bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the Nav1.6:GSK3β Protein:Protein Interaction Complex to Mitigate Hippocampal Hyperexcitability in Early‐Stage Alzheimer’s Disease
Authors: Baumgartner Timothy J , Dvorak Nolan M , Singh Aditya K , Laezza Fernanda , Group Laezza Research 
Published: December 2022

AbstractBackgroundNav1.6 is the most densely expressed sodium channel isoform in the adult brain and is a primary determinant of action potential initiation and propagation due to its subcellular localization at the axon initial segment (AIS). Importantly, it has been shown that the firing frequency and Na+ currents of Nav 1.6 channels in hippocampal neurons are specifically increased by Aβ exposure in a concentration‐dependent manner. Nav1.6 is regulated through its interactions with key auxiliary proteins, notably Glycogen Synthase Kinase 3‐β (GSK3β), which has increased expression in the hippocampus of AD patients as well as peripheral circulating lymphocytes in both MCI and AD patients. We have shown that GSK3β regulates Nav1.6 channel activity through phosphorylation of and direct binding to the Nav1.6’s intracellular C‐terminal domain (CTD). Furthermore, genetic silencing of GSK3Ββ significantly decreased both Na+ currents and intrinsic firing compared to controls specifically through Nav1.6, while GSK3Ββ over‐expression or pharmacological disinhibition produced opposing phenotypes. Multiple lines of evidence indicate that hippocampal hyperactivity is present in patients with MCI and early‐stage AD and it is observed that reduction of hippocampal hyperactivity in MCI patients improves cognition and memory performance. We hypothesize that small‐molecule modulation of the Nav1.6:GSK3β PPI interface can counteract hippocampal hyperexcitability and could be used to treat early phases of AD, preventing the onset of cognitive decline.MethodHEK293 cells co‐transfected with WT or mutant Nav1.6 and GSK3β were utilized to interrogate the Nav1.6:GSK3β PPI and screen a series of 50 validated hit compounds using split‐luciferase complementation (LCA). Whole‐cell patch‐clamp electrophysiology was performed in heterologous cells and acute slice preparations to validate GSK3β‐mediated regulation of Nav1.6 activity and evaluate lead compound efficacy.ResultMutagenesis screening revealed putative interaction sites of the Nav1.6:GSK3β PPI. Counter‐screening of 50 validated hits revealed 5 compounds that inhibit Nav1.6:GSK3β complex assembly at low micromolar concentrations (Figure 1). Compound 5671063, identified from the counter‐screen, exhibits functional modulation of Nav1.6 activity in heterologous cells (Figure 2).ConclusionThe Nav1.6:GSK3β complex is a critical mediator of neuronal activity and represents a novel target for treatment of pathological hippocampal hyperexcitability associated with cognitive decline.
Mobile Toolbox: Age‐related change on remote, smartphone‐based measures of cognition
Authors: Nowinski Cindy J. , Kaat Aaron J. , Slotkin Jerry , La Forte Erica M , Shono Yusuke , Novack Miriam , Pila Sarah , Amagai Saki , Hosseinian Zahra , Adam Hubert , Gershon Richard C. 
Published: December 2022

AbstractBackgroundDifferentiating normal from pathological cognitive change in adults is essential for both preventing and treating abnormal cognitive decline. The Mobile Toolbox (MTB) is an app‐based research platform and expandable test library enabling remote assessment of cognition using participants’ own smartphones (iOS and Android). MTB facilitates conduct of diverse types of cognitive research with a broad range of participants, including those who may be hard to reach. However, evidence for MTB test validity, including demonstration of expected age‐related changes in adulthood, is needed to support MTB use. We present findings on associations between age and MTB performance.Method1,120 English‐speaking participants, ages 18–90, were recruited by a market research company as part of a larger study. Participants completed MTB remote measures of executive function, episodic and working memory, processing speed, and language on their smartphones. Measure order was fixed ((Vocabulary, Memory for Sequences, Spelling, Picture Sequence Memory (PSM), Flanker, Face Name (FNAME) Learning, Dimensional Change Card Sort (DCCS), Number Match, Face Name Memory)); individual tests could be taken anytime within a 14‐day period. Spearman correlation coefficients were calculated to evaluate relationships between age and test scores.ResultOur participant sample was 57% female, 13% Hispanic, 72% white; mean age = 45 (sd = 21). Education distribution was: < high school (2%); high school (34%); some college (34%), college (20%), graduate degree (11%). Measures of executive function (DCCS and Flanker: r = ‐0.50; ‐0.57) and processing speed (r = ‐0.56) showed decreased performance with age (all p < 0.001). Episodic memory scores also decreased with age, but correlations were weaker (PSM and FNAME: ‐0.2, ‐0.35; p.<.001). Performance on language tests did not significantly decrease with age.ConclusionMost MTB measures correlated with age in the expected directions. Fluid cognition (e.g., executive function and processing speed) and memory typically decrease with age, and this decrease was reflected in MTB test performance. In contrast, crystallized abilities (e.g., spelling and vocabulary), which are typically preserved as we age, did not decrease in our sample. Initial results suggest MTB can be used to identify abnormal cognitive decline and support its use in cognitive aging research.
Chimeric Phagocytic Receptors (CPR) to target Alzheimer’s disease pathology
Authors: Levites Yona , Ran Yong , Erquizi Aya , Iturbe Andrea , Dillon Kristy , Ryu Danny , Moore Brenda D , Golde Todd E 
Published: December 2022

AbstractBackgroundBased on the premise that protein aggregation and accumulation in AD and many other neurodegenerative disorders is a key, causal, pathologic event, therapeutic strategies need to focus on i) prevention of aggregate formation ii) enhancement of clearance of the aggregate or iii) neutralization of “toxic” signaling by the aggregate. Enhancing clearance of the target protein via phagocytic mechanisms is the most direct way to test the hypothesis that enhancing clearance will be beneficial. We cloned two novel chimeric phagocytic receptors (CPRs), fused to a previously characterized anti‐Abeta scFv. The present work aims to explore whether astrocyte expressed CPRs targeting Aβ enhance phagocyte clearance and alter the target pathology, when delivered into the brain of the Alzheimer’s disease mouse model, CRND8, as a prevention paradigm, before the pathology develops, or after amyloid aggregation already occurred.MethodAnti‐Abeta recombinant scFvs fused to two most promising CPRs were packaged in AAV under astrocytic GFAP promoter and delivered into the brains of newborn CRND8 mice (prevention paradigm) as well as older mice with preexisting pathology (treatment paradigm). Amyloid burden and Aβ levels in the soluble, SDS soluble and SDS‐insoluble, Formic Acid soluble fractions, as well as the state of astrocytosis and astrogliosis were compared between various cohorts. Backbone of the CPR without the scFv as well as pAAV‐EGFP served as controls.ResultInitially we evaluated expression, amyloid burden and GFAP and IBA staining in mice that were injected with 2 CPRs, pAAV‐MRC1‐GFAP‐scFv9, pAAV‐FCRG‐GFAP‐scFv9, as well as pAAV‐MRC1‐BB (backbone control) and pAAV‐EGFP control. Amyloid staining revealed a significant clearance of amyloid staining in the area around the injection site, which overlapped with the expression of CPR. Additionally, expression of CPRs resulted in increased astrocytes and microglia burden.ConclusionThese results suggest a significant amyloid alteration by chosen CPRs. Future studies will optimize brain delivery as well as determine therapeutic potential of CPRs following transplantation of the CPR expressing microglia/monocytes into the brain mice with preexisting pathology.
Challenges and opportunities in designing dementia‐friendly communities with local governments
Authors: Karamacoska Diana , Salunke Pranal , Shatnawi Eman , Caballero Gabriela , Steiner Genevieve Z. , Dadich Ann , DiGiacomo Michelle , Morrison Nicky , Alliance Canterbury‐Bankstown Dementia 
Published: December 2022

AbstractBackgroundCommunities that do not accommodate the needs and preferences of people with dementia can exacerbate disability and isolation. Although dementia‐friendly communities (DFCs) were established to foster understanding and acceptance of dementia, the built environment remains underexplored. We identified the challenges and opportunities for fostering dementia‐enabling environments among community planners.MethodThis study is set in South‐West Sydney, Australia, where a DFC is being established. The policies of seven local governments were analysed for actions that aligned with Dementia Australia’s 41 DFC recommendations: 13 for social, 14 for outdoor, and 14 for indoor environments. An online workshop was then held with 30 community planners to raise awareness for dementia‐enabling environments. Participants were surveyed about their dementia beliefs and attitudes. Facilitated discussions identified challenges and opportunities for designing DFCs. Qualitative and quantitative data across all sources were triangulated.ResultAlthough none of the local government policies specifically mentioned dementia, up to 20/41 DFC actions were met. Most of these were in social engagement (with ≤10/13 recommendations met by each local government). Less action was taken on outdoor and indoor environments (with ≤9/14 outdoor and ≤4/14 indoor recommendations met by up to six local governments). Although beliefs and attitudes about dementia among planners were generally positive, only 48% indicated that they had a good understanding of it and nearly 80% noted they would feel anxious and depressed about a diagnosis. Key DFC challenges included a lack of awareness and conflicting priorities between government bodies. Opportunities included engaging with universities to conduct demographically relevant awareness raising, facilitate multisectoral collaboration, developing an evidence‐base, and involving service providers to engage with the dementia community.ConclusionThis study triangulated data to identify gaps in community planning efforts, confirming that more action is required to design dementia‐friendly communities. We are now leading a multisectoral collaboration to educate community planners and the public, and are advocating for the recognition of dementia‐friendly environments in government plans. This study provides practical guidance to assist planners with DFC designs.
One Minute Early Dementia Screening Test for Indigent Countryside Indian Population: A Community Based Study
Authors: Singh Saranshi , IV Veer Bahadur Singh , Singh Saransh 
Published: December 2022

AbstractBackgroundWith the ageing of our populations there are increasing numbers of older adults with memory complaints and possible dementia. A new case of dementia in some form is diagnosed every 70 seconds according to the 2010 Alzheimer’s Disease Facts and Figures; moreover countryside population especially indigent population mostly remain undiagnosed. Hence to develop an easy to use dementia detection system has become an international priority for improving care of patients with prevalent neuropsychiatric disorders of later life.Method242 patients were enrolled justifying predesigned inclusion and exclusion criteria after approval from Institutional Ethics Committee. One minute dementia test was administered to them. The 1 minute dementia test is screening tool that had 4 components, testing immediate & delayed recall, orientation, and visuo‐spatial cognition. The Clock Drawing Test (CDT) component of this tool allows clinicians to administer this test among illiterate population and quickly assess numerous cognitive domains. A cutoff score of < 12 was considered abnormal. Receiver operating characteristic, partial correlation and logistic regression analyses were employed for evaluation.ResultIn this study, majority of subjects were greater than 65 years of age. Males accounted for 68% (n = 164) and females for 34% (n = 78). Mean age of the study population was 59.7 ± 13.46 years. A statistically significant decline in cognitive domain were noted in relation to patient education (p<0.001), locality predominantly rural based uneducated population (p<0.001) as well as increasing age (p<0.01) however, no statistically significant correlation (p>0.05) was observed in relation to patient’s sex. Delayed word recall was the most frequently impaired parameter (92.5%; n = 224) followed by visuo‐spatial cognition (82%; n = 198).Immediate recall (4.9%; n = 12) was minimally effected. CDT was abnormal among 69% (n = 168) patientsConclusionIn the present study 87% (n = 210) of the patients had abnormal test. Delayed word recall was the earliest domain to get impaired followed by visuo‐spatial cognition. A cutoff score of < 12 best correlated with risk of detecting dementia. Thus, 1 minute dementia test can be a useful screening tool for detecting dementia in outdoor basis patients though larger studies are required to validate its clinical implications.
Positive Affect and Cognitive Functioning in Older African American Adults
Authors: Halter Colt M , Moll Allison C. , Kero Katherine , Hanna Sophie , DiCerbo Loraine M. , Woodard John L. , Giordani Bruno , Daugherty Ana M. , Kavcic Voyko 
Published: December 2022

AbstractBackgroundPrevious research has demonstrated a link between affect and cognitive functioning, particularly showing that negative affect is related to lower cognitive performance across several cognitive domains. However, the relationship between positive affect (PA) and cognitive functioning is not as thoroughly characterized, though some previous work suggests that PA may be related to improved memory consolidation and greater cognitive flexibility. There is little research, if any, on the relation between PA and cognition in older adults from diverse racial backgrounds, who are also at greater risk for Alzheimer’s disease. PA may be a modifiable factor and target for intervention to deter cognitive decline. Therefore, we investigated whether PA was related to cognitive functioning in a sample of community‐dwelling, older African American adults. We predicted that greater PA would be associated with greater global cognitive functioning, immediate memory recall, and delayed memory recall while controlling for age.MethodTelephone screenings were administered to 194 older African Americans (aged 64‐94 years). Global cognitive functioning, immediate recall, and delayed recall were measured via the Telephone Interview for Cognitive Status‐Modified (TICSm). Immediate and delayed recall scores were excluded from global cognitive functioning scores to reduce conceptual overlap. PA was measured with a questionnaire of emotional functioning. We used hierarchical linear regression to determine whether PA was positively associated with cognitive functioning while controlling for age.ResultHigher PA was predictive of greater global cognitive functioning, after accounting for the effect of age (F(2,191) = 15.70, p<.001; ΔR2 = .05, b = 0.68, SE = 0.21, p = .002). Similarly, higher PA was predictive of greater immediate recall (F(2,191) = 14.10, p<.001; ΔR2 = .03, b = 0.45, SE = 0.19, p = .019) and delayed recall (F(2,191) = 7.44, p<.001; ΔR2 = .02, b = 0.48, SE = 0.23, p = .035).ConclusionIn support of our hypothesis, we have demonstrated that greater PA is associated with greater global cognitive functioning, immediate memory recall, and delayed memory recall among older African American adults. Past studies report some relationships between PA and cognition, though little, if any, work has been done with aging adults from diverse racial backgrounds. Understanding how PA relates to cognition in late life is crucial because it may be a modifiable protective factor and a target for intervention.
Apigenin restores memory function in stressed mice
Authors: Olayinka Juliet Nnenda , Okosun Maureen Omoazagba , Amadi Manuchim Chibuzor , Ikpen Joshua Oghenemudiakewve 
Published: December 2022

AbstractBackgroundStress, a known cause of neuropsychiatric disorders, is associated with cognitve dysfunction, neuroendocrine systems breakdown and altered brain oxidative status and proteins (Roozendaal, 2002; Radecki et al., 2005; Lupien et al., 2007). Apigenin (API), a natural flavonoid, with diverse biological activity, is thought to possess neuroprotective potentials (Li et al., 2015). This study investigated whether API administration abrogates chronic unpredictable mild stress (CUMS)‐induced cognitive impairment, as well as exploring its probable underlying mechanisms.MethodSwiss male mice (n = 10) were treated with API (12.5 ‐ 25 mg/kg, intraperitoneally) 30 min before exposure to CUMS daily for 14 days, thereafter tested for memory function using the Y‐maze and novel object recognition (NOR) tests. Levels of malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), and corticosterone levels were assessed using enzyme‐linked immunosorbent assay. The expressions of brain derived neurotrophic factor (BDNF), phosphorylated extracellular signal‐regulated kinase (pERK), and cAMP response element‐binding protein (pCREB) were assessed using immunohistochemistry.ResultCUMS produced cognitive impairment in mice as shown in the Y‐maze and NOR tests. CUMS significantly elevated MDA, and serum corticosterone levels, including reducing GSH and SOD levels, decreasing BDNF, pERK, and pCREB levels in the prefrontal cortex and hippocampus. However, chronic administration of API significantly prevented all these CUMS‐induced behavioral and biochemical alterations.ConclusionAPI may be a potential therapeutic agent for cognitive disturbances as seen within the stress model and its neuroprotective effect was partly mediated by restoring oxidative status, serum corticosterone levels, up‐regulating BDNF, pCREB and pERK levels.
References
Lupien SJ, Maheu F, Tu M, Fiocco A, Schramek TE. The effects of stress and stress hormones on human cognition: implications for the field of brain and cognition. Brain Cogn 2007; 65:209‐37Roozendaal B. Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval. Neurobiol Learn Mem 2002;78: 578‐95Radecki DT, Brown LM, Martinez J, Teyler TJ. BDNF protects against stress‐induced impairments in spatial learning and memory and LTP. Hippocampus 2005;15: 246‐53.Li R, Zhao D, Qu R, Fu Q, Ma S. The effects of apigenin on lipopolysaccharide‐induced depressive‐like behavior in mice. Neuroscience letters. 2015 May 6;594:17‐22.
Effect of Matcha green tea on cognitive functions and sleep quality in elderly adults with cognitive decline: a randomized controlled study over 12 months
Authors: Uchida Kazuhiko , Meno Kohji , Suzuki Hideaki , Korenaga Tatsumi , Ito Hitomi , Inoue Makoto , Shan Liu , Ota Miho , Shiraki Noeru , Nakamura Shin , Yomota Satoshi , Akinaga Nobuyuki , Baba Yoshitake , Tagata Chika , Araki Yoshiharu , Tsunemi Shuto , Aso Kenta , Inagaki Shun , Nakagawa Sae , Kobayashi Makoto , Asada Takashi , Arai Tetsuaki , Takihara Takanobu 
Published: December 2022

AbstractBackgroundNutrition is a pivotal factor in the prevention of dementia. Matcha green tea powder, which contains L‐theanine, caffeine, and epigallocatechin gallate, has the beneficial effects of each constituent on cognitive functions and mood. However, no long‐term clinical study has yet been performed to evaluate the effect of Matcha on psychological functions. Here, we performed a randomized, double‐blinded, placebo‐controlled, clinical study, conducted over 12 months, to investigate the effect of Matcha on cognitive functions and sleep quality. Furthermore, the relationship between blood and neuroimaging biomarkers and the effect of Matcha was investigated.MethodsWe recruited 939 community‐dwelling older adults aged 60–84 years and enrolled subjects with a diagnosis of subjective cognitive decline (SCD) and mild cognitive impairment (MCI). A total of 99 subjects (64 SCD, 35 MCI) were randomized, with 49 receiving Matcha (2 g/day, male 23, female 26) and 50 receiving placebo (male 20, female 30). The groups were adjusted for age, sex, and APOE4 genotype. Cognitive functions were assessed by MMSE, MoCA, ADAS‐cog, RBANS, and the CNS Vital Signs computerized neurocognitive battery. Sleep quality was measured by the Pittsburg Sleep Quality Index (PSQI). Plasma biomarkers and neuroimaging (Amyloid PET, MRI, SPECT, fNIRS) were also assessed. The change of outcome variables from the baseline to 12‐month was tested statistically using a mixed‐effects model.ResultsCompared to the placebo, the consumption of Matcha induced a significant improvement in social acuity assessed by perception of facial emotion (P = 0.034), while continuous performance showed a trend towards improvement. The PSQI differed by 0.86 between the groups, indicating an improvement in sleep quality in the Matcha group compared to the placebo group (P = 0.087). The MMSE score showed a slight increase in the Matcha group. Amyloid PET SUVR showed no change from baseline to 12‐month in either group, while the plasma Aβ42 was reduced in the Matcha group, suggesting increased clearance of peripheral Aβ42.ConclusionFacial emotion recognition is impaired in cognitive impairment. This long‐term intervention study suggests that Matcha consumption can improve emotion perception and attention, and sleep quality in elderly adults with cognitive decline.
Impact of Decentralized Clinical Trial Methodologies on Alzheimer’s research
Authors: Kalali Amir 
Published: December 2022

AbstractBackgroundThe Decentralized Trials and Research Alliance represents over 120 organizational members including regulatory authorities, biopharmaceutical companies, technology companies, patient advocates, clinical trial sites, and service companies. Four priority areas have been identified to accelerate the adoption of decentralized methodologies where appropriate in clinical research. Within these four priority areas, 12 initiatives were launched.MethodThe more than 120 organization members took part in a formal process to identify priority areas and initiatives that would drive these priorities. Leaders and group members were assigned to these initiatives and clear outputs. For this project we looked at the relevant initiatives that would specifically be relevant to Alzheimer’s disease clinical research and improve the conduct of these trials in areas such as recruitment, patient focus, and diversity.ResultThis presentation will discuss how these initiatives that will have an impact on improving the efficiency and success of research in Alzheimer’s disease.ConclusionAlzheimer’s disease research faces many challenges that include attracting enough clinical trial participants, improving access in an equitable way, including to patients not geographically near clinical trial centers. Decentralized research methodologies can assist clinical trial sponsors and clinical research sites improve on these and many other aspects of clinical research.