bluuebunny/crossref_metadata_2025_split huggingface dataset:
REAL‐TIME AI‐BASED VOLUMETRIC ANALYSIS OF THE HIPPOCAMPUS IN PATIENTS WITH ALZHEIMER DISEASE
Authors: Salokhiddinov Marufjon , Stamou Elisabeth , Ismailova Munojat , Nuruddinov Ramziddin 
Published: December 2022

AbstractBackgroundPatients suffering from a neurodegenerative condition such as Alzheimer's disease are more likely to experience hippocampal atrophy. Unfortunately, manually segmenting the hippocampus on a brain MRI scan is a time‐consuming procedure. Delineating the structure on several slices can consume a significant amount of radiologists' valuable time. We aim to use the real‐time AI method for hippocampal segmentation in patients with Alzheimer diseaseMethodThe study involved 65 participants in total, with a mean age of 72.65 5.35 years. The hippocampus volumes and asymmetry index (AI) were calculated using a 3D T1 isotropic sequence on United Imaging Healthcare 1.5 T scanner. Volumes were determined automatically using uAI‐Discovery Brain software. We used the T1‐3D sequence (voxel size [mm3]: 0.8 × 0.8 × 1; time [ms]: TE = 2.6; TR = 2000; TI = 900; duration [min]: 9:19) for manual and automatic segmentation of the hippocampus.ResultThe study revealed a high degree of concordance (ICC = 0.95) for both hippocampi. As a result, no major disparities existed between them. The subjects' mean right (2985.65344.25 mm3) and left (2898.69 225.2 mm3) volume was determined. These volumes and the asymmetry index were significantly different from those found in a sample of healthy participants (p = 0.00001 and p = 0.003, respectively), but were comparable to those obtained in a sample of subjects with ADConclusionTo emphasize, precise segmentation of the hippocampus via AI‐method can provide critical diagnostic information and open a new path in clinical settings
Development of Clinical Trial Simulation Tools for Alzheimer’s Disease through the Critical Path for Alzheimer’s Disease (CPAD) Consortium
Authors: Sivakumaran Sudhir , Cui Zihan , Priest Eileen , Lau Corissa , White Hazel , Irizarry Michael C , Romero Klaus , Karten Yashmin 
Published: December 2022

AbstractBackgroundCritical Path Institute (C‐Path) coordinates the Critical Path for Alzheimer’s Disease (CPAD) Consortium. To accelerate DRUG DEVELOPMENT for Alzheimer’s Disease (AD), CPAD developed two regulatory‐endorsed clinical trial simulation (CTS) that sponsors can use to help optimize clinical trial design in 1) the pre‐dementia stages of AD, using CDR‐SB as the primary endpoint, and 2) mild‐to‐moderate AD, using ADAS‐cog as the primary cognitive endpoint. Recently, CPAD members have shared data from several contemporary Phase III clinical trials, offering an opportunity to enrich and expand these model‐based tools with additional fluid and imaging biomarker information, data from predementia subjects and treatment arms.MethodBy integrating patient‐level data from high quality Alzheimer’s disease (AD) clinical trials, models will be developed for multiple endpoints, and including demographics, time from and to diagnosis, genetic status (APOE4), and will be assessed using non‐linear mixed effects methods. Monte Carlo simulations will be performed to compare the statistical power by sample size in trials with and without enrichment using relevant covariates.ResultAs of January 2022, CPAD’s clinical trial repository contains 55 studies with 36,344 individual anonymized patient records. Analysis subsets generated from 6 key datasets, rich in fluid and imaging biomarkers, were used to develop of a preliminary set of disease progression models that characterize the time course of clinically relevant measures (ADAS‐Cog, CDR‐SB, other clinical assessment scales and biomarkers). A two‐level regression model was applied to predict baseline CDR‐SB using baseline covariates (demography, ApoE4 status, fluid and imaging biomarkers) and identify significant variables. Base models using parametric mixed‐effects approaches were developed with selection based on goodness‐of‐fit plots.ConclusionThe disease progression models will serve as the basis for clinical trial simulation tools to facilitate informed decision making in the DRUG DEVELOPMENT process and optimize patient and endpoint selection, as well as design of efficacy studies. CPAD will advance the tools through the formal FDA Fit for Purpose pathway, to achieve regulatory endorsement and provide confidence to sponsors for the adoption of the tools.
Characterizing the relationship between telomere length and DNA methylation age in induced pluripotent stem cells during neuronal differentiation
Authors: Imm Jennifer L , Cope Emma L , Jones Kimberly M , Burrage Joe , Allen Nicholas D , Lunnon Katie 
Published: December 2022

AbstractBackgroundInduced pluripotent stem cells (iPSCs) and their resultant neurons are popular models for studying diseases of aging, such as Alzheimer’s disease (AD). One hallmark of aging is the decreasing length of telomeres, the repetitive, protective DNA sequences at the end of each chromosome. We have previously demonstrated that whilst epigenetic age does increase with differentiation, iPSC‐derived neurons still have a fetal DNA methylation profile. It has also been shown by others that telomere length in iPSC‐derived neurons is shorter than the that of the stem cells from which they are derived. However, to our knowledge no one has looked at both epigenetic age and telomere length in the same samples. Therefore, we have collected DNA from different stages of the differentiation of iPSCs into neurons in order to look at the relationship between epigenetic age and telomere length.MethodHuman fibroblast cells were reprogrammed using lentiviral transfection. The resulting iPSC colonies were expanded, differentiated and collected at four different time points: day0 (iPSCs), day16 (neuronal progenitor cells), day37 and day58 (mature neurons). DNA methylation was assessed using the Illumina EPIC array and epigenetic age was derived using both the Horvath skin and blood clock and the Steg fetal brain clock. Absolute telomere length was determined using quantitative real‐time PCR.ResultThis study has identified the telomere dynamics of iPSCs as they undergo differentiation into cortical neurons. Not only this, but by also calculating the epigenetic age in the same samples we have been able to look at the relationship between telomere length and epigenetic age using two differentiation DNA methylation age calculators.ConclusionWe have outlined the relationship between telomere length and DNA methylation age of iPSCs as they differentiate into cortical neurons. This information is important to consider when using iPSCs to model age‐related diseases such as AD.
The Effects of COVID‐19 on Australian Family Caregivers of People with Dementia: Caregiver COVID‐19 Limitations Scale.
Authors: Chen Maddysen , Thompson Claire L , Parkinson Lynne 
Published: December 2022

AbstractBackgroundThere is limited research on the effects of COVID‐19 and accompanying psychological and health related outcomes among Australian family caregivers. The aim of this research was to examine caregiver limitations as a result of COVID‐19, and measure this perceived impact on caregiving using the newly developed Caregiver COVID‐19 Limitations Scale (CCLS‐9). Psychometric properties of the CCLS‐9 were also examined.MethodForty‐four Australian family caregivers of individuals living with dementia completed a cross‐sectional online survey between May and September 2021. Outcome measures included psychological distress, caregiver burden, caregiver self‐efficacy, social support, quality of life, and COVID‐19 related caregiver limitations.ResultPsychological distress and social support significantly predicted caregiver limitations. Australian family caregivers reported high levels of psychological distress and caregiver burden, low levels of self‐efficacy, moderate levels of perceived social support and quality of life. Overall COVID‐19 had a moderate impact on Australian family caregivers. The CCLS‐9 demonstrated good internal consistency and test‐retest reliability, poor concurrent validity, and results provided support for a two‐factor model of the CCLS‐9.ConclusionFindings from this study offer preliminary insight into the negative effects of COVID‐19 on Australian family caregivers. Distinctly, the pandemic continues to pose a significant threat to the health and psychological wellbeing of Australian family caregivers of individuals living with dementia. Therefore, Australian family caregivers should receive increased and ongoing support during these unprecedented times.
Declining Gait Speed is associated with Deteriorating Executive Performance in people with Mild Cognitive Impairment
Authors: Dolphin Helena , Fallon Aoife , McHale Cathy , Dookhy Joshi , Kennelly Sean P 
Published: December 2022

AbstractBackgroundThe Motoric Cognitive Risk Syndrome has highlighted the link between cognitive and motor performance, and the associated incremental higher risk of developing dementia. There is considerable debate regarding what aspects of cognition (working memory, executive function, attention) are most associated with gait changes. This study investigates the relationship between mobility scores and cognitive profiles in individuals with Mild Cognitive Impairment (MCI) specifically with regard to executive performance and amnestic/non‐amnestic profiles.MethodParticipants diagnosed with MCI, (Clinical Dementia Rating scale global score of ≤0.5, sum of boxes score ≤4.0), attending a regional specialist memory service had a three‐meter Timed Up and Go (TUG) gait assessment and multi‐domain neuropsychiatric assessment undertaken. Amnestic neuropsychiatric profile was defined as Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) delayed memory subset score <1SD i.e. ≤16th centile below norm for age/ education. Executive function performance was assessed using the Executive Interview (EXIT‐25) where higher scores reflect poorer executive performance.ResultData was reviewed for 161 patients with MCI; 53% (86/161) women. 80% (129/161) had an amnestic neuropsychiatric profile, mean age 73.8 ±7.2 (51‐94). 20% (32/161) had non‐amnestic MCI, mean age 74 ±7.07 (60‐87). There was no significant difference in TUG results between amnestic and non‐amnestic MCI patients (11.2 ±3.3 vs 10.7 ±3.1 p = NS). There was a significant increase in TUG values with worsening executive function performance [EXIT‐25 score 0–9 (88/161) mean TUG = 10.5 ±3.3 seconds vs EXIT‐25 score 10–14 (43/161) mean TUG = 11.9 ±2.8 seconds vs EXIT‐25 score 15–25 (30/161) mean TUG = 12.1 ±3.9 seconds; p = 0.021] which persisted after controlling for age, gender and other relevant cofactors.ConclusionReflective of the importance of frontal lobe integration to the respective tasks, subtle differences in gait performance are associated with executive function performance regardless of predominant amnestic or non‐amnestic MCI profile.
Geo‐cultural influences on the relationship between the CDR and MMSE
Authors: Kamat Rujvi , Appleman Erica R. , Chen Zinan , Stenclik Jessica , Machizawa Sayaka , Feaster H Todd 
Published: December 2022

AbstractBackgroundThe increasingly global scope of clinical trials in Alzheimer’s disease (AD) has led to the recruitment of subjects from various geo‐cultural regions. Recent studies suggest that commonly used objective measures of cognition such as the MMSE as well as subjective, clinician‐rated global measures such as the CDR might be impacted by cultural and/or linguistic differences. This raises the question regarding the impact of cultural differences on the convergent validity of the CDR and MMSE.In this analysis, we examined the extent to which the correspondence between the CDR and MMSE varied across seven geo‐cultural regions in multinational AD clinical trials.MethodThis study included electronic CDR (eCDR) and electronic MMSE (eMMSE) data from four multinational AD clinical trials of subjects with Prodromal to Mild AD. Data were collected at screening from seven geo‐cultural regions: East Asia (n = 1916), Eastern Europe (n = 1882), South America (n = 1601), Middle East/Africa (n = 188), North America (n = 9311), Oceania (n = 363), and Western Europe (n = 5174).ResultPearson correlations between eCDR Sum of Boxes (SOB) and eMMSE across the 7 geo‐cultural regions ranged from r = ‐.31 (East Asia, Western Europe) to r = ‐.48 (Mideast/Africa). A linear regression model with geo‐cultural regions entered as covariates further demonstrated that the relationship between eMMSE and eCDR SoB scores differed by region (Adjusted R2 = 0.14, p<0.001).ConclusionFindings indicate the strength of the correlation between the CDR SOB and MMSE total score varied by geo‐cultural region. These results build on prior findings indicating that CDR SOB and MMSE scores vary across regions independent of each other. A growing body of literature suggests these differences might be due to cultural and/or linguistic factors.
APOE Allele Switching in a Novel Transgenic Mouse Model as a Therapeutic Approach for Alzheimer’s Disease
Authors: Golden Lesley R , Johnson Lance A 
Published: December 2022

AbstractBackgroundIndividuals homozygous for the ε4 allele of Apolipoprotein E (APOE) face up to a 15‐fold increase in Alzheimer’s Disease (AD) risk. In comparison, those carrying two ε2 alleles have nearly a 99.6% reduction in risk. Given APOE’s strong risk profile and multitude of effects, APOE itself has emerged as a promising therapeutic target. CRISPR‐Cas9 technology has been used to successfully edit APOE in vitro, where iPSC‐derived glia and neurons edited from ε4 to ε3 show pronounced transcriptional and phenotypic changes. However, whether the putatively beneficial effects of switching to APOE2 holds true in in vivo models has yet to be fully determined.MethodsWe developed a novel transgenic mouse model, the APOE “switch mouse” (4S2) which allows for an inducible (CreERT2) transition from expression of ApoE4 to ApoE2. Gene expression, western blotting, ELISA, and mass spectrometry based proteomic analysis were used to confirm that 4S2 mice synthesize full‐length human ApoE4 at baseline (pre‐switch) and full‐length human ApoE2 after tamoxifen administration (post‐switch). Analysis of plasma lipids, metabolomics, and transcriptomic analyses were used to identify downstream, physiological effects of replacing ApoE4 with ApoE2.ResultsPhysiological phenotyping, gene expression measures, and proteomic analyses further show that following tamoxifen injection, the inducible switch successfully results in efficient (>98%) recombination and expression of human ApoE2. Global genetic replacement of ApoE4 with ApoE2 results in changes to plasma lipids. Mass spec imaging revealed changes in multiple classes of lipids, while single‐cell and spatial RNAseq analyses shows distinct alterations in glial cell transcriptomes. Together these data suggest a successful transition from ApoE4 to ApoE2 that has broad impact on the glial transcriptome as well as on peripheral and cerebral metabolism.ConclusionsOur exciting preliminary studies have leveraged this new mouse as a promising model to assess the feasibility and therapeutic window of replacing APOE4 with APOE2, along with any potential off‐target effects. Ongoing studies aim to determine whether cell‐specific replacement of ApoE4 with APOE2 will rescue E4 associated metabolic dysfunction, disease associated gene signatures, and AD pathology. We hope that this new model will be a valuable resource for the AD/APOE research community.
Risk of unexpected mortality is increased by evoked seizures in the APP/PSEN1, but not PSEN2‐N141I transgenic, mouse model of Alzheimer’s disease
Authors: Sanz Aaron Del Pozo , Knox Kevin M , Davidson Stephanie , Lehmann Leanne M , Barker‐Haliski Melissa 
Published: December 2022

AbstractBackgroundPatients with early‐onset Alzheimer’s disease (AD) with amyloid precursor protein (APP) duplication are at significantly elevated risk of seizures (Zarea et al, Neurology 2016). Deaths specifically from AD in patients with epilepsy have increased over 200% in the last 20 years (DeGiorgio et al, BMJ Open 2020). The incidence of sudden, unexpected death in epilepsy (SUDEP; Harden et al, Neurology 2017) remains unchanged. The co‐occurrence of epilepsy and AD critically increase risks for mortality yet whether specific AD‐associated risk genes more significantly escalate mortality risk is unclear.MethodMale and female 2‐month‐old APP/PS1 and wild‐type littermates (WT) of C57Bl/6J mice, were subjected to the corneal kindling model of temporal lobe epilepsy, which is routinely used for antiseizure drug discovery (Barker‐Haliski et al, Neurochem Res 2017). PSEN2‐N141I transgenic mice and WT controls were similarly kindled to assess whether AD‐associated risk factors differentially influence mortality risk. APP/PS1 and PSEN2‐N141I mice (n=5‐10 mice/genotype/sex) were kindled with a twice‐daily subthreshold electrical stimulus (3 sec 60 Hz 1.6‐3 mA current) for 2‐3 weeks until each mouse presented with 5 consecutive Racine stage 5 seizures. Survival during kindling acquisition was compared across all genotypes within sexes. Post‐kindling survival was assessed with each twice‐weekly baseline stimulation for up to 2 months.ResultBoth male and female APP/PS1 mice were more rapidly kindled than WT littermates, whereas male and female PSEN2‐N141I mice were slower to kindle versus WT controls. The survival of fully kindled male, but not female, APP/PS1 mice was significantly different from age‐matched WT littermates (males: X2=8.635, p<0.01; females: X2=3.00, p>0.05). Conversely, there was no difference in post‐kindling mortality for PSEN2‐N141I mice in either sex versus WT controls. The time‐related effects of corneal kindling on serotonin receptor and transporter expression assessed by western blot will be further discussed, with changes in serotoninergic tone known to increase mortality risk in patients with epilepsy alone.ConclusionsOur study suggests that discrete AD‐associated risk factors differentially increase mortality risk in the context of chronic seizures in young adult mice. Future studies are necessary to determine whether AD‐specific genetic risk factors influence seizure‐induced mortality and identify preventative agents.
Ranolazine Effectively Ameliorated Brain Pathologies and Cognitive Decline in Rats with Trastuzumap‐Induced Chemobrain
Authors: Chunchai Titikorn , Arinno Apiwan , Ongnok Benjamin , Pantiya Patcharapong , Khuanjing Thawatchai , Prathumsap Nanthip , Maneechote Chayadom , Pintana Hiranya , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: December 2022

AbstractBackgroundChemotherapy can increase survival rate of cancer patients. One of the chemotherapeutic drugs for breast cancer patients is trastuzumap (Trz). Chemotherapy not only helps to kill cancers, but it also causes several adverse effects in the patients, particularly in the brain, known as chemobrain. Chemobrain has been characterized by cognitive decline with brain mitochondrial dysfunction, hippocampal microglial activation, and loss of dendritic spines. Although several types of chemotherapy induce chemobrain, Trz‐induced chemobrain are not clearly elucidated. Ranolazine, a drug that is commonly used to treat the patients with chronic angina, shows benefits on cognitive function in doxorubicin‐induced chemobrain. However, the effects of ranolazine on brain mitochondrial function, hippocampal microglial function, hippocampal dendritic spines, and cognitive function in Trz‐induced chemobrain have never been investigated.MethodsEighteen male Wistar rats were randomly divided into two groups including control group (0.9% NSS, intraperitoneal (i.p.) injection, n=8) and Trz‐treated group (4 mg/kg for 7 days, i.p. injection, n=16). All Trz‐treated rats were randomly divided into two subgroups (n=8/ subgroup) to receive either vehicle (0.9% NSS, daily via oral gavage) or ranolazine (305 mg/kg/day, daily via oral gavage). At the end of experiment protocol, cognitive function was measured, and brains were obtained for further molecular investigation.ResultsThe results demonstrated that vehicle‐treated Trz‐rats significantly increased brain mitochondrial ROS production, increased brain mitochondrial membrane potential change, and increased brain mitochondrial swelling, suggesting brain mitochondrial dysfunction (p<0.05, Figure 1). These parameters were attenuated in ranolazine‐treated Trz‐rats (p<0.05, Figure 1). In addition, the microglial activation was found in vehicle‐treated Trz‐rats as indicated by increased the number of microglial cells, which was suppressed by the ranolazine treatment (p<0.05, Figure 1). Consistently, the dendritic spine density decreased in vehicle‐treated Trz‐rats, leading to cognitive decline (p<0.05, Figure 1). Ranolazine‐treated Trz‐rats showed an increase in dendritic spine density, resulting in the improvement of cognitive function (p<0.05, Figure 1).ConclusionsAll findings suggest that ranolazine effectively ameliorated cognitive decline in rats with Trz‐induced chemobrain. The novel findings obtained from the present study provided the therapeutic strategies which can be translated into clinical settings for better preventing chemobrain in the future.
Acetylcholinesterase Inhibitor Exerted Neuroprotection Against Trastuzumab‐Induced Chemobrain
Authors: Ongnok Benjamin , Khuanjing Thawatchai , Chunchai Titikorn , Pintana Hiranya , Pantiya Patcharapong , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: December 2022

AbstractBackgroundChemobrain has recently gained attention as a serious neurobehavioral consequence of chemotherapy in cancer patients. Even well‐recognized among conventional chemotherapeutic agents, trastuzumab (TRZ), an oncogene‐targeted therapy for treating breast cancer, has been shown to intricately caused symptoms of chemobrain elicited by impaired cerebral glucose metabolism and long‐term cognitive function. Noticeably, the inhibition of acetylcholinesterase using donepezil (DPZ), a medication widely used to treat Alzheimer’s disease (AD), possesses several pleiotropic effects including mitochondrial protection and immunomodulation. However, the mechanistic insights regarding the pathophysiology and therapeutic benefit of DPZ have never been holistically determined in a rat model of TRZ‐induced chemobrain.MethodFifteen male Wistar rats were randomized to receive either a 0.9% normal saline solution (Control; n=5) or 4 mg/kg of TRZ via intraperitoneal injection for 7 consecutive days. Then, TRZ‐treated rats were subdivided into 2 groups to receive either drinking water (TRZ, n=5) or 5 mg/kg of DPZ (TRZ+DPZ; n=5) via oral gavage as co‐treatment with TRZ for 7‐day duration. After cessation of the treatment paradigm, cognitive performance was assessed using the novel object location task (NOLT). The brain tissues were obtained for further molecular investigation.ResultTRZ‐treated rats showed impaired long‐term spatial memory as demonstrated by a reduction of preference index in the NOLT (Figure A). Systemic TRZ administration compromised mitochondrial anti‐oxidant capacity (Figure B) and potentiated the activation of mitochondrial‐fission related protein. Furthermore, the upregulation of neuroinflammation was observed in TRZ‐treated rats presented by increased TNF‐α mRNA level (Figure C) and microglial morphological changes into neurotoxic amoeboid‐shaped (Figure D). Additionally. Administration of TRZ triggered the phosphorylation of Tau protein (Figure E) and reduced dendritic spine density in CA1 region (Figure F). Strikingly, co‐administration with DPZ effectively rescued cognitive performance of TRZ‐treated rats by improving mitochondrial anti‐oxidant capacity, reducing mitochondrial fission, mitigating neuroinflammation and microglial polarization, attenuating Tau hyperphosphorylation, and preserving dendritic spine density (Figure A‐F).ConclusionThese findings suggested that DPZ exerted neuroprotective effects against TRZ‐induced chemobrain. Our findings pave the way for parasympathetic activation using DPZ as a therapeutic approach in the prevention of chemobrain in patients who received chemotherapy in the future.