Neurotoxic effects of metals on blood brain barrier impairment and possible therapeutic approaches.

Exposure to neurotoxic and heavy metals (Pb2+, As3+, Mn2+, Cd2+, etc) has increased over time and has shown to negatively affect brain health. Heavy metals can cross the blood brain barrier (BBB) in various ways including receptor or carrier-mediated transport, passive diffusion, or transport via gaps in the endothelial cells of the brain. In high concentrations, these metals have been shown to cause structural and functional impairment to the BBB, by inducing oxidative stress, ion dyshomeostasis, tight junction (TJ) loss, astrocyte/pericyte damage and interference of gap junctions. The structural and functional impairment of the BBB results in increased BBB permeability, which ultimately leads to accumulation of these heavy metals in the brain and their subsequent toxicity. As a result of these effects, heavy metals are correlated with various neurological disorders. The pathological effects of these heavy metals can be effectively mitigated via chelation. In addition, it is possible to treat the associated disorders by counteracting the molecular mechanisms associated with the brain and BBB impairment.

Daidzin improves neurobehavioral outcome in rat model of traumatic brain injury.

Traumatic brain injury (TBI) is associated with the etiology of multiple neurological disorders, including neurodegeneration, leading to various cognitive deficits. Daidzin (obtained from kudzu root and soybean leaves) is known for its neuroprotective effects through multiple mechanisms. This study aimed to investigate the pharmacological effects of Daidzin on sensory, and biochemical parameters, cognitive functions, anxiety, and depressive-like behaviors in the TBI rat model. Rats were divided into four groups (Control, TBI, TBI + Ibuprofen (30 mg/kg), and TBI + Daidzin (5 mg/kg)). Rats were subjected to TBI by dropping a 200 g rod from a height of 26 cm, resulting in an impact force of 0.51 J on the exposed crania. Ibuprofen (30 mg/kg) was used as a positive control reference/standard drug and Daidzin (5 mg/kg) as the test drug. Neurological severity score (NSS) assessment was done to determine the intactness of sensory and motor responses. Brain tissue edema and acetylcholine levels were determined in the cortex and hippocampus. Cognitive functions such as hippocampus-dependent memory, novel object recognition, exploration, depressive and anxiety-like behaviors were measured. Treatment with Daidzin improved NSS, reduced hippocampal and cortical edema, and improved levels of acetylcholine in TBI-induced rats. Furthermore, Daidzin treatment improved hippocampus-dependent memory, exploration behavior, and novel object recognition while reducing depressive and anxiety-like behavior. Our study revealed that Daidzin has a therapeutic potential comparable to Ibuprofen and can offer neuroprotection and enhanced cognitive and behavioral outcomes in rats after TBI.

A simplified framework for orientation control of synthetic fibers in engineered cementitious composites using magnetic field.

Fiber reinforced concrete (FRC) is attracting many researchers' attention due to its excellent mechanical and fracture properties. However, its widespread implementation is hampered by the issues related to the dispersion and orientation of its fibers. According to the fracture mechanics, the reinforcement would provide maximum bridging when placed perpendicular to the crack propagation. This study is focused on the magnetic-based orientation of synthetic fibers which are mostly used in strain hardening FRC also termed as Engineered Cementitious Composites (ECC). Initially, the PVA fibers were coated with waste iron particles using a hydrothermal synthesis procedure. This was done to make synthetic fibers magnetically responsive by the formation of a physical bond between iron and PVA fibers. A solenoid was used to provide a high-intensity magnetic flux to orient these fibers in the direction of magnetic lines. Three different ECC mixes were prepared and cast in wooden molds. The molds were then placed one by one into the magnetic field for the orientation of the fibers. The fibers were successfully aligned perpendicular to the flexure cracks in only flexure dominant regions with the aid of a magnetic field. The orientation of fibers was verified with the help of microscopic images of the tortured surfaces. As a result of well aligned fibers dispersed in the ECC mix, the flexural strength was increased by 21%.

Post-exposure self-recovery reverses oxidative stress, ameliorates pathology and neurotransmitters imbalance and rescues spatial memory after time-dependent aluminum exposure in rat brain.

Aluminum is a potent neurotoxin, responsible for memory impairment and cognitive dysfunction. The neurotoxic effect of aluminum on cognitive impairment is well documented, however, exposure to aluminum in a time-dependent manner and post-exposure self-recovery still needs to be elaborated. This research aimed to (1) study the time-dependent effect of aluminum exposure by administering a total dose of 5850 mg/kg of Al over two different time periods: 30 and 45 days (130 and 195 mg/kg of AlCl3 respectively), and (2) study 20 days post-exposure self-recovery effect in both aluminum-exposed groups by giving distilled water. Cognitive abilities were investigated through Morris water maze test and hole board test and compared in both exposure and recovery groups. Oxidative stress markers and neurotransmitter levels were measured for both exposure and recovery groups. To understand the mechanism of aluminum exposure and recovery, immunohistochemical analysis of synaptophysin (Syp) and glial fibrillary acidic protein (GFAP) was performed. Results showed cognitive dysfunction, oxidative stress-induced damage, reduced neurotransmitter levels, decreased immunoreactivity of Syp, and increased GFAP. However, these parameters showed a larger improvement in the recovery group where rats were given aluminum for 30 days period in comparison to recovery group followed by 45 days of aluminum exposure. These results suggest that restoration of cognitive ability is affected by the duration of aluminum exposure. The study findings provide us with insight into the adverse effects of aluminum exposure and can be utilized to guide future preventive and therapeutic strategies against aluminum neurotoxicity.

Sex-specific effects of neuromodulatory drugs on normal and stress-induced social dominance and aggression in rats.

BACKGROUND: Social hierarchies are important for individual's well-being, professional and domestic growth, harmony of the society, as well as survival and morbidity. Studies have revealed sexual dimorphism in the social abilities; however, data is limited on the sex-specific effects of various drugs used to treat psychiatric disorders and social deficits. OBJECTIVE: The present study aimed at evaluating the sex-dependent effects of Risperidone (antipsychotic that targets D2 dopaminergic, 5HT2A serotonergic, and α-adrenergic receptors), Donepezil (a reversible acetylcholinesterase inhibitor), and Paroxetine (a selective serotonin reuptake inhibitor) on social hierarchy in rats under normal and stressed states. METHODS: 8-12 weeks old male and female Wistar rats were divided into sex-wise 4-4 groups, i.e., 1. control group, 2. Risperidone treated group (3 mg/kg/day), 3. Donepezil treated group (5 mg/kg/day), and Paroxetine treated group (10 mg/kg/day). Rats were treated with these drugs in phase I for 21 days in distilled drinking water, followed by a no (drugs) treatment break of 10 days. After the break phase II started with the administration of drugs (same as in phase I) along with tilt-cage stress for 21 days. Home cage activity assessment was performed once a week during both phases (I & II), while tube dominance and resident intruder tests were performed at the end of each phase. RESULTS: In phase I in both sexes, Risperidone treatment decreased social interaction and motor activity while Paroxetine treatment increased these in both sexes compared to their respective control groups. Social dominance and aggression were reduced after treatment with both of these drugs. In contrast, Donepezil treatment caused an increase in motor activity in females whereas reduced motor activity in males. Furthermore, Donepezil treatment caused reduction in interaction but increased social dominance and aggression were observed in both sexes. In phase II, stress led to an overall decrease in motor activity and social interaction of animals. Treatment with Risperidone, Paroxetine, and Donepezil caused a sex-specific effect on, motor activity, social interaction, and social exploration. CONCLUSION: These results showed that Risperidone has stronger effects on male social behavior whereas Paroxetine and Donepezil differentially affect social abilities in both sexes during normal and stressed situations.

Sexually Dimorphic Effects of Neuromodulatory Drugs on Normal and Stress-Induced Social Interaction in Rats.

Social behavior is a complex term which involves different interactions between various individuals of a community. It is controlled by different neurotransmitter systems in a sexually dimorphic way. Certain environmental factors, like stress, cause various neurological disorders with associated social abnormalities in a sexually dimorphic way. Multiple drugs are used in clinical settings to treat behavioral disorders. However, the sexually dimorphic effects of these drugs, particularly on social behavior, still need to be studied. The present study was designed to investigate the sex-dependent effects of Risperidone, Donepezil, and Paroxetine in 8-12 weeks old male and female rats under normal and stressed conditions. There were four male and four female groups, i.e., control group (no drug treatment), Risperidone (3 mg/kg/day) treated group, Donepezil (5 mg/kg/day) treated group, and Paroxetine (10 mg/kg/day) treated group. Each group received its respective drug during phase 1 for 21 days, followed by a 10-day break with no drug treatment. After the break, same groups received the same drugs along with tilt-cage stress for an additional 21 days during phase 2. A social preference and novelty test was performed at the end of both phases (1 and 2). During phase 1, Risperidone treatment caused impaired social behavior and reduced locomotion in the male group only, compared to its control group. Donepezil treatment caused a reduction in social interaction, while Paroxetine treatment caused increased social interaction and locomotion in a sex-dependent manner. During phase 2, social novelty was affected in both male and female stress groups. Treatment with drugs along with stress showed differential sex-dependent effects. The study showed a predominant effect of Risperidone on males while there were differential effects of Donepezil and Paroxetine on both sexes. This study has paved the way for the development of more targeted and effective neuromodulatory drugs for use against various psychiatric and social deficits.

Comparative Study of Time-Dependent Aluminum Exposure and Post-Exposure Recovery Shows Better Improvement in Synaptic Changes and Neuronal Pathology in Rat Brain After Short-Term Exposure.

Aluminum is a ubiquitous metal that causes multiple brain pathologies such as, cognitive dysfunction and Alzheimer's disease like symptoms. Exposure to aluminum through drinking water is responsible for hampering learning and memory. This study aimed to compare (1) the time-dependent effect of aluminum exposure (keeping total exposure of 5850 mg/kg same) in two durations, 30 and 45 days, and (2) to compare post-exposure self-recovery effect after 20 days in both (30 and 45 days exposure) groups. Rats were given 130 and 195 mg/kg of AlCl3·6H2O for 45 and 30 days respectively, to see the time-dependent exposure effect. At the end of exposure, rats were given distilled water and allowed to self-recover for 20 days to study the recovery. Expression levels of synaptic genes (Syp, SNAP25, Nrxn1/2, PSD95, Shank1/2, Homer1, CamkIV, Nrg1/2 and Kalrn) were measured using qPCR and compared in the exposure and recovery groups. Cellular morphology of the rat brain cortex and hippocampus was also investigated. Damage in lipid and protein profile was measured by employing FTIR. Results showed downregulation of mRNA expression of synaptic genes, plaques deposition, disorganization in lipid and protein profile by increasing membrane fluidity, and disorder and alteration of protein secondary structure after both exposure periods. However, better improvement/recovery in these parameters were observed in recovery group of 30 days aluminum exposure compared to 45 days aluminum exposure group. Taken together, these results suggested that short-term exposure resulted in better restoration of lipid and protein profile after time-dependent exposure of aluminum than prolonged exposure.

Influence of Sex and Muscarinic Activity on Memory Retrieval in Mouse Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a serious global risk factor leading to the onset of cognitive impairment and neurodegenerative diseases. Cognitive and memory impairment following a TBI is associated with the dysregulation of cholinergic neurotransmission in the brains of subjects. The extent of memory impairment following a TBI is linked with the sex of the subject. This study aimed to identify the sex-dimorphic role of muscarinic cholinergic modulation in neurological functioning and episodic memory retrieval in a mouse model of TBI. Balb/c mice were divided into four groups of males and four groups of females (i.e., Sham, TBI, TBI + Scopolamine 1 mg/kg, and TBI + Donepezil 1 mg/kg). After training with the Morris water maze test and fear conditioning, all groups were subjected to brain injury (7.84 × 10-5 J impact force) except for the Sham mice. Following brain injury, scopolamine or donepezil was administered to the respective groups for 5 days. Acute scopolamine immediately after brain trauma showed a neuroprotective effect in the males only, while subchronic donepezil significantly impaired neurological functioning in both sexes. Subchronic scopolamine and donepezil treatment reversed the TBI-induced retrograde amnesia for spatial memory in male mice. Contextual fear memory retrieval was not affected by the TBI and treatments in both sexes. Thus, we concluded that the sex-dimorphic response of the muscarinic receptors in TBI-induced memory impairment depends on the type of memory. This study highlights the potential for therapeutic modalities in TBI subjects.

Neuroprotective Effects of Shogaol in Metals (Al, As and Pb) and High-fat diet-induced Neuroinflammation and Behavior in Mice.

BACKGROUND: Increased exposure of humans to toxic metals and high-fat diet (HFD) consumption severely damages brain health. Natural plant extracts have shown huge potential to treat multiple human diseases. OBJECTIVE: The present study was designed to evaluate the protective effects of Shogaol (an active component of ginger) in neuroinflammation and behavioral paradigms in mice treated with metals and HFD. METHODS: 8-11 weeks old male mice model was developed by giving a combination of metals, i.e., Arsenic (As), Lead (Pb) and Aluminum (Al), 25mg/kg each mixed in drinking water with laboratory prepared HFD (40% fat) for a total duration of 72 days. Shogaol treated groups received two doses (2mg/kg & 12mg/kg) of Shogaol along with metals and HFD. The biochemical parameters, including body weights, blood glucose, and kidney and liver functions, were assessed along with the integrity of the blood-brain barrier (BBB). The expression analysis of neuroinflammatory genes (TNF-α, IL-1ß & GFAP) was performed using q-PCR in the hippocampus and cortex. The exploratory and anxiety-like behavior was assessed using an open field test, and depressive behavior was assessed through the forced swim test, while learning and memory were assessed using the Morris water maze test and y-maze test. RESULTS: Shogaol (2mg/kg & 12mg/kg) treatment improved metabolic profile and reduced expression of neuroinflammatory genes in the cortex and the hippocampus. Shogaol treatment improved BBB integrity. Results of the behavioral analysis showed that Shogaol treatment (2mg/kg & 12mg/kg) rescued behavioral impairment and improved anxiety and depression. CONCLUSION: Shogaol treatment showed strong therapeutic potential in metals & HFD induced neuroinflammation and improved cognitive functions; thus, can be considered a potential drug candidate in the future.

A Predictive Mimicker of Fracture Behavior in Fiber Reinforced Concrete Using Machine Learning.

Due to the exceptional qualities of fiber reinforced concrete, its application is expanding day by day. However, its mixed design is mainly based on extensive experimentations. This study aims to construct a machine learning model capable of predicting the fracture behavior of all conceivable fiber reinforced concrete subclasses, especially strain hardening engineered cementitious composites. This study evaluates 15x input parameters that include the ingredients of the mixed design and the fiber properties. As a result, it predicts, for the first time, the post-peak fracture behavior of fiber-reinforced concrete matrices. Five machine learning models are developed, and their outputs are compared. These include artificial neural networks, the support vector machine, the classification and regression tree, the Gaussian process of regression, and the extreme gradient boosting tree. Due to the small size of the available dataset, this article employs a unique technique called the generative adversarial network to build a virtual data set to augment the data and improve accuracy. The results indicate that the extreme gradient boosting tree model has the lowest error and, therefore, the best mimicker in predicting fiber reinforced concrete properties. This article is anticipated to provide a considerable improvement in the recipe design of effective fiber reinforced concrete formulations.

Aptamer-based diagnostic and therapeutic approaches in animals: Current potential and challenges.

Fast and precise diagnosis of infectious and non-infectious animal diseases and their targeted treatments are of utmost importance for their clinical management. The existing biochemical, serological and molecular methods of disease diagnosis need improvement in their specificity, sensitivity and cost and, are generally not amenable for being used as points-of-care (POC) device. Further, with dramatic changes in environment and farm management practices, one should also arm ourselves and prepare for emerging and re-emerging animal diseases such as cancer, prion diseases, COVID-19, influenza etc. Aptamer - oligonucleotide or short peptides that can specifically bind to target molecules - have increasingly become popular in developing biosensors for sensitive detection of analytes, pathogens (bacteria, virus, fungus, prions), drug residues, toxins and, cancerous cells. They have also been proven successful in the cellular delivery of drugs and targeted therapy of infectious diseases and physiological disorders. However, the in vivo application of aptamer-mediated biosensing and therapy in animals has been limited. This paper reviews the existing reports on the application of aptamer-based biosensors and targeted therapy in animals. It also dissects the various modifications to aptamers that were found to be successful in in vivo application of the aptamers in diagnostics and therapeutics. Finally, it also highlights major challenges and future directions in the application of aptamers in the field of veterinary medicine.

Gender dimorphic effect of dopamine D2 and muscarinic cholinergic receptors on memory retrieval.

Episodic memory retrieval is fundamental for daily activities of humans and animals. Muscarinic cholinergic signaling is important for memory functioning and shows gender-dependent response in episodic memory retrieval. Dopamine D2 receptors influence memory formation and retrieval by influencing cholinergic signaling in the brain. This study aimed to determine the gender-dependent effects of D2 and muscarinic activity on memory retrieval. Male and female mice were trained for Morris water maze test and contextual fear conditioning. Memory retrieval was assessed following sub-chronic treatment (for 5 days) with D2 antagonist (risperidone 2.5 mg/kg) alone or in combination with scopolamine (1 mg/kg) or donepezil (1 mg/kg). Open field test was performed prior to the retrieval test to evaluate effects of risperidone treatment on locomotor activity and exploratory behavior. Risperidone co-treatment with donepezil impaired spatial memory retrieval in males only. Muscarinic and D2 simultaneous antagonism tend to impair fear retrieval in males but significantly enhanced retrieval of fear memories in female mice. These results suggest that D2 signaling influence muscarinic receptor activity during memory retrieval in gender-dependent manner.

Rosmarinic acid and ursolic acid alleviate deficits in cognition, synaptic regulation and adult hippocampal neurogenesis in an Aß1-42-induced mouse model of Alzheimer's disease.

BACKGROUND: Rosmarinus officinalis, commonly known as rosemary, is a medicinal herb that presents significant biological properties such as antimicrobial, antioxidant, anti-inflammatory, anti-diabetic and anti-depressant activities. Recent findings correlate impaired adult neurogenesis, which is crucial for the maintenance of synaptic plasticity and hippocampal functioning, synaptic regulation with the pathological hallmarks of Alzheimer's disease (AD). These observations call for the need to developing compounds that promote neurogenesis and alleviates deficits in cognition and synaptic regulation. PURPOSE AND STUDY DESIGN: The present study was conducted to determine the proneurogenic effects of R. officinalis and its active compounds (ursolic acid and rosmarinic acid) in comparison to Donepezil in an Aß1-42-induced mouse model of AD. METHODS: BALB/c mice were divided into ten groups. Half were injected with Aß1-42 in the hippocampus through stereotaxic surgery to generate the disease groups. The other half received control injections. Each set of five groups were administered orally with vehicle, an ethanolic extract of R. officinalis, ursolic acid, rosmarinic acid or donepezil. Behavior analysis included the Morris water maze test, the novel object recognition test and the Elevated plus maze. The mice were then sacrificed and the hippocampal tissue was processed for immunohistochemistry and gene expression analysis. RESULTS: The results show a protective effect by rosmarinic acid and ursolic acid in reversing the deficits in spatial and recognition memory as well as changes in anxiety induced by Aß1-42. The neuronal density and the expression levels of neurogenic (Ki67, NeuN and DCX) and synaptic (Syn I, II, III, Synaptophysin and PSD-95) markers were also normalized upon treatment with rosmarinic and ursolic acid. CONCLUSION: Our findings indicate the potential of R. officinalis and its active compounds as therapeutic agents against Aß1-42-induced neurotoxicity in AD.

Expression of DnMTs and MBDs in AlCl3-Induced Neurotoxicity Mouse Model.

Alteration in DNA methylation after aluminum exposure has been shown to contribute in pathogenesis of Alzheimer's disease (AD). This study is aimed to determine the effect of Al exposure (42 and 60 days) on learning and memory and the expression of proteins involved in DNA methylation (MBD1, MBD2, MBD3, MeCP2 (methyl CpG binding protein 2), DnMT1 and DnMT3a). Male BALB/c mice were treated with AlCl3 for either 42 days or 60 days. After treatment completion, learning and memory were compared to the control group using novel object recognition test, elevated plus maze test, open field test, and Morris water maze test. The treated animals and their respective controls were sacrificed after cognitive testing and samples from their whole cortex and hippocampus were harvested for gene expression analysis. Mice treated with AlCl3 showed significant cognitive deficit with impaired short-term memory, elevated anxiety, and deterioration in spatial and reference memory. The AlCl3 treatment showed significant reduction in the expression of MBDs in the whole cortex at 60 days of treatment as compared to control. AlCl3-treated animals showed decreased expression of MBDs and DnMT3a in the hippocampus for longer treated animals but strikingly, MBD2 showed significantly increased expression in AlCl3-treated animals at 60 days p ≤ 0.001. In conclusion, this study showed that AlCl3-treated animals showed significant memory and cognitive deficits and it is associated with significant changes in the expression of proteins involved in DNA methylation mechanism. Moreover, different Al exposure duration had slightly different effects.

Oral exposure to aluminum leads to reduced nicotinic acetylcholine receptor gene expression, severe neurodegeneration and impaired hippocampus dependent learning in mice.

Aluminum (Al) is known for its neurotoxicity for over a century and is reported to have specifically high toxicity for cholinergic system. The effect of Al on muscarinic acetylcholine receptors is widely reported, but its effect on nicotinic acetylcholine receptors (nAChRs) is less well known. The aim of this study was to determine the effects of Al on hippocampus dependent learning and memory, function and expression of nAChRs in the hippocampus. Al concentration and neurodegeneration were also measured in the hippocampus following Al treatment. The mice were treated with 250 mg/kg AlCl3.6H2O in drinking water for a period of 42 days. Results show that Al treated animals have significantly reduced spatial reference memory as compared to control animals in Morris water maze test. Similarly, Al treated animals showed reduced contextual memory for Pavlovian fear compared to control animals. Al treated animals show higher anxiety in elevated plus maze as compared to control animals. The analysis of nAChR expression via RT-PCR showed reduced expression of α7, α4 and ß2 nAChR gene expression in the hippocampus of Al treated animals. High Al accumulation was observed in Al-treated animals (688.14 ± 242.82 µg/g) compared to the control group (115.14 ± 18.18 µg/g) that resulted in severe neurodegeneration in the hippocampus. These results demonstrated that Al exposure caused neurotoxicity in mice hippocampus which is manifested by reduced memory and elevated anxiety. The results were further validated by high Al accumulation in the hippocampus, severe neurodegeneration and reduced expression of nAChRs.

Amyloid-beta Induced Neurotoxicity Impairs Cognition and Adult Hippocampal Neurogenesis in a Mouse Model for Alzheimer's Disease.

BACKGROUND: Neurogenesis, the key mechanism to generate new neurons from existing stem cell niches continues throughout the life in the adult mammalian brain, although decelerate with aging or the progression of neurodegenerative disorders like Alzheimer's disease (AD). In the past few years, impaired adult hippocampal neurogenesis emerged as a contributing hallmark of AD pathophysiology along with amyloid beta (Aß) and tau hyper phosphorylation-induced neurotoxicity. However, no conclusive evidence exists that indicates the up/down-regulation of adult hippocampal neurogenesis during the course of AD progression. METHODS: In this study, we examined alterations in adult hippocampal neurogenesis and cognitive deficits using Aß(1-42)-induced mouse model of AD. RESULTS: Our results demonstrate that Aß administration induces an anxiety like behavior and impairs spatial and non-spatial memory and learning in BALB/c mice. Extensive neuronal loss was also evident in the dentate gyrus (DG), CA1, CA2 and CA3 regions of hippocampus in Aß-treated animals. Furthermore, Aß-exposure markedly reduced the real-time expression of markers of cell proliferation and migration i.e. Ki67 and DCX, whereas immunohistochemistry analysis revealed a substantial reduction in the expression levels of Ki67 and NeuN. CONCLUSION: Our findings highlight the association of Aß-induced neurotoxicity with altered neurogenesis and memory formation; however further insight is warranted to explore the underlying molecular pathway(s). Moreover, the treatment strategies aiming to repair the adult hippocampal neurogenesis hold potential as AD therapeutics.

Acute Effects of Aerobic Exercise on Somatosensory-Evoked Potentials in Patients with Mild Cognitive Impairment.

Mild cognitive impairment (MCI) is becoming a serious problem for developing countries as the lifespan of populations increases. Exercise is known to be clinically beneficial for MCI patients. Somatosensory-evoked potentials (SEPs) may be a potential diagnostic and prognostic marker for this population. The objective of this study was to determine the acute effects of aerobic exercise on SEPs in patients with MCI, to test whether SEPs are sensitive enough to detect improvements in early somatosensory processing. The study had a randomized parallel-group design and included 28 MCI subjects (14 in the experimental group and 14 in the control group). The experimental intervention was 20 min of aerobic exercise using a stationary bicycle. The control intervention involved 20 min of movements and stretches. Subjects were assessed before and after a single intervention session. SEPs were recorded by stimulating the median nerve of the dominant hand. Analysis of normalized SEP peak amplitudes showed that a single session of aerobic activity significantly reduced the N30 peak at the F3 channel (p = 0.03). There were no significant effects of aerobic exercise on SEP peak latencies. The results indicate that 20 min of aerobic exercise has a significant effect on the N30 SEP peak amplitude in MCI patients. The results suggest that aerobic exercise is likely to provide sensory-enriching inputs that enhance sensorimotor integration. Future studies should assess the effects of aerobic exercise on somatosensory processing in progressive stages of Alzheimer's disease, longer exercise durations, and multiple exercise sessions.

Blood-Based Biomarkers for Predictive Diagnosis of Cognitive Impairment in a Pakistani Population.

Numerous studies have identified an association between age-related cognitive impairment (CI) and oxidative damage, accumulation of metals, amyloid levels, tau, and deranged lipid profile. There is a concerted effort to establish the reliability of these blood-based biomarkers for predictive diagnosis of CI and its progression. We assessed the serum levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, total cholesterol, selected metals (Cu, Al, Zn, Pb, Mn, Cad), and total-tau and amyloid beta-42 protein in mild (n = 71), moderate (n = 86) and severe (n = 25) cognitively impaired patients and compared them with age-matched healthy controls (n = 90) from Pakistan. We found that a decrease in HDL cholesterol (correlation coefficient r = 0.467) and amyloid beta-42 (r = 0.451) were associated with increased severity of CI. On the other hand, an increase in cholesterol ratio (r = -0.562), LDL cholesterol (r = -0.428), triglycerides, and total-tau (r = -0.443) were associated with increased severity of CI. Increases in cholesterol ratio showed the strongest association and correlated with increases in tau concentration (r = 0.368), and increased triglycerides were associated with decreased amyloid beta-42 (r = -0.345). Increased Cu levels showed the strongest association with tau increase and increased Zn and Pb levels showed the strongest association with reduced amyloid beta-42 levels. Receiver Operating Characteristic (ROC) showed the cutoff values of blood metals (Al, Pb, Cu, Cad, Zn, and Mn), total-tau, and amyloid beta-42 with sensitivity and specificity. Our data show for the first time that blood lipids, metals (particularly Cu, Zn, Pb, and Al), serum amyloid-beta-42/tau proteins modulate each other's levels and can be collectively used as a predictive marker for CI.