bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mannose‐labeled nanoparticle exclusive delivery of antagomirs to microglia alleviate Alzheimer’s Disease pathobiology
Authors: AMER AMAL 
Published: December 2023

AbstractBackgroundUnder normal conditions, amyloid (Aβ) is released extracellularly by neurons as a neuroprotective molecule while healthy microglia ingest and degrade Aβ to maintain a balance between production and clearance. One of the hallmarks of Alzheimer’s Disease (AD) is the presence of plaques composed of aggregated, fibrillar amyloid beta (Aβ) that usually precedes the deposition of Tau. Aggregated Aβ can be degraded within healthy microglia largely by autophagy. Most vacuoles containing Aβ acquire the autophagy marker LC3 in primary WT microglia but not in AD microglia. It is still unclear why microglia in the AD brain fail to clear Aβ. Microglia in human AD brain sections and in the 5XFAD (AD) mouse model congregate around Aβ plaques and express high levels of miR‐17 which we found targets autophagy effectors.MethodWe examined the effect of targeting microRNA miR‐17 in vitro and in vivo using designed mannose‐labeled nanoparticles for the delivery of antagomirs exclusively to microglia.ResultIsolated primary microglia from adult AD mouse fail to degrade Aβ in comparison to wild‐type (WT) microglia. The expression of autophagy effectors Nbr1, Atg5 and Atg7, which are targets of miR‐17, are significantly reduced in AD mouse microglia (CD11b+) and not in CD11b− fraction which contains astrocytes and neuronal cells. This is the first report of significant increase of miR‐17 in the microglia of AD humans and mice. The increased expression of miR‐17 in AD microglia reduces the expression of autophagy effectors leading to defective autophagy in AD microglia. We show that reducing the expression of miR‐17 using specific antagomir (Anti‐17) in AD microglia in vitro, is sufficient to significantly improve their ability to degrade Aβ. Importantly, we successfully injected live AD mice with Anti‐17 enclosed within mannose‐labeled nanoparticles (Man‐NPs) which specifically target the mannose receptor mainly expressed on microglia. This delivery method significantly and explicitly reduced the elevated expression of miR‐17 in microglia, reduced the expression of Aβ in the brain and reduced hyperactivity behavior in live AD mice.ConclusionTogether, we describe Man‐NPs for the delivery of antagomirs specifically to microglia. We show that targeting miR‐17 in microglia is sufficient to prevent AD pathobiology.
Signatures of abnormal deviations in excitation‐inhibition balance for amyloid positive individuals
Authors: Fortel Igor , Zhan Liang , Ajilore Olusola , Wu Yichao , Mackin Scott R , Leow Alex 
Published: December 2023

AbstractBackgroundDysfunctional excitation‐inhibition balance (EIB) is hypothesized to precede cognitive impairment in Alzheimer’s disease (AD); however, overlapping neuropathology (like amyloid plaques) can develop in cognitively normal (CN) and impaired (CI) individuals. We investigate EIB trajectories for individuals with significant amyloid (Aβ+).MethodMultimodal imaging was used to construct hybrid resting‐state structural connectomes (Fortel, Igor, et al. Network Neuroscience 6.2 (2022): 420‐444.), computing whole‐brain EIB based on 105 ROIs. This cohort (N = 185, 94 Female) aged 55‐90 (μ
FEMALES = 74.9, and μ
MALES 73) was limited to Aβ+ individuals with APOE genotyping (ε3/ε3, ε3/ε4, ε4/ε4); grouped further by clinical dementia rating (CDR), with CDR > 0 indicating CI. Imaging, Aβ+ classifications, CDR, and APOE were obtained from OASIS‐3: Longitudinal Multimodal Neuroimaging: Principal Investigators: T. Benzinger, D. Marcus, J. Morris; NIH P30 AG066444, P50 AG00561, P30 NS09857781, P01 AG026276, P01 AG003991, R01 AG043434, UL1 TR000448, R01 EB009352. AV‐45 doses were provided by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly.ResultResults presented in Figure 1 suggest whole‐brain EIB in both CN sexes with Aβ+ decreases with increasing age (APOE‐ε4 agnostic). However, sex differences are highlighted with CI; regression analyses produce a marginally significant 4‐way interaction of age, sex, cognitive status, and APOE (P = 0.085, β = ‐0.013). Partial correlation of EIB with age, controlling for sex, APOE and cognitive status is also significant (P = 0.016, r = ‐0.18). Results indicate sex‐mediated EIB differences in individuals with CI, dominated by APOE‐ε4 in women rather than amyloid.ConclusionWe’ve demonstrated EIB deviations in cognitively impaired men and women that may be associated with AD neuropathology. Our findings are consistent with known AD sex differences and suggest novel multimodal connectomics may capture subtle disruptions in brain dynamics that traditional methods may not.
Figure. 1.
Whole‐brain excitation‐Inhibition balance (EIB) trajectories for amyloid positive (Aβ+) men and women. The cognitively normal (CN) group (rows A‐B) suggests no sex differences in EIB trajectories with age, while the cognitively impaired (CI) group (rows C‐D) begins to reveal distinct patterns of dysfunction (more significantly in women with APOE‐ε4). Note a value of 0.5 indicates perfect balance.
Neurobiological mechanisms involved in the relationship between loneliness, depression, and cognitive decline in older adults
Authors: Dabiri Sanaz , Mwendwa Denée T , Campbell Alfonso L 
Published: December 2023

AbstractBackgroundLoneliness among older adults is one of the risk factors for developing dementia. Yet, little is known about the neurobiological and psychological conditions that link loneliness to cognitive decline. The current study had several aims: First, it sought to determine whether the relationship between loneliness and cognitive decline is sex‐specific in older adults. Second, it sought to identify neurobiological and psychological pathways that may account for the relationship between loneliness and decline across several cognitive domains. These pathways included depressive symptoms, gray matter volume, and conditional analyses of pro‐inflammatory cytokines and brain‐derived neurotrophic factor (BDNF) expression. Third, it examined loneliness as a predictor of mild cognitive impairment (MCI) and Alzheimer’s disease (AD).MethodLongitudinal data were collected from 2130 Rush Memory and Aging Project MAP participants. Participants underwent annual cognitive and psychological assessments and neuroimaging procedures. BDNF gene expression was measured in the dorsolateral prefrontal cortex, and the final clinical diagnosis was identified upon autopsy at death. Cytokines were measured in serum. Linear mixed models and multinomial logistic regression analyses were used. All models controlled for age at baseline, education, and sex.ResultParticipants were largely women (73%), and Caucasian (93%). The average age at baseline was 80.05 (SD = 7.57) and education was 14.93 (SD = 3.34). Results showed that gray matter volume and depressive symptoms partially mediated the relationship between loneliness and cognitive decline. BDNF expression was positively related to cognitive performance, and its interaction with loneliness was related to slower cognitive decline in semantic memory and better visuospatial performance. Finally, the current study also established that loneliness was a predictor of the incidence of AD and other dementias.ConclusionThe present findings suggest that loneliness may elicit physiological changes in our brains that lead to cognitive decline over time. Future research can explore a wide range of biological and psychological expressions of loneliness to clarify how loneliness relates to dementia.
A feasibility study to explore the use of real‐time caregiver reports for people living with dementia at home to label multi‐modal sensor data
Authors: Chu Charlene H , Abedi Ali , Dayyani Faranak , Khan Shehroz 
Published: December 2023

AbstractBackgroundMulti‐modal sensor systems, consisting of sensors throughout the home, are able to collect data on the person living with dementia’s (PlwD’s) activities. However, caregivers may have challenges interpreting the data, leading to a lack of actionable information. It’s important to get real‐time reports from caregivers to label the sensor data to build relevant machine learning algorithms; yet, this has not been done with PlwD. The aim of this feasibility study was to explore if the use of a multi‐modal sensor system in conjunction with real‐time caregiver reports can provide valuable insights into the daily lives of PlwD.MethodWe developed the MAISON (Multimodal AI‐based Sensor platform for Older Individuals) system and deployed it into the homes of dyads (PlwD and their family caregiver) for 8‐weeks. MAISON includes: a smartphone, a smartwatch to continuously collect heart rate, step, and accelerometer data to infer walking, and running, as well as a smart mattress that can collect sleep time and quality. A digital diary was added to the MAISON system that automatically sends the caregiver 2‐3 pre‐set questions every day about their loved one. Caregivers could also report any significant occurrences throughout the day, as they see fit, through the app.ResultTwo dyads were recruited to date. Only about 15% of data was missing from the sensor system by the end of the study. Caregivers were providing their reports with high adherence. The caregivers’ reports were used to label the sensor data successfully, and upon analysis, we found that caregivers’ reports were reflected in the sensor data and the labels derived from their reports were accurate. Results indicate this study methodology is an innovative approach to utilize the family caregiver’s reports.ConclusionThis is the first longitudinal study to demonstrate the feasibility of a multi‐modal sensor system used by caregivers and PwlD. Findings show that caregivers' reports can be useful sources of data for labeling sensor data. The conjunction of caregiver reports and sensor data will provide valuable information to build accurate machine learning models about behaviors of PlwD which is a foundational step to support dyads at home using technology.
A brain‐wide risk score of Alzheimer’s disease based on multimodal neuroimaging predicts cognition in large N>37000 population data
Authors: Zendehrouh Elaheh , Sendi Mohammad S.E. , Calhoun Vince D 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most frequent age‐related dementia impairing memory, thinking, and social skills. Much research has been conducted in recent years to investigate the genetic risk of AD, but little effort has been made to find a brain imaging‐based AD risk evaluation. Here, we proposed a multimodal neuroimaging‐based measure of AD risk, called brain‐wide risk score (BRS).MethodFunctional network connectivity (FNC) and voxelwise gray matter (GM) from the Open Access Series of Imaging Studies (OASIS)‐3 (N = 1302 samples) cohort was used as a reference dataset to define mild cognitive impairment (MCI) and control (CN)group to evaluate individuals in the UK Biobank (N = 37,784) dataset. We calculated the mean of FNC and GM of MCI and CN. Next, we removed the mean FNC and GM from each sample FNC and GM of the target dataset. Then, we calculated the distance between the target dataset and CN (i.e., dist_CN) and MCI (i.e., dist_MCI) of the reference dataset using Euclidian distance. Finally, we calculated Δdiff = dist_CN‐dist_MCI as a BRS of AD, where the positive values are associated with higher AD BRS. Using two BRSs estimated based on FNC and GM for target dataset, we identified four AD biotypes. Samples with two negative Δdist represent low AD risk (Biotype1), samples with two positive Δdist represent high AD risk (Biotype4), and samples with one negative and one positive Δdist represent moderate AD risk (Biotype2/3). Next, we compared cognitive scores including fluid intelligence (FI) and reaction time (RT) across four biotypes.ResultFig.1 shows the 2D histogram of two BRS estimated from FNC and GM. We identified 11704 participants as biotype1, 10910 as biotype2, 7804 as biotype3 and 7366 as biotype4. We also found that Biotype1, with lower AD BRS, significantly shows a higher FI score than Biotype3 and Biotype4 (Fig.2, FI panel). Additionally, Biotype 4, with the highest BRS, had the most increased RT among all four AD biotypes (Fig.2, RT panel).ConclusionWe develop a new multimodal neuroimaging‐based BRS based which we identified four AD biotypes. We found that BRS predict cognitive scores in the identified biotypes.
Behavioral, biochemical, and neuropathological outcomes in amyloid‐bearing mice treated long‐term with a range of doses of BACE inhibitor
Authors: Watkins Elyse , Gallagher Declan , Mahesh Shreya , Reed Myles , Vassar Robert J. 
Published: December 2023

AbstractBackgroundSmall molecule BACE inhibitors, while promising for the treatment of AD, have been discontinued in clinical trials due to early and non‐progressive cognitive worsening. There is great interest in finding a dose of inhibitors that can protect from AD pathology while sparing cognitive issues. Furthermore, there is interest in determining which substrate(s) is mediating the cognitive worsening.MethodPDAPP mice, which express human APP that lack mutations affecting BACE cleavage, were treated with five doses of BACE inhibitor in their chow. Mice were treated from 8 months to 14 months, and Morris Water Maze, Novel Object Recognition, and Rotarod were performed immediately prior to the study’s completion. Cleavage of BACE substrates, including APP, Sez6, Sez6L, APLP1, CHL1, and others were assessed by western blot, and correlated with cognitive assessments. The extent of amyloid buildup during treatment was quantified.ResultTreatment with BACE inhibitor led to a dose dependent protection from amyloid plaque buildup. There were treatment‐dependent effects on behavior.ConclusionThis study has implications for determining a potential safe and effective dose of BACE inhibitors in humans.
Cognitive and Exercise Training Improves Intraindividual Variability in Cognitive Performance in Older Adults: Secondary Findings of A Randomized Controlled Trial
Authors: Silva Nárlon Cássio Boa Sorte , Brinke Lisanne F Ten , Bielak Allison AM , Handy Todd C , Liu‐Ambrose Teresa 
Published: December 2023

AbstractBackgroundIncreased intraindividual variability of cognitive performance is a marker of cognitive decline. Whether computerized cognitive training (CCT) and aerobic exercise counteracts cognitive decline by reducing intraindividual variability is unknown. We investigated the effects of CCT with or without aerobic exercise on reaction time intraindividual variability in older adults.MethodThis was a secondary analysis of an 8‐week randomized controlled trial. Older adults (aged 65‐85 years) were randomized to CCT alone (n = 41), CCT with aerobic exercise (n = 41), or an active control group (n = 42). The CCT group trained using the Fit Brains® platform 3×/week for 1 hour (plus 3×/week of home‐based training). The CCT with aerobic exercise group received 15 min of walking plus 45 min of Fit Brains® 3×/week (plus 3×/week of home‐based training). The control group received sham exercise and cognitive training (3×/week for 1 hour). We extracted reaction times from the Dimensional Change Card Sort Test, Flanker Inhibitory Control and Attention Test (Flanker), and Pattern Comparison Processing Speed Test (PACPS). Intraindividual variability was measured as residual intraindividual standard deviation (residual ISD) of raw reaction time latencies. Residual ISD is an unbiased measure of variability that accounts for within and between participant source of variation that could influence reaction time latencies. We also calculated reaction time intraindividual SD (raw‐score ISD) and intraindividual coefficient of variation (ICV).ResultCompared with the control group, residual ISD improved in a processing speed task (PACPS) following CCT alone (mean difference [95% confidence interval]: ‐0.147 [‐0.230 to ‐0.065], p<0.001) and CCT with aerobic exercise (‐0.111 [‐0.195 to ‐0.027], p<0.01). Also, for processing speed, both CCT (‐0.173 [‐0.261 to ‐0.084], p<0.001) and CCT with aerobic exercise (‐0.122 [‐0.213 to ‐0.032], p<0.01) showed greater reduction in raw‐score ISD compared with controls, while only CCT reduced ICV for this task (‐0.108 [‐0.176 to ‐0.040], p<0.001). Inhibitory attention (Flanker) improved only after CCT with aerobic exercise (congruent = ‐0.128 [‐0.250 to ‐0.006], incongruent = ‐0.121 [‐0.237 to ‐0.005], both p<0.05).ConclusionA CCT program promoted cognitive health via reductions in intraindividual variability of cognitive performance and combining it with aerobic exercise resulted in broader benefits.
The effect of aquaporin‐4 mis‐localization on Aβ pathology in mice
Authors: Pedersen Taylor J , Keil Samantha A , Han Warren , Wang Marie X , Iliff Jeffrey J 
Published: December 2023

AbstractBackgroundThe reduced clearance of amyloid‐beta (Aβ) is thought to contribute to the development of Alzheimer’s disease (AD) pathology, characterized by the deposition of Aβ plaques. Previous studies have shown that Aβ is cleared via the glymphatic system, a brain‐wide network of perivascular pathways that support exchange between cerebrospinal fluid and interstitial fluid within the brain. Such exchange is mediated by the water channel aquaporin‐4 (AQP4), localized at astrocytic endfeet. Research has found that the deletion or mislocalization of Aqp4 is associated with reduced Aβ clearance and, in turn, Aβ plaque formation.MethodIn this study, we evaluated how the deposition of Aβ plaques within a 5xFAD mouse model is impacted by either the mislocalization or deletion of perivascular AQP4. We utilized both the AQP4 knockout mouse and α‐syntrophin (Snta1) knockout mouse, which lacks perivascular AQP4 localization, and crossed them with a mouse model line of amyloidosis (5xFAD) to determine the effect on Aβ deposition. Mice were perfused at 18 weeks and amyloid‐beta, AQP4, and lectin were assessed by immunofluorescence. Amyloid β distribution was evaluated anterior to posterior through the brain utilizing regions of interests for entire slice, cortex, corpus callosum, hippocampus, subiculum, sub cortical structures, and amygdala when applicable.ResultWe observed that both the absence (Aqp4KO) and mislocalization (Snta1KO) of AQP4 significantly increases amyloid distribution across the brain, when compared with 5xFAD littermate controls. Further, the mislocalization of AQP4 resulted in a significant increase in the size of Aβ plaque deposition not present with AQP4 deletion.Conclusions highlights that the mislocalization of perivascular AQP4 has a greater impact on increased amyloid burden than the deletion of AQP4. In suggesting that the mechanism of AQP4 mislocalization may lie upstream of amyloid or tau pathology, targeting perivascular AQP4 localization may be provide a novel pathway toward secondary, or potentially primary prevention of Alzheimer’s disease.
Association of GAB2 genotype with EEG characteristics and vascular reactivity to hyperventilation in nondemented adults during aging
Authors: Ponomareva Natalya V , Andreeva Tatiana , Protasova Maria , Kunizheva Svetlana , Kolesnikova Ekaterina P , Malina Daria , Fokin Vitaly , Illarioshkin Sergey , Rogaev Evgeny I 
Published: December 2023

AbstractBackgroundGAB2 rs2373115 genotype increases the risk of Alzheimer’s (AD) and vascular (VD) diseases (Reiman et al., 2007; Lambert et al., 2013; Kondreddy et al., 2021). EEG reactivity to hyperventilation (HV) depends on hypocapnia‐induced cerebral vasoconstriction, which may be impaired in subjects with preclinical AD and VD. EEG differences in the carriers of GAB2 genotype in nondemented adults remain unknown. The study was aimed to determine the possible effect of GAB2 rs2373115 genotype on resting EEG and EEG reactivity to HV in non‐demented adults during aging.MethodThe enrolled cohort included 151 healthy volunteers, age range 20‐80 years, stratified by GAB2 rs2373115 genotype. Informed written consent was obtained from all participants. All subjects underwent a neurological examination and cognitive screening. The significance of the differences between the EEG in different subgroups was estimated using ANOVA in the general linear model. APOE and sex was included in the analysis as covariates.ResultIn the entire sample the presence of GAB2 C allele was associated with higher alpha2 relative power in resting EEG, with more pronounced differences in the right parietal area.EEG reactivity to HV decreased with aging, and the decrease was more pronounced in the carriers of GAB2 C allele. Under HV the older GAB2 AC&CC carriers as compared with the older GAB2 AA carriers had lower theta power. The HV reactivity of blood pressure and heart rate was decreased in aging to a greater extend in the GAB2 C allele carriers than in the homozygous GAB2 AA individuals.ConclusionThe results show that GAB2 genotype is associated with alpha2 relative power difference in non‐demented adults. Reduced EEG and vascular reactivity to HV in the older GAB2 C allele carriers indicates altered cerebrovascular reactivity to hypocapnia and suggests that vascular factors can mediate GAB2‐related AD susceptibility.The study was supported by Russian Science Foundation (Project N 22‐15‐00448, Project N 19‐75‐30039 genotyping) and the National Institutes of Health, United States (grant R01AG054712 to ER statistical analysis).
Neuroprotective effect of Tropisetron in Streptozotocin induced animal model of Alzheimer’s disease
Authors: Kumari Shilpa , Deshmukh Rahul Renukadas , Sharma Rupali 
Published: December 2023

AbstractBackgroundAlzheimer’s disease is a neurodegenerative pathology having genetic and non‐genetic forms. Non‐genetic forms of AD dominate over the genetic condition and is mainly sporadic. However, both forms affect cognitive functions. Although exact mechanisms are not fully understood, amyloid β deposition & tau tangle formation are considered central mechanisms to cause neurodegenerative changes in the AD brain. On the other hand, cognitive deterioration began way before the accumulation of amyloid or tau tangle formation. Cognitive functions, including learning and memory, have been majorly controlled/regulated by the cholinergic system. Here in the present study, we have explored the neuroprotective effect of tropisetron in streptozotocin‐induced animal model of Alzheimer’s disease. During the last two decades, the involvement of other neurotransmitter systems has been explored, and the serotonergic system has been demonstrated to play an essential role in memory and learning. The serotonergic system is the most extensive monoaminergic system in the brain, and alterations in serotonergic signals have been linked with Aβ and tau tangle formation. Moreover, serotonin acting through its receptor antagonist has been reported beneficial in various experimental AD models.MethodIn the present study animals were infused with STZ alternatively on 1st and 3rd day. From 15th day animals were treated with tropisteron with two subsequent doses (2.2.5mg/kg) and (5mg/kg). On 28th day animals were sacrificed. Further animals were tested for behavioral, biochemical and histopathological parameters.ResultTropisetron significantly attenuated oxidative damage and restored the reduced levels of anti‐oxidant enzymes. ICV‐STZ treatment had shown significant neuronal damage in hippocampal and cortical regions of AD brain in histopathological examination. Moreover, hippocampal neurons were observed to be irregular in morphology with dark pyknotic nuclei. This confirms the neurodegeneration in ICV‐STZ animals. Target drug tropisetron resulted in significant neuroprotection against ICV‐STZ.ConclusionThe observed outcomes of the present study suggest the neuroprotective effect of tropisteron in STZ induced animal model of Alzheimer’s disease.It would be safe to conclude that tropisetron may improve the behavioral outcomes by attenuating oxidative burden & its neuroprotective potential as seen in our histological assessment.