bluuebunny/crossref_metadata_2025_split huggingface dataset:
RXR agonist bexarotene modulates the cell‐fate and migration abilities of adult neural stem cells in vitro
Authors: Saibro‐Girardi Carolina , Matsubara Ingrid Scheibel , Santos Lucas , Bittencourt Reykla Ramon , Moreira José Claudio Fonseca , Gelain Daniel Pens 
Published: June 2023

AbstractBackgroundTargeting the nuclear RXR receptors has been associated with brain‐specific roles with striking therapeutic potential for Alzheimer’s Disease (AD), with similar observations to its dimerization partners such as LXR and PPAR whose responses are also under influence of RXR activation. Treatment with bexarotene, a selective RXR agonist, leads to significant recovery of cognitive loss in variable mice AD‐like models ‐ and also activates neurodevelopment and plasticity pathways in adult mice brains. Our hypothesis is that neural stem cells (NSC) residing in the adult brain directly respond to bexarotene, leading to improved neurogenesis and other effects compatible with brain recovery.MethodWe employed an in vitro strategy using NSCs isolated from the subventricular zone of adult rats’ brains. Adult NCSs were treated with bexarotene from neurosphere proliferative stage to differentiated states, and the cell‐fate consequences were evaluated through morphometric analysis and immunofluorescence of cell markers.ResultIn proliferative stages, bexarotene‐treated adult NSCs exhibited increased cell outgrowth from neurospheres. Bexarotene treatment also led to changes in the cell fate of differentiating cells, with a marked increase in GFAP staining after differentiation. Relatively to newborn neurons, we found a decrease in DCX positive staining of neuroblasts after bexarotene treatment. However, Tuj1 staining of neurons was preserved. Neurite number, length, and bifurcations in differentiated neurons were unaffected by bexarotene.ConclusionAdult NSCs respond to bexarotene by increasing migration abilities and generating more GFAP+ cells. Results indicate that RXR activation by bexarotene in adult NSCs preserves, but does not activate, neuronal differentiation and neurite complexity. The significance of the increased GFAP+ glial cell population, as well as the decreased DCX+ young neurons, remains to be unrevealed. Finally, we did not observe clear bexarotene‐induced changes in neurosphere proliferation, but the effect of RXR activation over pluripotency in these cells needs further investigation. These findings address a gap in our knowledge regarding the brain effects of bexarotene, substantiating the search and possible application of RXR‐based approaches to AD.
Support for verbal memory reserve in women using an epigenetic marker of age acceleration
Authors: O'Shea Deirdre , Alaimo Hannah 
Published: June 2023

AbstractBackgroundTo determine whether characterizing men and women based on rates of biological aging indexed by DNA methylation “GrimAge” reflect differences on measures of verbal and non‐verbal memory.MethodCross‐sectional data from 1,930 adults aged 65 or older (mean age = 75, SD = 7.4, Male = 43%, non‐Hispanic White = 74.8%, non‐Hispanic Black = 13.5%, Hispanic = 9.6%, other race/ethnicity = 2.1%) were included. The standardized residual from regressing chronological age on the DNA methylation GrimAge clock as the measure of age acceleration. Slow and accelerated “DNAmGrimAgers” were defined as individuals below or above 1 SD of their sex‐specific GrimAge acceleration Mean, respectively. Individuals between these cutoffs were categorized as “normal agers” resulting in six different groups (i.e., 3 female and 3 male). Performances on measures of verbal and non‐verbal memory and processing speed were compared across these six different groups, controlling for education, depressive symptoms and chronological age. We reran analysis adjusting for processing speed.ResultWhen comparing men and women’s performances based on their matching DNAmGrimAge category, there was no difference in processing speed or visual memory (e.g., accelerated male DNAmGrimAgers performed similarly to accelerated female DNAmGrimAgers on speed). In contrast, women, regardless of their DNAmGrimAge category, outperformed men on verbal memory measures (in speed and non‐speed adjusted models). Additionally, while accelerated female DNAmGrimAgers had significantly lower memory performances compared to slow female DNAmGrimAgers, this group difference was no longer significant in the speed‐adjusted models.ConclusionWomen maintained a verbal memory advantage over men, despite different rates of age acceleration, which was not accounted for by faster processing speed. These findings strengthen prior support for verbal memory reserve that is specific to women. Thus, relying on verbal memory assessments in women at risk of Alzheimer’s disease (AD) may not be sensitive enough to detect hippocampal impairment in the earliest stages. However, performances on visual memory measures may be a more accurate representation of hippocampal function in women and should be included in assessments where AD is suspected.
Multidisciplinary characterization of potential inhibitors of the MSUT‐2 protein using molecular dynamics, mechanosensation assays, and deep AI‐based hit optimization for the treatment of Alzheimer’s disease
Authors: Ganesh Rithvik 
Published: June 2023

AbstractBackgroundAlzheimer’s disease is a type of tauopathy, which is a broad category of diseases marked by abnormal aggregation and hyperphosphorylation of the tau protein. The MSUT‐2 protein has gained traction as a promising target for the treatment of tauopathies, given the protein’s RNA‐binding activity linked to tau aggregation. Previously in this research endeavor, using techniques like Quantum Machine Learning and Virtual Screening, 5 potential MSUT‐2 inhibitors have been identified from an initial set of 500,000 candidate compounds. The primary research aim is to further analyze these 5 potential hits using a new combination of computational methodologies and laboratory characterization.MethodA myriad of tests were performed with strains of C. elegans (microscopic roundworms that are established models for neurodegeneration) to validate previous computational indications. A series of motion evaluations, mechanosensation assays, and behavioral assessments were performed with CL2319 C. elegans (mutated to overexpress neuronal tau) with all 5 compounds. One of the compounds, named R128, was found to improve the health and behavior of tau mutant worms across experimental assessments at increasing doses of the compound. A 100 nanosecond simulation of the MSUT2‐R128 complex using the GROMOS96 43a1 force field and SPC Water Model was used to computationally validate protein‐ligand stability based on RMSD fluctuation values. DeepFrag, a fragment‐based lead optimization tool with a deep convolutional neural network backend, was then used to generate 20 potential optimized compounds, nine of which were found to retain R128’s druglikeliness profile yet have improved binding affinities to MSUT‐2.ResultThis multidisciplinary workflow has uncovered a promising hit for the MSUT‐2 protein, named R128, with 9 optimized derivatives with improved drug‐like qualities. This methodology can be used to efficiently identify promising treatment candidates for new protein targets involved in neurodegenerative diseases, with the prospect of expediting the drug discovery process significantly.ConclusionTo conclude, a translational approach, combining molecular dynamics, mechanosensation assessments with C. elegans, and an AI‐based hit optimization strategy has been used to identify new treatment candidates for Alzheimer’s disease. R128, a promising inhibitor for MSUT‐2 (an understudied target for Alzheimer’s disease), has also been identified in this study.
The interaction between APOE‐e4 gene and paid work for women in predicting ADAS 13 scores
Authors: Lee Lisa J , Liu Stephanie , Morin Ruth , Bennett Lauren 
Published: June 2023

AbstractBackgroundThe associated risk of Alzheimer’s disease linked to the APOE‐e4 gene is similar in males and females. However, there is a disproportionate rate of Alzheimer’s in women (two‐thirds) compared to men. Mayeda et al. (2020) found that women who worked for pay during early adulthood and midlife, whether married or unmarried, had a slower rate of memory decline in later life compared to women who did not work for pay. Although there has been much research on the association between type of paid work or work environment and dementia; for instance, work complexity, job control, and job strain, there has been little research that includes unpaid work in ascertaining its effect on women and neurocognitive functioning later in life. This study aims to find the interaction between paid work and the APOE‐e4 gene in predicting the risk for Alzheimer’s disease (operationalized as ADAS13 total score at baseline) in women.MethodA two‐way ANOVA was performed using data at initial visit from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database for 340 female participants.ResultThere were significant main effects for APOE‐e4 gene on ADAS‐Cog‐13 total score (F (2,334) = 4.697, p = .010) as well as paid work on ADAS‐Cog‐13 total score (F (1,334) = 5.450, p = .020). The interaction between APOE‐e4 gene and paid work on ADAS‐Cog‐13 total was not significant (F (2,334) = 215.725, p = .091).ConclusionAPOE‐e4 gene as well as unpaid work are independently linked to higher scores on the ADAS‐Cog‐13 (Alzheimer’s Disease Assessment Scale) for women. There is no interaction between APOE‐e4 gene and type of work on ADAS‐Cog‐13 scores for women.
Differences in rate of change of retinal structural and microvasculature parameters in parkinson’s disease compared to controls
Authors: Kundu Anita , Ma Justin , Robbins Cason B , Pant Praruj , Soundararajan Srinath , Stinnett Sandra , Scott Burton , Moore Kathryn , Grewal Dilraj S , Fekrat Sharon 
Published: June 2023

AbstractBackgroundPrior cross‐sectional studies have revealed decreased macular perfusion density (PFD) and increased peripapillary PFD in Parkinson’s disease (PD). We assess longitudinal rate of change of retinal microvascular and structural parameters in PD vs controls with normal cognition.MethodSubjects were imaged using Zeiss Cirrus HD‐5000 AngioPlex. Those with confounding medical or ocular comorbidities were excluded. Superficial capillary plexus (SCP) PFD and vessel density (VD) were assessed within ETDRS 6×6 circle, inner ring, outer ring and 3×3 circle and inner ring. SCP foveal avascular zone (FAZ) area was assessed. PFD, VD, FAZ, peripapillary retinal nerve fiber layer (RNFL), ganglion cell‐inner plexiform layer (GCIPL), and central subfield thickness (CST) were measured at 2 time points 1 year apart. Rate of change per year was calculated. Generalized estimating equations analyzed associations between rate of change of imaging parameters and PD.Result74 eyes of 40 patients with PD (60% male, mean age 67.47.9 years) & 149 eyes of 78 controls (28% male, mean age 70.35.8 years) were included. No demographic differences were observed between groups except higher proportion of females in controls (p = 0.001). PD had a greater decline in PFD in 6×6 circle (mean change per year = 0.021, control = 0.00, p = 0.001), 6×6 inner ring (PD = 0.018, control = 0.001, p = .007), 6×6 outer ring (PD = 0.022, control = 0.00, p = 0.001), 3×3 circle (PD = 0.016, control = 0.002, p<.001), 3×3 inner ring (PD = 0.016, control = 0.002, p<0.001). PD had greater decline in VD in 6×6 circle (mean change per year in PD = 0.72/mm, control = 0.054/mm, p = 0.006), 6×6 inner ring (PD = 0.636/mm, control = 0.048/mm, p = 0.03), 6×6 outer ring (PD = 0.746/mm, control = 0.054/mm, p = 0.005), 3×3 circle (PD = 0.939/mm, control = 0.006/mm, p<0.001), 3×3 inner ring (PD = ‐0.942/mm, control = 0.013/mm, p<0.001). PD had greater decrease in GCIPL (mean change per year in PD = 0.403µm, control = 0.128µm control, p = 0.01). There were no significant differences in rate of change in FAZ area, RNFL thickness, CST, and no significant differences in rate of change when stratified by PD severity.ConclusionPD may be associated with more rapid loss of retinal microvascular perfusion and vessel densities and more rapid thinning of GCIPL compared to normal aging in controls with normal cognition.
Rightward lateralization of frontal cortex tau pathologies is associated with late‐onset psychosis: A PET study with 18F‐PM‐PBB3
Authors: Kurose Shin , Takahata Keisuke , Moriguchi Sho , Tagai Kenji , Kubota Manabu , Sano Yasunori , Yamamoto Yasuharu , Endo Hironobu , Hirata Kosei , Matsuoka Kiwamu , Oya Masaki , Matsumoto Hideki , Kokubo Naomi , Koreki Akihiro , Suzuki Hisaomi , Ogyu Kamiyu , Mashima Yuki , Mimura Yu , Nakajima Shinichiro , Bun Shogyoku , Seki Chie , Takado Yuhei , Sahara Naruhiko , Onaya Mitsumoto , Mimura Masaru , Higuchi Makoto 
Published: June 2023

AbstractBackgroundSeveral cohort studies have recently reported associations between late‐life psychosis and dementia, and postmortem studies have demonstrated that most individuals with late‐onset schizophrenia and delusional disorder had tau pathologies. The present study was aimed to assess the prevalence and topology of tau pathologies by positron emission tomography (PET) with a specific probe, 18F‐PM‐PBB3 (18F‐APN‐1607), in patients with late‐onset psychosis (LOP).MethodWe included LOP patients who experienced the first episode of psychosis after 65 years old and excluded those with dementia. Fourteen patients with LOC (74.2 ± 4.0 years old; 7 females and 7 males)and 16 age‐matched healthy controls (HCs) (72.6 ± 5.7 years old; 9 females and 7 males) underwent PET scans with 18F‐PM‐PBB3 and an amyloid‐β probe, 11C‐PiB. The radioprobe retention was calculated as standardized uptake value ratio (SUVR), and the laterality index (LI) of SUVR was estimated as [Left‐Right/(Left+Right)]. We compared 18F‐PM‐PBB3 SUVRs and LIs in the frontal, temporal, parietal, and occipital cortices between patients and HCs using an independent t‐test after Bonferroni correction (p‐value ≤ 0.05/4).ResultAll HCs were negative for 11C‐PiB‐PET. By contrast, unequivocally increased 18F‐PM‐PBB3 retentions were found in 4 out of 4 11C‐PiB‐positive patients (100%) and 7 out of 10 11C‐PiB‐negative patients (70%) with variable localizations. Tau topologies in four 11C‐PiB‐positive cases were characteristic of Alzheimer’s disease and consisted of limbic predominant (N = 2), medial temporal lobe‐sparing (N = 1), and lateral temporal (N = 1) deposition subtypes. Meanwhile, tau topologies in 7 11C‐PiB‐negative cases were composed of lateral‐posterior diffuse (N = 3), posterior mild (N = 2), lateral temporal local (N = 1), and progressive supranuclear palsy‐like (N = 1) accumulations. None of the target regions exhibited significant differences in 18F‐PM‐PBB3 SUVR between patients and HCs, reflecting the heterogeneous distributions of tau deposits in patients. There was significant rightward lateralization of tau pathologies indicated by a reduced LI in the frontal cortex (P = 0.0093) but not the other cortical regions.ConclusionOur findings indicate that LOP is associated with tau topologies of diverse Alzheimer’s and non‐Alzheimer’s disease subtypes. The rightward lateralization of tau pathologies in the frontal cortex might be involved in the development of psychotic manifestations.
Comparing visuospatial construction ability of MoCA and MMSE in cognitive assessment of patients with dementia of Alzheimer’s type
Authors: Rai Pooja , Singh Indramani L. , Singh Tara , Tiwari Trayambak , Joshi Deepika 
Published: June 2023

AbstractBackgroundThe ability to see an object or picture as a set of parts and then to construct a replica of the original from these parts is known as visuospatial constructive cognition. Examples of visuospatial construction include drawing, buttoning shirts, constructing models, making a bed, and putting together furniture that arrives unassembled. Visuospatial construction is a central cognitive ability. At the same time, there are enormous individual differences among people in their ability to perform visuospatial constructive tasks. The MoCA had greater sensitivity than MMSE in detecting MCI versus HCs (; however, specificity was lower for the MoCA than MMSE.MethodThe present study has considered visuospatial construction ability in cognitive neuropsychological screening tool. The neuropsychological screening tool were Mini‐mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The intersecting pentagons copy sub‐item was administered as part of the MMSE whereas there was cube figure to copy where subjects have to initially convert a two‐dimensional contour to a three‐dimensional cube. The sample consisted of 15 patients with mild Dementia of Alzheimer’s type.ResultThe result showed that both the MoCA and the MMSE were successful in differentiating between patients with and without cognitive domain deficits and cognitive impairment. The scores in visuospatial construction ability on MoCA and MMSE are different on visuospatial domain which on further analysis showed significant differences in cognitive performance.ConclusionThe cognitive scores of mild Dementia of Alzheimer’s patient differs which showed the differences in the ability to complete a cognitive task as and thus revealed greater sensitivity of MoCA as compared to MMSE.
Co‐design of an Aboriginal Health Practitioner‐led dementia prevention program (DAMPAA) using a Theory of Change framework
Authors: Arriero Irene Mateo , Lalovic Alex , Flicker Leon , Almeida Osvaldo P , Thompson Sandra , Etherton‐Beer Christopher , Hill Keith , LoGiudice Dina , Cox Kay L , Milte Rachel , Ratcliffe Julie , Pestell Carmela , Dowden Glennette , Bynder Michael , Bulten Samuel , Yappo Lynette , Markey Lesley , Lin Ivan , Woods Deborah , Smith Kate 
Published: June 2023

AbstractBackgroundDementia prevalence and incidence in Aboriginal Australians is three to five times that of the general population. Many of the known risk factors for dementia in this population are modifiable (e.g., head injury, hypertension, previous stroke and poor mobility). However, there is currently no evidence‐base on how to delay or prevent cognitive decline and dementia in Aboriginal Australians. Therefore, a comprehensive program to target dementia risk factors in this population is required.MethodIn partnership with three Aboriginal Community Controlled Health Services (ACCHS) in Western Australia, we have developed an Aboriginal health practitioner‐led health program (DAMPAA) to target key dementia risk factors for Aboriginal people over 45 years. The DAMPAA program was co‐designed by the research team, Elders and Aboriginal community‐controlled organisations. Qualitative data to inform the co‐design was collected through ACCHS staff workshops, Elders yarning groups and interviews with DAMPAA Aboriginal and non‐Aboriginal researchers using a Theory of Change framework. Additionally, a small pilot study was conducted in 2020, which included participant exit interviews conducted by Aboriginal researchers. Qualitative data from all data sources was analysed thematically by a qualitative researcher, and member checked by two DAMPAA Aboriginal researchers and the Elders Governance group.ResultThe DAMPAA program includes group physical activity, education, goal setting and medication management. Program enablers identified by ACCHS, research staff and participants include (but not limited to) group Aboriginal community controlled organisation based walking and yarning sessions, with additional activities such as aqua aerobics, tai chi and boot scooting, a buddy system for home exercising, connecting with others, transport, healthy food, being Aboriginal led, and the ACCHS partnership. An additional enabler identified by the Elders governance group include Aboriginal language education sessions. Program barriers identified include (but not limited to) family commitments, caring for grandchildren, travel for funerals and other appointments and participant contact details changed.ConclusionThe barriers and enablers identified from participants, ACCHS and DAMPAA staff have informed the development of the program protocol. DAMPAA will be evaluated through a randomised controlled trial implemented at four sites in Western Australia and process evaluation using a Theory of Change framework.
The Link between Brain age and Alzheimer’s Disease development using different neuroimaging modalities
Authors: Doering Elena , Antonopoulos Georgios , Hönig Merle C. , van Eimeren Thilo , Eickhoff Simon B. , Patil Kaustubh , Drzezga Alexander 
Published: June 2023

AbstractBackgroundBrain age (BA) provides a proxy of general brain health through the prediction of chronological age (CA) from neuroimaging data of healthy individuals. During aging, the adult brain undergoes changes both on the morphological and metabolic level. Here, we compare the link between BA predicted from morphology (structural MRI) or metabolism (18F‐FDG‐PET) and cognitive function, as well as pathophysiological measures of Alzheimer’s disease (AD) in cognitively normal individuals (CN) and patients with mild cognitive impairment (MCI).MethodSeveral machine learning algorithms were trained to predict BA from 256 matched MRI or 18F‐FDG‐PET scans of CN from the Alzheimer’s Disease Neuroimaging Initiative. Trained algorithms were then used to predict BA in a test sample of CN (n = 123) and MCI (n = 621). Partial spearman correlations between brain‐predicted age difference (BA – CA; BPAD) and composite scores of cognitive function (memory: ADNI‐MEM; executive function: ADNI‐EF), as well as pathophysiological measures of AD (amyloid (cerebrospinal fluid (CSF) and PET) and tau pathology (CSF tau and p‐tau)) were subsequently calculated in these test samples correcting for sex.Result
18F‐FDG‐PET‐ and MRI‐predicted brain age showed a mean absolute error of 2.77 and 1.81 years in CN, respectively.ADNI‐MEM scores declined with increasing 18F‐FDG‐PET‐BPAD, while ADNI‐EF scores declined with increasing MRI‐BPAD in CN.Higher BPAD was significantly associated with worse cognitive function in MCI in both modalities, while stronger associations were found for MRI‐BPAD and cognitive function.
18F‐FDG‐PET‐, but not MRI‐BPAD was correlated with CSF amyloid load in CN.In MCI, higher BPAD from both modalities was associated with more amyloid and CSF p‐tau pathology, while only MRI‐BPAD was significantly associated with an increase of CSF tau pathology. Associations of MRI‐BPAD and pathology were generally stronger.ConclusionBrain age can be reliably predicted on the basis of 18F‐FDG‐PET and MRI. Amyloid‐neuropathology, predisposing for AD, as well as initial memory decline is related to features of advanced BPAD in 18F‐FDG‐PET ahead of clinical onset of disease. Onset of tau‐related neurodegeneration and of objective cognitive decline is more strongly associated with signals of increasing BPAD on MRI.