Magnetic Resonance Spectroscopy Changes Research Articles

Radiological hints for differentiation of cerebellar multiple system atrophy from spinocerebellar ataxia

Differentiation cerebellar multiple systemic atrophy (MSA-C) from spinocerebellar ataxia (SCA) is important. The “hot cross bun” sign (HCBS) at pons and magnetic resonance spectroscopy (MRS) are helpful. However, the prevalence of HCBS and the alteration of cerebellar MRS parameters are evolving with disease progression. We hypothesized that since the HCBS and MRS are evolving with time, different parameters for differentiation of MSA-C and SCA are required at different disease stages. The aim of this study was to evaluate the HCBS and MRS changes in patients with MSA-C and SCA at different disease stages. A total of 398 patients with molecularly confirmed SCA (SCA1, 2, 3, 6, 17) and 286 patients diagnosed with probable MSA-C (without mutations in SCA1, 2, 3, 6, 17 genes), who had received brain magnetic resonance imaging (MRI) and MRS from January 2000 to January 2020, were recruited. Twenty-five patients were molecularly identified as having SCA1, 68 as SCA2, 253 as SCA3, 34 as SCA6, and 18 as SCA17. We compared their clinical parameters and neuroimaging features at different disease stages. The presence of HCBS was assessed using an axial T2 fast spin-echo or FLAIR sequence. Proton MRS was recorded with voxel of interest focusing on cerebellar hemispheres and cerebellar vermis and avoiding cerebrospinal fluid spaces space using a single-voxel stimulated echo acquisition mode sequence. We found that patients with MSA-C tend to have a higher prevalence of pontine HCBS, worse Scale for the Assessment and Rating of Ataxia scores, lower cerebellar N-acetyl aspartate (NAA)/creatinine (Cr), and choline (Cho)/Cr, compared to patients with SCA at corresponding disease stages. In MSA-C patients with a disease duration < 1 year and without pontine HCBS, a cerebellar NAA/Cr ≤ 0.79 is a good indicator of the possibility of MSA-C. By using the pontine HCBS and cerebellar MRS, discerning MSA-C from SCA became possible. This study provides cutoff values of MRS to serve as clues in differentiating MSA-C from SCAs.

Author response: Meta-analysis of magnetic resonance spectroscopy in the diagnosis of hepatic encephalopathy.

The authors thank Dr. Gupta for the comment on our article.1 Hepatic encephalopathy (HE) is associated with significant morbidity and mortality in cirrhosis; its pathophysiology is incompletely understood. Our meta-analysis was a review of magnetic resonance spectroscopy (MRS) data in HE, which confirmed a specific metabolic pattern, consisting of increased glutamine/glutamate—with reduced choline—and myo-inositol, particularly in the parietal lobes.1 The changes increased with the severity of HE. We agree that this would have limited diagnostic utility in overt HE, which is clinically obvious. We strongly disagree, however, about covert or minimal HE (MHE), which are defined as the presence of neuropsychologic or neurophysiologic abnormalities in patients with no obvious—i.e., at least disorientation for time or asterixis—clinical signs of overt HE. Here, there is a potential role for MRS in diagnosis, monitoring, and investigation. In a recent French cohort of cirrhotic individuals with and without MHE, HE pattern MRS changes in the pallidum were present in 95% of MHE vs 0% of unimpaired patients ( p < 0.001), suggesting MRS could outperform other modalities of MHE diagnosis.2 MRS may also have a significant role in future pathophysiologic and pharmacologic HE studies.

Longitudinal Magnetic Resonance Spectroscopy andDiffusion Tensor Imaging in Sheep (Ovis aries) With Quinolinic Acid Lesions of the Striatum: Time-Dependent Recovery of N-Acetylaspartate and Fractional Anisotropy.

We created an excitotoxic striatal lesion model of Huntington disease (HD) in sheep, using the N-methyl-d-aspartate receptor agonist, quinolinic acid (QA). Sixteen sheep received a bolus infusion of QA (75 µL, 180 mM) or saline, first into the left and then (4 weeks later) into the right striatum. Magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) of the striata were performed. Metabolite concentrations and fractional anisotropy (FA) were measured at baseline, acutely (1 week after each surgery) and chronically (5 weeks or greater after the surgeries). There was a significant decrease in the neuronal marker N-acetylaspartate (NAA) and in FA in acutely lesioned striata of the QA-lesioned sheep, followed by a recovery of NAA and FA in the chronically lesioned striata. NAA level changes indicate acute death and/or impairment of neurons immediately after surgery, with recovery of reversibly impaired neurons over time. The change in FA values of the QA-lesioned striata is consistent with acute structural disruption, followed by re-organization and glial cell infiltration with time. Our study demonstrates that MRS and DTI changes in QA-sheep are consistent with HD-like pathology shown in other model species and that the MR investigations can be performed in sheep using a clinically relevant human 3T MRI scanner.

SLC1A3 variant associated with hemiplegic migraine and acetazolamide-responsive MRS changes.

Familial hemiplegic migraine (FHM) is a group of rare familial disorders caused, in most cases, by mutations in CACNA1A and ATP1A2 .1 Heterozygous mutations in solute carrier family 1 member 3 ( SLC1A3 ), encoding glial glutamate transporter, are associated with episodic ataxia type 6 (EA6).2–5 In addition to episodic ataxia (EA), alternating hemiplegia and hemiplegic migraine have been reported twice in patients with EA6.2,4 Mutations in SLC1A3 are very rare; screenings in cohorts of EA and alternating hemiplegia have yielded either negative results3,6–8 or variants of unclear significance.e-1--e-3 Herein, we characterize a patient featuring sporadic hemiplegic migraine (SHM) responsive to acetazolamide (ACZ) and mild cerebellar atrophy associated with a new variant in SLC1A3. We also report the utility of proton magnetic resonance spectroscopy (MRS) for this condition. The authors are grateful to the patients for their kind participation in this study. They thank Dr. Mattias Andreasson for evaluating the index case during a hemiplegic spell.

Meta-analysis of magnetic resonance spectroscopy in the diagnosis of hepatic encephalopathy.

Various imaging modalities have been used to explore pathogenic mechanisms and stratify the severity of hepatic encephalopathy (HE). The hypothesis of this meta-analysis was that there is a progressive identifiable derangement of imaging measures using magnetic resonance spectroscopy (MRS) related to the severity of the HE. Studies with more than 10 cases and HE diagnosis were identified from the electronic databases PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Literatura Latino Americana em Ciências da Saúde (LILACS), and Cochrane Central Register of Controlled Trials (CENTRAL) through July 25, 2018. Participants were stratified into healthy controls and patients with non-HE (NHE) (cirrhosis without HE), minimal HE (MHE), and overt HE (OHE). Analyses were organized by metabolite studied and brain region examined. Statistical meta-analysis was performed using the metafor package in R (v3.4.1). Pooled standardized mean differences between patient groups were calculated using a random effects model. We identified 31 studies (1,481 patients) that included data for cirrhosis-related HE. We found the parietal region to be the most reliable in differentiating between patients with and without MHE, with standard mean differences of +0.82 (95% confidence interval [CI] +0.49 to +1.15, p < 0.0001, I 2 = 37.45%) for glutamine/glutamate, -0.36 (95% CI -0.61 to -0.10, p = 0.007, I 2 = 20.00%) for choline, and-0.77 (95% CI -1.19 to -0.34, p = 0.0004, I 2 = 67.48%) for myo-inositol. We also found that glutamine/glutamate was the metabolite that reliably correlated with HE grade in all brain regions. The meta-analysis reveals that MRS changes in glutamine/glutamate, choline, and myo-inositol, particularly in the parietal lobe, correlate with the severity of HE. MRS may be of value in the assessment of HE.

Brain myoinositol as a potential marker of amyloid-related pathology: A longitudinal study.

ObjectiveTo investigate the association between longitudinal changes in proton magnetic resonance spectroscopy (MRS) metabolites and amyloid pathology in individuals without dementia, and to explore the relationship between MRS and cognitive decline.MethodsIn this longitudinal multiple time point study (a subset of the Swedish BioFINDER), we included cognitively healthy participants, individuals with subjective cognitive decline, and individuals with mild cognitive impairment. MRS was acquired serially in 294 participants (670 individual spectra) from the posterior cingulate/precuneus. Using mixed-effects models, we assessed the association between MRS and baseline β-amyloid (Aβ), and between MRS and the longitudinal Mini-Mental State Examination, accounting for APOE, age, and sex.ResultsWhile baseline MRS metabolites were similar in Aβ positive (Aβ+) and negative (Aβ−) individuals, in the Aβ+ group, the estimated rate of change was +1.9%/y for myo-inositol (mI)/creatine (Cr) and −2.0%/y for N-acetylaspartate (NAA)/mI. In the Aβ− group, mI/Cr and NAA/mI yearly change was −0.05% and +1.2%; however, this was not significant across time points. The mild cognitive impairment Aβ+ group showed the steepest MRS changes, with an estimated rate of +2.93%/y (p = 0.07) for mI/Cr and −3.55%/y (p < 0.01) for NAA/mI. Furthermore, in the entire cohort, we found that Aβ+ individuals with low baseline NAA/mI had a significantly higher rate of cognitive decline than Aβ+ individuals with high baseline NAA/mI.ConclusionWe demonstrate that the longitudinal change in mI/Cr and NAA/mI is associated with underlying amyloid pathology. MRS may be a useful noninvasive marker of Aβ-related processes over time. In addition, we show that in Aβ+ individuals, baseline NAA/mI may predict the rate of future cognitive decline.

Abstract 2510: Interrogating liver metabolic stress due to cancer-induced cachexia

Abstract Cancer-induced cachexia accounts for approximately 20% of all cancer deaths 1. In pancreatic cancer, the syndrome affects nearly 80% of patients 2,3. Cachectic patients experience a wide range of symptoms affecting the function of several organs such as muscle, liver, brain, and heart, that decrease quality of life and worsen prognosis. A major characteristic of cachexia is the accelerated skeletal muscle and fat storage wasting causing nutrient mobilization both directly as lipid and amino acids, and indirectly as glucose derived from the exploitation of liver gluconeogenesis that reaches the tumor through the bloodstream4. Patients with cachexia develop a wide range of metabolic stress from increased proteins and fat tissue burning resulting in increased energy expenditure. Here, for the first time, we have performed high-resolution quantitative 1H magnetic resonance spectroscopy (MRS) of liver tissue obtained from normal, noncachectic and cachectic mice bearing PDAC that are cachectic (Pa04C) and noncachectic (Panc1). A significant reduction in liver weight and significant changes in 1H MRS derived metabolite profiles were detected with cachexia. Human pancreatic cancer cell lines, Panc1 and Pa04C, were used for the study. Six to 8 week old male severe combined immunodeficient mice were inoculated in the right flank with cancer cells (5×106) and in the right hind leg muscle with reporter myoblasts (2×106) to monitor the development of cachexia in mice5. Live animal optical imaging was done using a Xenogen IVIS® Spectrum (PerkinElmer) optical scanner. Dual phase solvent extraction was performed on liver tissue to extract water soluble metabolites. All 1H MR spectra were acquired on an Avance 750 MHz Bruker NMR spectrometer. We found, for the first time, that the liver in Pa04C tumor bearing mice underwent a profound weight loss; although Panc1 tumor bearing mice showed some liver weight loss this was not as profound as observed with Pa04C tumors. Significant decreases in lactate, glucose and glutathione were observed in cachectic mouse liver compared to noncachectic mouse liver, and the liver from healthy control mice. The significant decrease of these metabolites in cachectic livers may reflect increased utilization of glucose, lactate and glutathione by the tumor or other organs during the cachexia cascade4. These results provide new insights into changes in liver metabolism during cachexia, and support investigating metabolic strategies such as supplementing glutathione or glucose to reduce cachexia associated morbidity.

Accuracy of deep brain stimulation electrodes implanted by frameless system -Nexframe©

s / Brain Stimulation 8 (2015) 412e427 425 l Centre for Healthy Brain Ageing, University of New South Wales, Sydney, Australia m Stony Brook University, Stony Brook, NY n Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX Introduction: There are reports of increases in hippocampal volume after ECT, but the relevance of this finding to antidepressant effects of ECT is uncertain. This study used a novel magnetic resonance spectroscopy (MRS) method to assess for evidence of ECT-induced neurogenesis, and examined the relationship of MRS changes to hippocampal volume change and antidepressant outcomes at the end of the ECT course. Methods: 20 depressed patients (9 female; mean age 53.9 years, range 33-79 years) treated with a course of ECT (N1⁄48 right unilateral, N1⁄412 bilateral) underwent MRS (1.28ppm signal) and structural MRI imaging prior to ECT, after 1-3 ECT, and at end of the ECT course. Mood was rated using MADRS score at the same time points. Results: ECT treatment was associated with significant improvement in mood (70% reduction in mean MADRS score, 71% response rate, 53% remission rate) and increase in hippocampal volume. Increase in the 1.28ppm MRS signal early in the ECT course was correlated with lower end-of-treatment MADRS scores (r1⁄4-0.57, p1⁄40.034) and with hippocampal volume expansion (r1⁄40.73, p1⁄40.003). This increased hippocampal volume was also correlated with lower MADRS scores (r1⁄4-0.64, p1⁄40.008). Conclusions: This is the first study in humans to suggest hippocampal neurogenesis may be linked to the antidepressant efficacy of ECT.

Regional proton magnetic resonance spectroscopy patterns in dementia with Lewy bodies

Magnetic resonance spectroscopy (MRS) characteristics of dementia with Lewy bodies (DLB) Alzheimer's disease (AD) and cognitively normal controls were compared. DLB (n = 34), AD (n = 35), and cognitively normal controls (n = 148) participated in a MRS study from frontal, posterior cingulate, and occipital voxels. We investigated DLB patients with preserved hippocampal volumes to determine the MRS changes in DLB with low probability of overlapping AD pathology. DLB patients were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) in the occipital voxel. AD patients were characterized by lower NAA/Cr in the frontal and posterior cingulate voxels. Normal NAA/Cr levels in the frontal voxel differentiated DLB patients with preserved hippocampal volumes from AD patients. DLB and AD patients had elevated choline/creatine, and myo-Inositol/creatine in the posterior cingulate. MRS abnormalities associated with loss of neuronal integrity localized to the occipital lobes in DLB, and the posterior cingulate gyri and frontal lobes in AD. This pattern of MRS abnormalities may have a role in differential diagnosis of DLB and in distinguishing DLB patients with overlapping AD pathology.

The Phosphoinositide 3-Kinase Inhibitor PI-103 Downregulates Choline Kinase α Leading to Phosphocholine and Total Choline Decrease Detected by Magnetic Resonance Spectroscopy

The phosphoinositide 3-kinase (PI3K) pathway is a major target for cancer drug development. PI-103 is an isoform-selective class I PI3K and mammalian target of rapamycin inhibitor. The aims of this work were as follows: first, to use magnetic resonance spectroscopy (MRS) to identify and develop a robust pharmacodynamic (PD) biomarker for target inhibition and potentially tumor response following PI3K inhibition; second, to evaluate mechanisms underlying the MRS-detected changes. Treatment of human PTEN null PC3 prostate and PIK3CA mutant HCT116 colon carcinoma cells with PI-103 resulted in a concentration- and time-dependent decrease in phosphocholine (PC) and total choline (tCho) levels (P < 0.05) detected by phosphorus ((31)P)- and proton ((1)H)-MRS. In contrast, the cytotoxic microtubule inhibitor docetaxel increased glycerophosphocholine and tCho levels in PC3 cells. PI-103-induced MRS changes were associated with alterations in the protein expression levels of regulatory enzymes involved in lipid metabolism, including choline kinase alpha (ChoK(alpha)), fatty acid synthase (FAS), and phosphorylated ATP-citrate lyase (pACL). However, a strong correlation (r(2) = 0.9, P = 0.009) was found only between PC concentrations and ChoK(alpha) expression but not with FAS or pACL. This study identified inhibition of ChoK(alpha) as a major cause of the observed change in PC levels following PI-103 treatment. We also showed the capacity of (1)H-MRS, a clinically well-established technique with higher sensitivity and wider applicability compared with (31)P-MRS, to assess response to PI-103. Our results show that monitoring the effects of PI3K inhibitors by MRS may provide a noninvasive PD biomarker for PI3K inhibition and potentially of tumor response during early-stage clinical trials with PI3K inhibitors.

1H-MRS for the diagnosis of acute disseminated encephalomyelitis: insight into the acute-disease stage

Acute disseminated encephalomyelitis (ADEM) is a demyelinating disorder of the central nervous system (CNS). Differentiating ADEM from other inflammatory disorders, such as multiple sclerosis, is not always conclusive using conventional MRI. To evaluate longitudinal magnetic resonance spectroscopy (MRS) changes that distinguish ADEM from other inflammatory disorders. MRI/MRS scans were performed in seven patients with ADEM during the acute and chronic phases of the disease. Partial recovery was detected between the acute and chronic phases in choline/creatine ratio. Major elevation of lipids and reduction in myo-inositol/creatine ratio was detected in all patients during the acute phase, followed by a reduction in lipids peak and elevation above normal in myo-inositol/creatine ratio during the chronic phase. Consistent and unique MRS changes in metabolite ratios between the acute and chronic presentations of the disease were found. To the best of our knowledge, these patterns have not been described in other inflammatory disorders and might assist in the early diagnosis of ADEM.

Imaging Intratumoral Convection: Pressure-Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors

Low-molecular weight (LMW) chemotherapeutics are believed to reach tumors through diffusion across capillary beds as well as membrane transporters. Unexpectedly, the delivery of these agents seems to be augmented by reductions in tumor interstitial fluid pressure, an effect typically associated with high-molecular weight molecules that reach tumors principally through convection. We investigated the hypothesis that improved intratumoral convection can alter tumor metabolism and enhance the delivery of a LMW chemotherapeutic agent to solid tumors. For this purpose, we applied 31P/19F magnetic resonance spectroscopy (MRS) and magnetic resonance spectroscopic imaging (MRSI) to examine the influence of type I collagenase on tumor bioenergetics and the delivery of 5-fluorouracil (5FU) to HT29 human colorectal tumors grown s.c. in mice. Collagenase effected a 34% reduction in tumor interstitial fluid pressure with an attendant disintegration of intratumoral collagen. Neither mice-administered collagenase nor controls receiving PBS showed changes in (31)phosphorus MRS-measured tumor bioenergetics; however, a time-dependent increase in the content of extracellular inorganic phosphate (Pi(e)) was observed in tumors of collagenase-treated animals. (31)Phosphorus MRSI showed that this increase underscored a more homogeneous distribution of Pi(e) in tumors of experimental mice. (19)Fluorine MRS showed that these changes were associated with a 50% increase in 5FU uptake in tumors of experimental versus control animals; however, this increase resulted in an increase in 5FU catabolites rather than fluoronucleotide intermediates that are required for subsequent cytotoxicity. These data indicate that the modulation of convective flow within tumors can improve the delivery of (LMW) chemotherapeutics and show the potential role for noninvasive imaging of this process in vivo.

Neurocognitive Impairment and Dementia in Mood Disorders

Neurocognitive Impairment and Dementia in Mood Disorders

Magnetic resonance spectroscopy changes following haemopoietic stem cell transplantation in children with cerebral adrenoleukodystrophy

X-linked cerebral adrenoleukodystrophy is an aggressive, rapidly progressive disorder resulting in considerable morbidity and, left untreated, mortality. Patients typically present before the age of 10 years with progressive symptomatology including ataxia, spasticity, and focal neurological deficits. Current therapeutic options are limited, the treatment of choice being haemopoietic stem cell transplantation (HSCT). Intervention is beneficial to those children with early disease and characteristic magnetic resonance (MR) imaging changes. Developments in MR imaging have led to the incorporation of MR spectroscopy in the assessment tools; however, it is yet to be included in stratified assessment tools to guide treatment choice. Furthermore, there remains a paucity of outcome data on MR spectroscopy changes following HSCT. We describe our experience in two males with confirmed cerebral adrenoleukodystrophy treated, at the mean age of 5 years 6 months, with HSCT and report the pronounced spectroscopic changes observed following treatment. Both children, observed for a minimum period of 14 months following treatment, demonstrate complete reversal in previously deteriorating spectroscopy with marked increase in N-acetyl-aspartate (NAA)/choline (Cho) ratios and reduction in Cho/creatine (Cr) ratios following HSCT treatment with concomitant stabilization of clinical status.

Etiology and functional status of liver cirrhosis by31P MR spectroscopy

To assess the functional status and etiology of liver cirrhosis by quantitative (31)P magnetic resonance spectroscopy (MRS). A total of 80 patients with liver cirrhosis of different etiology and functional status described by Child-Pugh score were examined and compared to 11 healthy volunteers. MR examination was performed on a 1.5 T imager using a (1)H/(31)P surface coil by the 2D chemical shift imaging technique. Absolute concentrations of phosphomonoesters (PME), phosphodiesters (PDE), inorganic phosphate (Pi) and adenosine triphosphate (ATP) were measured. MRS changes reflected the degree of liver dysfunction in all the patients as well as in individual etiological groups. The most important change was a decrease of PDE. It was possible to distinguish alcoholic, viral and cholestatic etiologies based on MR spectra. Alcoholic and viral etiology differed in PDE (alcoholic, viral, controls: 6.5+/-2.3, 6.5+/-3.1, 10.8+/-2.7 mmol/L, P<0.001) and ATP (alcoholic, viral, controls: 2.9+/-0.8, 2.8+/-0.9, 3.7+/-1.0 mmol/L, P<0.01) from the control group. Unlike viral etiology, patients with alcoholic etiology also differed in Pi (alcoholic, controls: 1.2+/-0.4, 1.6+/-0.6 mmol/L, P<0.05) from controls. No significant changes were found in patients with cholestatic disease and controls; nevertheless, this group differed from both alcoholic and viral groups (cholestatic, alcoholic, viral: 9.4+/-2.7, 6.5+/-2.3, 6.5+/-3.1 mmol/L, P<0.005) in PDE. (31)P MRS can significantly help in non-invasive separation of different etiological groups leading to liver cirrhosis. In addition, MRS changes reflect functional liver injury.

In vivo magnetic resonance spectroscopy in chronic fatigue syndrome

The pathogenic mechanisms of chronic fatigue syndrome (CFS) are not clearly known. Fatigue, poor short-term memory and muscle pain are the most disabling symptoms in CFS. Research data on magnetic resonance spectroscopy (MRS) of muscles and brain in CFS patients suggest a cellular metabolic abnormality in some cases. 31P MRS of skeletal muscles in a subset of patients indicate early intracellular acidosis in the exercising muscles. 1H MRS of the regional brain areas in CFS have shown increased peaks of choline derived from the cell membrane phospholipids. Cell membrane oxidative stress may offer a common explanation for the observed MRS changes in the muscles and brain of CFS patients and this may have important therapeutic implications. As a research tool, MRS may be used as an objective outcome measure in the intervention studies. In addition, regional brain 1H MRS has the potential for wider use to substantiate a clinical diagnosis of CFS from other disorders of unexplained chronic fatigue.

A prospective longitudinal in vivo 1H MR spectroscopy study of the SIV/macaque model of neuroAIDS

BackgroundThe neurological complications of HIV infection remain poorly understood. Clinically, in vivo 1H magnetic resonance spectroscopy (MRS) demonstrates brain injury caused by HIV infection even when the MRI is normal. Our goal was to undertsand the dynamics of cerebral injury by performing a longitudinal in vivo 1H MRS study of the SIV/macaque model of neuroAIDS.ResultsEight rhesus macaques were infected with SIVmac251 and serially imaged with MRI and 1H MRS to terminal AIDS or the endpoint of 2 years. During acute infection, there were stereotypical brain MRS changes, dominated by a significant elevation of the Cho/Cr ratio in the frontal cortex. Subsequently, brain metabolic patterns diverged between animals. There was an elevation of basal ganglia Cho/Cr four weeks post-inoculation in 2 animals that developed SIV encephalitis (p = 0.022). Metabolite ratios averaged across all 8 animals were not significantly different from baseline at any time point after 2 weeks post inoculation. However, linear regression analysis on all 8 animals revealed a positive correlation between a change in frontal lobe Cho/Cr and plasma viral load (P < 0.001, R = 0.80), and a negative correlation between NAA/Cr in the basal ganglia and the plasma viral load (P < 0.02, R = -0.73). No MRI abnormalities were detected at any time.ConclusionsAfter infection with SIV, macaque brain metabolism changes in a complex manner that is dependent on brain region, host factors and viral load. An elevation of basal ganglia Cho/Cr 4 weeks after SIV infection may be marker of a propensity to develop SIV encephalitis. Elevations of Cho/Cr, often observed in CNS inflammation, were associated with increased plasma viral load during acute and chronic infection. Evidence of neuronal injury in the basal ganglia was associated with increased plasma viral load in the chronic stage of infection. These observations support the use of drugs capable of controlling the viral replication and trafficking of virus into the CNS, and may help explain the reduction in incidence of HIV-associated dementia in the era of HAART despite the inability of most of those drugs to effectively enter the CNS.

Applications of magnetic resonance spectroscopy to chronic liver disease

In vivo magnetic resonance spectroscopy (MRS) provides a non-invasive ‘window' on biochemical processes within the body. The technique is currently a research tool, but new developments in whole-body magnetic resonance imaging (MRI) may provide a role for clinical MRS in obtaining functional information at the end of a standard MRI examination. Applications of hepatic and cerebral MRS to chronic liver disease and its associated complications are specifically considered in this article. Changes in phosphorus-31 MRS with the underlying functional severity of the cirrhotic liver are discussed. These reflect increased turnover of cell membranes as the liver attempts to regenerate. Patterns of spectral abnormality in the transplanted liver are described, and also the potential use of the technique to assess the viability of the stored donor liver in the time period between organ harvesting and implantation in the transplant recipient. Metabolite abnormalities in the brain are defined in hepatic encephalopathy and in patients infected with the hepatitis C virus who have minimal hepatic inflammation. Future trends are considered: for example, the use of MRS as a non-invasive tool to assess the effectiveness of liver-directed gene therapy.

MR spectroscopy in stroke.

Magnetic resonance spectroscopy (MRS) is a non-invasive in vivo method that allows the investigation of biochemical changes in both animals and humans. The application of MRS to the study of stroke has made possible dynamic studies of intracellular metabolism of cerebral ischaemia. The majority of the stroke studies have been carried out using proton [1H]-MRS which allows the detection of N-acetyl aspartate (NAA), a neuronal marker. [1H]-MRS changes in humans demonstrate that after an infarct, lactate appears, while NAA and total creatine are reduced compared to the contralateral hemisphere. Longitudinal studies demonstrate a further reduction of NAA suggesting that ischaemic injury continues for more than a week following infarction. Major advances in the treatment of acute stroke require the accurate prediction of the mortality of stroke patients. Patients with large infarcts are known to do badly. In patients with small infarcts, less than 80 cm3, the addition of core NAA concentrations and cerebral blood flow have enabled the identification of some of the patients likely to benefit from new drug treatment.

Phase I trial of the selective mitochondrial toxin MKT 077 in chemo-resistant solid tumours

MKT077 is a rhodacyanine dye analogue which preferentially accumulates in tumour cell mitochondria. It is cytotoxic to a range of tumours. In this phase I study, MKT077 was administered as a five-day infusion once every three weeks. Ten patients, median age 59 (38-70) years, with advanced solid cancers were treated at three dose levels: 30, 40 and 50 mg/m2/day for a total of 18 cycles. 31Phosphorus magnetic resonance spectroscopy (MRS) was used to evaluate the effect of MKT077 on skeletal muscle mitochondrial function. The predominant toxicity was recurrent reversible functional renal impairment (grade 2, two patients). One patient with renal cancer attained stable disease and the remainder progressive disease. There were no MRS changes in the first or second treatment cycles but one patient received 11 treatment cycles and developed changes consistent with a mitochondrial myopathy. Mean values for all pharmacokinetic parameters were at sub micromolar levels and did not exceed IC50 values (> or = 1 microM). Because of the renal toxicity, and animal studies showing MKT077 causes eventual irreversible renal toxicity, further recruitment was halted. The study shows, however, that it is feasible to target mitochondria with rhodacyanine analogues, if drugs with higher therapeutic indices could be developed.