Biomedical subjects

Patrick J Cozzone

Publications and source records attributed to Patrick J Cozzone.

At least 19 recordsLinked to original sources

PubMed2006

A branched-chain organic acid linked to multiple sclerosis: first identification by NMR spectroscopy of CSF.

(1)H NMR spectroscopy of cerebrospinal fluid (CSF) is currently being used to study metabolic profiles characteristic of distinct multiple sclerosis (MS) manifestations. For select MS patient groups, we have previously detected significantly increased concentrations of several identified metabolites and one unidentified compound. We now present, for the first time, the identification of the latter molecule, beta-hydroxyisobutyrate (BHIB). A combination of dedicated 1D and 2D (1)H NMR experiments was employed for signal assignment. To our knowledge, BHIB has not previously been identified in (1)H NMR spectra of biofluids or biological tissues. Our assignment suggests new biochemical pathways involved in specific MS pathologies.

Acids↗

PubMed2006

Selective training-induced thigh muscles hypertrophy in professional road cyclists.

Muscular adaptations linked to a high volume and intensity of training have been scarcely reported. We aimed at documenting, using MRI, the cross-sectional area changes associated with a high volume and intensity of training in 11 thigh muscles of a population of professional road cyclists as compared with sport science students. We were also interested in determining, whether selective muscle hypertrophy in professional road cyclists, if any, was correlated to selective exercise-induced T (2) changes during a pedaling exercise on a cycloergometer. Cross-sectional area of 11 thigh muscles was quantified in sixteen subjects (i.e. eight professional road cyclists and eight sport science students) using MRI. In addition, transverse relaxation times (T (2)) were measured before and just after a maximal standardized constant-load exercise in order to investigate exercise-related T (2) changes in these muscles. Professional road cyclists had a significantly higher relative amount of muscle (including the whole set of thigh muscles, 90.5+/-3.3%) as compared to controls (81.6+/-7.3%). Regarding relative values expressed with respect to the total thigh muscles CSA, Vastus lateralis and Biceps femoris CSA were significantly larger in cyclists whereas CSA of the Vastus intermedius was smaller. However, this selective hypertrophy was not correlated to the exercise-induced T (2)-increase. We have reported, for the first time, a selective hypertrophy of Vastus lateralis and Biceps femoris in professional road cyclists confirming their involvement in pedaling task and suggesting a possible cause-effect relationship between muscle activation and hypertrophy, associated with a specific pedaling skill.

Adult↗

PubMed2006

Functional magnetic resonance imaging and cognition at the very early stage of MS.

Dysfunction of high controlled information processing is present in patients with multiple sclerosis (MS) right at the beginning of the disease. One hypothesis is that disruption of communication inside large-scale cortical networks, occurring as a consequence of white matter damage, may constitute the anatomical substrate of cognitive impairment at the very early stage of MS. Disturbance of interregional synchronization might be the main pathogenic factor in controlled information processing deficiency in early MS. Preliminary functional MRI studies (fMRI) have provided important clues to corroborate the connectivity hypotheses. First, brain connectivity assessed by fMRI has brought new data about the influence of diffuse white matter damage on connectivity efficiency inside large-scale networks. These studies have suggested that connectivity disturbances occur inside the working memory network in patients at the very early stage of MS and appear related to the extent of structural white matter damage. Also, fMRI studies have suggested that patients may partially compensate for connectivity impairment by a greater cognitive control. Such a compensatory mechanism could limit the determinant functional impact of diffuse white matter damage on high controlled information processing.

Age of Onset↗

PubMed2006

Structural and functional surrogates of cognitive impairment at the very early stage of multiple sclerosis.

Following our previous reports based on parametric MRI methods (T(2)-weighted MRI, statistical mapping analysis of magnetization transfer ratio images and functional MRI) applied to a population of 18 patients with clinically isolated syndrome suggestive of multiple sclerosis, we have reviewed the possible structural and functional surrogates of MS that could explain the subtle cognitive impairment related to attention and working memory deficits evaluated with paced auditory serial addition test (PASAT). We propose that the brain substrates underlying cognitive impairment observed at the very early stage of MS are multifactorial. Several components could influence PASAT performances in patients: i) the extent of diffuse white matter damage, ii) the location of visible and non visible lesions, iii) the connectivity efficiency between distant brain functional areas involved in working memory processes and iv) the cortical reorganization. Nevertheless, individually, each of these parameters may have few influences on PASAT performance in patients. Using a multiregression model built with independent MR parameters, a very good evaluation of PASAT scores has been obtained in this limited number of patients explaining 90% of the variance. In conclusion, the different aspects of tissue and functional pathological brain underpinnings must be accounted to monitor accurately new therapeutic strategies for the treatment of early cognitive deficits related to MS.

Adult↗

PubMed2006

Block of neural Kv1.1 potassium channels for neuroinflammatory disease therapy.

OBJECTIVE: We asked whether blockade of voltage-gated K+ channel Kv1.1, whose altered axonal localization during myelin insult and remyelination may disturb nerve conduction, treats experimental autoimmune encephalomyelitis (EAE). METHODS: Electrophysiological, cell proliferation, cytokine secretion, immunohistochemical, clinical, brain magnetic resonance imaging, and spectroscopy studies assessed the effects of a selective blocker of Kv1.1, BgK-F6A, on neurons and immune cells in vitro and on EAE-induced neurological deficits and brain lesions in Lewis rats. RESULTS: BgK-F6A increased the frequency of miniature excitatory postsynaptic currents in neurons and did not affect T-cell activation. EAE was characterized by ventriculomegaly, decreased apparent diffusion coefficient, and decreased (phosphocreatine + beta-adenosine triphosphate)/inorganic phosphate ratio. Reduced apparent diffusion coefficient and impaired energy metabolism indicate astrocytic edema. Intracerebroventricularly BgK-F6A-treated rats showed attenuated clinical EAE with unexpectedly reduced ventriculomegaly and preserved apparent diffusion coefficient values and (phosphocreatine + beta-adenosine triphosphate)/inorganic phosphate ratio. Thus, under BgK-F6A treatment, brain damage was dramatically reduced and energy metabolism maintained. INTERPRETATION: Kv1.1 blockade may target neurons and astrocytes, and modulate neuronal activity and neural cell volume, which may partly account for the attenuation of the neurological deficits. We propose that Kv1.1 blockade has a broad therapeutic potential in neuroinflammatory diseases (multiple sclerosis, stroke, and trauma).

Animals↗

PubMed2006

Noninvasive diagnostic assessment of brain tumors using combined in vivo MR imaging and spectroscopy.

To determine the potential value of multimodal MRI for the presurgical management of patients with brain tumors, we performed combined magnetic resonance imaging (MRI) and proton MR spectroscopy (MRS) in 164 patients who presented with tumors of various histological subtypes confirmed by surgical biopsy. Univariate statistical analysis of metabolic ratios carried out on the first 121 patients demonstrated significant differences in between-group comparisons, but failed to provide sufficiently robust classification of individual cases. However, a multivariate statistical approach correctly classified the tumors using linear discriminant analysis (LDA) of combined MRI and MRS data. After initial separation of contrast-enhancing and non-contrast-enhancing lesions, 91% of the former and 87% of the latter were correctly classified. The results were stable when this diagnostic strategy was tested on the additional 43 patients included for validation after the initial statistical analysis, with over 90% of correct classification. Combined MRI and MRS had superior diagnostic value compared to MRS alone, especially in the contrast-enhancing group. This study shows the clinical value of a multivariate statistical analysis based on multimodal MRI and MRS for the noninvasive evaluation of intracranial tumors.

Artificial Intelligence↗

PubMed2006

Assessment of normal fetal brain maturation in utero by proton magnetic resonance spectroscopy.

Cerebral maturation in the normal human fetal brain was investigated by in utero localized proton MR spectroscopy ((1)H MRS). Fifty-eight subjects at 22-39 weeks of gestational age (GA) were explored. A combination of anterior body phased-array coils (four elements) and posterior spinal coils (two to three elements) was used. Four sequences were performed (point-resolved spectroscopy (PRESS) sequence with short and long TEs (30 and 135 ms), with and without water saturation). A significant reduction in myo-inositol (myo-Ins) and choline (Cho) levels, and an increase in N-acetylaspartate (NAA) and creatine (Cr) content were observed with progressing age. A new finding is the detection of NAA as early as 22 weeks of GA. This result is probably related to the fact that oligodendrocytes (whether mature or not) express NAA, as demonstrated by in vitro studies. Cho and myo-inositol were the predominant resonances from 22 to 30 weeks and decreased gradually, probably reflecting the variations in substrate needed for membrane synthesis and myelination. The normal MRS data for the second trimester of gestation (when fetal MRI is usually performed) reported here can help determine whether brain metabolism is altered or not, especially when subtle anatomic changes are observed on conventional images.

Aging↗

PubMed2006

In vivo characterization of brain morphometric and metabolic endophenotypes in three inbred strains of mice using magnetic resonance techniques.

C57BL6J, FVB/N and 129/SvJ mice are commonly used as background strains to engineer genetic models of brain pathologies and psychiatric disorders. Magnetic resonance imaging (MRI) and spectroscopy provide alternative approaches to neuroanatomy, histology and neurohistochemistry for investigating the correlation between genes and brain neuroanatomy and neurometabolism in vivo. We used these techniques to non-invasively characterize the cerebral morphologic and metabolic endophenotypes of inbred mouse strains commonly used in neurological and behavioral research. We observed a great variability in the volume of ventricles and of structures involved in cognitive function (cerebellum and hippocampus) among these strains. In addition, distinct metabolic profiles were evidenced with variable levels of N-acetylaspartate, a neuronal marker, and of choline, a compound found in membranes and myelin. Besides, significant differences in high-energy phosphates and phospholipids were detected. Our findings demonstrate the great morphologic and metabolic heterogeneity among C57BL/ 6J, FVB/N and 129/SvJ mice. They emphasize the importance of selecting the appropriate genetic background for over-expressing or silencing a gene and provide some directions for modeling symptoms that characterize psychiatric disorders such as autism, schizophrenia and depression.

Animals↗

PubMed2006

Recovery kinetics throughout successive bouts of various exercises in elite cyclists.

PURPOSE: In the present study we investigated whether a high volume of cycling training would influence the metabolic changes associated with a succession of three exhaustive cycling exercises. METHODS: Seven professional road cyclists (VO2max: 74.3 +/- 3.7 mL.min.kg; maximal power tolerated: 475 +/- 18 W; training: 22 +/- 3 h.wk) and seven sport sciences students (VO2max: 54.2 +/- 5.3 mL.min.kg; maximal power tolerated: 341 +/- 26 W; training: 6 +/- 2 h.wk) performed three different exhaustive cycling exercise bouts (progressive, constant load, and sprint) on an electrically braked cycloergometer positioned near the magnetic resonance scanner. Less than 45 s after the completion of each exercise bout, recovery kinetics of high-energy phosphorylated compounds and pH were measured using P-MR spectroscopy. RESULTS: Resting values for phosphomonoesters (PME) and phosphodiesters (PDE) were significantly elevated in the cyclist group (PME/ATP: 0.82 +/- 0.11 vs 0.58 +/- 0.19; PDE/ATP: 0.27 +/- 0.03 vs 0.21 +/- 0.05). Phosphocreatine (PCr) consumption and inorganic phosphate (Pi) accumulation measured at end of exercise bouts 1 (PCr: 6.5 +/- 3.2 vs 10.4 +/- 1.6 mM; Pi: 1.6 +/- 0.7 vs 6.8 +/- 3.4 mM) and 3 (PCr: 5.6 +/- 2.4 vs 9.3 +/- 3.9 mM; Pi: 1.5 +/- 0.5 vs 7.7 +/- 3.3 mM) were reduced in cyclists compared with controls. During the recovery period after each exercise bout, the pH-recovery rate was larger in professional road cyclists, whereas the PCr-recovery kinetics were significantly faster for cyclists only for bout 3. DISCUSSION: Whereas the PDE and PME elevation at rest in professional cyclists may indicate fiber-type changes and an imbalance between glycogenolytic and glycolytic activity, the lower PCr consumption during exercise and the faster pH-recovery kinetic clearly suggest an improved mitochondrial function.

Adult↗

PubMed2005

Brain magnetic resonance study of Mecp2 deletion effects on anatomy and metabolism.

Rett syndrome, a neurodevelopmental X-linked disorder, represents the most important genetic cause of severe mental retardation in the female population and results from a mutation in the gene encoding methyl-CpG-binding protein 2 (MECP2). We report here the first characterization of Mecp2-null mice, by in vivo magnetic resonance imaging and spectroscopy, delineating the cerebral phenotype associated with the lack of Mecp2. We performed a morphometric study that revealed a size reduction of the whole brain and of structures involved in cognitive and motor functions (cerebellum and motor cortex). Significant metabolic anomalies, including reduced N-acetylaspartate, myo-inositol, and glutamine plus glutamate, and increased choline levels were evidenced. These findings indicate that not only neuronal but also glial metabolism is affected in Mecp2-null mice. Furthermore, we uncovered an important reduction of brain ATP level, a hitherto undetected anomaly of energy metabolism that may reflect and contribute to cerebral injury and dysfunction.

Adenosine Triphosphate↗

PubMed2005

Non-invasive diagnostic of cardiac allograft vasculopathy by 31P magnetic resonance chemical shift imaging.

BACKGROUND: Coronary angiography is still the gold standard for the diagnosis of cardiac allograft vasculopathy (CAV) for which alternative non-invasive diagnostic approaches are currently investigated. In this study, we assessed whether 31P magnetic resonance chemical shift imaging can diagnose CAV by studying variations in cardiac high-energy phosphates in a population of adult heart transplant recipients. METHODS AND RESULTS: CAV was defined by coronary angiography as the presence of diffuse coronary irregularities with significant concentric narrowing on epicardial or distal coronary arteries. Eight patients with CAV (group A), and 18 patients without CAV (group B) were included in this study and compared to nine healthy volunteers (group C). Patients and volunteers underwent 31P three-dimensional chemical shift imaging to determine the ratio of phosphocreatine (PCr) and adenosine tri-phosphate (ATP). PCr/ATP was significantly lower in group A (1.51+/-0.50) than in groups B and C (1.98+/-0.53 (p=0.003) and 2.14+/-0.31 (p=0.001)), respectively. Time from transplant, number of episodes of acute rejection, and left ventricular ejection fraction (LVEF) were not significantly different between patient groups. A PCr/ATP value of 1.59 was the optimal cut-off value to predict CAV (specificity and sensitivity of 100% and 72%, respectively). CONCLUSION: Clinically, in vivo 31P chemical shift imaging is a promising, non-invasive method to detect the potential modifications of high-energy phosphates related to CAV and to better screen indications for coronary angiograms. This may be relevant for coronary angiography follow-up and adjustments of immunotherapy regimen.

Adenosine Triphosphate↗

PubMed2005

Imaging experimental cerebral malaria in vivo: significant role of ischemic brain edema.

The first in vivo magnetic resonance study of experimental cerebral malaria is presented. Cerebral involvement is a lethal complication of malaria. To explore the brain of susceptible mice infected with Plasmodium berghei ANKA, multimodal magnetic resonance techniques were applied (imaging, diffusion, perfusion, angiography, spectroscopy). They reveal vascular damage including blood-brain barrier disruption and hemorrhages attributable to inflammatory processes. We provide the first in vivo demonstration for blood-brain barrier breakdown in cerebral malaria. Major edema formation as well as reduced brain perfusion was detected and is accompanied by an ischemic metabolic profile with reduction of high-energy phosphates and elevated brain lactate. In addition, angiography supplies compelling evidence for major hemodynamics dysfunction. Actually, edema further worsens ischemia by compressing cerebral arteries, which subsequently leads to a collapse of the blood flow that ultimately represents the cause of death. These findings demonstrate the coexistence of inflammatory and ischemic lesions and prove the preponderant role of edema in the fatal outcome of experimental cerebral malaria. They improve our understanding of the pathogenesis of cerebral malaria and may provide the necessary noninvasive surrogate markers for quantitative monitoring of treatment.

Animals↗

PubMed2005

Magnetic resonance study of the influence of tissue damage and cortical reorganization on PASAT performance at the earliest stage of multiple sclerosis.

We sought to determine the influence of tissue damage and the potential impact of cortical reorganization on the performance to the Paced Auditory Serial Addition Test (PASAT) in patients at the earliest stage of multiple sclerosis (MS). Magnetization transfer ratio (MTR) imaging and functional magnetic resonance imaging (fMRI) experiments using PASAT as paradigm were carried out in 18 patients with clinically isolated syndrome suggestive of MS (CISSMS) compared to 18 controls. MTR histogram analyses showed structural abnormalities in patients involving the normal-appearing white matter (NAWM) but also the gray matter (GM). Mean PASAT scores were significantly lower in the group of patients taken as a whole, and were correlated with the mean NAWM MTR value. No correlation was observed between PASAT scores and GM MTR. However, in the subgroup of patients with normal PASAT performance (n = 9), fMRI showed larger activations in bilateral Brodmann area 45 (BA45) and right BA44 compared to that in controls (n = 18). In these areas with potentially compensatory reorganization, the whole group of patients (n = 18) showed significantly greater activation than controls (n = 18). Activation in the right BA45 was inversely correlated with the mean NAWM MTR and the peak position of GM MTR histograms of patients. This study indicates that even at the earliest stage of MS, cortical reorganization is present inside the executive system of working memory and could tend to limit the determinant functional impact of NAWM injury on the execution of the PASAT.

Adult↗

PubMed2005

In vivo assessment of myocardial blood flow in rat heart using magnetic resonance imaging: effect of anesthesia.

PURPOSE: To assess the influence of isoflurane and pentobarbital anesthesia and the carrier gases on myocardial blood flow (MBF) in the rat heart in vivo. MATERIALS AND METHODS: MBF was quantified in vivo using arterial spin-labeling (ASL) magnetic resonance imaging (MRI). Left ventricular (LV) function was estimated during the same experiment using cine-MRI. Thirty-four male Wistar-Kyoto rats were divided in four groups, one anesthetized with isoflurane in oxygen:nitrous oxide mix (ISO), the three others with intraperitoneal pentobarbital, and breathing either room air (PB), oxygen:nitrous oxide (PB + N(2)O), or oxygen:nitrogen (PB + N(2)). RESULTS: MBF was significantly higher in the ISO and PB + N(2)O groups vs. PB and in ISO vs. PB + N(2), with the following respective MBF values: ISO, 5.9 +/- 1.1; PB, 4.0 +/- 0.8; PB + N(2)O, 5.1 +/- 1.4; and PB + N(2), 4.6 +/- 0.8 mL/g/minute, mean +/- SD. Ejection fractions were reduced by 10% in PB and PB + N(2)O rats vs. ISO rats. Cardiac output (CO) and index (CI) were 25 to 30% lower in all rats anesthetized with pentobarbital than with isoflurane. CONCLUSION: Isoflurane and nitrous oxide induce a higher MBF than pentobarbital. Isoflurane also induces a higher ejection fraction in healthy rats.

Anesthesia, Inhalation↗

PubMed2005

Myocardial blood flow mapping in mice using high-resolution spin labeling magnetic resonance imaging: influence of ketamine/xylazine and isoflurane anesthesia.

Genetically modified mouse models of many human diseases reflecting cardiovascular alterations are currently available. To date, little information on absolute myocardial perfusion in mice is found in the literature. High-resolution quantitative myocardial blood flow maps (in-plane resolution 156 x 312 mum(2), slice thickness 1.5 mm) have been obtained noninvasively within 25 min at 4.7 T in 30 freely breathing C57/Bl6J mice using electrocardiogram- and respiration-gated spin labeling magnetic resonance imaging (MRI). Regional myocardial blood flow measurements were carried out, and the effects of isoflurane at two different concentrations and ketamine/xylazine anesthesia were assessed. The mean blood flow value in the left ventricular myocardium was 6.0 +/- 1.9 mL g(-1) min(-1) under ketamine/xylazine and 6.9 +/- 1.7 mL g(-1) min(-1) (group average +/- SD) under isoflurane (1.25%). Under the influence of higher isoflurane concentration (2.00%), myocardial blood flow increased dramatically to 16.9 +/- 1.8 mL g(-1)min(-1) with no significant change in heart rate. This work illustrates the feasibility of noninvasive quantitative myocardial perfusion mapping in mice using MRI. The study of the influence of anesthesia shows that myocardial blood flow is highly sensitive to isoflurane concentration. The method employed offers a noninvasive approach to longitudinal studies of murine models of cardiac disease.

Adrenergic alpha-Agonists↗

PubMed2005

New experimental setup for studying strictly noninvasively skeletal muscle function in rat using 1H-magnetic resonance (MR) imaging and 31P-MR spectroscopy.

Traditional setups for in situ MR investigation of skeletal muscle function in animals use invasive systems for muscle stimulation and force measurement. These systems require surgical preparation and therefore exclude repetitive investigations on the same animal. This article describes a new experimental setup allowing strictly noninvasive MR investigations of muscle function in contracting rat gastrocnemius muscle using 1H-MR imaging and 31P-MR spectroscopy. The novelty of this setup is the integration of two noninvasive systems allowing muscle contraction by transcutaneous stimulation and force measurement with a dedicated ergometer. Muscle function was investigated in 20 rats (275-300 g) through a fatiguing stimulation protocol, either with this noninvasive setup (n = 10) or with a traditional MR setup (n = 10). T2-weighted images demonstrated that transcutaneous stimulation activated mainly the gastrocnemius muscle. Moreover, the changes in force development and in energy metabolism obtained with the noninvasive setup were qualitatively and quantitatively similar to those obtained with the traditional setup. This noninvasive setup is thus suitable for investigating skeletal muscle function in situ. It offers the possibility to repeat investigations in the same animal, avoiding individual variability and enabling longitudinal follow-up studies. This opens up new perspectives in various research areas including pharmaceutical research.

Adenosine Triphosphate↗

PubMed2005

31P MRS of heart grafts provides metabolic markers of early dysfunction.

OBJECTIVE: Early graft failure (EGF) is a life-threatening event still accounting for a significant percentage of early deaths after heart transplantation. We tested whether selected metabolic markers, including high-energy phosphate concentrations measured ex vivo in pre-transplant heart grafts by (31)P magnetic resonance spectroscopy (MRS) are related with early post-transplant outcome. METHODS: During a 3-year period, 26 heart grafts harvested in the vicinity of the transplantation centre were studied. Evaluation of transplantability was done conventionally. (31)P MRS was performed ex vivo approximately 60min after aortic cross-clamp to quantify ATP, P(i) and PCr concentration ratios. A MRS-score was defined as a combination of intracellular pH (pHi) and the PCr/P(i) ratio. EGF was defined as the need to abnormally extend circulatory support or to use more than two inotropes before weaning the patient from CPB after transplantation. The grafts were attributed to three groups as follows: A1, transplanted with uneventful outcome (n=14); A2, transplanted with subsequent EGF (n=3) and B, not suitable for transplantation (n=9). RESULTS: Significant differences between groups existed for the following metabolic markers: PCr/ATP (P=0.013), PCr/P(i) (P=0.0004), pHi (P=0.0016) and MRS-score (P=0.0001). The sensitivity, specificity and positive likelihood ratio for EGF with a MRS-score<or=1.95 were, respectively, 100%, 86% and 7. CONCLUSIONS: In the setting of this study, post-transplant outcome was related to the pre-transplant MRS-score of grafts evaluated ex vivo. This result might help to more securely use grafts from marginal donors.

Adenosine Triphosphate↗

PubMed2005

Pathophysiology and clinical presentations of rhabdomyolysis.

Rhabdomyolysis has sparked new interest in recent years. The causes of rhabdomyolysis include drugs and other toxic agents, infections, physical exertion, crush injury, and muscle diseases (dystrophinopathies and metabolic myopathies). Prompt identification of the pathophysiological mechanism is the key to rapid control of the acute episode and to prevention of recurrences. In this update, we discuss the pathophysiological mechanisms and nosology of rhabdomyolysis, as well as diagnostic investigations, with special emphasis on noninvasive methods.

Humans↗