David Neil Manners

Abnormal Cardiac and Skeletal Muscle Energy Metabolism in Patients With Type 2 Diabetes

Background It is well known that patients with type 2 diabetes have increased risk of cardiovascular disease, but it is not known whether they have underlying abnormalities in cardiac or skeletal muscle high‐energy phosphate metabolism. Methods and Results We studied 21 patients with type 2 diabetes with no evidence of coronary artery disease or impaired cardiac function, as determined by echocardiography, and 15 age‐, sex‐, and body mass index‐matched control subjects. Cardiac high‐energy phosphate metabolites were measured at rest using 31P nuclear magnetic resonance spectroscopy (MRS). Skeletal muscle high‐energy phosphate metabolites, intracellular pH, and oxygenation were measured using 31P MRS and near infrared spectrophotometry, respectively, before, during, and after exercise. Although their cardiac morphology, mass, and function appeared to be normal, the patients with diabetes had significantly lower phosphocreatine (PCr)/ATP ratios, at 1.50±0.11, than the healthy volunteers, at 2.30±0.12. The cardiac PCr/ATP ratios correlated negatively with the fasting plasma free fatty acid concentrations. Although skeletal muscle energetics and pH were normal at rest, PCr loss and pH decrease were significantly faster during exercise in the patients with diabetes, who had lower exercise tolerance. After exercise, PCr recovery was slower in the patients with diabetes and correlated with tissue reoxygenation times. The exercise times correlated negatively with the deoxygenation rates and the hemoglobin (Hb)A1c levels and the reoxygenation times correlated positively with the HbA1c levels. Conclusions Type 2 diabetic patients with apparently normal cardiac function have impaired myocardial and skeletal muscle energy metabolism related to changes in circulating metabolic substrates. (Circulation. 2003;107:3040‐3046.)

Abnormal in vivo skeletal muscle energy metabolism in Huntington's disease and dentatorubropallidoluysian atrophy.

We studied in vivo muscle energy metabolism in patients with Huntingtons disease (HD) and dentatorubropallidoluysian atrophy (DRPLA) using 31P magnetic resonance spectroscopy (MRS). Twelve gene‐positive HP patients (4 presymptomatic patients) and 2 gene—positive DRPLA patients (1 presymptomatic patient) were studied. 31P‐MRS at rest showed a reduced phosphocreatine‐to‐inorganic phosphate ratio in the symptomatic HD patients and DRPLA patient. Muscle adenosine triphosphate/(phosphocreatine + inorganic phosphate) at rest was significantly reduced in both groups of symptomatic and presymptomatic HD subjects and was below the normal range in the 2 DRPLA subjects. During recovery from exercise, the maximum rate of mitochondrial adenosine triphosphate production was reduced by 44% in symptomatic HD patients and by 35% in presymptomatic HD carriers. The maximum rate of mitochondrial adenosine triphosphate production in muscle was also reduced by around 46% in the 2 DRPLA subjects. Our findings show that HD and DRPLA share a deficit of in vivo mitochondrial oxidative metabolism, supporting a role for mitochondrial dysfunction as a factor involved in the pathogenesis of these polyglutamine repeat–mediated neurodegenerative disorders. The identification of 31P‐MRS abnormalities may offer a surrogate biochemical marker by which to study disease progression and the effects of treatment in HD and DRPLA. Ann Neurol 2000;48:72–76

Antioxidant treatment improves in vivo cardiac and skeletal muscle bioenergetics in patients with friedreich's ataxia

Friedreichs ataxia (FA) is the most common form of autosomal recessive spinocerebellar ataxia and is often associated with a cardiomyopathy. The disease is caused by an expanded intronic GAA repeat, which results in deficiency of a mitochondrial protein called frataxin. In the yeast YFH1 knockout model of the disease there is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration, intramitochondrial iron accumulation, and associated production of oxygen free radicals. Recently, the analysis of FA cardiac and skeletal muscle samples and in vivo phosphorus magnetic resonance spectroscopy (31P‐MRS) has confirmed the deficits of respiratory chain complexes in these tissues. The role of oxidative stress in FA is further supported by the accumulation of iron and decreased aconitase activities in cardiac muscle. We used 31P‐MRS to evaluate the effect of 6 months of antioxidant treatment (Coenzyme Q10 400 mg/day, vitamin E 2,100 IU/day) on cardiac and calf muscle energy metabolism in 10 FA patients. After only 3 months of treatment, the cardiac phosphocreatine to ATP ratio showed a mean relative increase to 178% (p = 0.03) and the maximum rate of skeletal muscle mitochondrial ATP production increased to 139% (p = 0.01) of their respective baseline values in the FA patients. These improvements, greater in prehypertrophic hearts and in the muscle of patients with longer GAA repeats, were sustained after 6 months of therapy. The neurological and echocardiographic evaluations did not show any consistent benefits of the therapy after 6 months. This study demonstrates partial reversal of a surrogate biochemical marker in FA with antioxidant therapy and supports the evaluation of such therapy as a disease‐modifying strategy in this neurodegenerative disorder.

Diffusion-weighted brain imaging study of patients with clinical diagnosis of corticobasal degeneration, progressive supranuclear palsy and Parkinson's disease

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are two neurodegenerative disorders within the category of tauopathies, which must be considered in differential diagnosis of Parkinsons disease. Although specific clinical and neuroradiological features help to guide the clinician to a likely diagnosis of Parkinsons disease, CBD or PSP, differential diagnosis remains difficult. The aim of our study was to analyse apparent diffusion coefficient (ADC(ave)) maps from patients with clinical diagnosis of CBD (corticobasal syndrome, CBS), classical phenotype of PSP (Richardsons syndrome, RS) and Parkinsons disease (PD) in order to identify objective markers to discriminate between these groups. Thirteen Parkinsons disease patients, 10 RS patients, 7 CBS patients and 9 healthy volunteers were recruited and studied in a 1.5 T MR scanner. Axial diffusion-weighted images were obtained and the ADC(ave) map was generated. Regions of interest (ROIs) included mesencephalon, corpus callosum and left and right superior cerebellar peduncle (SCP), thalamus, caudate, putamen, pallidus, posterior limb of internal capsule, frontal and parietal white matter. Histograms of ADC(ave) were generated for all voxels in left and right cerebral hemispheres and in left and right deep grey matter regions separately, and the 50th percentile values (medians) were determined. The ratio of the smaller to the larger median value (symmetry ratio) was calculated for left and right hemispheres and for left and right deep grey matter regions (1 = perfect symmetry). Putaminal ADC(ave) values in CBS and RS were significantly greater than those in Parkinsons disease and healthy volunteers, but could not distinguish CBS from RS patients. In CBS patients, the values of the medians of cerebral hemispheres histograms were significantly higher than those in RS, Parkinsons disease and healthy volunteers, while the hemispheric symmetry ratio in CBS (0.968, range 0.952-0.976) was markedly reduced compared with RS (0.993, range 0.992-0.994), Parkinsons disease (0.991, range 0.988-0.993) and healthy controls (0.990, range 0.988-0.993). The hemispheric symmetry ratio differentiated CBS patients from RS and Parkinsons disease patients with a sensitivity and specificity of 100%. In RS patients, the ADC(ave) values of the SCPs were significantly greater than those in Parkinsons disease and healthy volunteers. Our findings confirm that putaminal ADC(ave) values evaluation provides a good discrimination between Parkinsons disease and atypical parkinsonisms, including RS and CBS. Furthermore, diffusion-weighted imaging, by detecting the brain microstructural correlates of the typical asymmetric signs and symptoms in CBS and the SCP involvement in RS, was shown to aid characterization and differentiation of atypical parkinsonism.

Diffusion tensor MRI changes in cerebellar structures of patients with familial essential tremor

Objective: The aim of our study was to investigate the microstructural integrity of brain regions functionally involved in the tremor loop in patients with familial essential tremor (FET), using diffusion tensor imaging (DTI). Methods: Twenty-five patients with FET, 15 patients with Parkinson disease (PD), and 15 healthy subjects were studied. DTI was performed to measure fractional anisotropy (FA) and mean diffusivity (MD) in various regions of interest: red nucleus, dentate nucleus (DN), cerebellar white matter, middle (MCP) and superior cerebellar peduncle (SCP), and ventrolateral thalamus. Results: In patients with FET, FA values in the DN (median 0.19, range 0.13–0.23) were reduced (p < 0.001) compared with patients with PD (median 0.37, range 0.32–0.58) and healthy controls (median 0.36, range 0.33–0.40). In patients with FET, FA was also reduced (p = 0.003) and MD values increased (p < 0.001) in the SCP compared with patients with PD and healthy controls. Among patients with FET, those with longer disease duration showed FA values in the DN lower than those with shorter disease duration (p = 0.018). Patients with FET could be completely distinguished from both patient with PD and healthy controls using FA values of the DN alone. Conclusion: Neuroimaging evidence of microstructural changes consistent with neurodegeneration was found in the dentate nucleus (DN) and SCP of patients with familial essential tremor. This suggests that neurodegenerative pathology of cerebellar structures may play a role in essential tremor. Further studies are needed to assess the role of fractional anisotropy and mean diffusivity changes in DN and SCP in the differential diagnosis of essential tremor and Parkinson disease, which may present similar clinical signs at the onset of disease.

Visual system involvement in patients with Friedreich's ataxia

Optic neuropathy is common in mitochondrial disorders, but poorly characterized in Friedreichs ataxia (FRDA), a recessive condition caused by lack of the mitochondrial protein frataxin. We investigated 26 molecularly confirmed FRDA patients by studying both anterior and posterior sections of the visual pathway using a new, integrated approach. This included visual field testing and optical coherence tomography (OCT), pattern visual evoked potentials (P-VEPs) and diffusion-weighted imaging. The latter was used to study optic radiation by calculating water apparent diffusion coefficients (ADC). All patients suffered optic nerve involvement with their disorder. Different patterns of visual field defects were observed and a variably reduced retinal nerve fiber layer thickness was seen by OCT in all cases. P-VEPs were abnormal in approximately half of the patients. Decreased visual acuity and temporal optic disc pallor were present in advanced stages of the disease, but only five patients were symptomatic. Two of these patients suffered a sudden loss of central vision, mimicking Lebers hereditary optic neuropathy (LHON), and of the other three symptomatic patients two were noted to be compound heterozygotes. ADC values of optic radiations in patients were significantly higher than controls (P < 0.01). Retinal nerve fiber layer thickness at OCT and P-VEPs correlated with age at onset and ICARS total score. ADC values correlated with age at onset, disease duration, GAA triplet expansion size, ICARS total score and P-VEPs. Visual pathway involvement is found consistently in FRDA, being previously underestimated, and we here document that it also involves the optic radiations. Occasional LHON-like cases may occur. However, optic neuropathy in FRDA substantially differs from classic mitochondrial optic neuropathies implying a different pathophysiology of visual system degeneration in this mitochondrial disease.

Quantitative proton magnetic resonance spectroscopy of the cervical spinal cord

Proton MR spectroscopy (1H‐MRS) provides indices of neuronal damage in the central nervous system (CNS); however, it has not been extensively applied in the spinal cord. This work describes an optimized proton spectroscopy protocol for examination of the human cervical spinal cord. B0 field mapping of the cord revealed periodic inhomogeneities due to susceptibility differences with surrounding tissue. By combining field maps and experimental data, we found that the optimum voxel size was 9 × 7 × 35 mm3 placed with the inferior end of the voxel above vertebral body C2. Metabolite concentrations were determined in the cervical cord in six healthy controls by short‐echo point‐resolved spectroscopy (PRESS) volume localization. The results were compared with metabolite concentrations in the brainstem, cerebellum, and cortex in the same individuals. The concentrations in the cervical cord were as follows: N‐acetyl‐aspartate (NAA) 17.3 ± 0.5, creatine (Cr) 9.5 ± 0.9, and choline 2.7 ± 0.5 mmol/l. The NAA concentration was significantly lower in the cord than in the brainstem (Mann‐Whitney, P < 0.025), and higher than in the cortex (P < 0.005) and cerebellum (P < 0.005). Cr was significantly lower in the cord than in the cerebellum (P < 0.05). There were no significant differences between Cr concentrations in the spinal cord compared to the cortex and brainstem. Magn Reson Med 51:1122–1128, 2004.

Creatine therapy for Huntington's disease: Clinical and MRS findings in a 1-year pilot study

Human and transgenic animal studies have implicated defective energy metabolism and oxidative stress in Huntington’s disease (HD), with evidence for deficiencies of respiratory chain activity and defective adenosine triphosphate (ATP) synthesis in brain and skeletal muscle.1,2⇓ Correlation of the muscle bioenergetic defect and CAG repeat length provides a link between this biochemical abnormality and the HD molecular defect.1 The role of calcium-mediated excitotoxicity and mitochondrial dysfunction is also supported by recent findings of a mitochondrial calcium handling defect.3 In the R6/2 HD transgenic mouse, 2% dietary creatine supplementation significantly improved survival, delayed motor progression, and slowed development of brain atrophy.4 Creatine has several potential neuroprotective effects, including buffering intracellular mitochondrial energy reserves, stabilizing intracellular calcium, and inhibiting activation of the mitochondrial permeability transition pore, which have all been linked to apoptotic and oxidative cell death. Two trials have been reported where patients with HD were given 5 g for 12 months5 and 3g for 2 months followed by 5 g for 2 months. …

High-dose creatine therapy for Huntington disease: A 2-year clinical and MRS study

Calcium-mediated excitotoxicity and defective energy metabolism have been implicated in the pathogenesis of Huntington disease (HD).1 In R6/2 HD transgenic mice, administration of 2% dietary creatine presymptomatically at 6 and 8 weeks improved survival, delayed motor progression, and reduced weight loss and brain atrophy.2,3 Creatine buffers intracellular energy reserves and has several neuroprotective effects demonstrated both in vivo and in vitro.4 A placebo-controlled pilot trial of 5 g/day of creatine for 1 year appeared ineffective in 26 patients with HD,5 although this dose was lower than the equivalent dose given to R6/2 HD mice. We previously reported clinical and MR spectroscopy (MRS) findings in a 1-year open-label pilot study of high-dose creatine (10 g/day) supplementation in 13 patients with HD.6 Serial 31P-MRS of muscle monitored changes in energy metabolism in vivo, and 1H-MRS was used to determine creatine levels in brain tissue. High-dose creatine was well tolerated, and total motor score (TMS), functional capacity, and neuropsychology testing remained stable at 12 months. We now report …

Apparent diffusion coefficient of the superior cerebellar peduncle differentiates progressive supranuclear palsy from Parkinson's disease

The early diagnosis of progressive supranuclear palsy (PSP) may be challenging, because of clinical overlapping features with Parkinsons disease (PD) and other parkinsonian syndromes such as the Parkinsonian variant of multiple system atrophy (MSA‐P). Conventional MRI can help in differentiating parkinsonian disorders but its diagnostic accuracy is still unsatisfactory. On the basis of the pathological demonstration of superior cerebellar peduncle (SCP) atrophy in patients with PSP, we assessed the SCP apparent diffusion coefficient (ADC) values in patients with PSP, PD, and MSA‐P in order to evaluate its differential diagnostic value in vivo. Twenty‐eight patients with PSP (14 with possible‐PSP and 14 with probable‐PSP), 15 PD, 15 MSA‐P, and 16 healthy subjects were studied by using diffusion weighted imaging (DWI). ADC was calculated in regions of interest defined in the left and right SCP by two clinically blinded operators. Intrarater (r = 0.98, P < 0.001) and interrater reliability (r = 0.97; P < 0.001) for SCP measurements were high. Patients with PSP had higher SCP rADC values (median 0.98 × 10−3mm2/s) than patients with PD (median 0.79 × 10−3 mm2/s, P < 0.001), MSA‐P (median 0.79 × 10−3 mm2/s, P < 0.001), and healthy controls (median 0.80 × 10−3 mm2/s, P < 0.001). DWI discriminated patients with PSP from PD and healthy subjects on the basis of SCP rADC individual values (100% sensitivity and specificity) and from patients with MSA‐P (96.4% sensitivity and 93.3% specificity). The higher values of rADC in SCP of patients with PSP correspond with the in vivo microstructural feature of atrophy detected postmortem and provide an additional support for early discrimination between PSP and other neurodegenerative parkinsonisms.