Ophthalmic and Neuroimaging Associations In Optic Nerve Hypoplasia/Septo-Optic-Pituitary Dysplasia.

BACKGROUND: Optic nerve hypoplasia (ONH) and septo-optic-pituitary dysplasia (SOD) are neurodevelopmental disorders associated with congenital visual impairment. Our aim was to investigate associations between several ophthalmic and neuroimaging features in patients with ONH/SOD. METHODS: A retrospective chart and neuroimaging review was performed in patients with ONH/SOD. Ophthalmic signs (e.g., monocular best-corrected visual acuity [BCVA], nystagmus, and strabismus) and neuroimaging data were extracted and their associations were investigated. RESULTS: There were 128 patients (70 males) with ONH/SOD who had neuroimaging. Their mean age at the end of the study was 13.2 (SD: 7.5) years. Ophthalmic data were available on 102 patients (58 males). BCVA varied from normal to no light perception. There were statistically significant associations between: (A) Reduced optic nerve or chiasm size on neuroimaging and more severely impaired BCVA and (B) laterality of the reduced optic nerve or chiasm size on neuroimaging and laterality of: (1) The eye with reduced BCVA, (2) small optic disc size, and (3) RAPD, if present (p ≤ 0.0002 each). The presence of symmetrically small optic nerves on MRI was significantly more common in patients with nystagmus than when nystagmus was absent (N = 96, 75% vs. 38.6%, p < 0.0001). The presence of neuronal migration disorders, their type and laterality were not associated with BCVA and laterality of the reduced BCVA. CONCLUSION: The functional and structural associations in ONH are consistent with the impaired visual function that results from the hypoplastic anterior visual pathways. However, these associations were not perfectly concordant making prediction of adult BCVA challenging in these patients.

Establishment of a steroid binding assay for goldfish membrane progesterone receptor (mPR) by coupling with graphene quantum dots (GQDs).

A homogeneous assay was developed to evaluate ligands that target the membrane progesterone receptor alpha (mPRα) of goldfish. This was achieved by employing graphene quantum dots (GQDs), a type of semiconductor nanoparticle conjugated to the goldfish mPRα. When progesterone-BSA-fluorescein isothiocyanate (P4-BSA-FITC) was combined with the other agents, fluorescence was observed through Förster resonance energy transfer (FRET). However, this fluorescence was quenched by binding between the ligand and receptor. This established method demonstrated the ligand selectivity of the mPRα protein. Then, the methylotrophic yeast Pichia pastoris was used to express the goldfish mPRα (GmPRα) protein. The recombinant purified GmPRα protein was coupled with graphene quantum dots (GQDs) to generate GQD-conjugated goldfish mPRα (GQD-GmPRα). Fluorescence at a wavelength of 520 nm was observed through FRET upon the combination of P4-BSA-FITC and subsequent activation by ultraviolet (UV) light. Adding free P4 to the reaction mixture resulted in a decrease in fluorescence intensity at a wavelength of 520 nm. The fluorescence was reduced by the administration of GmPRα ligands but not by steroids that do not interact with GmPRα. The findings indicated that the interaction between the ligand and receptor led to the formation of a complex involving GQD-GmPRα and P4-BSA-FITC. The interaction between the compounds and GQD-GmPRα was additionally validated by a binding experiment that employed the radiolabeled natural ligand [3H]-17α,20ß-dihydroxy-4-pregnen-3-one. We established a ligand-binding assay for the fish membrane progesterone receptor that is applicable for screening compounds.

Tactile stimulation improves cognition, motor, and anxiety-like behaviors and attenuates the Alzheimer's disease pathology in adult APPNL-G-F/NL-G-F mice.

Alzheimer's disease (AD) is one of the largest health crises in the world. There are limited pharmaceutical interventions to treat AD, however, and most of the treatment options are not for cure or prevention, but rather to slow down the progression of the disease. The aim of this study was to examine the effect of tactile stimulation (TS) on AD-like symptoms and pathology in APPNL-G-F/NL-G-F mice, a mouse model of AD. The results show that TS reduces the AD-like symptoms on tests of cognition, motor, and anxiety-like behaviors and these improvements in behavior are associated with reduced AD pathology in APP mice. Thus, TS appears to be a promising noninvasive strategy for slowing the onset of dementia in aging animals.

Neuroimaging Features in Children with Optic Nerve Hypoplasia and Septo-Optic-Pituitary Dysplasia.

BACKGROUND: Optic nerve hypoplasia (ONH) and septo-optic-pituitary dysplasia (SOD) are common causes of congenital visual impairment. Our primary aim was to investigate the prevalence of abnormal neuroimaging features in patients with these disorders in Manitoba, Canada, and compare them with published reports. METHODS: A retrospective neuroimaging review was performed in patients resident in Manitoba with ONH/SOD. RESULTS: There were 128 patients (M = 70) with ONH/SOD who had neuroimaging. Their mean age (SD) at the end of the study was 13.2 (7.5) years. Males were significantly more likely to have bilateral ONH and a small optic chiasm size, while females were more likely to have a left ONH and a small left optic chiasm size on neuroimaging (p = 0.049). ONH and small optic chiasm size were seen in most patients on neuroimaging. Absent septum pellucidum was noted in 40%, small pituitary gland size in 28%, neuronal migration disorders (NMD) in 20% (>1 type and bilateral in 13 cases), corpus callosum abnormalities were present in 9%, while olfactory bulbs-tracts and olfactory sulci were absent in 8.6% of cases. Unilateral ONH was not significantly associated with other structural brain abnormalities, while NMD were significantly associated with other midline brain abnormalities including a symmetrically small optic chiasm size. CONCLUSION: The prevalence of structural neuroimaging abnormalities in our cohort with ONH/SOD was generally in the same range reported in other studies with corpus callosum abnormalities being relatively less common in our study. Bilateral NMD were relatively common among patients with NMD. The association between sex and ONH laterality requires further study.

Selected Ophthalmological Features in Children with Septo-Optic Dysplasia and Optic Nerve Hypoplasia.

Septo-optic dysplasia (SOD) and optic nerve hypoplasia (ONH) cause congenital visual impairment. Their aetiology is mostly unknown. Our aim was to investigate the prevalence of selected ophthalmological features in patients with these disorders. A chart review was performed on patients with SOD/ONH. Ophthalmological data were extracted. There were 102 patients (56 males). The median age at the end of the study was 12.7 years. Best-corrected visual acuity ranged from normal to no light perception. Bilateral ONH was more common than unilateral ONH. Strabismus (85%) and to a lesser extent nystagmus (52%) were both very common in our cohort. Patients with esotropia had worse visual acuity than those who had exotropia. The presence of nystagmus was more likely in cases with bilateral ONH. Therefore, patients with SOD/ONH may have normal visual acuity. Many have strabismus, which may cause amblyopia thereby further decreasing visual acuity. Nystagmus occurs commonly and its presence typically indicates bilateral ONH.

Neonatal Stress Has a Long-Lasting Sex-Dependent Effect on Anxiety-Like Behavior and Neuronal Morphology in the Prefrontal Cortex and Hippocampus.

The long-lasting effects of early stress on brain development have been well studied. Recent evidence indicates that males and females respond differently to the same stressor. We examined the chronic effects of daily maternal separation (MS) on behavior and cerebral morphology in both male and female rats. Cognitive and anxiety-like behaviors were evaluated, and neuroplastic changes in 2 subregions of the prefrontal cortex (dorsal agranular insular cortex [AID] and cingulate cortex [Cg3]) and hippocampus (CA1 and dentate gyrus) were measured in adult male and female rats. The animals were subjected to MS on postnatal day (P) 3-14 for 3 h per day. Cognitive and emotional behaviors were assessed in the object/context mismatch task, elevated plus maze, and locomotor activity test in early adulthood (P87-P95). Anatomical assessments were performed in the prefrontal cortex (i.e., cortical thickness and spine density) and hippocampus (i.e., spine density). Sex-dependent effects were observed. MS increased anxiety-related behavior only in males, whereas locomotor activity was higher in females, with no effects on cognition. MS decreased spine density in the AID and increased spine density in the CA1 area in males. Females exhibited an increase in spine density in the Cg3. Our findings confirm previous work that found that MS causes long-term behavioral and anatomical effects, and these effects were dependent on sex and the duration of MS stress.

Sedimentological and petrophysical characterization of the Bokabil Formation in the Surma Basin for CO2 storage capacity estimation.

Large-scale geological sequestration of CO2 is one of the most effective strategies to limit global warming to below 2 °C, as recommended by the Intergovernmental Panel on Climate Change (IPCC). Therefore, identifying and characterizing high-quality storage units is crucial. The Surma Basin, with its four-way dip closed structures, high-quality reservoirs, and thick regional cap rocks, is an ideal location for CO2 storage. This study focuses on the Bokabil Formation, the most prominent reservoir unit in the Surma Basin. Detailed petrographic, petrophysical, XRD, and SEM analyses, along with mapping, have been conducted to evaluate the properties of the reservoir and cap rock within this formation. The Upper Bokabil Sandstone in the Surma Basin ranges from 270 to 350 m in thickness and consists of fine- to medium-grained subarkosic sandstones composed of 70-85% quartz and 5-12% feldspar, with good pore connectivity. Petrophysical analysis of data from four gas fields indicates that this unit has a total porosity of 21-27.4% and a low shale volume of 15-27%. Cross plots and outcrop observations suggest that most of the shales are laminated within the reservoir. The regional cap rock, known as the Upper Marine Shale (UMS), ranges in thickness from 40 to 190 m and contains 10-40 nm nano-type pores. A higher proportion of ductile materials with a significant percentage of quartz in the UMS indicates higher capillary entry pressures, enhancing its capacity to hold CO2. Using the CSLF method with a 6% cut-off of the available pore volume, it is estimated that 103 Mt, 110 Mt, 205 Mt, and 164 Mt of CO2 can be effectively stored in the Sylhet, Kailashtila, Habiganj, and Fenchuganj structures, respectively. Due to the shallow depth of the storage unit and the thick cap rock, the southern Surma Basin is the optimal location for CO2 injection.

Ensemble learning methods of inference for spatially stratified infectious disease systems.

Individual level models are a class of mechanistic models that are widely used to infer infectious disease transmission dynamics. These models incorporate individual level covariate information accounting for population heterogeneity and are generally fitted in a Bayesian Markov chain Monte Carlo (MCMC) framework. However, Bayesian MCMC methods of inference are computationally expensive for large data sets. This issue becomes more severe when applied to infectious disease data collected from spatially heterogeneous populations, as the number of covariates increases. In addition, summary statistics over the global population may not capture the true spatio-temporal dynamics of disease transmission. In this study we propose to use ensemble learning methods to predict epidemic generating models instead of time consuming Bayesian MCMC method. We apply these methods to infer disease transmission dynamics over spatially clustered populations, considering the clusters as natural strata instead of a global population. We compare the performance of two tree-based ensemble learning techniques: random forest and gradient boosting. These methods are applied to the 2001 foot-and-mouth disease epidemic in the U.K. and evaluated using simulated data from a clustered population. It is shown that the spatially clustered data can help to predict epidemic generating models more accurately than the global data.

Entropy generation analysis and thermal synergy efficiency in the T-shaped micro-kenics.

In this work, three different twist angles of a micro helical insert in a T-shaped are studied numerically in order to evaluate the laminar steady flow behavior of Newtonian fluid in chaotic geometry. In the geometries under consideration, thermal mixing behavior is carried out using fluids having two distinct input temperatures. Under the influence of chaotic advection and low rates of Reynolds number, the second law of thermodynamics is controlled in terms of the entropy generation caused by hydrodynamic and thermal processes. The governing equations are numerically solved using the CFD Fluent code. Thus, the micromixer's configuration demonstrated a very significant improvement in mixing degree while minimizing friction and thermal irreversibilities. The synergy coefficient, which depicts the link between velocity and heat transfer in angle form, is analyzed and the results are provided.

Establishment of a graphene quantum dot (GQD) based steroid binding assay for the nuclear progesterone receptor (pgr).

Previously, we established a homogeneous assay for membrane progesterone receptor alpha (mPRα) ligands by conjugating semiconductor nanoparticles known as graphene quantum dots (GQDs) to mPRα. When mixed with a progesterone-BSA-fluorescein isothiocyanate conjugate (P4-BSA-FITC), fluorescence occurred by fluorescence resonance energy transfer (FRET) but was reduced by the ligand-receptor binding activity. The established way showed ligand specificity as mPRα protein. In this study, we tried to establish the same way for nuclear progesterone receptor (Pgr). The ligand-binding domain (LBD) of zebrafish Pgr (zPgrLBD) was expressed as a fusion protein with glutathione S-transferase (GST) (GST-zPgrLBD). The recombinant protein was then purified and coupled with GQDs to produce GQD-conjugated GST-zPgrLBD (GQD-GST-zPgrLBD). When mixed with a P4-BSA-FITC and activated by 370 nm light, fluorescence at 520 nm appeared by FRET mechanism. Fluorescence at 520 nm was reduced by adding free progesterone to the reaction mixture. Reduction of fluorescence was induced by zPgr ligands but not by steroids or chemicals that do not interact with zPgr. The results showed the formation of a complex of GQD-GST-zPgrLBD and P4-BSA-FITC with ligand-receptor binding. The binding of the compounds was further confirmed by a radiolabeled steroid binding assay. A homogenous ligand-binding assay for nuclear progesterone receptor has been established.

An efficient estimation approach to joint modeling of longitudinal and survival data.

The joint models for longitudinal and survival data have recently received significant attention in medical and epidemiological studies. Joint models typically combine linear mixed effects models for repeated measurement data and Cox models for survival time. When we are jointly modeling the longitudinal and survival data, variable selection and efficient estimation of parameters are especially important for performing reliable statistical analyzes, both of which are currently lacking in the literature. In this paper we discuss the pretest and shrinkage estimation methods for jointly modeling longitudinal data and survival time data when some of the covariates in both longitudinal and survival components may not be relevant for predicting survival times. In this situation, we fit two models: the full model that contains all the covariates and the subset model that contains a reduced number of covariates. We combine the full model estimators and the estimators that are restricted by a linear hypothesis to define pretest and shrinkage estimators. We provide their numerical mean squared errors (MSE) and relative MSE. We show that if the shrinkage dimension exceeds two, the risk of the shrinkage estimators is strictly less than that of the full model estimators. Our proposed methods are illustrated by extensive simulation studies and a real-data example.

Early tactile stimulation influences the development of Alzheimer's disease in gestationally stressed APP NL-G-F adult offspring NL-G-F/NL-G-F mice.

Alzheimer's disease (AD) is associated with cerebral plaques and tangles, reduced synapse number, and shrinkage in several brain areas and these morphological effects are associated with the onset of compromised cognitive, motor, and anxiety-like behaviours. The appearance of both anatomical and behavioural symptoms is worsened by stress. The focus of this study was to examine the effect of neonatal tactile stimulation on AD-like behavioural and neurological symptoms on APP NL-G-F/NL-G-F mice, a mouse model of AD, who have been gestationally stressed. Our findings indicate that neonatal tactile stimulation improves cognition, motor skills, and anxiety-like symptoms in both gestationally stressed and non-stressed adult APP mice and that these alterations are associated with reduced Aß plaque formation. Thus, tactile stimulation appears to be a promising non-invasive preventative strategy for slowing the onset of dementia in aging animals.

Visual Acuity Outcomes in Children With Optic Nerve Hypoplasia and Septo-Optic-Pituitary Dysplasia.

BACKGROUND: To investigate best-corrected visual acuity (BCVA) outcomes in patients with optic nerve hypoplasia (ONH)/septo-optic-pituitary dysplasia (SOD). Our primary hypothesis was that BCVA in patients with ONH/SOD does not change significantly over time. METHODS: A chart review was undertaken in patients with a confirmed diagnosis of ONH/SOD. Demographic and clinical ophthalmologic data were extracted. Quantitative BCVA data were investigated across clinic visits after converting acuities to the logarithm of the minimum angle of resolution (logMAR). RESULTS: There were 102 patients (56 males). Median age at the end of the study was 12.7 years. Median duration of follow-up was 4.5 years. BCVA significantly worsened slightly in the most affected eyes (0.056 average increase in logMAR/year, 95% confidence interval [CI]: 0.037 to 0.075) and significantly improved mildly in the lesser or equally affected eyes (0.014 average decrease in logMAR/year, 95% CI: 0.009 to 0.019) (P < 0.0001). CONCLUSIONS: Although the overall BCVA data showed a statistically significant change with time, the actual changes were small and are of doubtful meaningful clinical significance (less than one line change on a Snellen chart). Our data suggest that ONH/SOD are nonprogressive neurodevelopmental disorders. The mild worsening of BCVA in the most affected eyes may be caused by amblyopia, whereas the small improvement in the lesser or equally affected eyes may be caused by developmental maturation. In addition, the changes in BCVA may also be due to increasing reliability of visual assessments with increasing age.

Municipal solid waste treatment for bioenergy and resource production: Potential technologies, techno-economic-environmental aspects and implications of membrane-based recovery.

World estimated municipal solid waste generating at an alarming rate and its disposal is a severe concern of today's world. It is equivalent to 0.79 kg/d per person footprint and causing climate change; health hazards and other environmental issues which need attention on an urgent basis. Waste to energy (WTE) considers as an alternative renewable energy potential to recover energy from waste and reduce the global waste problems. WTE reduced the burden on fossil fuels for energy generation, waste volumes, environmental, and greenhouse gases emissions. This critical review aims to evaluate the source of solid waste generation and the possible routes of waste management such as biological landfill and thermal treatment (Incineration, pyrolysis, and gasification). Moreover, a comparative evaluation of different technologies was reviewed in terms of economic and environmental aspects along with their limitations and advantages. Critical literature revealed that gasification seemed to be the efficient route and environmentally sustainable. In addition, a framework for the gasification process, gasifier types, and selection of gasifiers for MSW was presented. The country-wise solutions recommendation was proposed for solid waste management with the least impact on the environment. Furthermore, key issues and potential perspectives that require urgent attention to facilitate global penetration are highlighted. Finally, practical implications of membrane and comparison membrane-based separation technology with other conventional technologies to recover bioenergy and resources were discussed. It is expected that this study will lead towards practical solution for future advancement in terms of economic and environmental concerns, and also provide economic feasibility and practical implications for global penetration.

Repeated multi-domain cognitive training prevents cognitive decline, anxiety and amyloid pathology found in a mouse model of Alzheimer disease.

Education, occupation, and an active lifestyle, comprising enhanced social, physical, and mental components are associated with improved cognitive functions in aged people and may delay the progression of various neurodegenerative diseases including Alzheimer's disease. To investigate this protective effect, 3-month-old APPNL-G-F/NL-G-F mice were exposed to repeated single- or multi-domain cognitive training. Cognitive training was given at the age of 3, 6, & 9 months. Single-domain cognitive training was limited to a spatial navigation task. Multi-domain cognitive training consisted of a spatial navigation task, object recognition, and fear conditioning. At the age of 12 months, behavioral tests were completed for all groups. Then, mice were sacrificed, and their brains were assessed for pathology. APPNL-G-F/NL-G-F mice given multi-domain cognitive training compared to APPNL-G-F/NL-G-F control group showed an improvement in cognitive functions, reductions in amyloid load and microgliosis, and a preservation of cholinergic function. Additionally, multi-domain cognitive training improved anxiety in APPNL-G-F/NL-G-F mice as evidenced by measuring thigmotaxis behavior in the Morris water maze. There were mild reductions in microgliosis in the brain of APPNL-G-F/NL-G-F mice with single-domain cognitive training. These findings provide causal evidence for the potential of certain forms of cognitive training to mitigate the cognitive deficits in Alzheimer disease.

Arctic-like rabies virus, Bangladesh.

Arctic/Arctic-like rabies virus group 2 spread into Bangladesh ≈32 years ago. Because rabies is endemic to and a major public health problem in this country, we characterized this virus group. Its glycoprotein has 3 potential N-glycosylation sites that affect viral pathogenesis. Diversity of rabies virus might have public health implications in Bangladesh.

Validation of administrative data sources for endoscopy utilization in colorectal cancer diagnosis.

BACKGROUND: Validation of administrative data is important to assess potential sources of bias in outcome evaluation and to prevent dissemination of misleading or inaccurate information. The purpose of the study was to determine the completeness and accuracy of endoscopy data in several administrative data sources in the year prior to colorectal cancer diagnosis as part of a larger project focused on evaluating the quality of pre-diagnostic care. METHODS: Primary and secondary data sources for endoscopy were collected from the Alberta Cancer Registry, cancer medical charts and three different administrative data sources. 1672 randomly sampled patients diagnosed with invasive colorectal cancer in years 2000-2005 in Alberta, Canada were included. A retrospective validation study of administrative data for endoscopy in the year prior to colorectal cancer diagnosis was conducted. A gold standard dataset was created by combining all the datasets. Number and percent identified, agreement and percent unique to a given data source were calculated and compared across each dataset and to the gold standard with respect to identifying all patients who underwent endoscopy and all endoscopies received by those patients. RESULTS: The combined administrative data and physician billing data identified as high or higher percentage of patients who had one or more endoscopy (84% and 78%, respectively) and total endoscopy procedures (89% and 81%, respectively) than the chart review (78% for both). CONCLUSIONS: Endoscopy data has a high level of completeness and accuracy in physician billing data alone. Combined with hospital in/outpatient data it is more complete than chart review alone.

Evaluation of Hydrodynamic and Thermal Behaviour of Non-Newtonian-Nanofluid Mixing in a Chaotic Micromixer.

Three-dimensional numerical investigations of a novel passive micromixer were carried out to analyze the hydrodynamic and thermal behaviors of Nano-Non-Newtonian fluids. Mass and heat transfer characteristics of two heated fluids have been investigated to understand the quantitative and qualitative fluid faction distributions with temperature homogenization. The effect of fluid behavior and different Al2O3 nanoparticles concentrations on the pressure drop and thermal mixing performances were studied for different Reynolds number (from 0.1 to 25). The performance improvement simulation was conducted in intervals of various Nanoparticles concentrations (φ = 0 to 5%) with Power-law index (n) using CFD. The proposed micromixer displayed a mixing energy cost of 50-60 comparable to that achieved for a recent micromixer (2021y) in terms of fluid homogenization. The analysis exhibited that for high nanofluid concentrations, having a strong chaotic flow enhances significantly the hydrodynamic and thermal performances for all Reynolds numbers. The visualization of vortex core region of mass fraction and path lines presents that the proposed design exhibits a rapid thermal mixing rate that tends to 0.99%, and a mass fraction mixing rate of more than 0.93% with very low pressure losses, thus the proposed micromixer can be utilized to enhance homogenization in different Nano-Non-Newtonian mechanism with minimum energy.

Complex housing partially mitigates low dose radiation-induced changes in brain and behavior in rats.

PURPOSE: In recent years, much effort has been focused on developing new strategies for the prevention and mitigation of adverse radiation effects on healthy tissues and organs, including the brain. The brain is very sensitive to radiation effects, albeit as it is highly plastic. Hence, deleterious radiation effects may be potentially reversible. Because radiation exposure affects dendritic space, reduces the brain's ability to produce new neurons, and alters behavior, mitigation efforts should focus on restoring these parameters. To that effect, environmental enrichment through complex housing (CH) and exercise may provide a plausible avenue for exploration of protection from brain irradiation. CH is a much broader concept than exercise alone, and constitutes exposure of animals to positive physical and social stimulation that is superior to their routine housing and care conditions. We hypothesized that CHs may lessen harmful neuroanatomical and behavioural effects of low dose radiation exposure. METHODS: We analyzed and compared cerebral morphology in animals exposed to low dose head, bystander (liver), and scatter irradiation on rats housed in either the environmental enrichment condos or standard housing. RESULTS: Enriched condo conditions ameliorated radiation-induced neuroanatomical changes. Moreover, irradiated animals that were kept in enriched CH condos displayed fewer radiation-induced behavioural deficits than those housed in standard conditions. CONCLUSIONS: Animal model-based environmental enrichment strategies, such as CH, are excellent surrogate models for occupational and exercise therapy in humans, and consequently have significant translational possibility. Our study may thus serve as a roadmap for the development of new, easy, safe and cost-effective methods to prevent and mitigate low-dose radiation effects on the brain.

Dramatic impacts on brain pathology, anxiety, and cognitive function in the knock-in APPNL-G-F mouse model of Alzheimer disease following long-term voluntary exercise.

BACKGROUND: An active lifestyle is associated with improved cognitive functions in aged people and may prevent or slow down the progression of various neurodegenerative diseases including Alzheimer's disease (AD). To investigate these protective effects, male APPNL-G-F mice were exposed to long-term voluntary exercise. METHODS: Three-month-old AD mice were housed in a cage supplemented with a running wheel for 9 months for long-term exercise. At the age of 12 months, behavioral tests were completed for all groups. After completing behavioral testing, their brains were assessed for amyloid pathology, microgliosis, and cholinergic cells. RESULTS: The results showed that APPNL-G-F mice allowed to voluntarily exercise showed an improvement in cognitive functions. Furthermore, long-term exercise also improved anxiety in APPNL-G-F mice as assessed by measuring thigmotaxis in the Morris water task. We also found reductions in amyloid load and microgliosis, and a preservation of cholinergic cells in the brain of APPNL-G-F mice allowed to exercise in their home cages. These profound reductions in brain pathology associated with AD are likely responsible for the observed improvement of learning and memory functions following extensive and regular exercise. CONCLUSION: These findings suggest the potential of physical exercise to mitigate the cognitive deficits in AD.