Hung-Wen Yeh

Altered Neurochemical Profile after Traumatic Brain Injury: 1H-MRS Biomarkers of Pathological Mechanisms

Specific neurochemicals measured with proton magnetic resonance spectroscopy (1H-MRS) may serve as biomarkers of pathological mechanism in the brain. We used high field in vivo 1H-MRS to measure a detailed neurochemical profile after experimental traumatic brain injury (TBI) in rats. We characterized neurochemical changes in the contused cortex and the normal-appearing perilesional hippocampus over a time course from 1 hour to 2 weeks after injury. We found significant changes in 19 out of 20 neurochemicals in the cortex, and 9 out of 20 neurochemicals in the hippocampus. These changes provide evidence of altered cellular metabolic status after TBI, with specific compounds proposed to reflect edema, excitotoxicity, neuronal and glial integrity, mitochondrial status and bioenergetics, oxidative stress, inflammation, and cell membrane disruption. Our results support the utility of 1H-MRS for monitoring cellular mechanisms of TBI pathology in animal models, and the potential of this approach for preclinical evaluation of novel therapies.

Effects of acute and chronic hyperglycemia on the neurochemical profiles in the rat brain with streptozotocin-induced diabetes detected using in vivo ¹H MR spectroscopy at 9.4 T.

J. Neurochem. (2012) 121, 407–417.

Primary Motor Cortex in Stroke A Functional MRI-Guided Proton MR Spectroscopic Study

Background and Purpose— Our goal was to investigate whether certain metabolites, specific to neurons, glial cells, or the neuronal–glial neurotransmission system, in primary motor cortices (M1), are altered and correlated with clinical motor severity in chronic stroke. Methods— Fourteen survivors of a single ischemic stroke located outside the M1 and 14 age-matched healthy control subjects were included. At >6 months after stroke, N-acetylaspartate, myo-inositol, and glutamate/glutamine were measured using proton magnetic resonance spectroscopic imaging (in-plane resolution=5×5 mm2) in radiologically normal-appearing gray matter of the hand representation area, identified by functional MRI, in each M1. Metabolite concentrations and analyses of metabolite correlations within M1 were determined. Relationships between metabolite concentrations and arm motor impairment were also evaluated. Results— The stroke survivors showed lower N-acetylaspartate and higher myo-inositol across ipsilesional and contralesional M1 compared with control subjects. Significant correlations between N-acetylaspartate and glutamate/glutamine were found in either M1. Ipsilesional N-acetylaspartate and glutamate/glutamine were positively correlated with arm motor impairment and contralesional N-acetylaspartate with time after stroke. Conclusions— Our preliminary data demonstrated significant alterations of neuronal–glial interactions in spared M1 with the ipsilesional alterations related to stroke severity and contralesional alterations to stroke duration. Thus, MR spectroscopy might be a sensitive method to quantify relevant metabolite changes after stroke and consequently increase our knowledge of the factors leading from these changes in spared motor cortex to motor impairment after stroke.

High-field proton magnetic resonance spectroscopy reveals metabolic effects of normal brain aging.

Altered brain metabolism is likely to be an important contributor to normal cognitive decline and brain pathology in elderly individuals. To characterize the metabolic changes associated with normal brain aging, we used high-field proton magnetic resonance spectroscopy in vivo to quantify 20 neurochemicals in the hippocampus and sensorimotor cortex of young adult and aged rats. We found significant differences in the neurochemical profile of the aged brain when compared with younger adults, including lower aspartate, ascorbate, glutamate, and macromolecules, and higher glucose, myo-inositol, N-acetylaspartylglutamate, total choline, and glutamine. These neurochemical biomarkers point to specific cellular mechanisms that are altered in brain aging, such as bioenergetics, oxidative stress, inflammation, cell membrane turnover, and endogenous neuroprotection. Proton magnetic resonance spectroscopy may be a valuable translational approach for studying mechanisms of brain aging and pathology, and for investigating treatments to preserve or enhance cognitive function in aging.

Motor and Premotor Cortices in Subcortical Stroke Proton Magnetic Resonance Spectroscopy Measures and Arm Motor Impairment

Background. Although functional imaging and neurophysiological approaches reveal alterations in motor and premotor areas after stroke, insights into neurobiological events underlying these alterations are limited in human studies. Objective. We tested whether cerebral metabolites related to neuronal and glial compartments are altered in the hand representation in bilateral motor and premotor areas and correlated with distal and proximal arm motor impairment in hemiparetic persons. Methods. In 20 participants at >6 months postonset of a subcortical ischemic stroke and 16 age- and sex-matched healthy controls, the concentrations of N-acetylaspartate and myo-inositol were quantified by proton magnetic resonance spectroscopy. Regions of interest identified by functional magnetic resonance imaging included primary (M1), dorsal premotor (PMd), and supplementary (SMA) motor areas. Relationships between metabolite concentrations and distal (hand) and proximal (shoulder/elbow) motor impairment using Fugl-Meyer Upper Extremity (FMUE) subscores were explored. Results. N-Acetylaspartate was lower in M1 (P = .04) and SMA (P = .004) and myo-inositol was higher in M1 (P = .003) and PMd (P = .03) in the injured (ipsilesional) hemisphere after stroke compared with the left hemisphere in controls. N-Acetylaspartate in ipsilesional M1 was positively correlated with hand FMUE subscores (P = .04). Significant positive correlations were also found between N-acetylaspartate in ipsilesional M1, PMd, and SMA and in contralesional M1 and shoulder/elbow FMUE subscores (P = .02, .01, .02, and .02, respectively). Conclusions. Our preliminary results demonstrated that proton magnetic resonance spectroscopy is a sensitive method to quantify relevant neuronal changes in spared motor cortex after stroke and consequently increase our knowledge of the factors leading from these changes to arm motor impairment.

Resting-state brain connectivity after surgical and behavioral weight loss.

Changes in food‐cue neural reactivity associated with behavioral and surgical weight loss interventions have been reported. Resting functional connectivity represents tonic neural activity that may contribute to weight loss success. This study explores whether intervention type is associated with differences in functional connectivity after weight loss.

A high fat diet alters metabolic and bioenergetic function in the brain: A magnetic resonance spectroscopy study.

Diet-induced obesity and associated metabolic effects can lead to neurological dysfunction and increase the risk of developing Alzheimers disease (AD) and Parkinsons disease (PD). Despite these risks, the effects of a high-fat diet on the central nervous system are not well understood. To better understand the mechanisms underlying the effects of high fat consumption on brain regions affected by AD and PD, we used proton magnetic resonance spectroscopy ((1)H-MRS) to measure neurochemicals in the hippocampus and striatum of rats fed a high fat diet vs. normal low fat chow. We detected lower concentrations of total creatine (tCr) and a lower glutamate-to-glutamine ratio in the hippocampus of high fat rats. Additional effects observed in the hippocampus of high fat rats included higher N-acetylaspartylglutamic acid (NAAG), and lower myo-inositol (mIns) and serine (Ser) concentrations. Post-mortem tissue analyses revealed lower phosphorylated AMP-activated protein kinase (pAMPK) in the striatum but not in the hippocampus of high fat rats. Hippocampal pAMPK levels correlated significantly with tCr, aspartate (Asp), phosphoethanolamine (PE), and taurine (Tau), indicating beneficial effects of AMPK activation on brain metabolic and energetic function, membrane turnover, and edema. A negative correlation between pAMPK and glucose (Glc) indicates a detrimental effect of brain Glc on cellular energy response. Overall, these changes indicate alterations in neurotransmission and in metabolic and bioenergetic function in the hippocampus and in the striatum of rats fed a high fat diet.

Neuronal–glial alterations in non-primary motor areas in chronic subcortical stroke

Whether functional changes of the non-primary motor areas, e.g., dorsal premotor (PMd) and supplementary motor (SMA) areas, after stroke, reflect reorganization phenomena or recruitment of a pre-existing motor network remains to be clarified. We hypothesized that cellular changes in these areas would be consistent with their involvement in post-stroke reorganization. Specifically, we expected that neuronal and glial compartments would be altered in radiologically normal-appearing, i.e., spared, PMd and SMA in patients with arm paresis. Twenty survivors of a single ischemic subcortical stroke and 16 age-matched healthy controls were included. At more than six months after stroke, metabolites related to neuronal and glial compartments: N-acetylaspartate, myo-inositol, and glutamate/glutamine, were quantified by proton magnetic resonance spectroscopy in PMd and SMA in both injured (ipsilesional) and un-injured (contralesional) hemispheres. Correlations between metabolites were also calculated. Finally, relationships between metabolite concentrations and arm motor impairment (total and proximal Fugl-Meyer Upper Extremity, FMUE, scores) were analyzed. Compared to controls, stroke survivors showed significantly higher ipsilesional PMd myo-inositol and lower SMA N-acetylaspartate. Significantly lower metabolite correlations were found between ipsilesional and contralesional SMA. Ipsilesional N-acetylaspartate was significantly related to proximal FMUE scores. This study provides evidence of abnormalities in metabolites, specific to neuronal and glial compartments, across spared non-primary motor areas. Ipsilesional alterations were related to proximal arm motor impairment. Our results suggest the involvement of these areas in post-stroke reorganization.

Cerebral β-Amyloid Angiopathy Is Associated with Earlier Dementia Onset in Alzheimer's Disease

Background: Cerebral β-amyloid angiopathy (CAA) occurs when β-amyloid (Aβ) is deposited in the vascular media and adventitia. It is a common pathology in the brains of older individuals and has been linked to cognitive decline, but relatively little is known about the influence that CAA has on the clinical manifestation of Alzheimers disease (AD). The aim of this retrospective analysis was to quantify the effect that CAA had on the manifestation of initial AD-related cognitive change and subsequent progression of dementia. Methods: We analyzed neuropathological data from the National Alzheimers Coordinating Centers data set, performing parametric analyses to assess differences in age of progression to moderate-stage dementia. Results: We found that individuals with both CAA burden and Aβ neuritic plaque burden at death had the greatest risk of earlier conversion to very mild and moderate-stage dementia, but not necessarily faster progression. Conclusions: Our results suggest that CAA contributes to changes in early AD pathogenesis. This supports the idea that vascular change and neuritic plaque deposition are not just parallel processes but reflect additive pathological cascades that influence the course of clinical AD manifestation. Further inquiry into the role of CAA and its contribution to early cognitive change in AD is suggested.

Simultaneous evaluation of abstinence and relapse using a Markov chain model in smokers enrolled in a two-year randomized trial

BackgroundGEE and mixed models are powerful tools to compare treatment effects in longitudinal smoking cessation trials. However, they are not capable of assessing the relapse (from abstinent back to smoking) simultaneously with cessation, which can be studied by transition models.MethodsWe apply a first-order Markov chain model to analyze the transition of smoking status measured every 6 months in a 2-year randomized smoking cessation trial, and to identify what factors are associated with the transition from smoking to abstinent and from abstinent to smoking. Missing values due to non-response are assumed non-ignorable and handled by the selection modeling approach.ResultsSmokers receiving high-intensity disease management (HDM), of male gender, lower daily cigarette consumption, higher motivation and confidence to quit, and having serious attempts to quit were more likely to become abstinent (OR = 1.48, 1.66, 1.03, 1.15, 1.09 and 1.34, respectively) in the next 6 months. Among those who were abstinent, lower income and stronger nicotine dependence (OR = 1.72 for ≤ vs. > 40 K and OR = 1.75 for first cigarette ≤ vs. > 5 min) were more likely to have relapse in the next 6 months.ConclusionsMarkov chain models allow investigation of dynamic smoking-abstinence behavior and suggest that relapse is influenced by different factors than cessation. The knowledge of treatments and covariates in transitions in both directions may provide guidance for designing more effective interventions on smoking cessation and relapse prevention.Trial Registrationclinicaltrials.gov identifier: NCT00440115