Metabolomics Profiling of Age-Associated Metabolites in Malay Population.

Aging is a complex process characterized by progressive loss of functional abilities due to the accumulation of molecular damages. Metabolomics could offer novel insights into the predictors and mechanisms of aging. This cross-sectional study is aimed at identifying age-associated plasma metabolome in a Malay population. A total of 146 (90 females) healthy participants aged 28-69 were selected for the study. Untargeted metabolomics profiling was performed using liquid chromatography-tandem mass spectrometry. Association analysis was based on the general linear model. Gender-associated metabolites were adjusted for age, while age-associated metabolites were adjusted for gender or analyzed in a gender-stratified manner. Gender-associated metabolites such as 4-hydroxyphenyllactic acid, carnitine, cortisol, and testosterone sulfate showed higher levels in males than females. Deoxycholic acid and hippuric acid were among the metabolites with a positive association with age after being adjusted for gender, while 9(E),11(E)-conjugated linoleic acid, cortisol, and nicotinamide were negatively associated with age. In gender-stratified analysis, glutamine was one of the common metabolites that showed a direct association with age in both genders, while metabolites such as 11-deoxy prostaglandin F2ß, guanosine monophosphate, and testosterone sulfate were inversely associated with age in males and females. This study reveals several age-associated metabolites in Malays that could reflect the changes in metabolisms during aging and may be used to discern the risk of geriatric syndromes and disorders later. Further studies are required to determine the interplay between these metabolites and environmental factors on the functional outcomes during aging.

Disruption of white matter integrity and its relationship with cognitive function in non-severe traumatic brain injury.

Background: Impairment in cognitive function is a recognized outcome of traumatic brain injury (TBI). However, the degree of impairment has variable relationship with TBI severity and time post injury. The underlying pathology is often due to diffuse axonal injury that has been found even in mild TBI. In this study, we examine the state of white matter putative connectivity in patients with non-severe TBI in the subacute phase, i.e., within 10 weeks of injury and determine its relationship with neuropsychological scores. Methods: We conducted a case-control prospective study involving 11 male adult patients with non-severe TBI and an age-matched control group of 11 adult male volunteers. Diffusion MRI scanning and neuropsychological tests were administered within 10 weeks post injury. The difference in fractional anisotropy (FA) values between the patient and control groups was examined using tract-based spatial statistics. The FA values that were significantly different between patients and controls were then correlated with neuropsychological tests in the patient group. Results: Several clusters with peak voxels of significant FA reductions (p < 0.05) in the white matter skeleton were seen in patients compared to the control group. These clusters were located in the superior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus, and cingulum, as well as white matter fibers in the area of genu of corpus callosum, anterior corona radiata, superior corona radiata, anterior thalamic radiation and part of inferior frontal gyrus. Mean global FA magnitude correlated significantly with MAVLT immediate recall scores while matrix reasoning scores correlated positively with FA values in the area of right superior fronto-occipital fasciculus and left anterior corona radiata. Conclusion: The non-severe TBI patients had abnormally reduced FA values in multiple regions compared to controls that correlated with several measures of executive function during the sub-acute phase of TBI.

Alteration in the Functional Organization of the Default Mode Network Following Closed Non-severe Traumatic Brain Injury.

The debilitating effect of traumatic brain injury (TBI) extends years after the initial injury and hampers the recovery process and quality of life. In this study, we explore the functional reorganization of the default mode network (DMN) of those affected with non-severe TBI. Traumatic brain injury (TBI) is a wide-spectrum disease that has heterogeneous effects on its victims and impacts everyday functioning. The functional disruption of the default mode network (DMN) after TBI has been established, but its link to causal effective connectivity remains to be explored. This study investigated the differences in the DMN between healthy participants and mild and moderate TBI, in terms of functional and effective connectivity using resting-state functional magnetic resonance imaging (fMRI). Nineteen non-severe TBI (mean age 30.84 ± 14.56) and twenty-two healthy (HC; mean age 27.23 ± 6.32) participants were recruited for this study. Resting-state fMRI data were obtained at the subacute phase (mean days 40.63 ± 10.14) and analyzed for functional activation and connectivity, independent component analysis, and effective connectivity within and between the DMN. Neuropsychological tests were also performed to assess the cognitive and memory domains. Compared to the HC, the TBI group exhibited lower activation in the thalamus, as well as significant functional hypoconnectivity between DMN and LN. Within the DMN nodes, decreased activations were detected in the left inferior parietal lobule, precuneus, and right superior frontal gyrus. Altered effective connectivities were also observed in the TBI group and were linked to the diminished activation in the left parietal region and precuneus. With regard to intra-DMN connectivity within the TBI group, positive correlations were found in verbal and visual memory with the language network, while a negative correlation was found in the cognitive domain with the visual network. Our results suggested that aberrant activities and functional connectivities within the DMN and with other RSNs were accompanied by the altered effective connectivities in the TBI group. These alterations were associated with impaired cognitive and memory domains in the TBI group, in particular within the language domain. These findings may provide insight for future TBI observational and interventional research.

Neural alterations in working memory of mild-moderate TBI: An fMRI study in Malaysia.

Working memory (WM) encompasses crucial cognitive processes or abilities to retain and manipulate temporary information for immediate execution of complex cognitive tasks in daily functioning such as reasoning and decision-making. The WM of individuals sustaining traumatic brain injury (TBI) was commonly compromised, especially in the domain of WM. The current study investigated the brain responses of WM in a group of participants with mild-moderate TBI compared to their healthy counterparts employing functional magnetic resonance imaging. All consented participants (healthy: n = 26 and TBI: n = 15) performed two variations of the n-back WM task with four load conditions (0-, 1-, 2-, and 3-back). The respective within-group effects showed a right hemisphere-dominance activation and slower reaction in performance for the TBI group. Random-effects analysis revealed activation difference between the two groups in the right occipital lobe in the guided n-back with cues, and in the bilateral occipital lobe, superior parietal region, and cingulate cortices in the n-back without cues. The left middle frontal gyrus was implicated in the load-dependent processing of WM in both groups. Further group analysis identified that the notable activation changes in the frontal gyri and anterior cingulate cortex are according to low and high loads. Though relatively smaller in scale, this study was eminent as it clarified the neural alterations in WM in the mild-moderate TBI group compared to healthy controls. It confirmed the robustness of the phenomenon in TBI with the reproducibility of the results in a heterogeneous non-Western sample.

Clinical implications of blood pressure variability (BPV) in pregnancies: a review.

Background Hypertension disorder in pregnancy (HDP) is the second most common contributor to maternal morbidity and mortality worldwide. Blood pressure variability (BPV), with the assistance of ambulatory blood pressure monitoring (ABPM), measures blood pressure readings in pregnant women and has the potential to predict the occurrence of pregnancy-induced hypertension (PIH) or preeclampsia (PE) before any symptoms develop. Methodology Studies involving ABPM among pregnant women were identified using electronic databases such as PubMed, Scopus, Google Scholar, ScienceDirect, Medscape, Ovid and ProQuest. These electronic databases were assessed from 1990 to 2018. Keywords used to search for literatures included a combination of BPV matched with pregnancy, pregnant women and HDP, gestational hypertension and/or PE. Results Out of 21,526 articles identified, a total of 10 studies met the criteria. Seven articles used the spectral analysis method while another two articles used a combination of spectral analysis, time domain and a non-linear method for BPV analysis. The final article described BPV as vagal baroreflex. Four articles agreed that high frequency (HF) BPV was mainly dominant from the second trimester until 4 days postpartum in HDP patients. This reflects the dominant features of parasympathetic activities among these patients. Two articles that used time domain also agreed that standard deviation (SD) BPV increased in PE patients. Conclusions In pregnancy, BPV has a strong impact on the knowledge understanding of the disease in clinical fields, allows a superior ability to predict PIH and PE in mid-pregnancy and offers potential value for addressing hypertension in pregnancy.

Effect of Age on the Protein Profile of Healthy Malay Adults and its Association with Cognitive Function Competency.

BACKGROUND: Many studies on biochemical and psychological variables have aimed to elucidate the association between aging and cognitive function. Demographic differences and protein expression have been reported to play a role in determining the cognitive capability of a population. OBJECTIVE: This study aimed to determine the effect of age on the protein profile of Malay individuals and its association with cognitive competency. METHODS: A total of 160 individuals were recruited and grouped accordingly. Cognitive competency of each subject was assessed with several neuropsychological tests. Plasma samples were collected and analyzed with Q Exactive HF Orbitrap. Proteins were identified and quantitated with MaxQuant and further analyzed with Perseus to determine differentially expressed proteins. PANTHER, Reactome, and STRING were applied for bioinformatics output. RESULTS: Our data showed that the Malay individuals are vulnerable to the deterioration of cognitive function with aging, and most of the proteins were differentially expressed in concordance. Several physiological components and pathways were shown to be involved, giving a hint of a promising interpretation on the induction of aging toward the state of the Malays' cognitive function. Nevertheless, some proteins have shown a considerable interaction with the generated protein network, which provides a direction of focus for further investigation. CONCLUSION: This study demonstrated notable changes in the expression of several proteins as age increased. These changes provide a promising platform for understanding the biochemical factors affecting cognitive function in the Malay population. The exhibited network of protein-protein interaction suggests the possibility of implementing regulatory intervention in ameliorating Malay cognitive function.

DNA damage and protein oxidation associated with ageing correlate with cognitive dysfunction in a Malaysian population.

Ageing is associated with increased oxidative stress accompanied by cognitive decline. The aim of this study was to evaluate oxidative stress biomarkers and their possible relationship with cognitive performances during ageing among the Malay population. Approximately 160 healthy Malay adults aged between 28 and 79 years were recruited around Selangor and Klang Valley. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA), forward digit span (FDS), backward digit span (BDS), digit symbol, Rey Auditory Verbal Learning Test immediate recalled [RAVLT(I)] and delayed recalled [RAVLT(D)], and visual reproduction immediate recalled (VR-I) and delayed recalled (VR-II). DNA damage, plasma protein carbonyl and malondialdehyde (MDA) levels were also determined. Cognitive function test showed significant lower scores of MoCA, BDS, RAVLT(I), RAVLT(D), digit symbol, VR-I, and VR-II in the older age group (60 years old) compared with the 30-, 40-, and 50-year-old group. The extent of DNA damage was sequential with age: 60 > 50 > 40 > 30, whereas protein carbonyl was higher in 40-, 50-, and 60-year-old groups compared with the youngest group (30 years old). However, the MDA level was observed unchanged in all age groups. Approximately 21.88% of the participants had cognitive impairment. Multiple logistic regression analysis revealed that DNA damage and protein carbonyl levels are predictors for cognitive impairment in healthy Malays. In conclusion, cognitive decline occurred in healthy adult Malay population at an early age of 30 years old with corresponding higher DNA damage and protein oxidation.

Exploring Cortical Plasticity and Oscillatory Brain Dynamics via Transcranial Magnetic Stimulation and Resting-State Electroencephalogram.

Transcranial magnetic stimulation (TMS) is a non-invasive, non-pharmacological technique that is able to modulate cortical activity beyond the stimulation period. The residual aftereffects are akin to the plasticity mechanism of the brain and suggest the potential use of TMS for therapy. For years, TMS has been shown to transiently improve symptoms of neuropsychiatric disorders, but the underlying neural correlates remain elusive. Recently, there is evidence that altered connectivity of brain network dynamics is the mechanism underlying symptoms of various neuropsychiatric illnesses. By combining TMS and electroencephalography (EEG), the functional connectivity patterns among brain regions, and the causal link between function or behaviour and a specific brain region can be determined. Nonetheless, the brain network connectivity are highly complex and involve the dynamics interplay among multitude of brain regions. In this review article, we present previous TMS-EEG co-registration studies, which explore the functional connectivity patterns of human cerebral cortex. We argue the possibilities of neural correlates of long-term potentiation/depression (LTP-/LTD)-like mechanisms of synaptic plasticity that drive the TMS aftereffects as shown by the dissociation between EEG and motor evoked potentials (MEP) cortical output. Here, we also explore alternative explanations that drive the EEG oscillatory modulations post TMS. The precise knowledge of the neurophysiological mechanisms underlying TMS will help characterise disturbances in oscillatory patterns, and the altered functional connectivity in neuropsychiatric illnesses.

Theta-burst Transcranial Magnetic Stimulation Alters the Functional Topography of the Cortical Motor Network.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a non-invasive tool that is able to modulate the electrical activity of the brain depending upon its protocol of stimulation. Theta burst stimulation (TBS) is a high-frequency TMS protocol that is able to induce prolonged plasticity changes in the brain. The induction of plasticity-like effects by TBS is useful in both experimental and therapeutic settings; however, the underlying neural mechanisms of this modulation remain unclear. The aim of this study was to investigate the effects of continuous TBS (cTBS) on the intrahemispheric and interhemispheric functional connectivity of the resting and active brain. METHODS: A total of 26 healthy humans were randomly divided into two groups that received either real cTBS or sham (control) over the left primary motor cortex. Surface electroencephalogram (EEG) was used to quantify the changes of neural oscillations after cTBS at rest and after a choice reaction time test. The cTBS-induced EEG oscillations were computed using spectral analysis of event-related coherence (ERCoh) of theta (4-7.5 Hz), low alpha (8-9.5 Hz), high alpha (10-12.5 Hz), low beta (13-19.5 Hz), and high beta (20-30 Hz) brain rhythms. RESULTS: We observed a global decrease in functional connectivity of the brain in the cTBS group when compared to sham in the low beta brain rhythm at rest and high beta brain rhythm during the active state. In particular, EEG spectral analysis revealed that high-frequency beta, a cortically generated brain rhythm, was the most sensitive band that was modulated by cTBS. CONCLUSION: Overall, our findings suggest that cTBS, a TMS protocol that mimics the mechanism of long-term depression of synaptic plasticity, modulates motor network oscillations primarily at the cortical level and might interfere with cortical information coding.

A neurophysiological insight into the potential link between transcranial magnetic stimulation, thalamocortical dysrhythmia and neuropsychiatric disorders.

Altered neural oscillations and their abnormal synchronization are crucial factors in the pathophysiology of several neuropsychiatric disorders. There is increasing evidence that the perturbation with an abnormal increase of spontaneous thalamocortical neural oscillations lead to a phenomenon termed Thalamocortical dysrhythmia (TCD) which underlies the symptomatology of a variety of neurological and psychiatric disorders including Parkinson's disease, schizophrenia, epilepsy, neuropathic pain, tinnitus, major depression and obsessive-compulsive disorder. In addition, repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurophysiological tool that has been shown to both induce a modulation of neural oscillations and alleviate a wide range of human neuropsychiatric pathologies. However, little is known about the precise electrophysiological mechanisms behind the therapeutic effect of rTMS and its potential to improve abnormal oscillations across diverse neuropsychiatric disorders. Here we show, using combined rTMS and surface electroencephalography (EEG), a short lasting frequency-dependent rTMS after-effect on thalamocortical rhythmic interplay of low-frequency oscillations in healthy humans at rest. In particular, high-frequency rTMS (10 Hz) induces a transient synchronised activity for delta (δ) and theta (θ) rhythms thus mimicking the pathological TCD-like oscillations. In contrast, rTMS 1 and 5 Hz have the opposite outcome of de-synchronising low-frequency brain rhythms. These results lead to a new neurophysiological insight of basic mechanisms underlying neurological and psychiatric disorders and a probable electrophysiological mechanism underlying the therapeutic effects of rTMS. Thus, we propose the use of rTMS and EEG as a platform to test possible treatments of TCD phenotypes by restoring proper neural oscillations across various neuropsychiatric disorders.

Long lasting modulation of cortical oscillations after continuous theta burst transcranial magnetic stimulation.

Transcranial magnetic theta burst stimulation (TBS) differs from other high-frequency rTMS protocols because it induces plastic changes up to an hour despite lower stimulus intensity and shorter duration of stimulation. However, the effects of TBS on neuronal oscillations remain unclear. In this study, we used electroencephalography (EEG) to investigate changes of neuronal oscillations after continuous TBS (cTBS), the protocol that emulates long-term depression (LTD) form of synaptic plasticity. We randomly divided 26 healthy humans into two groups receiving either Active or Sham cTBS as control over the left primary motor cortex (M1). Post-cTBS aftereffects were assessed with behavioural measurements at rest using motor evoked potentials (MEPs) and at active state during the execution of a choice reaction time (RT) task in combination with continuous electrophysiological recordings. The cTBS-induced EEG oscillations were assessed using event-related power (ERPow), which reflected regional oscillatory activity of neural assemblies of θ (4-7.5 Hz), low α (8-9.5 Hz), µ (10-12.5 Hz), low ß (13-19.5 Hz), and high ß (20-30 Hz) brain rhythms. Results revealed 20-min suppression of MEPs and at least 30-min increase of ERPow modulation, suggesting that besides MEPs, EEG has the potential to provide an accurate cortical readout to assess cortical excitability and to investigate the interference of cortical oscillations in the human brain post-cTBS. We also observed a predominant modulation of ß frequency band, supporting the hypothesis that cTBS acts more on cortical level. Theta oscillations were also modulated during rest implying the involvement of independent cortical theta generators over the motor network post cTBS. This work provided more insights into the underlying mechanisms of cTBS, providing a possible link between synchronised neural oscillations and LTD in humans.