bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Executive Functioning between Ageing Urban and Rural Participants in India: A Cross‐sectional Analysis
Authors: Menon Meenakshi , Lingegodwa Abhishek Mensegere , Stezin Albert , Hameed Shafeeq K Shahul , Malo Palash Kumar , Narayanasamy Rajitha , R Meghana , Mallikarjun Divya N , Partha Ajith , M Amitha C , HS Sunitha , Velavarajan Goutham , Singh Sadhana , Diwakar Latha , Kommaddi Reddy Peera , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: December 2023

Background

Older adults living in urban areas differ from their rural counterparts in many ways, including the cognitive performance. Executive functioning is one of the few cognitive domains that is implicated to be affected in early stages of dementia. However, there are very few studies that have explored differences in cognitive functioning across rural and urban contexts in India. Our objective was to evaluate differences in executive functioning across urban and rural participants.

Method

Our study sample includes ageing individuals (≥ 45 years): 1089 from the urban Tata Longitudinal Study on Ageing (TLSA) cohort and 4913 from the rural Srinivaspura Ageing, Neuro Senescence and COGnition (SANSCOG) study cohort. The TLSA and SANSCOG are parallel, harmonised, community‐based cohort studies in urban and rural India exploring the risk and protective factors associated with cognitive changes due to normal ageing, dementia and other related disorders. The difference in executive functioning measured by Categorical fluency, Letter fluency, Visuospatial span and Stroop tests were compared across both cohorts.

Result

Urban participants were older, had more years of education had less Geriatric Depression Score (GDS) as shown in Table 1. They did not differ in gender and proportion of cognitive impairment. Multiple Linear Regression analysis was performed to examine the effects of each executive functioning tests between both the cohorts (urban participants were coded as reference category) while age, years of education and GDS were adjusted.

Urban participants performed better than Rural participants on Categorical fluency (β = ‐2.379, p < 0.001), Letter fluency (β = ‐4.343, < 0.001), Visuospatial span (β = ‐0.279, < 0.001) and Stroop (β = 0.934, < 0.001). Similar results were obtained after gender stratification as shown in Table 2.

Conclusion

Urban participants performed better than their rural counterparts in all tests examining executive functioning. Poorer cognitive functioning in the rural ageing cohort could be due to a number of reasons including limited or less cognitively demanding occupations. There is a need for more such longitudinal studies in India that explore community environment on cognitive function across different cohorts.
LatAm‐FINGERS and U.S. POINTER: Design and Cohort Characteristics of Parallel Harmonized Trials of Multidomain Lifestyle Interventions Targeting Cognition
Authors: Suemoto Claudia Kimie , Allegri Ricardo Francisco , Baker Laura D , Brucki Sonia Maria Dozzi , Crivelli Lucía , Calandri Ismael Luis , Caramelli Paulo , Carrillo Maria C. , Cleveland Maryjo , Farias Sarah Tomaszewski , Gitelman Darren R. , Kivipelto Miia , Lopera Francisco , Nitrini Ricardo , Pavlik Valory , Salinas‐Contreras Rosa Maria , Salloway Stephen , Sevlever Gustavo , Snyder Heather M , Sosa‐Ortiz Ana Luisa , Tangney Christy C , Vellila Lin , Whitmer Rachel A. , Wing Rena R. , Yassuda Monica Sanches , Yu Melissa , Espeland Mark A. ,   LatAm FINGERS Consortium and U.S. POINTER Study Group
Published: December 2023

Background

Multidomain lifestyle interventions hold great promise world‐wide as interventions to slow cognitive aging, and delay and prevent Alzheimer’s Disease and Related Disorders (ADRD). To have the greatest reach, they must be tailored for and assessed within local cultures in clinical trials. For trials to have the greatest impact, it’s important that they are designed with common features that promote comparisons and potential harmonization.

Method

World‐Wide FINGERS was launched in 2017 as a global network of multidomain lifestyle intervention trials to adapt, test, and optimize multidomain lifestyle intervention trials in regions worldwide. Two participating trials, the Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm‐FINGERS) and the U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) have collaborated to promote harmonization to support joint initiatives. This presentation is organized to describe, in parallel, their study protocols, and cohort characteristics, and demonstrate how cross‐trial collaboration may expand the impact of individual trials.

Result

The trials have overlapping aims, eligibility criteria, interventions, and assessment protocols. LatAm‐FINGERS and U.S. POINTER will enroll 1,200 and 2,000 participants, respectively. Table 1 describes sample characteristics. The samples of the two studies share similar sociodemographic and clinical characteristics with a few exceptions. In U.S. POINTER, there is a larger proportion of participants with a family history of memory impairment and physical inactivity, and a higher frequency of White participants. Additionally, mild memory impairment (Clinical Dementia Rating = 0.5) is more common in LatAm‐FINGERS participants.

Conclusion

Harmonization of LatAm‐FINGERS and U.S. POINTER protocols provides unique opportunities for collaborative science for identifying effective strategies to promote cognitive resilience and reduce risks for Alzheimer’s disease, and significantly expand the potential for scientific investigation in diverse populations.
Colocalization of tau PET uptake and cerebral blood flow alterations within subjects with MCI and AD
Authors: Scott David , Bracoud Luc , Conklin Chris , Ingalhalikar Madhura , Suhy Joyce
Published: December 2023

Background

The accumulation of neurofibrillary tangles contributes to a neurodegenerative cascade toward Alzheimer’s disease, of which altered cerebral metabolism is also a feature. 18F‐Flortaucipir PET allows visualization of tau pathology in vivo, while MRI‐based arterial spin labeling techniques assess metabolism via cerebral blood flow. We sought to characterize the within‐subject relationship between tau burden and cerebral blood flow throughout the brain.

Method

130 ADNI3 subject visits with concurrent MRI ASL and flortaucipir PET scans were selected from the database (http://adni.loni.ucla.edu) for analysis. ADNI PET core PVC values referencing inferior cerebellar cortex were used to index SUVR across the entire FreeSurfer parcellation, and ADNI MRI core regional CBF values were identified from an overlapping set of 71 FreeSurfer regions. Linear partial correlation coefficients were calculated for tau PET SUVR and CBF in each brain region, controlling for age and amyloid PET SUVR. Lasso logistic regression returned penalized maximum‐likelihood fitted coefficients for a generalized linear model estimating meta‐temporal tau SUVR from regional CBF; regions with non‐zero coefficients in the sparsest model are reported.

Result

Following correction for age and amyloid load, significant within‐subject partial correlations between tau PET uptake and ASL CBF were observed throughout the brain. The associations were strongest in amyloid positive subjects with MCI or AD. Correlation strength was regionally specific and strongly positive (marginal p < 0.005) in subcortical and early Braak regions, while strongly negative (marginal p < 0.005) across frontal and later Braak regions. The strongest tau burden associations were observed with hypermetabolism in hippocampus (p = 0.0005, partial r = 0.59), and hypometabolism in posterior cingulate gyrus (p = 0.0001, partial r = ‐0.63). Lasso regression revealed a subset of non‐zero coefficients in the sparsest model including subcortical, temporal, parietal and frontal brain regions.

Conclusion

Tau PET uptake is associated with a pattern of hypermetabolism in early Braak stages, and hypometabolism in later Braak stages. This suggests a dynamic relationship where tau accumulation and cerebral blood flow alterations colocalize, but the direction of the effect is regionally specific.
NG‐001: A novel multi‐domain digital cognitive intervention for cognitive symptoms in mild cognitive impairment
Authors: Patterson Michael D. , Ng Kok Pin , Jabar Syaheed Bin , Leonardo Jacklyn , Chiew Hui Jin , Ng Adeline Su Lyn , Kandiah Nagaendran
Published: December 2023

Background

Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer’s disease that offers a window for early intervention prior to dementia onset. The cognitive impairment observed in MCI includes declines across several cognitive domains, including memory, processing speed, and executive function. Emerging evidence supports a multidomain intervention to improve cognitive performance. Therefore, we aim to investigate the utility of a novel, scalable multi‐domain digital intervention as a therapeutic solution to prevent or reverse cognitive decline.

Method

30 amnestic MCI patients were enrolled in a pilot open‐label clinical trial of a 10‐week digital therapeutic intervention using NG‐001 delivered via a tablet. 27 participants completed the trial and their data were analyzed. NG‐001 consisted of weekly 1‐hour trainings spread across several domains: cognitive games; physical exercise; mindfulness (e.g., yoga and meditation); health literacy; and reminiscence therapy. The outcome composite scores were calculated from the Neuropsychological Test Battery including Overall Cognition, Processing Speed, Executive Functioning, Overall Memory as well as Immediate and Delayed Memory. Composites were calculated into Z‐scores based on normative data from age and education‐adjusted reference groups. Changes in the Z‐scores were then assessed using paired Wilcoxon signed ranked tests (two‐tailed) and the effect size was calculated using Hedges’ g.

Result

Compared to baseline, at post‐intervention, MCI patients showed significant improvements in Overall Cognition (‐0.440 to ‐0.213, g = 0.352), Overall Memory (‐0.587 to ‐0.132, g = 0.407), Immediate Memory (‐0.549 to ‐0.030, g = 0.512) and Delayed Memory (‐0.626 to ‐0.233, g = 0.305). There were no significant changes in Processing Speed or in Executive Functioning (ps > .05).

Conclusion

NG‐001 significantly improved memory (both immediate and delayed) for amnestic MCI patients, indicating its potential as a form of digital therapeutics for early intervention of memory impairment in MCI. Further research is needed to investigate the mechanisms involved in this improvement, and whether modifications can be made to extend its facilitatory effect to other cognitive domains such as executive functioning and language.
Characterizing the Retinal and Choroidal Microvasculature and Structure in Individuals with Dementia with Lewy Bodies
Authors: Joseph Suzanna , Allen Ariana , Haystead Alice , Kundu Anita , Hemesath Angela , Robbins Cason B , Ma Justin , Johnson Kim G , Stinnett Sandra , Grewal Dilraj S , Fekrat Sharon ,   iMIND Study Group, Duke University School of Medicine
Published: December 2023

Background

Dementia with Lewy Bodies (DLB) accounts for about 7% of dementia cases. Multimodal retinal imaging may identify biomarkers in this population since there is a growing link between retinal alterations in DLB, with exploratory studies showing phosphorylated alpha‐synuclein retinal deposits, parafoveal thinning of ganglion cell inner‐plexiform layer (GC‐IPL), and electroretinography alterations (Beach et al., 2014, Murueta‐Goyena et al., 2019, Maurage et al., 2003). We used optical coherence tomography (OCT) and OCT angiography (OCTA) to characterize differences in retinal and choroidal microvasculature and structure in individuals with DLB compared to controls with normal cognition.

Method

A cross‐sectional comparison of patients with DLB and age‐ and sex‐matched cognitively normal controls. Exclusion criteria included retinal or optic nerve pathology, glaucoma, and diabetes. The Zeiss Cirrus HD‐5000 with AngioPlex was used to obtain OCT and OCTA images. OCT parameters measured includes central subfield thickness (CST), retinal nerve fiber layer (RNFL) thickness, GC‐IPL thickness, and choroidal vascularity index (CVI). OCTA parameters measured include superficial capillary plexus foveal avascular zone (FAZ) area, fovea‐centered 3×3mm and 6×6mm vessel density (VD) and perfusion density (PD), and optic nerve head‐centered capillary perfusion density (CPD) and capillary flux index (CFI). Generalized estimating equations adjusted for correlation among eyes of the same subject.

Result

Thirty‐four eyes of 18 DLB patients and 85 eyes of 48 cognitively normal controls were analyzed. Cases were well‐matched to controls by age (p = 0.977) and sex (p = 0.607). DLB patients had lower Mini Mental State Exam (MMSE) scores (p < 0.001). Average GC‐IPL thickness was lower in patients with DLB compared to controls (p = 0.04). Average 4.5×4.5mm CPD was higher in patients with DLB compared to controls (p = 0.005). Average 4.5×4.5mm CFI was lower in patients with DLB compared to controls (p = 0.016).

Conclusion

DLB patients had attenuated GC‐IPL thickness and peripapillary CPD and CFI changes when compared to those with normal cognition. Retinal imaging metrics have the potential to serve as clinically relevant biomarkers for DLB diagnosis.
Scalable Multi‐Sensor At Home Assessment of Sleep and Activity in Adults At High Risk for Dementia
Authors: Lim Andrew , Centen Andrew Peter , Montazeri Nasim , Gibson Erin , Dang‐Vu Thien Thanh , Carrier Julie , Chan Senny , Belleville Sylvie , Nygaard Haakon B. , Montero‐Odasso Manuel , Feldman Howard H. , Chertkow Howard ,   CCNA‐CAN‐THUMBS‐UP Study Group
Published: December 2023

Background

Sleep disruption is common in older adults, and emerging evidence suggests that differences in sleep whether measured by electroencephalography (EEG) or actigraphy, may be associated with clinical cognitive outcomes, and with specific dementia‐associated pathologies. However, whether EEG and actigraphic sleep features may predict cognitive response to lifestyle interventions for dementia, or whether they may themselves respond to these lifestyle interventions, is unknown. A major challenge is to develop sleep assessment in virtual studies where subjects do not attend a research center.

Methods

In the Canada‐wide Brain Health Support Program (BHSP), 350 adults at high risk for dementia have been recruited to receive an online lifestyle risk factors intervention. At baseline, and at 12‐month follow‐up, we are assessing 3 nights of sleep EEG and 10‐days of wrist accelerometry at home using a mailed‐out package. Wearable devices are mailed to subjects, who are instructed in their use, and data is collected remotely. The wearables are then mailed back to the study center. We used the MUSE‐S (Interaxon, Toronto, Canada), which is a multimodal wearable headband combining 4‐channel dry‐electrode EEG, with accelerometry and photoplethysmography, along with the AX3 wrist triaxial accelerometer (Axivity, Newcastle, UK).

Results

EEG headbands and wrist accelerometers were sent to 348 participants with a total of 1116 nights of EEG recording and obtained. Of the 348 participants, 15 withdrew from the EEG component of the study; of the remaining 333, 316 (95%) completed at least 1 night of recording, and 301 (90%) obtained at least 1 night of recording with signal quality meeting quality control criteria (adequate signal quality in at least 1 frontal and 1 temporal electrode for at least 80% of the recording). For the wrist acclerometry data, 342 completed at least 7 days of wear meeting QC criteria.

Conclusion

Fully remote sleep EEG and accelerometry data collection is feasible in a geographically dispersed cohort of older adults at high risk for dementia. The BHSP will provide an opportunity to assess whether EEG and accelerometric sleep features may predict the cognitive response to lifestyle interventions for dementia, or whether they themselves may respond to these lifestyle interventions.
APOE genotype‐specific lipidomic signatures in primary human hepatocytes
Authors: Patra Kalicharan , Almeida Francisco , Giannisis Andreas , Niesnerova Anezka , Nandakumar Renu , Ellis Ewa , Oliveira Tiago Gil , Nielsen Henrietta M.
Published: December 2023

Background

Apolipoprotein E (APOE) is primarily responsible for cholesterol homeostasis in the periphery and in the brain through independently regulated pathways, as it does not cross the blood‐brain barrier (BBB). Carriers of the APOE ε4 allele have a 3‐ to 15‐fold higher risk of developing Alzheimer’s disease (AD). Recently, we demonstrated that hepatic APOE4 was associated with alterations in AD‐relevant brain functions, suggesting clinical significance of plasma APOE, 90% of which is derived from the liver. How APOE genotype affects the hepatic lipidome is yet unknown. In this study, we assessed APOE genotype‐specific lipidomic profiles of primary human hepatocytes and their association with hepatic APOE.

Method

We conducted a lipidomic analysis of primary human hepatocytes isolated from 77 subjects by use of Ultra Performance Liquid Chromatography‐Tandem Mass Spectrometry. Lipid class levels over age across ε2/ε3, ε3/ε3 and ε3/ε4 genotypes were assessed using Pearson correlation analysis and between‐group comparisons for lipid class and species levels, controlled for demographic variables, were performed using one‐way ANOVA with Tukey HSD correction for multiple comparisons. We assessed hepatic APOE levels by ELISA in order to compare APOE expression between APOE genotypes and investigate correlations with lipid levels.

Result

We found APOE allele‐specific lipidomic patterns over age and between groups. APOE genotype differentially modulated the relationship between age and lipid levels across multiple lipid classes. The ε4 carriers had higher acylcarnitines (AC) and acylphosphatidylglycerol (AcylPG) as a class, as well as higher medium and long‐chain ACs, AcylPG, bis(monoacylglycerol)phosphate (BMP), monoacylglycerol and diacylglycerol species compared to ε2 carriers. Hepatocyte APOE levels decreased with age in the whole cohort, but correlated with monoacylglycerols (MG) and phosphatidylcholine (PC) only in ε4 carriers. We observed no differences in APOE hepatocyte levels specific to genotype or sex of the donor.

Conclusion

APOE genotype dictates a differential lipidome in primary human hepatocytes but has no effect on APOE levels. The lipids involved suggest mitochondrial dysfunction with accompanying alterations in neutral lipid storage, reflective of a general disturbance of free fatty acid metabolism in human hepatocytes with the ε4 allele.
Efforts toward discovering inhibitors of the SYK SH2–FCER1γ interaction as potential Alzheimer’s disease chemical probes and therapeutics
Authors: Sikdar Arunima , Bashore Frances M. , Katis Vittorio , Bradshaw William , Rygiel Karolina , Du Yuhong , Wang Dongxue , Leisner Tina , Hardy Brian P. , Kireev Dmitri B. , Pearce Kenneth H. , Fu Haian , Frye Stephen V. , Axtman Alison D.
Published: December 2023

Background

Spleen associated tyrosine kinase (SYK) plays a potential role in several neurodegenerative conditions. To date, a few pharmacological inhibitors have been developed, targeting the ATP‐binding kinase domain, and some of these inhibitors have been reported to show beneficial effects on the pathophysiology of Alzheimer’s (PMC: 9179326).In 2015, the Accelerating Medicines Partnership: Alzheimer’s Disease (AMP‐AD) Knowledge Portal analyzed and identified SYK and the FC gamma receptor (FCεR1γ) as targets for Alzheimer’s Disease (AD), through multidimensional human “omic” (genomic, epigenomic, RNAseq, and proteomic) data (PMID: 26853544). Thus, the interaction between FCER1G p‐ITAM and SYK tandem SH2 domain was selected for further target validation and small molecule hit discovery efforts through the portfolio of novel targets to treat the Alzheimer’s disease via the Target Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT‐AD) program were initiated. As part of the TREAT‐AD effort, we aim to provide experimental validation of a SYK–FCεR1γ interaction inhibitor for AD and begin drug discovery campaigns to identify novel inhibitors of this interaction, with the goal of developing an in vivo chemical probe.

Method

Using purified SYK tandem‐SH2 (tSH2) domain protein, a time‐resolved fluorescence energy transfer (TR‐FRET) based assay platform was developed with a fluoroprobe‐labeled phospho‐ITAM peptide of FCεR1γ. This assay was miniaturized for ultra‐high‐throughput screening (uHTS) of 100K compounds in parallel with a DNA encoded library (DEL) screening approach (Ref: X‐Chem). The hits from these screening methods were evaluated in secondary assays in an attempt to validate the initial hits.

Result

We have previous crystallography data of the SYK tSH2 domains bound to phospho‐ITAM peptides and have established a TR‐FRET based assay to discover and characterize inhibitors of the interaction between the FCεR1γ peptide and SYK tSH2 domains. Several thio‐uric acids hit compounds have been identified from uHTS. Most of them demonstrate potency in the TR‐FRET based assay of <10 µM. Although, orthogonal experimental validation is still under process.

Conclusion

Through the TREAT‐AD program, we have explored the SYK–FCεR1γ interaction and demonstrated novel screening strategies, which can be further exploited to generate novel inhibitors of this interaction.
An analysis of psychosocial predictors of cognitive impairment in older people living in social housing ‐ data from longitudinal study: “Porto. Importa‐se”
Authors: Martins Sónia , Alves Hélder , Machado Idalina , Melo Sara , Guedes Joana
Published: December 2023

Background

Cognitive Impairment (CI) is a growing public health problem among the older population, with well‐established risk factors. However, the role of psychosocial predictors still needs to be clarified. This study aimed to analyze whether psychosocial factors may be predictors of CI in older persons.

Method

In the framework of “Porto. Importa‐se” longitudinal project, this study included older persons (≥70y.o. living alone and couples ≥75y.o.), living in social housing in Porto city, Portugal. The research protocol included: Six‐item Cognitive Impairment Test (CI), Barthel and Lawton Index (Basic/Instrumental Activities of Daily Living‐BADLs/IADLs), Geriatric Depression Scale‐15 (depressive symptoms) and Lubben Social Network Scale‐6 (social isolation). Loneliness was assessed with a categorical question: Do you feel lonely?. A logistic regression analysis was conducted to identify predictors of CI. Odds Ratio (OR) and its 95% Confidence Interval (95%CI) were calculated. A p<0.05 was considered statistically significant.

Result

Of the 1213 older persons (mean age 81±5.7) included, most were female (74%) and 36% had low education level (<4years). About 11% were severely dependent on IADLs and 27% presented CI. Around 35% of participants were at risk of social isolation, 54% reported loneliness and 48% showed depressive symptoms.

The logistic regression model was statistically significant [X2(5,N = 1213) = 148.596,p<.001], explaining 19.7%(Nagelkerke R2) of variance in CI (correctly classified 77% of cases). The adjusted model had a moderate sensitivity (63%) and specificity (78%). The oldest persons (≥80 years old) were 1.77 as likely to have CI than younger (OR = 1.77, 95%CI[1.3, 2.4]). Those with less education (<4years) were 0.26 times as likely to present CI than reference group (≥4years) (OR = 0.26, 95%CI[0.2, 0.4]) and females 1.5 times more than males (OR = 1.50, 95%CI[1.0, 2.2]). Older persons at risk of social isolation were 1.85 as likely to have CI (OR = 1.85, 95%CI[1.4, 2.5] and those with depressive symptoms were 1.39 likely to present CI (OR = 1.39, 95%CI[1.0, 1.9]).

Conclusion

Older age, female gender, low education, depressive symptoms and social isolation were predictors of CI. The existence of potentially modifiable factors (e.g., social isolation, depression), means that CI prevention is possible through the implementation of effective individual and community‐level interventions, aiming to protect older persons from CI.
Safety profile of pimavanserin therapy in elderly patients with neurodegenerative disease‐related neuropsychiatric symptoms: a Phase 3b study
Authors: Alva Gustavo , Cubała Wiesław J. , Berrio Ana , Abler Victor , Coate Bruce , Pathak Sanjeev
Published: December 2023

Background

Patients with neurodegenerative diseases including Parkinson’s disease often experience neuropsychiatric symptoms, including hallucinations and delusions, apathy, and agitation.1,2 These symptoms can greatly impair daily function and lead to reduced quality of life and significant caregiver burden. These patients are generally elderly and often frail. Treatment options are limited, representing a substantial unmet need. Pimavanserin, a 5‐HT2A receptor inverse agonist/antagonist, is FDA‐approved to treat hallucinations and delusions associated with Parkinson’s disease psychosis.3

Method

This Phase 3b, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study evaluated the safety of pimavanserin (34 mg) versus placebo in frail adults and elderly patients with neuropsychiatric symptoms related to neurodegenerative disease. The primary endpoint was safety and tolerability as measured by treatment‐emergent adverse events. Secondary safety endpoints included change from baseline in motor (Extrapyramidal Symptom Rating Scale‐Abbreviated [ESRS‐A]) and cognitive function (Mini‐Mental State Examination [MMSE]) at Week 8. Suicidality was assessed using the Columbia‐Suicide Severity Rating Scale (C‐SSRS) or Global Clinician Assessment of Suicidality (GCAS). Exploratory efficacy endpoints included Clinical Global Impression‐Severity (CGI‐S) and ‐Improvement (CGI‐I), 5‐level version of EQ‐5D (EQ‐5D‐5L), and Sleep Disorders Inventory (SDI).

Result

Overall, incidence of TEAEs were similar between pimavanserin (n = 392) and placebo (n = 392); 29.8% reported ≥1 TEAE (pimavanserin: 30.4%; placebo: 29.3%) and 1.8% reported serious TEAEs (pimavanserin: 2.0%; placebo: 1.5%) (Table 1). TEAEs leading to discontinuation or study termination were reported in 2.6% and 2.3% of patients on pimavanserin and placebo, respectively. The most frequently reported TEAEs included urinary tract infection (pimavanserin: 6.4%; placebo: 4.1%) and headache (pimavanserin: 2.0%; placebo: 3.8%). Mortality due to TEAEs was similar between groups (0.5% each). Pimavanserin did not impact motor‐ or cognition‐related function (ESRS‐A and MMSE, respectively); an improvement was seen in CGI‐I (MMRM LSM [SE]: ‐0.2 [0.07], p = 0.0140] and sleep function (SDI) at Week 8 (MMRM LSM [SE]: ‐0.3 [0.06], p<0.0001] compared to placebo (Figures 1, 2); no differences were observed across other measures.

Conclusion

Pimavanserin was well tolerated in patients with neuropsychiatric symptoms related to neurodegenerative disease, consistent with the known safety profile of pimavanserin, informing its use in Parkinson’s disease psychosis. Pimavanserin was not associated with cognitive decline or motor dysfunction.
Comparison of Human Primary microglia and Human iPSC derived microglia cells as in vitro models for microglia activation
Authors: Bsibsi Malika , Lo Kimberly , Zanella Matteo , Geerts Lieke , Kostense Stefan , De Groot Jeroen , Fisher David F , Vlaming Marijn
Published: December 2023

Background

Microglia are resident immune effector cells in the CNS and play an essential role in neuroinflammation, ischemic and neurodegenerative disease. Therefore, microglia cells are considered a potential therapeutic target for neurodegenerative diseases. To fully understand the role of microglia, the preferred strategy would be to study primary human microglia isolated from post‐mortem human brain tissue. Microglia can be isolated from both control and diseased human brain tissue with confirmed neuropathology. However, the obvious limitation on brain collection and yield of isolated cells restricts the ability to perform screening studies. Induced pluripotent stem cells (iPSCs)‐derived microglia, may provide a suitable alternative for screening studies and large‐scale compound validation. Yet, to effectively use iPSC‐derived microglia, one must characterize the extent to which these cells faithfully represent biological processes in primary brain tissue.

Method

Here, we compared the gene expression and cytokine release from primary human microglia cells obtained from tissue provided by the Netherlands Brain Bank and iPSC‐derived microglia.

Result

Exposure of primary and iPSC‐derived microglia to LPS resulted in increased TNF‐α secretion in a concentration and time dependent manner. LPS‐mediated TNF‐α secretion was strongly inhibited by dexamethasone. Priming of primary and iPSC‐derived microglia with LPS and treatment with nigericin, a potent inflammasome activator, resulted in robust secretion of IL‐1β and IL‐18. Furthermore, nigericin induced IL‐1β and IL‐18 release was blocked by the inflammasome inhibitor MCC950 in both cell types. In addition, similarly to in‐house differentiated microglia, commercially available iPSC‐derived microglia (Bit.bio) showed a strong expression of specific markers as well as cytokine response upon LPS treatment.

Conclusion

Taken together, we successfully demonstrated that primary and iPSC‐derived microglia respond similarly to LPS and nigericin treatment. For these reasons, these cell types could serve as a reliable tool for evaluating the potency and efficacy of prospective drugs for multiple neurological diseases associated with microglia activation, such as Alzheimer’s and Parkinson’s Disease.
A novel DYRK1a inhibitor, DYR533, reduces tau pathology and TNF alpha in the 3xTg‐AD and PS19 mouse models
Authors: Bartholomew Samantha , Winslow Wendy , Rokey Samantha , Hulme Christopher , Dunckley Travis , Velazquez Ramon
Published: December 2023

Background

Dual specificity tyrosine phosphorylation kinase 1a (DYRK1a) directly phosphorylates tau and amyloid precursor protein and is upregulated in postmortem brain tissue of patients with disorders including Alzheimer’s (AD) and Picks disease (a tauopathy). Our lab has shown that treatment with a DYRK1a inhibitor (DYR219) reduced Aβ plaque deposition and decreased phosphorylated tau at Serine 396 (pTauSer396) in the 3xTg‐AD mouse model. Here, we developed and tested a novel DYRK1a inhibitor (DYR533), which has an increased half‐life and bioavailability, in 3xTg‐AD mice that develop both Aβ and pathological tau, and PS19 mice that develop solely pathological tau.

Method

We dosed eight‐month‐old 3xTg‐AD and four‐month‐old PS19 mice daily with either 1.0‐, 2.5‐, or 5.0‐mg/kg DYR533 or a vehicle dose for two or four months respectively per model. Treatment start age occurred at the onset of neuropathology. Mice underwent rotarod testing to assess motor function and water maze testing to assess spatial learning and memory, with testing starting 2 weeks prior to the end of treatment. Blood and brain tissue were collected for neuropathology assessment. We assessed Aβ 40‐42 in the 3xTg‐AD mice, and pTauSer396 and the pro‐inflammatory cytokine tumor necrosis factor (Tnf)α in the hippocampus of both models. Blood plasma was extracted and analyzed for Tnfα levels.

Result

In both 3xTg‐AD and PS19 mice, DYR533 reduced soluble and insoluble fractions of pTau Ser396 in a dose dependent manner. Notably, DYR533 in 3xTg‐AD mice reduced pTau at threonine 217, which was recently identified as an early marker of AD progression. Soluble cortical Aβ42 levels were significantly reduced in the 1.0 mg/kg and 5.0 mg/kg 3xTg‐AD groups. DYR533 significantly reduced the levels of Tnfα in blood plasma and the hippocampus of both 3xTg‐AD and PS19 mice.

Conclusion

In conclusion, the DYRK1a inhibitor, DYR533, reduces pTauSer396, as well as blood plasma and hippocampal levels of Tnf α in both 3xTg‐AD and PS19 models. Ongoing efforts include testing the effects of DYR533 in a rodent model of Down syndrome (Ts65Dn), which harbors three copies of DYRK1a, and completion of 3xTg‐AD and PS19 experiments. Thus far, these results support DYR533 as a potential therapeutic for AD and the tauopathies.
NODDI May Be More Sensitive to Neurodegenerative Changes Than Structural MRI
Authors: Yu Xi , Gebre Robel K , Przybelski Scott A. , Reid Robert I. , Raghavan Sheelakumari , Lesnick Timothy G. , Lowe Val J. , Machulda Mary M. , Knopman David S. , Petersen Ronald C. , Kantarci Kejal , Graff‐Radford Jonathan , Jack Clifford R. , Vemuri Prashanthi
Published: December 2023

Background

Neurite orientation dispersion and density imaging (NODDI) measures from diffusion MRI provide information about tissue microstructure. Our goal was to compare the sensitivity of NODDI to structural MRI (sMRI) in capturing neurodegenerative changes in the gray matter due to aging and dementia.

Method

We included 815 participants [644 cognitively unimpaired (CU), 103 MCI, 68 AD] from the Mayo Clinic Study of Aging (MCSA) and Mayo ADRC with sMRI and multi‐shell diffusion MRI. We assessed gray matter volumes scaled by head size and cortical thicknesses from sMRI and neurite density index (NDI) and isotropic volume fraction (ISOVF) from NODDI. Pairwise Spearman correlations were calculated between imaging measures and Tau‐PET SUVRs in Braak I‐II, III‐IV, and V‐VI regions of interest (ROI) in participants ≥ 60 years. Separate multivariable linear regression models were fit for the prediction of brain age using sMRI and NODDI in 515 CU participants. The predicted age gaps were calculated as chronological age minus predicted age in the remaining participants. We compared age gaps computed by sMRI and NODDI using disease surrogates (APOE4 genotype, AD pathologies via PET, WMH via FLAIR‐MRI, vascular risk, cognition via MMSE).

Result

Braak ROIs, sMRI, and NODDI measures were correlated. The correlations between ISOVF and Tau‐PET SUVRs were stronger than correlations between NDI, volume, and thickness and Tau‐PET SUVR (Fig.1). MMSE was more associated with ISOVF than Tau‐PET and other imaging measures. The sMRI regression models had a higher mean absolute error (MAE) of 4.13 years than NODDI models with an MAE of 4.02 years. The NODDI model better predicted age gap separation between CU, MCI, and AD compared to the sMRI model (Fig.2). The NODDI predicted age gap showed stronger correlations with global amyloid‐PET SUVR, meta‐ROI Tau‐PET SUVR, CMC, APOE4, and MMSE (Fig. 3).

Conclusion

NODDI, especially ISOVF, had stronger correlations with MMSE and Tau‐PET SUVRs across all Braak ROIs. The brain age prediction model trained using NODDI was more sensitive in detecting neurodegeneration changes than sMRI based on associations with disease surrogates. Our work suggests that NODDI in gray matter may be a more sensitive surrogate of neurodegeneration compared to sMRI.
In vivo TurboID proximity labeling to capture astrocyte proteomic and transcriptomic signatures under homeostatic and neuroinflammatory conditions
Authors: Ramelow Christina C , Sunna Sydney N , Rayaprolu Sruti , Nelson Ruth S , Sampson Maureen , Xiao Hailian , Cheng Lihong , Kumar Prateek , Seyfried Nicholas T , Sloan Steven A , Rangaraju Srikant
Published: December 2023

Background

Despite decades of research into the cellular and molecular contributions of brain cell types to Alzheimer’s disease (AD) pathogenesis, there are no glial‐specific disease‐modifying therapies. To address this, our group has developed the innovative cell‐specific in vivo biotinylation of proteins (CIBOP) approach to quantify astrocyte‐specific in vivo proteomic and transcriptomic contributions to AD under homeostatic and neuroinflammatory conditions.

Method

In the CIBOP approach, TurboID, a biotin ligase, is selectively expressed in the cell type of interest using a conditional Cre/lox genetic strategy to label the cellular proteome. Using mass spectrometry (MS)‐based proteomics, we have found that TurboID biotinylates many RNA‐binding and ribosomal proteins. Leveraging this, we extended the CIBOP approach to obtain representative cell type‐specific transcriptomes, along with the proteome. We crossed astrocyte specific Cre (Aldh1l1‐Cre‐ert2) and Rosa26TurboID/wt floxed mice for astrocyte‐specific proteomic labeling (astrocyte‐CIBOP). Astrocyte‐CIBOP and control (Cre‐only) mice received tamoxifen, followed by biotin‐containing water and systemic lipopolysaccharide (via intraperitoneal injections) to induce a neuroinflammatory state. Biofluids (CSF and plasma) and cortical tissue were collected. While maintaining RNA‐protein interactions, cortical tissue was lysed, biotinylated proteins were enriched via streptavidin beads, and then RNA was eluted. Immunofluorescent microscopy (IF) and biochemical assays were performed to confirm astrocyte‐specific proteomic biotinylation.

Result

Western blot analysis of the cortex and CSF confirmed biotinylation of the cellular proteome of astrocyte‐CIBOP mice under homeostatic and neuroinflammatory conditions when compared to controls. IF images show that the biotinylation signal is astrocyte specific, proteomic labeling does not impact astrocyte morphology, and high levels of signal was detected at astrocytic end‐feet. RNA gel electrophoresis shows low RNA yield from control mouse brain streptavidin pulldowns, and high levels of RNA from astrocyte‐CIBOP brain pulldowns. MS‐based proteomics of astrocyte‐derived biotinylated proteins and RNA‐sequencing from biotinylated protein‐RNA interactions are underway.

Conclusion

We validate the CIBOP approach to capture the cortical Aldh1l1‐positive astrocyte proteome and transcriptome in vivo under homeostatic and neuroinflammatory conditions and demonstrate labeling of astrocyte‐derived CSF proteins. Our novel in vivo cell type‐specific and native‐state dual ‐omics approach provides complementary transcriptomic and proteomic information to investigate disease mechanisms, discover new biomarkers, and identify novel therapeutic targets.
A short‐hybrid scale for detecting anosognosia from the prodromal stage of Alzheimer’s disease
Authors: Andrade Katia , Guieysse Thomas , Houot Marion , Pantazis Dimitrios
Published: December 2023

Background

While not originally developed for this purpose, evidence suggests that the Healthy Aging Brain Care Monitor questionnaire (HABC‐M; Monahan et al, 2012, 2014) may be a valuable instrument for assessing unawareness of cognitive decline (i.e., anosognosia) from preclinical stages of Alzheimer’s disease (AD) (Cacciamani et al, 2017). This is relevant because anosognosia may delay AD diagnosis and therapeutic interventions, with adverse consequences for patients and caregivers. However, several open questions remain: What is the actual effectiveness of this instrument across the AD spectrum? How do the cognitive, functional, and psychological subscales of the HABC‐M differ in their sensitivity to anosognosia in AD? Does the caregiver burden subscale provide additional information about AD patient’s anosognosia? The present study aimed to address these specific questions.

Methods

The HABC‐M was administered to 60 participants (30 AD patients and 30 healthy controls) and their partners (caregivers/informants). A measure of self‐awareness was then estimated by computing the discrepancy scores between the participants and their partners for the different subscales of HABC‐M (with the exception of the caregiver burden subscale, which is a caregiver‐exclusive questionnaire). To evaluate whether these measures can discriminate between patients at different stages of AD and controls, we fit linear models adjusted for age, sex, and education, and computed receiver operating characteristic curves.

Results

All HABC‐M discrepancy scores, as well as the caregiver burden score, were able to discriminate controls from patients in distinct AD stages. For best performance, the area‐under‐curve for the HABC‐M cognitive subscale discriminated prodromal AD versus controls with a value 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden score raised it to 0.94 [0.86;0.99].

Conclusion

The HABC‐M cognitive subscale (six items) can detect anosognosia from the earliest stages of AD. Separately, the caregiver burden subscale (four items) may corroborate the suspicion of anosognosia. A short‐hybrid scale combining these 10 items, instead of the 31 items of the total HABC‐M questionnaire, could provide a practical and efficient instrument for detection of anosognosia in the clinical setting. Importantly, such an instrument could further contribute to a timely AD diagnosis.
Investigating 4R tau isoform imbalance as a mediator of astrocyte dysfunction in tauopathies
Authors: Schoch Kathleen M. , Ezerskiy Lubov A. , Hu Miwei , Beltcheva Mariana , Rigo Frank , Miller Timothy M.
Published: December 2023

Background

Select primary tauopathies exhibit MAPT (tau) mis‐splicing to produce an imbalance of 3R and 4R tau isoforms. Further, 3R and 4R tau isoforms deposit in neurons and glia in tauopathy patients, although it remains unclear whether tau isoform deposition is a cause or consequence of disease. Our group and others have identified a role for 4R tau in increased tau phosphorylation and aggregation, suggesting that 4R tau‐mediated mechanisms may influence disease. Therefore, therapeutic strategies targeted against 4R tau may be beneficial.

Method

We developed antisense oligonucleotides (ASOs) that enable control of 3R and 4R tau splicing without altering total tau levels in human tau‐expressing mice, primary mouse astrocytes, and astrocytes derived from human induced pluripotent stem cells (iPSCs). We quantified gene markers of astrocyte reactivity and measures of astrocyte function, including glutamate uptake and response to oxidative stress. Finally, we performed bulk RNAseq from mouse brain tissue following tau splicing manipulation.

Result

Increasing 4R tau in human tau mice and primary mouse astrocytes induced a neurotoxic gene signature, including evidence for complement pathway involvement. Astrocytes derived from iPSCs of tauopathy patients expressing the MAPT mutation IVS 10+16 (biases toward 4R tau expression) exhibited increased expression of genes associated with neurotoxicity, were vulnerable to oxidative stress, and had reduced glutamate uptake. 4R tau‐expressing astrocytes, including IVS 10+16 mutation carriers, promoted hyperexcitability characteristics in co‐cultured neurons compared to controls. Bulk RNAseq analysis supported isoform‐specific changes in gene expression.

Conclusion

Astrocytes appear particularly vulnerable to increased 4R tau in vivo and in vitro, inducing dysfunction that may leave neurons prone to hyperexcitability and degeneration. Although tau isoform imbalance toward greater 4R tau likely induces both neuronal and glial changes, tau‐mediated toxicity within astrocytes may reveal unique mechanisms of disease progression and targets for therapeutics.
The effect of vitamin D on neurite length and neurite elongation velocity during development
Authors: Keskin Ebru , Gezen‐Ak Duygu , Dursun Erdinc
Published: December 2023

Background

Studies have shown that vitamin D plays an important role in the brain (1). In an animal model of nerve trauma, vitamin D2 (ergocalciferol) was shown to be a potent neuromodulatory compound that increases axogenesis, axon diameter, and physiological maturation (2). In addition, the administration of high‐dose vitamin D3 (cholecalciferol) has been demonstrated to enhance the number of preserved or newly formed axons at the proximal end, axon diameter at the distal end, and neurite myelination at both the distal and proximal ends in another animal model of nerve trauma (3). Vitamin D has been shown to increase neurite outgrowth when added to cultured hippocampal cells. However, when removed from the diet of pregnant rats, decreased expression of NGF (neuron growth factor (NGF) was observed in the brains of newborns and adults. Recently, vitamin D has been shown to increase the expression of microtubule‐associated protein‐2 (MAP2), axonal growth‐associated protein‐43 (GAP43), and synapsin‐1 protein in rat cortical neurons (4). Based on this knowledge, we sought to determine whether vitamin D treatment during development might affect neurite length, and elongation velocity.

Method

In our study, primary cortical neuron culture was performed using 16‐day‐old rat embryos. 10−8 M 1,25‐dihydroxyvitamin D3 was applied 24 hours after the culture. Following vitamin D administration, neurite length measurements were made at 30‐second intervals for 30 min and at half‐hour intervals for 12 h under a live cell imaging microscope at 20X magnification.

Result

The results of our study showed that 30 min after vitamin D administration, neurite length and elongation velocity significantly increased in the vitamin D group compared to the control group (p = 0.0029 and p = 0.0310, respectively). In addition, the neurite outgrowth rate and neurite length increased in the vitamin D group 12 h after vitamin D administration compared to the control group (p = 0.0275, p = 0.0398, respectively).

Conclusion

Only a few research have examined at how vitamin D affects neurite outgrowth. As a result of vitamin D administration in primary cortical neurons during the developmental phase, our study’s results demonstrated that neurite length and velocity increase in the first 12 hours.
Altered brain connectivity, neuroinflammation and AD‐related markers following 7 days after repetitive mild traumatic brain injury in young wild‐type mice
Authors: Criado‐Marrero Marangelie , Ravi Sakthivel , Hery Gabriela P , Bolen Mackenzie L , Febo Marcelo , Grudny Matteo M , Prokop Stefan , Abisambra Jose F. F
Published: December 2023

Background

Traumatic brain injuries (TBI) substantially increase the risk for neurodegenerative disorders including tauopathies and synucleinopathies. Repetitive mild TBI (rmTBI) exacerbate damage in brain impacting cognitive and emotional processes through lifetime. Therefore, there is a critical need to identify the molecular mechanisms underlying TBI‐mediated brain dysfunction. In doing so, we can develop effective therapies as the etiology for dementia remain poorly understood. Our goal is to identify early, unbiased, and novel biomarkers of brain dysfunction following rmTBI. These include defects in the brain connectome and protein expression in the areas most functionally susceptible to damage following rmTBI.

Method

To do this, we exposed young male and female C57BL/6J wild‐type mice to two rmTBI (2 × 0.6 J impacts/24 h apart) using the closed head injury model of engineered rotational acceleration (CHIMERA) or sham procedures. We measured changes in brain functional connectivity (FC) using resting state functional MRI (rsfMRI) and graph theory, examined microstructural differences in white and grey matter regions through diffusion tensor imaging (DTI) analyses, surveyed neuropathological proteins using NanoString‐GeoMx Digital spatial protein profiling spatial profiling (DSP).

Result

The rsfMRI data revealed that rmTBI induces aberrant changes in the graph metrics such as node clustering coefficient, global and local efficiency, participation coefficient, eigenvector centrality, and betweenness centrality in brain regions processing visual, auditory, and somatosensory information. The optic tract and thalamus were the most affected regions showing significant differences in phospho‐tau (S199), neuroinflammatory markers (GFAP, Iba‐1, GPNMB), and other proteolytic (cathepsin‐D) and proliferation (ki‐67) cell markers. We identified extensive white matter damage, defects in brain FC, and exacerbated anatomically distinct protein profiles.

Conclusion

These findings align with results reported in individuals with TBI such as diffuse axonal damage, glial activation, and functional network disruption in the visual tract and specific thalamic regions. Upcoming studies will evaluate the potential use of using brain imaging along with molecular markers to predict longitudinal damage after rmTBI.