Valproic acid adjunctive therapy for HIV-associated cognitive impairment: a first report.

In vitro and animal model data demonstrate that valproic acid (VPA) can ameliorate HIV-associated neurotoxicity. The authors conducted a pilot 10-week placebo-controlled study of VPA 250 mg twice daily in 22 HIV-infected individuals with (n = 16) and without (n = 6) cognitive impairment. VPA was safe and well tolerated, with trends toward improved neuropsychological performance and brain metabolism in the impaired subjects.

Coregistration of quantitative proton magnetic resonance spectroscopic imaging with neuropathological and neurophysiological analyses defines the extent of neuronal impairments in murine human immunodeficiency virus type-1 encephalitis.

Relatively few immune-activated and virus-infected mononuclear phagocytes (MP; perivascular macrophages and microglia) may affect widespread neuronal dysfunction during human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD). Indeed, histopathological evidence of neuronal dropout often belies the extent of cognitive impairment. To define relationships between neuronal function and histopathology, proton magnetic resonance spectroscopic imaging (1H MRSI) and hippocampal long-term potentiation (LTP) were compared with neuronal and glial immunohistology in a murine model of HIV-1 encephalitis (HIVE). HIV-1(ADA)-infected human monocyte-derived macrophages (MDM) were stereotactically injected into the subcortex of severe combined immunodeficient (SCID) mice. Sham-operated and unmanipulated mice served as controls. Seven days after cell injection, brain histological analyses revealed a focal giant cell encephalitis, with reactive astrocytes, microgliosis, and neuronal dropout. Strikingly, significant reductions in N-acetyl aspartate concentration ([NAA]) and LTP levels in HIVE mice were in both injected and contralateral hemispheres and in brain subregions, including the hippocampus, where neuropathology was limited or absent. The data support the importance of 1H MRSI as a tool for assessing neuronal function for HAD. The data also demonstrate that a highly focal encephalitis can produce global deficits for neuronal function and metabolism.

Contrasts in cortical magnesium, phospholipid and energy metabolism between migraine syndromes.

BACKGROUND: Previous single voxel (31)P MRS pilot studies of migraine patients have suggested that disordered energy metabolism or Mg(2+) deficiencies may be responsible for hyperexcitability of neuronal tissue in migraine patients. These studies were extended to include multiple brain regions and larger numbers of patients by multislice (31)P MR spectroscopic imaging. METHODS: Migraine with aura (MWA), migraine without aura (MwoA), and hemiplegic migraine patients were studied between attacks by (31)P MRS imaging using a 3-T scanner. RESULTS: Results were compared with those in healthy control subjects without headache. In MwoA, consistent increases in phosphodiester concentration [PDE] were measured in most brain regions, with a trend toward increase in [Mg(2+)] in posterior brain. In MWA, phosphocreatine concentration ([PCr]) was decreased to a minor degree in anterior brain regions and a trend toward decreased [Mg(2+)] was observed in posterior slice 1, but no consistent changes were found in phosphomonoester concentration [PME], [PDE], inorganic phosphate concentration ([Pi]), or pH. In hemiplegic migraine patients, [PCr] had a tendency to be lower, and [Mg(2+)] was significantly lower than in the posterior brain regions of control subjects. Trend analysis showed a significant decrease of brain [Mg(2+)] and [PDE] in posterior brain regions with increasing severity of neurologic symptoms. CONCLUSIONS: Overall, the results support no substantial or consistent abnormalities of energy metabolism, but it is hypothesized that disturbances in magnesium ion homeostasis may contribute to brain cortex hyperexcitability and the pathogenesis of migraine syndromes associated with neurologic symptoms. In contrast, migraine patients without a neurologic aura may exhibit compensatory changes in [Mg(2+)] and membrane phospholipids that counteract cortical excitability.

Single-voxel proton MRS of the human brain at 1.5T and 3.0T.

Single-voxel proton spectra of the human brain were recorded in five subjects at both 1.5T and 3.0T using the STEAM pulse sequence. Data acquisition parameters were closely matched between the two field strengths. Spectra were recorded in the white matter of the centrum semiovale and in phantoms. Spectra were compared in terms of resolution and signal-to-noise ratio (SNR), and transverse relaxation times (T(2)) were estimated at both field strengths. Spectra at 3T demonstrated a 20% improvement in sensitivity compared to 1.5T at short echo times (TE = 20 msec), which was lower than the theoretical 100% improvement. Spectra at long echo times (TE = 272 msec) exhibited similar SNR at both field strengths. T(2) relaxation times were almost twofold shorter at the higher field strength. Spectra in phantoms demonstrated significantly improved resolution at 3T compared to 1.5T, but resolution improvements in in vivo spectra were almost completely offset by increased linewidths at higher field.

Automated three-dimensional signature model for assessing brain injury in emergent stroke.

This presentation will focus on the value of established and newer MR methods that can be applied to the diagnosis and management of ischemic stroke with emphasis on future applications of MR to provide previously unmet needs of the treating clinician and clinical trials. Time alone is an inadequate indicator of the therapeutic window, especially when the time of stroke onset is uncertain. Thus, there is a need to predict the evolution of stroke in a way that more precisely and with greater resolution identifies the progression of cellular damage at the moment of investigation. This also would be of value for thrombolysis when knowledge of the degree and extent of tissue necrosis and the consequent potential for brain hemorrhage is of the utmost importance. To provide this, we perform postprocessing of diffusion-, T(1)- and T(2)-weighted images to produce the apparent diffusion coefficient of water, and T(1) and T(2) maps that are then further processed to provide maps and quantitation of the tissue signatures of ischemic histopathology. By these means, we can accomplish objective volumetric analysis of infarct size and of the proportions of potentially viable and salvageable tissue. We will show how this has the potential to predict long-term stroke outcome and facilitate decision-making in terms of safety of reperfusion strategies and the appropriateness of cytoprotective treatment. The value of our approach is to replace time as the therapeutic window and extend the opportunity of treatment to those patients presenting beyond the stringent time limits employed in current investigative clinical trials. Further, used as a surrogate marker of clinical outcome, this form of stroke analysis may speed proof of principle clinical trials in small numbers of stroke patients.

Phosphorus 31 nuclear magnetic resonance spectroscopy suggests a mitochondrial defect in claudicating skeletal muscle.

OBJECTIVE: Decreased oxygen supply is generally accepted as the primary cause of muscle dysfunction in patients with peripheral arterial occlusive disease (PAOD) and intermittent claudication, although reported morphologic changes in the mitochondria of claudicating muscle suggest that impaired energy utilization may also play a role. With the measurement of the phosphate-rich compounds of muscle energy metabolism (adenosinetriphosphate [ATP], adenosinediphosphate [ADP], and phosphocreatine [PCr]) and pH, phosphorus P 31 magnetic resonance spectroscopy ((31)P MRS) provides a unique, noninvasive method to investigate this hypothesis further. METHODS: Calf muscle bioenergetics were studied in 12 men with moderate claudication (ankle-brachial index >/=0.5 and .5, Pearson moment correlation). CONCLUSIONS: Phosphorus 31 MRS provides the first direct evidence of defective energy metabolism in the mitochondria of claudicating calf muscle. This defect appears to be independent of both arterial flow and the severity of occlusive disease in patients with mild to moderate claudication. Coupled with documented ultrastructural and DNA abnormalities in the mitochondria of claudicating skeletal muscle, these data provide evidence for a secondary cause of muscle dysfunction in intermittent claudication.

Effects of the anti-migraine drug sumatriptan on muscle energy metabolism: relationship to side-effects.

Sumatriptan succinate (Imitrex) is a 5-HT (5-hydroxytryptamine) agonist used for relief of migraine symptoms. Some individuals experience short-lived side-effects, including heaviness of the limbs, chest heaviness and muscle aches and pains. The effects of this drug on skeletal muscle energy metabolism were studied during short submaximal isometric exercises. We studied ATP flux from anaerobic glycolysis (An Gly), the creatine kinase reaction (CK) and oxidative phosphorylation (Ox Phos) using 31P nuclear magnetic resonance spectroscopy (31P MRS) kinetic data collected during exercise. It was found that side-effects induced acutely by injection of 6 mg sumatriptan succinate s.c. were associated with reduced oxygen storage in peripheral skeletal muscle 5-20 min after injection as demonstrated by a transient reduction in mitochondrial function at end-exercise. These results suggest that mild vasoconstriction in peripheral skeletal muscle is associated with the action of sumatriptan and is likely to be the source of the side-effects experienced by some users. Migraine with aura patients were more susceptible to this effect than migraine without aura patients.

31P MRS studies of exercising human muscle at high temporal resolution.

Methods for measuring mitochondrial activity from 31P magnetic resonance spectroscopy data collected during and after exercise were compared in controls, weight lifters, and peripheral vascular occlusive disease (PVOD) patients. There were trends toward increasing mitochondrial activity during exercise in order from PVOD patients, moderately active controls, highly active controls, to weight lifters. Results from PVOD patients show divergence of some measures due to 1) the non-exponential nature of phosphocreatine recovery, and 2) potential breakdown of [ADP] control of the mitochondria due to lack of oxygen (for Qmax calculation). These results demonstrate the utility of obtaining and directly analyzing high time resolution data rather than assuming monoexponential behavior of metabolite recovery.

T1 and magnetization transfer at 7 Tesla in acute ischemic infarct in the rat.

T1 and magnetization transfer at a field strength of 7 Tesla were used to discriminate between water accumulation and protein mobilization in tissue undergoing infarction. Twelve rats subjected to acute stroke via intralumenal suture occlusion of the middle cerebral artery, and 19 controls, were studied. In MRI studies to 6 hr post-ictus, serial data acquisition allowed the measurement of cerebral blood flow (CBF), apparent diffusion coefficient of water (ADCw), equilibrium magnetization (M0) and T1, and equilibrium magnetization and T1 under an off-resonance partial saturation of the macromolecular pool (Msat and T1sat). Using these parameters, the apparent forward transfer rate of magnetization between the free water proton pool and the macromolecular proton pool, k(fa), was calculated. Regions of interest (ROIs) were chosen using depressed areas in maps of the ADCw. T1 measurements in bovine serum albumin at 7T were not affected by the mobility of the macromolecular pool (P > 0.2), but magnetization transfer between free water and protein depended strongly on the mobility of the macromolecular pool (P < 0.001). For 6 hr after ictus, k(fa) uniformly and strongly decreased in the region of the infarct (P < 0.0001). Ratios (ischemic/non-ischemic) of parameters M0, Msat, T1, and T1sat all uniformly and strongly increased in the infarct. The ratio T1/T1sat in the region of infarction showed that a progressive accumulation of free water in the region of interest was the major (>80%) contribution to the decrease in k(fa). There also existed a small contribution due to changes at the water-macromolecular interface, possibly due to proteolysis (P = 0.005).

T1 measurements of 31P metabolites in resting and exercising human gastrocnemius/soleus muscle at 1.5 Tesla.

This study has measured the apparent 31P T1 times at 1.5 T in human gastrocnemius/soleus muscle groups at rest, during exercise, and during recovery from a 90-sec submaximal plantar flexion exercise. T1 times were measured with a 10-sec time resolution in 11 normally active volunteers using a surface coil with a nine-point progressive saturation technique. A two-point short repetition time technique was also used. Both techniques showed similar trends in the apparent T11 times of all the 31P metabolites at rest, during exercise, and during recovery. For the nine-point progressive saturation technique, the apparent T1 of PCr and beta-ATP decreased approximately 20% to a steadystate value (P = 0.027 and P = 0.004, respectively). The two-point short repetition time technique demonstrated a 10% reduction in the apparent T1 of PCr and beta-ATP Both techniques demonstrated an apparent T1 increase of 58% for inorganic phosphate at the beginning of exercise (P<0.0001) and a return to resting value during the 90-sec submaximal isometric contraction. Neither technique showed any significant differences between resting and exercising T1 times of the alpha-ATP and gamma-ATP resonances (P = 0.06 and P>0.40, respectively).

Magnesium and pH imaging of the human brain at 3.0 Tesla.

Multislice, two-dimensional phosphorus 31 spectroscopic imaging (SI) of human brain was performed in 15 normal volunteers on a 3-Tesla magnetic resonance system. Images of free magnesium concentrations and pH as well as phosphoesters, inorganic phosphate, phosphocreatine, and adenosine triphosphate (ATP), were calculated from the SI data. By using the equations of Golding and Golding (Magn. Reson. Med. 1995;33: 467-474), average [Mg2+] for all brain regions studied was 0.42+/-0.05 mM, whereas average brain pH was found to be 7.07+/-0.03, with no significant regional variations. Phosphorus metabolite concentrations (relative to ATP, assumed to be 3.0 mM/kg wet weight)were 5.39+/-1.88, 1.30+/-0.39, 5.97+/-3.17, and 4.33+/-1.45 mM/kg wet weight for phosphomonoesters, inorganic phosphate, phosphodiesters, and phosphocreatine (PCr), respectively. These values are in good general agreement with those reported previously. Typical signal-to-noise ratios of 15:1 were obtained for PCr in spectra from nominal 31.5 cc voxel sizes with a 34-min scan time. Limits on spatial resolution and the likely error of the magnesium and pH values are discussed.

Non-P(i) buffer capacity and initial phosphocreatine breakdown and resynthesis kinetics of human gastrocnemius/soleus muscle groups using 0.5 s time-resolved (31)P MRS at 4.1 T.

High-time-resolution (0.5 s) (31)P MRS has been used to evaluate the initial phosphoreatine (PCr) breakdown and resynthesis kinetics, to calculate the non-P(i)(/non-bicarbonate) buffer capacity (betanon-P(i)(/non-bicarb)), and to calculate the constant relating the change in intracellular pH to the muscle's H(+) efflux rate (lambda). The slope of PCr vs time demonstrates that a slope calculated using the first 10 s of recovery underestimates initial PCr recovery rates by up to 56%. A 1-2 s time window is needed to produce a slope that is statistically equivalent to the slope measured using a 0.5 s time window (p = 0.008, one-way RM-ANOVA, Student-Newman-Keuls multiple comparison test). In addition, there was no delay or acceleration in PCr recovery after a 90 s maximum voluntary contraction (MVC) in normal subjects. This demonstrates that oxidative metabolism is occurring at the end of a 90-s MVC in normal individuals. Fitting recovery data has determined that betanon-P(i)(/non-bicarb) = 24.3 +/- 5.4 slyke (mmol/L/pH unit) and that lambda = 0.129 +/- 0.077 mM/(ph s) for human gastrocnemius/soleus muscle. betanon-P(i)(/non-bicarb) is in agreement with measurements in cat biceps, cat soleus and rat gastrocnemius muscles.

Time course of ADCw changes in ischemic stroke: beyond the human eye!

BACKGROUND AND PURPOSE: Using newly developed computerized image analysis, we studied the heterogeneity of apparent diffusion coefficient of water (ADCw) values in human ischemic stroke within 10 hours of onset. METHODS: Echo-planar trace diffusion-weighted images from 9 patients with focal cortical ischemic stroke were obtained within 10 hours of symptom onset. An Iterative Self-Organizing Data Analysis (ISODATA) clustering algorithm was implemented to segment different tissue types with a series of DW images. ADCw maps were calculated from 4 DW images on a pixel-by-pixel basis. The segmented zones within the lesion were characterized as low, pseudonormal, or high, expressed as a ratio of the mean+/-SD of ADCw of contralateral noninvolved tissue. RESULTS: The average ADCW in the ischemic stroke region within 10 hours of onset was significantly depressed compared with homologous contralateral tissue (626.6+/-76.8 versus 842.9+/-60.4x10(-6) mm2/s; P<0.0001). Nevertheless, ISODATA segmentation yielded multiple zones within the stroke region that were characterized as low, pseudonormal, and high. The mean proportion of low:pseudonormal:high was 72%:20%:8%. CONCLUSIONS: Despite low average ADCW, computer-assisted segmentation of DW MRI detected heterogeneous zones within ischemic lesions corresponding to low, pseudonormal, and high ADCw not visible to the human eye. This supports acute elevation of ADCw in human ischemic stroke and, accordingly, different temporal rates of tissue evolution toward infarction.

Preliminary clinical-radiological assessment of a MR tissue signature model in human stroke.

We evaluated the ability of an MR signature model (SM) of cerebral ischemic injury to stage the evolution of cellular damage in human stroke. In 19 patients with ischemic stroke of presumed embolic or non-embolic cause we carried out diffusion-weighted and T2-weighted MR imaging within 48 h of onset, and obtained apparent diffusion coefficient of water (ADCw), and T2 weighted images. We used the signatures obtained from these ADCw/T2 maps to formulate two patterns of damage signifying accelerated or non-accelerated progression of cellular death after stroke onset. Those patients with the accelerated pattern corresponded to those with the neuroradiological (NRC) and clinical diagnosis (TOAST.1 and TOAST.2) of presumed embolic stroke, with clinical diagnosis performed blinded both to NRC and to SM. Agreement between the SM and NRC was substantial (kappa=0.62), moderate (0.60

Adenosine triphosphate production rates, metabolic economy calculations, pH, phosphomonoesters, phosphodiesters, and force output during short-duration maximal isometric plantar flexion exercises and repeated maximal isometric plantar flexion exercises.

Measurements of adenosine triphosphate (ATP) production rates, metabolic economy, intracellular pH, phosphodiesters, and phosphomonoesters along with the force output were used to study 90-s maximum voluntary contractions and two new exercise protocols (20-10 and 30-16 exercises). The 20-10 exercise consisted of thirty-one 20-s maximal voluntary contractions separated by 10-s rest periods. The 30-16 exercise consisted of twenty 30-s maximal voluntary contractions separated by 16-s rest periods. There were no differences in ATP production rates, metabolic economy, intracellular pH, or force output between the 20-10 and 30-16 exercises. The 20-10 exercises accumulated more phosphomonoesters than the 30-16 exercises. These increases in phosphomonoesters may be attributed to increased accumulations of glucose-6-phosphate and/or inosine monophosphate. The increased perception of effort reported during and after the 20-10 exercises was not present during the 30-16 or 90-s exercises. This increased perception of effort may be related to increases in lactate, glucose-6-phosphate, inosine monophosphate, and/or NH3.

Optimal positioning for cervical immobilization.

STUDY OBJECTIVE: We hypothesized that optimal positioning of the head and neck to protect the spinal cord during cervical spine immobilization can be determined with reference to external landmarks. In this study we sought to determine the optimal position for cervical spine immobilization using magnetic resonance imaging (MRI) and to define this optimal position in a clinically reproducible fashion. METHODS: Our subjects were 19 healthy adult volunteers (11 women, 8 men). In each, we positioned the head to produce various degrees of neck flexion and extension. This positioning was followed by quantitative MRI of the cervical spine. RESULTS: The mean ratio of spinal canal and spinal cord cross-sectional areas was smallest at C6 but exceeded 2.0 at all levels from C2 to T1 (P < .05). At the C5 and C6 levels, the maximal area ratio was most consistently obtained with slight flexion (cervical-thoracic angle of 14 degrees) (P < .05). For a patient lying flat on a backboard, this corresponds to raising the occiput 2 cm. More extreme flexion or extension produced variable results. CONCLUSION: In healthy adults, a slight degree of flexion equivalent to 2 cm of occiput elevation produces a favorable increase in spinal canal/spinal cord ration at levels C5 and C6, a region of frequent unstable spine injuries.

Modulation of ATP production by oxygen in obstructive lung disease as assessed by 31P-MRS.

Inadequate O2 supply may impair intramuscular oxidative metabolism and O2 availability may modulate ATP production within exercising muscle. Therefore, we studied ATP flux from anaerobic glycolysis, the creatine kinase reaction, and oxidative phosphorylation using 31P-magnetic resonance spectroscopy kinetic data collected during exercise. We examined six chronic obstructive pulmonary disease (COPD) patients with severe hypoxemia (group 1), seven COPD patients with mild hypoxemia (group 2), and seven healthy control subjects. Exercise (90-s isometric contraction of the gastrocnemius-soleus muscle group, 40% of max) was performed on room air for all subjects; for COPD patients, it was repeated during supplemental O2 at identical power outputs, with 60-min rest between the two sets. In group 1 (air vs. O2), oxidative phosphorylation ATP production was lower (P < 0.05), anaerobic glycolysis ATP production was higher (P < 0.05), and anaerobic glycolysis plus creatine kinase ATP production tended to be higher (P = 0.06). In group 2, no differences were observed across conditions. Assuming that mitochondrial size, density, function, and redox state were not affected by acute changes in the inspired O2 fraction, reduced O2 availability is the remaining factor that could have limited oxidative ATP production during hypoxemia. In conclusion, in severely hypoxemic COPD patients, O2 availability apparently limits intramuscular oxidative metabolism because acute hypoxemia increases anaerobic and decreases aerobic ATP production.

Factors which influence alterations of phosphates and pH in exercising human skeletal muscle: measurement error, reproducibility, and effects of fasting, carbohydrate loading, and metabolic acidosis.

Previous studies have shown considerable variability in the metabolic response of human skeletal muscle during a standardized exercise protocol. The goal of these studies was to investigate the factors responsible for the broad range of metabolic changes produced by fatiguing exercise. Experiments were performed to quantitate the measurement error of 31P nuclear magnetic resonance spectroscopy of human muscle, the reproducibility of changes within a single subject, and the effects of fasting, carbohydrate loading, and metabolic acidosis. The results show that none of these factors appear to be responsible for the wide variation between subjects. However, the effects of training and genetic factors were not investigated and are likely to be responsible for the substantial variability between subjects.