Biomedical subjects

P Styles

Publications and source records attributed to P Styles.

At least 37 records · Page 2Linked to original sources

PubMed2001

Abnormal cerebral blood volume in regions of contused and normal appearing brain following traumatic brain injury using perfusion magnetic resonance imaging.

Following traumatic brain injury, there may be secondary alterations in cerebrovascular parameters leading to ischemia and further cellular damage. To assess possible subacute hemodynamic disturbances following traumatic brain injury, we used conventional and perfusion magnetic resonance imaging (MRI) in 18 patients, on average 10 days following injury. Six of the 18 patients had focal contusions or edema visible on conventional MRI. These six patients had a significantly reduced normalized regional cerebral blood volume (rCBV) in the regions of focal pathology compared to equivalent areas in control subjects (patients 0.47 +/- 0.20 [means +/- SD], controls 1.02 +/- 0.11, p < 0.001). In addition, four of these six patients had an increased rCBV (outside control range) in the region of normal appearing brain immediately surrounding the contusion. These six patients were more significantly injured and had a worse clinical outcome compared to the remaining patients (p = 0.004,p = 0.03, respectively). There were five patients who had a region of reduced rCBV (outside control range) in a quadrant of normal appearing white matter, away from any visible abnormality, who were not more significantly injured than the remaining patients but went on to have a significantly poorer clinical outcome (p = 0.27, p = 0.01, respectively). Traumatic brain injury is a heterogeneous insult causing a variety of pathology, not all of which is visible using conventional imaging methods. The current study has shown that regions of both normal appearing and contused brain may have an abnormal rCBV and that alterations in rCBV may play a role in determining the clinical outcome of patients.

Adult↗

PubMed2001

How useful is magnetic resonance imaging in predicting severity and outcome in traumatic brain injury?

Major advances have been made in the ever-expanding field of magnetic resonance imaging and related technologies, such as magnetic resonance spectroscopy, haemodynamic and functional imaging. Although these magnetic resonance modalities are of great research interest, it is still questionable as to how useful these investigations are in the clinical setting. All of these modalities strive to define a few variables that might dominate the heterogeneous but common aetiopathology of traumatic brain injury. Recent studies have found that the use of various magnetic resonance imaging techniques at early and delayed time points can provide useful information with regard to the severity and clinical outcome of patients following traumatic brain injury. These new observations offer opportunities for improved clinical management in such patients.

Brain Damage, Chronic↗

PubMed2001

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

Friedreich's 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.

Adolescent↗

PubMed2000

N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice.

Huntington's disease (HD) is an autosomal dominant condition involving progressive neurodegeneration, primarily the corpus striatum and cerebral cortex. We have used in vivo magnetic resonance spectroscopy (MRS) to assess specific neuronal markers in transgenic mice (R6/1 line) expressing exon I of the human huntingtin gene with an expanded CAG repeat. Levels of N-acetylaspartate (NAA), an indicator of healthy neuronal function, were significantly reduced (26%) in the corpus striatum of HD mice relative to wild-type littermates at 5 months of age. However, levels of cholines and creatine-phosphocreatine were not altered in the HD mice. Expression of dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32), was assessed by immunohistochemistry in the striatum of HD mice and found to be downregulated by 5 months and, even more dramatically, at 11 months of age. In contrast, expression of calbindin was not significantly decreased in HD mice. Our results suggest that the observed decreases in DARPP-32 and NAA may contribute to aberrant receptor signalling and neuronal dysfunction in HD.

Animals↗

PubMed2000

Magnetic resonance spectroscopy evidence of abnormal cardiac energetics in Xp21 muscular dystrophy.

OBJECTIVES: Our aim was to measure the cardiac phosphocreatine to adenosine triphosphate ratio (PCr/ATP) noninvasively in patients and carriers of Xp21 muscular dystrophy and to correlate the results with left ventricular (LV) function as measured by echocardiography. BACKGROUND: Duchenne and Becker muscular dystrophy (the Xp21 dystrophies) are associated with the absence or altered expression of dystrophin in cardiac and skeletal muscles. They are frequently complicated by cardiac hypertrophy and dilated cardiomyopathy. The main role of dystrophin is believed to be structural, but it may also be involved in signaling processes. Defects in energy metabolism have been found in skeletal muscle in patients with Xp21 muscular dystrophy. We therefore hypothesized that a defect in energy metabolism may be part of the mechanism leading to the cardiomyopathy of Xp21 muscular dystrophy. METHODS: Thirteen men with Becker muscular dystrophy, 10 female carriers and 23 control subjects were studied using phosphorus-31 magnetic resonance spectroscopy and echocardiography. RESULTS: The PCr/ATP was significantly reduced in patients (1.55+/-0.37) and carriers (1.37+/-0.25) as compared with control subjects (2.44+/-0.33; p<0.0001 for both groups). The PCr/ATP did not correlate with LV ejection fraction or mass index. CONCLUSIONS: Altered expression of dystrophin leads to a reduction in the PCr/ATP. Since this reduction did not correlate with indexes of left ventricular function, this raises the possibility of a direct link between altered dystrophin expression and the development of cardiomyopathy in such patients.

Adenosine Triphosphate↗

PubMed2000

Interleukin-1beta -induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study.

The cytokine interleukin-1beta (IL-1beta) is implicated in a broad spectrum of CNS pathologies, in which it is thought to exacerbate neuronal loss. Here, the effects of injecting recombinant rat IL-1beta into the striatum of 3-week-old rats were followed noninvasively from 2 to 123 hr using magnetic resonance imaging and spectroscopy. Four hours after injection of IL-1beta (1 ng in 1 microliter), cerebral blood volume was significantly increased, the blood-brain barrier (BBB) became permeable to intravenously administered contrast agent between 4.5 and 5 hr, and the apparent diffusion coefficient (ADC) of brain water fell by 6 hr (5.42 +/- 0. 35 x 10(-4) mm(2)/sec treated, 7.35 +/- 0.77 x 10(-)(4) mm(2)/sec control; p < 0.001). At 24 hr the BBB was again intact, but the ADC, although partially recovered, remained depressed at both 24 and 123 hr (p < 0.03). Depleting the animals of neutrophils before IL-1beta injection prevented the BBB permeability at all time points, but the ADC was still depressed at 6 hr (6.64 +/- 0.34 x 10(-4) mm(2)/sec treated, 7.49 +/- 0.38 x 10(-4) mm(2)/sec control; p < 0.005). No changes were seen in brain metabolites using proton spectroscopy at 6 hr after IL-1beta. Intraparenchymal injection of IL-1beta caused a neutrophil-dependent transient increase in BBB permeability. The presence of neutrophils within the brain parenchyma significantly contributed to the IL-1beta-induced changes in cerebral blood volume and the ADC of brain water. However, IL-1beta apparently had a direct effect on the resident cell populations, which persisted well after all recruited leukocytes had disappeared. Thus the action of IL-1beta alone can give rise to magnetic resonance imaging-visible changes that are normally attributed to alterations to cellular homeostasis.

Acute Disease↗

PubMed2000

Sympathetic denervation of the upper limb improves forearm exercise performance and skeletal muscle bioenergetics.

BACKGROUND: Sympathetic activation may limit exercise performance by restraining muscle blood flow or by negatively affecting skeletal muscle metabolic behavior. To test this hypothesis, we studied the effect of thoracoscopic sympathetic trunkotomy (TST) on forearm exercise duration, blood flow, and muscle bioenergetics in 13 patients with idiopathic palmar hyperhidrosis. METHODS AND RESULTS: Heart rate and beat-by-beat mean arterial pressure were recorded at rest and during right and left rhythmic handgrip before and 4 to 7 weeks after right TST. Forearm blood flow was measured bilaterally at rest and on the right during exercise. Right forearm muscle phosphocreatine content and intracellular pH were assessed by (31)phosphorus magnetic resonance spectroscopy. After right TST, exercise duration increased from 8.9+/-1.4 to 13.4+/-1.8 minutes (P<0.0001) with the right forearm and from 5.7+/-0.4 to 7.6+/-0.9 minutes (P<0.05) with the left (P<0.05 for the interaction between treatment and side). Right forearm blood flow at rest was 66% higher (P<0.01) after right TST, but this difference decreased as the exercise progressed. After right TST, a significant reduction occurred in muscle acidification and phosphocreatine depletion during ipsilateral forearm exercise. This was associated with a significantly reduced mean arterial pressure response to right handgrip, whereas the pressor response to left handgrip did not change. CONCLUSIONS: Sympathetic denervation of the upper limb significantly improves forearm skeletal muscle bioenergetics and exercise performance in patients with idiopathic palmar hyperhidrosis.

Adult↗

PubMed2000

Axonal injury or loss in the internal capsule and motor impairment in multiple sclerosis.

OBJECTIVE: To test the hypothesis that axonal damage extending into primarily normal-appearing white matter is clinically important by comparing the concentrations of N-acetylaspartate (NAA) bilaterally within the internal capsule with lateralization of motor impairment in patients with multiple sclerosis (MS) and persistent asymmetrical motor deficit. DESIGN: We performed magnetic resonance spectroscopy and T2-weighted imaging of the internal capsule, calculated central motor conduction times, and related these results to measures of motor function asymmetry in 12 patients with MS. RESULTS: Levels of NAA from normal-appearing white matter of the internal capsule in patients with MS were significantly lower than those in control subjects (P = .05). Side-to-side differences in NAA levels were also significantly greater in patients with MS than in controls (P = .01). There was a correlation between asymmetry in motor function for the left and right limbs and asymmetry of internal capsule NAA concentrations (r = 0.60; P = .04). This correlation seemed slightly stronger when tests specifically of arm and hand motor asymmetry were considered alone. Central motor conduction times were abnormal in most patients with MS and showed a side-to-side difference that also correlated with asymmetry in motor function. CONCLUSION: Our demonstration of a graded association between NAA concentrations within primarily normal-appearing white matter of a specific tract and functional impairments referable to that tract suggests that axonal pathology distant from macroscopic lesions might be an important determinant of disability in MS.

Adult↗

PubMed2000

Spin echo entrapped perfusion image (SEEPAGE). A nonsubtraction method for direct imaging of perfusion.

Arterial spin-labeled perfusion imaging is increasingly being applied to the study of the brain and other organs. To date, perfusion information has invariably been obtained by subtraction of images with and without spin-labeling of inflowing water. Due to the relatively small amount of blood which enters tissue over a typical inflow period (1-1.5 sec), subtraction errors due to image instability or, in certain circumstances, magnetization transfer effects, can lead to very significant amounts of artifactual image intensity. These problems are avoided in the nonsubtraction method described here. Initially, spins in the imaging slice are selectively saturated, leaving other spins unaffected. A subsequent spin-echo train traps these magnetizations irrespective of flow. Finally, an imaging module generates intensity only from those spins which have entered the imaging slice during the inflow period. A slight modification of the sequence facilitates validation by detecting any contaminating signal in a control image.

Artifacts↗

PubMed2000

The effect of bulk susceptibility on murine snapshot imaging at 7.0 T: a comparison of snapshot imaging techniques.

The sensitivity of several single-shot imaging techniques to local field gradients (LFGs) generated by discontinuities in bulk magnetic susceptibility (BMS) were compared in mouse brain at 7.0 T. At high field, differences in BMS can cause substantial signal attenuation and image distortion. Because susceptibility effects scale with B(o), mouse brain single-shot imaging at high field is particularly susceptible to the effects of LFGs. The spin-echo techniques GRASE and RARE were found to have a decreased sensitivity to LFGs compared to echo-planar imaging (EPI). Images obtained using EPI and SE-EPI exhibit severe signal attenuation in regions of high LFGs such as near air-tissue interfaces and at the brain edges. In applications such as functional MRI and diffusion MRI, GRASE and RARE are likely to provide more comprehensive whole brain coverage in mouse brain at high field than EPI techniques, which are likely to image regions of the brain with strong LFGs with low signal to noise, reducing the probability of detecting significant physiologically based changes.

Animals↗

PubMed2000

Diffusion weighted imaging and magnetic resonance spectroscopy in a low flow ischaemia model due to endothelin induced vasospasm.

The aim of this MR study was to determine if vasospasm induced by application of endothelin-1 (ET-1) in the rat brain would model the abnormalities attributed to vasospasm described in patients with subarachnoid haemorrhage (SAH) with reversible neurological deficits. Following application of ET-1 in concentrations of 10(-4) M or 10(-6) M to the middle cerebral artery, there was an immediate drop in pH, an increase in the inorganic phosphate (P(i)) to phosphocreatine (PCr) ratio and elevated lactate. There was gradual recovery to control in the 10(-6) M group, but in the 10(-4) M group there was a loss of approximately 10% in the absolute signal intensities of PCr and adenosine triphosphate (ATP). In a second similarly treated group of animals, the area of the hemisphere with a low apparent diffusion coefficient (ADC) was 27 +/- 6% at 30 min and remained at about 20-21% at 90 min and beyond. Together these data suggest that the regions with persistently low ADC were metabolically compromised, with incomplete recovery of PCr and ATP, and represent irreversibly damaged tissue. This raises the possibility that MR spectroscopy and imaging could be a sensitive indicator of tissue viability. This is a potentially useful model of low flow as seen in clinical vasospasm following SAH.

Adenosine Triphosphate↗

PubMed2000

Correlating magnetic resonance imaging markers of axonal injury and demyelination in motor impairment secondary to stroke and multiple sclerosis.

The primary pathological mechanisms in stroke and multiple sclerosis (MS) are very different but in both diseases, impairment may arise from a final common pathway of axonal damage. We aimed to examine the relationship between motor impairment, magnetisation transfer ratio (MTR) (an index of demyelination), and N-acetyl aspartate (NAA) loss (an index of axonal injury) localised to the descending motor pathways in stroke and MS. Twelve patients between 1 and 10 months after first ischaemic stroke causing a motor deficit and 12 patients with stable MS with asymmetric motor deficit were examined. T(2)-weighted imaging of the brain together with MTR and proton (voxel 1.5x2x2 cm(3)) MRS localised to the posterior limb of the internal capsule were performed and correlated to a composite motor deficit score. MTR and NAA in the internal capsule were reduced in both stroke and MS patients compared to controls. NAA loss correlated with motor deficit score in both stroke and MS (p<0.001 and p = 0.04, respectively). Correlations were seen between MTR and motor deficit (p<0.001) MTR and NAA loss (p <0.001) in stroke patients but not in MS patients. Axonal injury in the descending motor tracts would appear to be an important determinant of motor impairment in both stroke and MS. In stroke, MTR measures of demyelination are closely related to axonal damage and thus also correlate with motor deficit. However in MS, MTR measures of demyelination do not correlate with NAA loss or motor deficit suggesting that demyelination and gliosis may occur independently of axonal damage and are less closely linked with functional impairment.

Adult↗

PubMed2000

Early proton magnetic resonance spectroscopy in normal-appearing brain correlates with outcome in patients following traumatic brain injury.

The long-term clinical outcome following traumatic brain injury (TBI) can be difficult to predict. Proton magnetic resonance spectroscopy (MRS) has previously been used to demonstrate abnormalities in regions of white matter that appear normal on conventional imaging in patients following TBI. We report MRI and MRS studies of 26 patients performed at an early time point following injury (mean 12 days, n = 21) and at a later time point (mean 6.2 months, n = 15). The proton MRS was acquired from the posterior part of a normal-appearing frontal lobe containing predominantly white matter using stimulated echo acquisition mode to localize, with a relaxation time of 3000 ms and echo time of 30 ms. At both the early and late time points the N:-acetylaspartate/creatine ratio (NAA/Cr) was significantly reduced (P = 0.03, P = 0.005, respectively), the choline/creatine ratio (Cho/Cr) significantly increased (P = 0.001, P = 0.004, respectively) and the myo-inositol/creatine ratio (Ins/Cr) significantly increased (P = 0.03, P = 0.03, respectively) compared with controls. There was a small, but significant, further reduction (P = 0.02) in the NAA/Cr between the two studies in the 10 patients for whom data was available, at both time points. The NAA/Cr acquired at the early time point significantly correlated with the clinical outcome of the patients, assessed using either the Glasgow outcome scale (P = 0.005, n = 17) or the disability rating scale (P < 0.001, n = 17). We conclude that there is a sustained alteration in NAA and Cho. These findings provide possible evidence for cellular injury (NAA loss reflecting neuroaxonal cell damage and raised Cho and Ins reflecting glial proliferation) not visible by conventional imaging techniques. This may be relevant to understanding the extent of disability following TBI.

Adolescent↗

PubMed2000

Evidence for cellular damage in normal-appearing white matter correlates with injury severity in patients following traumatic brain injury: A magnetic resonance spectroscopy study.

Neuropsychological studies in patients who have suffered traumatic brain injury show that the eventual clinical outcome is frequently worse than might be predicted from using conventional (CT or T(1)/T(2)-weighted MRI) imaging. Furthermore, patients who have sustained an initial mild or moderate injury may show long-term disability. This implies that there may be abnormalities in areas of the brain that actually appear normal on conventional imaging. Proton magnetic resonance spectroscopy studies have shown that N-acetylaspartate and choline-containing compounds can provide measures of cellular injury. We report MRI and proton magnetic resonance spectroscopy studies of 19 head-injured patients performed once the patients were clinically stable (mean 11 days after injury, range 3-38 days). Proton magnetic resonance spectra were acquired from frontal white matter that on conventional MRI appeared normal. The brain N-acetylaspartate/creatine ratio was reduced [patients (mean +/- standard deviation), 1.28 +/- 0.25; controls, 1.47 +/- 0. 24; P = 0.04] and the choline/creatine ratio was increased (patients, 0.85 +/- 0.18; controls, 0.63 +/- 0.10; P < 0.001) compared with controls. When the severity of the injury was assessed using either the Glasgow coma scale or the length of post-traumatic amnesia, the increase in the choline/creatine ratio was significant even in the mildly injured group (P = 0.008 and P = 0.04, respectively). Furthermore, there was a significant correlation (P = 0.008) between the severity of head injury and the N-acetylaspartate/choline ratio. We conclude that there is an early reduction in N-acetylaspartate and an increase in choline compounds in normal-appearing white matter which correlate with head injury severity, and that this may provide a pathological basis for the long-term neurological disability that is seen in these patients.

Adolescent↗

PubMed2000

Relating MRI changes to motor deficit after ischemic stroke by segmentation of functional motor pathways.

BACKGROUND AND PURPOSE: Infarct size on T2-weighted MRI correlates only modestly with outcome, particularly for small strokes. This may be largely because of differences in the locations of infarcts and consequently in the functional pathways that are damaged. To test this hypothesis quantitatively, we developed a "mask" of the corticospinal pathway to determine whether the extent of stroke intersection with the pathway would be more closely related to clinical motor deficit and axonal injury in the descending motor pathways than total stroke lesion volume. METHODS: Eighteen patients were studied > or =1 month after first ischemic stroke that caused a motor deficit by use of brain T2-weighted imaging, MR spectroscopic (MRS) measurements of the neuronal marker compound N-acetyl aspartate in the posterior limb of the internal capsule, and motor impairment and disability measures. A corticospinal mask based on neuroanatomic landmarks was generated from a subset of the MRI data. The maximum proportion of the cross-sectional area of this mask occupied by stroke was determined for each patient after all brain images were transformed into a common stereotaxic brain space. RESULTS: There was a significant linear relationship between the maximum proportional cross-sectional area of the corticospinal mask occupied by stroke and motor deficit (r(2)=0.82, P<0.001), whereas the relationship between the total stroke volume and motor deficit was better described by a cubic curve (r(2)=0.76, P<0.001). Inspection of the data plots showed that the total stroke volume discriminated poorly between smaller strokes with regard to the extent of associated motor deficit, whereas the maximum proportion of the mask cross-sectional area occupied by stroke appeared to be a more discriminatory marker of motor deficit and also N-acetyl aspartate reduction. CONCLUSIONS: Segmentation of functional motor pathways on MRI allows estimation of the extent of damage specifically to that pathway by the stroke lesion. The extent of stroke intersection with the motor pathways was more linearly related to the magnitude of motor deficit than total lesion volume and appeared to be a better discriminator between small strokes with regard to motor deficit. This emphasizes the importance of the anatomic relationship of the infarct to local structures in determining functional impairment. Prospective studies are necessary to assess whether this approach would allow improved early estimation of prognosis after stroke.

Adult↗

PubMed2000

Very low levels of the mtDNA A3243G mutation associated with mitochondrial dysfunction in vivo.

We studied mitochondrial function in vivo in 2 brothers harboring the mitochondrial DNA A3243G mutation by using magnetic resonance spectroscopy. One brother presented with recurrent strokes and had a mitochondrial respiratory chain complex I defect, with 85% A3243G mutation in his quadriceps. The maximum rate of mitochondrial ATP production in his calf, measured in vivo, was reduced to 21% of the normal mean value. The second brother had mild exercise intolerance, normal muscle histochemistry, and normal respiratory chain activity in vitro. Despite a level of the A3243G mutation of only 5.95% (SD, 4.45; range, 0.7-16.1%) within single muscle fibers from the gastrocnemius muscle, the maximum rate of mitochondrial ATP production in his calf, measured in vivo, was reduced to 35% of the normal mean value. These findings suggest that there may not be a clear genetic threshold level for the expression of the A3243G mutation in skeletal muscle in vivo.

Adult↗

PubMed2000

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

We studied in vivo muscle energy metabolism in patients with Huntington's 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.

Adenosine Triphosphate↗

PubMed1999

Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia.

Friedreich ataxia (FRDA), the most common of the inherited ataxias, is an autosomal recessive degenerative disorder, characterized clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon reflexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs. FRDA is caused by a GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 in 97% of patients. The FRDA gene encodes a widely expressed 210-aa protein, frataxin, which is located in mitochondria and is severely reduced in FRDA patients. Frataxin function is still unknown but the knockout of the yeast frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration and loss of mtDNA associated with elevated intramitochondrial iron. Here we report in vivo evidence of impaired mitochondrial respiration in skeletal muscle of FRDA patients. Using phosphorus magnetic resonance spectroscopy we demonstrated a maximum rate of muscle mitochondrial ATP production (V(max)) below the normal range in all 12 FRDA patients and a strong negative correlation between mitochondrial V(max) and the number of GAA repeats in the smaller allele. Our results show that FRDA is a nuclear-encoded mitochondrial disorder affecting oxidative phosphorylation and give a rationale for treatments aimed to improve mitochondrial function in this condition.

Adaptor Proteins, Signal Transducing↗