Robert E. Lenkinski

Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure.

Background The purpose of this study was to investigate the prevalence of skeletal muscle atrophy and its relation to exercise intolerance and abnormal muscle metabolism in patients with heart failure (HF). Methods and Results Peak Vo2, percent ideal body weight (% IBW), 24-hour urine creatinine (Cr), and anthropometrics were measured in 62 ambulatory patients with HF. 31P magnetic resonance spectroscopy (MRS) and imaging (MRI) of the calf were performed in 15 patients with HF and 10 control subjects. Inorganic phosphorus (Pi), phosphocreatine (PCr), and intracellular pH were measured at rest and during exercise. Calf muscle volume was determined from the sum of the integrated area of muscle in 1-cm-thick contiguous axial images from the patella to the calcaneus. A reduced skeletal muscle mass was noted in 68% of patients, as evidenced by a decrease in Cr-to-height ratio of <7.4 mg/cm and/or upper arm circumference of <5% of normal. Calf muscle volume (MRI) was also reduced in the patients with HF (controls, 675±84 cm3/m2; HF, 567±112 cm3/m2; p < 0.05). Fat stores were largely perserved with triceps skinfold of <5% of normal and/or IBW of <80% in only 8% of patients. Modest linear correlations were observed between peak Vo2 and both calf muscle volume per meter squared (r = 0.48) and midarm muscle area (r = 0.36) (both p < 0.05). 31P metabolic abnormalities during exercise were observed in the patients with HF, which is consistent with intrinsic oxidative abnormalities. The metabolic changes were weakly correlated with muscle volume (r = −0.42, p<0.05). Conclusions These findings indicate that patients with chronic HF frequently develop significant skeletal muscle atrophy and metabolic abnormalities. Atrophy contributes modestly to both the reduced exercise capacity and altered muscle metabolism.

In vivo near-infrared fluorescence imaging of osteoblastic activity

In vertebrates, the development and integrity of the skeleton requires hydroxyapatite (HA) deposition by osteoblasts. HA deposition is also a marker of, or a participant in, processes as diverse as cancer and atherosclerosis. At present, sites of osteoblastic activity can only be imaged in vivo using γ-emitting radioisotopes. The scan times required are long, and the resultant radioscintigraphic images suffer from relatively low resolution. We have synthesized a near-infrared (NIR) fluorescent bisphosphonate derivative that exhibits rapid and specific binding to HA in vitro and in vivo. We demonstrate NIR light–based detection of osteoblastic activity in the living animal, and discuss how this technology can be used to study skeletal development, osteoblastic metastasis, coronary atherosclerosis, and other human diseases.

Metabolic Heterogeneity in Human Lung Tumors

Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. Here, we assessed the impact of these factors on human NSCLC metabolism in vivo using intraoperative (13)C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source. Moreover, metabolically heterogeneous regions were identified within and between tumors, and surprisingly, our data suggested potential contributions of non-glucose nutrients in well-perfused tumor areas. Our findings not only demonstrate the heterogeneity in tumor metabolism in vivo but also highlight the strong influence of the microenvironment on this feature.

Primer on gadolinium chemistry

Gadolinium is widely known by all practitioners of magnetic resonance imaging (MRI) but few appreciate the basic solution chemistry of this trivalent lanthanide ion. Given the recent linkage between gadolinium contrast agents and nephrogenic systemic fibrosis, some basic chemistry of this ion must be more widely understood. This short primer on gadolinium chemistry is intended to provide the reader the background principles necessary to understand the basics of chelation chemistry, water hydration numbers, and the differences between thermodynamic stability and kinetic stability or inertness. We illustrate the fundamental importance of kinetic dissociation rates in determining gadolinium toxicity in vivo by presenting new data for a novel europium DOTA‐tetraamide complex that is relatively unstable thermodynamically yet extraordinarily inert kinetically and also quite nontoxic. This, plus other literature evidence, forms the basis of the fundamental axiom that it is the kinetic stability of a gadolinium complex, not its thermodynamic stability, that determines its in vivo toxicity. J. Magn. Reson. Imaging 2009;30:1240–1248.

A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age.

OBJECTIVE Differences in diagnostic criteria and methods have led to mixed results regarding the metabolite pattern of HIV-associated brain injury in relation to neurocognitive impairment. Therefore, a multicenter MRS consortium was formed to evaluate the neurometabolites in HIV patients with or without cognitive impairment. METHODS Proton magnetic resonance spectroscopy (MRS) at short-echo time (30 ms) was assessed in the frontal white matter, basal ganglia, and parietal cortex of 100 HIV patients [61 with AIDS dementia complex (ADC) and 39 neuroasymptomatic (NAS)] and 37 seronegative (SN) controls. RESULTS Compared to SN, NAS had higher glial marker myoinositol-to-creatine ratio (MI/Cr) in the white matter (multivariate analyses, adjusted P=0.001), while ADC showed further increased MI/Cr in the white matter and basal ganglia (both P<0.001), and increased choline compounds (Cho)/Cr in white matter (P=0.04) and basal ganglia (P<0.001). Compared to NAS, ADC showed a reduction in the neuronal marker N-acetyl compound (NA)/Cr in the frontal white matter (P=0.007). CSF, but not plasma, viral load correlated with MI/Cr and Cho/Cr in white matter and NAA/Cr in parietal cortex. HIV infection and aging had additive effects on Cho/Cr and MI/Cr in the basal ganglia and white matter. CONCLUSIONS The results suggest that glial activation occurs during the NAS stages of HIV infection, whereas further inflammatory activity in the basal ganglia and neuronal injury in the white matter is associated with the development of cognitive impairment. Aging may further exacerbate brain metabolites associated with inflammation in HIV patient and thereby increase the risk for cognitive impairment.

The evaluation of human breast lesions with magnetic resonance imaging and proton magnetic resonance spectroscopy.

AbstractPurpose. MR spectroscopy (MRS) assists in lesion characterization and diagnosis when combined with magnetic resonance imaging (MRI). Cancerous lesions demonstrate elevated composite choline levels arising from increased cellular proliferation. Our study investigated if MR spectroscopy of the breast would be useful for characterizing benign and malignant lesions. Materials and methods. Single voxel proton MR spectroscopy (MRS) was acquired as part of an MR imaging protocol in 38 patients referred upon surgical consultation. The MR spectra were read independently in a blinded fashion without the MR images by three spectroscopists. The MRI exam was interpreted in two settings: (a) as a clinical exam with detailed histories and results from previous imaging studies such as mammography or ultrasound included and (b) as a blinded study without prior histories or imaging results. Results. Elevated choline levels were demonstrated by MRS in 19 of the 23 confirmed cancer patients. The sensitivity and specificity for determining malignancy from benign breast disease with MRS alone were 83 and 87%, respectively, while a blinded MRI review reported 95 and 86%, respectively. Conclusions. Proton MR spectroscopy provides a noninvasive, biochemical measure of metabolism. The technique can be performed in less than 10min as part of an MRI examination. MRI in combination with MRS may improve the specificity of breast MR and thereby, influence patient treatment options. This may be particularly true with less experienced breast MRI readers. In exams where MRI and MRS agree, the additional confidence measure provided by MRS may influence the course of treatment.

CEST: From basic principles to applications, challenges and opportunities

Chemical Exchange Saturation Transfer (CEST) offers a new type of contrast for MRI that is molecule specific. In this approach, a slowly exchanging NMR active nucleus, typically a proton, possessing a chemical shift distinct from water is selectively saturated and the saturated spin is transferred to the bulk water via chemical exchange. Many molecules can act as CEST agents, both naturally occurring endogenous molecules and new types of exogenous agents. A large variety of molecules have been demonstrated as potential agents, including small diamagnetic molecules, complexes of paramagnetic ions, endogenous macromolecules, dendrimers and liposomes. In this review we described the basic principles of the CEST experiment, with emphasis on the similarity to earlier saturation transfer experiments described in the literature. Interest in quantitative CEST has also resulted in the development of new exchange-sensitive detection schemes. Some emerging clinical applications of CEST are described and the challenges and opportunities associated with translation of these methods to the clinical environment are discussed.

Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease

X‐linked Charcot‐Marie‐Tooth disease (CMTX) is a hereditary demyelinating neuropathy caused by mutations in the connexin 32 (Cx32) gene. Cx32 is widely expressed in brain and peripheral nerve, yet clinical manifestations of CMTX mainly arise from peripheral neuropathy. We have evaluated two male patients with CMTX who on separate occasions developed transient ataxia, dysarthria, and weakness within 3 days of returning from ski trips at altitudes above 8,000 feet. Magnetic resonance imaging studies in both patients showed nonenhancing, confluent, and symmetrical white matter abnormalities that were more pronounced posteriorly and that resolved over several months. Magnetic transfer images in one patient demonstrated increased magnetization transfer ratios distinct from that seen in demyelination or edema. Both patients returned to their normal baseline within 2 to 3 weeks. These cases suggest that CMTX patients are at risk for developing an acute, transient, neurological syndrome when they travel to places at high altitudes and return to sea level. Cx32 mutations may cause central nervous system dysfunction by reducing the number of functioning gap junctions between oligodendrocytes and astrocytes, making both cells more susceptible to abnormalities of intercellular exchange of ions and small molecules in situations of metabolic stress.

A Concentration-Independent Method to Measure Exchange Rates in PARACEST Agents

The efficiency of chemical exchange dependent saturation transfer (CEST) agents is largely determined by their water or proton exchange kinetics, yet methods to measure such exchange rates are variable and many are not applicable to in vivo measurements. In this work, the water exchange kinetics of two prototype paramagnetic agents (PARACEST) are compared by using data from classic NMR line‐width measurements, by fitting CEST spectra to the Bloch equations modified for chemical exchange, and by a method where CEST intensity is measured as a function of applied amplitude of radiofrequency field. A relationship is derived that provides the water exchange rate from the X‐intercept of a plot of steady‐state CEST intensity divided by reduction in signal caused by CEST irradiation versus 1/ω12, referred to here as an omega plot. Furthermore, it is shown that this relationship is independent of agent concentration. Exchange rates derived from omega plots using either high‐resolution CEST NMR data or CEST data obtained by imaging agree favorably with exchange rates measured by the more commonly used Bloch fitting and line‐width methods. Thus, this new method potentially allows access to a direct measure of exchange rates in vivo, where the agent concentration is typically unknown. Magn Reson Med 63:625–632, 2010.

Memantine and HIV-associated cognitive impairment: A neuropsychological and proton magnetic resonance spectroscopy study

Objective:To assess the safety and efficacy of memantine, an uncompetitive antagonist of the N-methyl-D-aspartate receptor as treatment of HIV-associated cognitive impairment. Methods:This was a Phase II randomized, double-blind, placebo-controlled, multicenter trial within the Adult AIDS Clinical Trials Group. One-hundred and forty HIV-infected adults with mild to severe AIDS dementia complex receiving stable antiretroviral therapy were enrolled. Memantine was initiated at 10 mg daily escalated to 40 mg daily, or up to the maximum tolerated dose and continued for 16 weeks (primary evaluation visit) followed by a 4-week washout period and re-evaluation at week 20. Changes in cognitive performance were measured as percent change from baseline to week 16 in the average of eight neuropsychological test scores (NPZ-8). Brain metabolism was measured by magnetic resonance spectroscopy in a subgroup of subjects. Results:Sixty-one percent of subjects in the memantine group and 85% in the placebo group reached the 40 mg dose while the reported adverse experiences between the two groups were similar. There were no significant improvements in neuropsychological performance over 16 weeks; however, memantine was associated with a significant increase at week 16 in the N-acetyl aspartate to creatine ratio, in the frontal white matter (P = 0.040) and parietal cortex (P = 0.023). Conclusions:Memantine was safe and tolerated by HIV-infected subjects with cognitive impairment. Although we observed no significant differences in cognitive performance, the magnetic resonance spectroscopy data suggest that memantine may ameliorate neuronal metabolism, an important step to stabilizing or preventing neuronal injury. These results underscore the need for longer studies to assess the full potential of neuroprotective agents.