an important role in the dynamic interplay between cerebral blood flow and neuronal activity, leading to overall neural dysfunction and cognitive impairment.