phosphocreatine and Amyotrophic-Lateral-Sclerosis

Upper motor neuron (UMN) dysfunction in Amyotrophic Lateral Sclerosis (ALS) is not easy to identify clinically: Diffusion Tensor Imaging (DTI) and single-voxel Magnetic Resonance Spectroscopy (H-MRS) can identify markers of UMN involvement. The aim of this study was to correlate brain DTI and MRS data with clinical parameters in ALS patients (PALS). We studied 32 PALS using Magnetic Resonance Imaging. The subjects were subdivided into definite/probable (D/P) and possible/suspected (P/S). DTI indices included Fractional Anisotropy (FA) and averaged Apparent Diffusion Coefficient (avADC). Anatomical areas were sampled by positioning regions of interest along corticospinal tracts, from the precentral cortex to the bulb. H-MRS voxels were localized bilaterally in precentral regions. D/P-PALS showed significantly lower FA values than healthy controls in almost all regions, whereas P/S-PALS FA values were significantly lower only in the left precentral gray matter (GM), right precentral white matter (WM), cerebral peduncles (CP), left hemipons, and left bulbar pyramid (BP). Significantly higher avADC values were observed in the D/P-PALS right precentral GM, precentral WM, right semioval center-posterior limb of the internal capsule (SC-PLIC), and left CP; and in the precentral WM, right SC-PLIC, left CP, and right hemipons of P/S-PALS. With increasing disability, only D/P-PALS showed significantly reduced FA values in the left precentral WM and hemipons, and increased avADC values in the precentral WM. Significantly lower N-acetylaspartate (NAA)/creatine-phosphocreatine complex (Cr) and higher choline (Cho)/Cr and myoinositol (mI)/Cr ratios were found in D/P-PALS, while only higher Cho/Cr and mI/Cr ratios were found in P/S-PALS. Our data highlight the usefulness of DTI and H-MRS in assessing UMN involvement. Given FA sensitivity and specificity, despite the small number of PALS, our findings support its use as a diagnostic marker in D/P-PALS.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Aspartic Acid; Biomarkers; Choline; Creatinine; Diffusion Magnetic Resonance Imaging; Disability Evaluation; Disease Progression; Female; Humans; Male; Middle Aged; Phosphocreatine; Pyramidal Tracts; Reproducibility of Results; Sensitivity and Specificity

Mitochondrial dysfunction is postulated to be central to amyotrophic lateral sclerosis (ALS) pathophysiology. Evidence comes primarily from disease models and conclusive data to support bioenergetic dysfunction in vivo in patients is currently lacking. This study is the first to assess mitochondrial dysfunction in brain and muscle in individuals living with ALS using 31P-magnetic resonance spectroscopy (MRS), the modality of choice to assess energy metabolism in vivo. We recruited 20 patients and 10 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. 31P-MRS was acquired from cerebral motor regions and from tibialis anterior during rest and exercise. Bioenergetic parameter estimates were derived including: ATP, phosphocreatine, inorganic phosphate, adenosine diphosphate, Gibbs free energy of ATP hydrolysis (ΔGATP), phosphomonoesters, phosphodiesters, pH, free magnesium concentration, and muscle dynamic recovery constants. Linear regression was used to test for associations between brain data and clinical parameters (revised amyotrophic functional rating scale, slow vital capacity, and upper motor neuron score) and between muscle data and clinico-neurophysiological measures (motor unit number and size indices, force of contraction, and speed of walking). Evidence for primary dysfunction of mitochondrial oxidative phosphorylation was detected in the brainstem where ΔGATP and phosphocreatine were reduced. Alterations were also detected in skeletal muscle in patients where resting inorganic phosphate, pH, and phosphomonoesters were increased, whereas resting ΔGATP, magnesium, and dynamic phosphocreatine to inorganic phosphate recovery were decreased. Phosphocreatine in brainstem correlated with respiratory dysfunction and disability; in muscle, energy metabolites correlated with motor unit number index, muscle power, and speed of walking. This study provides in vivo evidence for bioenergetic dysfunction in ALS in brain and skeletal muscle, which appears clinically and electrophysiologically relevant. 31P-MRS represents a promising technique to assess the pathophysiology of mitochondrial function in vivo in ALS and a potential tool for future clinical trials targeting bioenergetic dysfunction.

Topics: Adenosine Triphosphate; Aged; Amyotrophic Lateral Sclerosis; Brain Chemistry; Cross-Sectional Studies; Energy Metabolism; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Motor Neurons; Muscle Contraction; Muscle Strength; Muscle, Skeletal; Oxidative Phosphorylation; Phosphocreatine; Walking

Mitochondrial dysfunction in the motor neuron has been suspected in amyotrophic lateral sclerosis (ALS). If mitochondrial abnormalities are also found in skeletal muscle, assessing skeletal muscle could serve as an important biomarker of disease progression.. Using 31P magnetic resonance (31P-MRS) and near infrared (NIRS) spectroscopy, we compared the absolute values and reproducibility of skeletal muscle oxidative capacity in people with ALS (n = 6) and healthy adults (young, n = 7 and age-matched, n = 4).. ALS patients had slower time constants for phosphocreatine (PCr) and muscle oxygen consumption (mVO2 ) compared with young, but not age-matched controls. The coefficient of variation for the time constant was 10% (SD = 2.8%) and 17% (SD = 6.2%) for PCr and mVO2 , respectively.. People with ALS had, on average, a small but not statistically significant, impairment in skeletal muscle mitochondrial function measured by both 31P-MRS and NIRS. Both methods demonstrated good reproducibility.

Topics: Adolescent; Adult; Age Factors; Aged; Amyotrophic Lateral Sclerosis; Cohort Studies; Disability Evaluation; Female; Hemoglobins; Humans; Leg; Male; Middle Aged; Muscle, Skeletal; Myoglobin; Oxidative Stress; Oxygen Consumption; Phosphocreatine; Phosphorus; Young Adult

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons, leading to limb paralysis and respiratory failure.. C1-C3 cord (1) H-magnetic resonance spectroscopy ((1) H-MRS) was performed in 19 patients with ALS and 20 controls. N-acetylaspartate (NAA), choline-containing compounds, creatine plus phosphocreatine (Cr), and myo-Inositol (m-Ins) were measured. ALS functional rating scale-revised (ALSFRS) and forced vital capacity (FVC) were assessed. The rates of decline were calculated at 6 months before and after (1) H-MRS.. NAA/Cr and NAA/m-Ins were decreased significantly, and m-Ins/Cr was increased significantly in ALS patients compared with controls. NAA/Cr and NAA/m-Ins were correlated with ALSFRS and FVC and inversely linked to the decline rates. NAA/Cr, NAA/m-Ins, and m-Ins/Cr were altered markedly in 9 patients with denervation and neurogenic changes in both C2 paraspinal and upper limb muscles.. These metabolite ratios were associated with disease progression and ongoing denervation in neck and hand muscles. C1-C3 cord (1) H-MRS might reflect anterior horn cell damage causing neck/arm weakness and respiratory dysfunction in ALS patients.

Topics: Amyotrophic Lateral Sclerosis; Cervical Vertebrae; Choline; Creatine; Disease Progression; Electromyography; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Motor Cortex; Motor Neurons; Phosphocreatine; Severity of Illness Index; Spinal Cord

To prospectively determine whether diffusion-tensor magnetic resonance (MR) imaging in conjunction with two-dimensional chemical shift imaging can assist in identifying upper motor neuron involvement and whether disease severity and duration can be predicted based on imaging parameters in patients with amyotrophic lateral sclerosis (ALS).. Institutional review board approval and informed consent were obtained for this HIPAA-compliant study. Fifteen patients with ALS (12 men, three women; mean age, 57.3 years) with clinical evidence of upper motor neuron involvement and 10 healthy control subjects (five men and five women; mean age, 49.4 years) were studied. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were measured from the corticospinal tracts at the level of the internal capsule. Average N-acetylaspartate (NAA)/creatine-phosphocreatine (Cr) and NAA/choline-containing compounds (Cho) ratios were calculated from the precentral gyrus. Student t test, multiple linear regression analysis, and Spearman correlation coefficients were employed to quantify relationships between imaging and clinical parameters.. Patients with ALS exhibited significantly reduced FA values and NAA/Cr and NAA/Cho ratios compared with values in control subjects (P<.05) for both affected and nonaffected sides of the brain. ADC was elevated significantly in the affected side (P<.05) and was an independent predictor of disease duration after adjusting for age; however, FA values and NAA/Cr ratios for the affected side were even stronger predictors of disease duration. Moderate but statistically significant correlation was found between the FA values for the affected side and the ALS Functional Rating Scale Revised (ALSFRS-R) score (r=0.51, P<.05). The NAA/Cr ratio also correlated with both the ALSFRS-R and upper motor neuron scores (r=0.50 and 0.54, respectively; P<.05).. Diffusion-tensor and two-dimensional chemical shift MR imaging spectroscopy can be used to identify upper motor neuron involvement and predict disease duration in patients with ALS.

Topics: Adult; Age Factors; Aged; Amyotrophic Lateral Sclerosis; Aspartic Acid; Choline; Creatine; Diffusion Magnetic Resonance Imaging; Female; Forecasting; Frontal Lobe; Humans; Image Processing, Computer-Assisted; Internal Capsule; Magnetic Resonance Spectroscopy; Male; Middle Aged; Motor Neuron Disease; Phosphocreatine; Prospective Studies; Pyramidal Tracts

To evaluate proton magnetic resonance spectroscopy for detection and monitoring of upper motoneuron degeneration in patients with amyotrophic lateral sclerosis.. Seventy patients with amyotrophic lateral sclerosis according to the El Escorial criteria were compared with 48 healthy control subjects. Single-volume proton magnetic resonance spectroscopy (echo time, 272 milliseconds; repetition time, 2000 milliseconds) was performed in both motor cortices for detection of N-acetylaspartate (NAA), phosphocreatine + creatine ([P]Cr), and choline-containing compounds (Cho) to calculate the metabolite ratios NAA/Cho, NAA/(P)Cr, and Cho/(P)Cr. In addition, absolute metabolite concentrations of NAA, (P)Cr, and Cho were obtained in 30 patients and 15 controls with the unsuppressed water signal used as an internal reference.. Absolute concentrations of NAA (P<.001) and (P)Cr (P<.05) were reduced in motor cortices of patients, whereas Cho concentrations remained unchanged. The NAA/Cho and NAA/(P)Cr ratios were reduced in all El Escorial subgroups (P<.001). The Cho/(P)Cr ratio was elevated in patients with definite amyotrophic lateral sclerosis (P<.05). Metabolite ratio changes corresponded to the lateralization of clinical symptoms and were weakly correlated with disease duration and disease severity. In follow-up observations of 16 patients during a mean (+/-SD) of 12.1 +/- 8.7 months, NAA/Cho dropped by 9.1% (P<.01), and Cho/(P)Cr increased by 7.0% (P<.01). Changes of metabolite ratios were significantly correlated with progression of disease severity.. Measurement of NAA concentrations and NAA/Cho ratios appear to be most suitable for detection of motor cortex degeneration by single-volume proton magnetic resonance spectroscopy. Reduced NAA/Cho ratios correspond to aspects of the clinical presentation and reflect disease progression in follow-up measurements.

Topics: Adult; Amyotrophic Lateral Sclerosis; Aspartic Acid; Choline; Creatine; Disease Progression; Female; Follow-Up Studies; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Motor Cortex; Phosphocreatine; Reference Values; Severity of Illness Index

To evaluate neuronal dysfunction in the motor region subcortical white matter in ALS using volumetric localized proton magnetic resonance spectroscopy (1H-MRS).. Sixteen patients with E1 Escorial definite, probable, or possible ALS and eight healthy age-matched control subjects were studied. The ALS patients were divided into those with limb onset (n = 8) and those with bulbar onset (n = 8). Measurements of the metabolic ratios N-acetylaspartate (NAA)/creatine and phosphocreatine (Cr+PCr), NAA/choline (Cho), and Cho/(Cr+PCr) were correlated with clinical assessments.. We found no differences in the metabolic peak area ratios in the motor region when comparing the total ALS group and the control subjects. However, correlations were found between the NAA/(Cr+PCr) ratio and the E1 Escorial category (p = 0.03), the ALS severity scale (p = 0.01), and the Medical Research Council score (p = 0.06). No correlations were found between the NAA/(Cr+PCr) ratio and the Ashworth Spasticity Scale, reflex score, or disease duration (p > 0.16). Bulbar-onset patients had a lower NAA/(Cr+PCr) ratio in the motor region compared with limb-onset patients (p = 0.03).. In vivo 1H-MRS of the subcortical white matter in the motor region is unlikely to be sensitive enough to detect early disease changes in ALS because there is considerable overlap between the metabolic peak area ratios from patients with ALS and normal control subjects. However, changes in the NAA/(Cr+PCr) metabolic peak area ratios correlate with clinical measures of disease severity, and this measure may be useful in monitoring disease progression.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Aspartic Acid; Choline; Creatinine; Humans; Magnetic Resonance Imaging; Middle Aged; Motor Cortex; Occipital Lobe; Parietal Lobe; Phosphocreatine; Protons

Proton magnetic resonance spectroscopy (1H-MRS) was used to measure the in vivo signal of N-acetylaspartate (NAA), a putative neuronal marker, in the brain of the mutant wobbler mouse, a model of motor neuron disease. The ratio of NAA to creatine-phosphocreatine, an internal standard, was significantly lower in five affected wobbler mice (0.79+/-0.05; mean+/-s.d.) than in five unaffected littermates (0.98+/-0.10, p = 0.006). Ubiquitin and phosphorylated heavy neurofilament immunoreactivities were increased in cortical neurons of affected animals. This is the first demonstration of cerebral neuronal pathology in the wobbler mouse, supporting its use as a model of amyotrophic lateral sclerosis. In vivo IH-MRS and correlative postmortem study of wobbler mouse brain will allow temporal monitoring of neuronal degeneration and responsiveness to neuroprotective pharmacotherapies.

Topics: Amyotrophic Lateral Sclerosis; Animals; Aspartic Acid; Axons; Caudate Nucleus; Creatine; Disease Models, Animal; Hippocampus; Immunohistochemistry; Magnetic Resonance Imaging; Mice; Mice, Neurologic Mutants; Motor Neuron Disease; Neocortex; Neurofilament Proteins; Neurons; Phosphocreatine; Putamen; Thalamus; Ubiquitins