Dehydration Reduces Posterior Leg and Trunk Flexibility and Increases Stiffness in Male Collegiate Age Runners

Dehydration reduces flexibility and increases stiffness in male collegiate age runners. Dehydration has been shown to negatively affect collagen in vitro; however the literature lacks works exploring the in vivo effects of dehydration on collagenous tissue. This study addresses this gap in the literature, by exploring the effects of dehydration on the muscles and connective tissues of the posterior leg. It was hypothesized that when dehydrated, the collagen within these tissues would become stiffer, decreasing flexibility and increasing stiffness. A cross-over cohort design was conducted to evaluate nineteen male collegiate runners. Each subject attended three sessions: baseline, dehydration and euhydration. The order of testing was randomly assigned and the PI was blinded throughout. Mean sit and reach (MSnR), mean terminal straight leg raise (MTSLR) and mean posterior leg stiffness (MPLS) scores for each testing condition were analyzed using a repeated measures ANOVA. Dehydrated, subjects demonstrated statistically significant decreases in MSnR scores, p\u3c0.001, d=0.469 (MSnR dehydrated 26.83 ± 7.53 cm and MSnR euhydrated 30.36 ± 7.53 cm) and MTSLR, p\u3c0.001, d=1.068 (MTSLR dehydrated 51.38 ± 9.39 and MTSLR euhydrated 60.58 ± 7.74), with a concurrent increase in MPLS, p=0.005, d=1.023 (MPLS dehydrated 0.899 ± 0.357 and MPLS euhydrated 0.508 ± 0.409), as compared to when they were euhydrated. The large effect size for MPLS and MTSLR and moderate for MSnR indicates that when dehydrated subjects became stiffer and has less flexibility as compared to when they are euhydrated. These changes may impede performance and increase the risk of injury in dehydrated individuals

Increased Action Potential Firing Rates of Layer 2/3 Pyramidal Cells in the Prefrontal Cortex are Significantly Related to Cognitive Performance in Aged Monkeys

The neurobiological substrates of significant age-related deficits in higher cognitive abilities mediated by the prefrontal cortex (PFC) are unknown. To address this issue, whole-cell current-clamp recordings were used to compare the intrinsic membrane and action potential (AP) firing properties of layer 2/3 pyramidal cells in PFC slices from young and aged behaviorally characterized rhesus monkeys. Most aged subjects demonstrated impaired performance in Delayed Non-Match to Sample (DNMS) task acquisition, DNMS 2 min delay and the Delayed Recognition Span task. Resting membrane potential and membrane time constant did not differ in aged relative to young cells, but input resistance was significantly greater in aged cells. Single APs did not differ in terms of threshold, duration or rise time, but their amplitude and fall time were significantly decreased in aged cells. Repetitive AP firing rates were significantly increased in aged cells. Within the aged group, there was a U-shaped quadratic relationship between firing rate and performance on each behavioral task. Subjects who displayed either low or very high firing rates exhibited poor performance, while those who displayed intermediate firing rates exhibited relatively good performance. These data indicate that an increase in AP firing rate may be responsible, in part, for age-related PFC dysfunction

Quantitative birefringence microscopy for imaging the structural integrity of CNS myelin following circumscribed cortical injury in the rhesus monkey

Significance: Myelin breakdown is likely a key factor in the loss of cognitive and motor function associated with many neurodegenerative diseases. Aim: New methods for imaging myelin structure are needed to characterize and quantify the degradation of myelin in standard whole-brain sections of nonhuman primates and in human brain. Approach: Quantitative birefringence microscopy (qBRM) is a label-free technique for rapid histopathological assessment of myelin structural breakdown following cortical injury in rhesus monkeys. Results: We validate birefringence microscopy for structural imaging of myelin in rhesus monkey brain sections, and we demonstrate the power of qBRM by characterizing the breakdown of myelin following cortical injury, as a model of stroke, in the motor cortex. Conclusions: Birefringence microscopy is a valuable tool for histopathology of myelin and for quantitative assessment of myelin structure. Compared to conventional methods, this label-free technique is sensitive to subtle changes in myelin structure, is fast, and enables more quantitative assessment, without the variability inherent in labeling procedures such as immunohistochemistry.Published versio

Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2

Alzheimer\u27s disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare variants occur within APP, PSEN1, and PSEN2 that may be risk factors, protective factors, or benign, non-pathogenic polymorphisms. Yet, to date, no single study has carefully examined the effect of all of the variants of unknown significance reported in APP, PSEN1 and PSEN2 on Aβ isoform levels in vitro. In this study, we analyzed Aβ isoform levels by ELISA in a cell-based system in which each reported pathogenic and risk variant in APP, PSEN1, and PSEN2 was expressed individually. In order to classify variants for which limited family history data is available, we have implemented an algorithm for determining pathogenicity using available information from multiple domains, including genetic, bioinformatic, and in vitro analyses. We identified 90 variants of unknown significance and classified 19 as likely pathogenic mutations. We also propose that five variants are possibly protective. In defining a subset of these variants as pathogenic, individuals from these families may eligible to enroll in observational studies and clinical trials

A non-human primate test of abstraction and set shifting: an automated adaptation of the Wisconsin Card Sorting Test

Abstract Functional assessment of the prefrontal cortices in the non-human primate began with the seminal work of Jacobsen in the 1930s. However, despite nearly 70 years of research, the precise nature of the cognitive function of this region remains unclear. One factor that has limited progress in this endeavor has been the lack of behavioral tasks that parallel most closely those used with humans. In the present study, we describe a test for the non-human primate that was adapted from the Wisconsin Card Sorting Task (WCST), perhaps the most widely used test of prefrontal cognitive function in humans. Our adaptation of this task, the Conceptual Set-Shifting Task (CSST), uses learning criteria and stimuli nearly identical to those of the WCST. The CSST requires the animal to initially form a concept by establishing a pattern of responding to a given stimulus class, maintain responding to that stimulus class, and then shift to a different stimulus class when the reward contingency changes. The data presented here establishes baseline performance on the CSST for young adult rhesus monkeys and demonstrates that components of prefrontal cognitive function can be effectively assessed in the non-human primate in a manner that parallels the clinical assessment of humans

Prenatal Protein Malnutrition Leads to Hemispheric Differences in the Extracellular Concentrations of Norepinephrine, Dopamine and Serotonin in the Medial Prefrontal Cortex of Adult Rats

Exposure to prenatal protein malnutrition (PPM) leads to a reprogramming of the brain, altering executive functions involving the prefrontal cortex (PFC). In this study we used in vivo microdialysis to assess the effects of PPM on extracellular concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) bilaterally in the ventral portion of the medial prefrontal cortex (vmPFC; ventral prelimbic and infralimbic cortices) of adult Long-Evans rats. Female Long-Evans rats were fed either a low protein (6%) or adequate protein diet (25%) prior to mating and throughout pregnancy. At birth, all litters were culled and fostered to dams fed a 25% (adequate) protein diet. At 120 days of age, 2 mm microdialysis probes were placed into left and right vmPFC. Basal extracellular concentrations of NE, DA, and 5-HT were determined over a 1-h period using HPLC. In rats exposed to PPM there was a decrease in extracellular concentrations of NE and DA in the right vmPFC and an increase in the extracellular concentration of 5-HT in the left vmPFC compared to controls (prenatally malnourished: N = 10, well-nourished: N = 20). Assessment of the cerebral laterality of extracellular neurotransmitters in the vmPFC showed that prenatally malnourished animals had a significant shift in laterality from the right to the left hemisphere for NE and DA but not for serotonin. In a related study, these animals showed cognitive inflexibility in an attentional task. In animals in the current study, NE levels in the right vmPFC of well-nourished animals correlated positively with performance in an attention task, while 5-HT in the left vmPFC of well-nourished rats correlated negatively with performance. These data, in addition to previously published studies, suggest a long-term reprogramming of the vmPFC in rats exposed to PPM which may contribute to attention deficits observed in adult animals exposed to PPM

The basal ganglia and thalamus of the long-tailed macaque in stereotaxic coordinates. A template atlas based on coronal, sagittal and horizontal brain sections

A stereotaxic brain atlas of the basal ganglia and thalamus of Macaca fascicularis presented here is designed with a surgical perspective. In this regard, all coordinates have been referenced to a line linking the anterior and posterior commissures (ac–pc line) and considering the center of the ac at the midline as the origin of the bicommissural space. The atlas comprises of 43 different plates (19 coronal levels, 10 sagittal levels and 14 horizontal levels). In addition to ‘classical’ cyto- and chemoarchitectural techniques such as the Nissl method and the acetylcholinesterase stain, several immunohistochemical stains have been performed in adjacent sections, including the detection of tyrosine hydroxylase, enkephalin, neurofilaments, parvalbumin and calbindin. In comparison to other existing stereotaxic atlases for M. fasicularis, this atlas has two main advantages: firstly, brain cartography is based on a wide variety of cyto- and chemoarchitectural stains carried out on adjacent sections, therefore enabling accurate segmentation. Secondly and most importantly, sagittal and horizontal planes are included. Sagittal planes are very useful for calculating oblique trajectories, whereas, clinical researchers engaged in neuroimaging studies will be more familiar with horizontal sections, as they use horizontal (also called “axial”) brain images in their daily routine of their clinical practices

Human-to-monkey transfer learning identifies the frontal white matter as a key determinant for predicting monkey brain age

The application of artificial intelligence (AI) to summarize a whole-brain magnetic resonance image (MRI) into an effective “brain age” metric can provide a holistic, individualized, and objective view of how the brain interacts with various factors (e.g., genetics and lifestyle) during aging. Brain age predictions using deep learning (DL) have been widely used to quantify the developmental status of human brains, but their wider application to serve biomedical purposes is under criticism for requiring large samples and complicated interpretability. Animal models, i.e., rhesus monkeys, have offered a unique lens to understand the human brain - being a species in which aging patterns are similar, for which environmental and lifestyle factors are more readily controlled. However, applying DL methods in animal models suffers from data insufficiency as the availability of animal brain MRIs is limited compared to many thousands of human MRIs. We showed that transfer learning can mitigate the sample size problem, where transferring the pre-trained AI models from 8,859 human brain MRIs improved monkey brain age estimation accuracy and stability. The highest accuracy and stability occurred when transferring the 3D ResNet [mean absolute error (MAE) = 1.83 years] and the 2D global-local transformer (MAE = 1.92 years) models. Our models identified the frontal white matter as the most important feature for monkey brain age predictions, which is consistent with previous histological findings. This first DL-based, anatomically interpretable, and adaptive brain age estimator could broaden the application of AI techniques to various animal or disease samples and widen opportunities for research in non-human primate brains across the lifespan

White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia