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Background Hemorrhage is the most devastating complication of brain arteriovenous malformations (bAVMs), and to date, there is still concern about the needing for treatment in case of unruptured and asymptomatic bAVM. In fact, the morbidity and mortality of treatments may exceed that of the AVM’s natural history. None of the classifications and scores for bAVM allows to predict the risk of bleeding. In this study, we aimed to identify the angio-architectural characteristics of brain AVMs associated with bleeding.Methods We retrospectively evaluated all consecutive patients diagnosed with cerebral AVMs, between January 2010 and December 2019 from our prospective bAVM database. Univariate and multivariate logistic regression analysis were used to evaluate relationships between angio-architectural features of ruptured and unruptured bAVMs.Results Of the 143 retrieved bAVMs, 65 were unruptured and 78 were ruptured. The univariate logistic regression analysis demonstrated statistically significant differences into angio-architectural features of unruptured and ruptured bAVMs. The multivariate logistic regression analysis fitted well (p=.113) with a good discrimination capacity (ROC = 0.83) of three independent angio-architectural features mainly related to bleeding in bAVMs: a smaller diameter of the nidus (p< .001), the absence of venous drainage alterations (p= .047), of the presence of prenidal aneurysms (p= .005).Conclusions In our study, several features resulted related to an increased probability of rupture for bAVMs, among which the more relevant were a small diameter of the nidus, the absence of venous drainage alterations, and the presence of prenidal aneurysms.

Introduction: Marfan syndrome (MFS) is the most common inherited connective tissue disorder and its association with intracranial aneurysms (ICAs) has been debated for more than two decades. Here, we report the prevalence of ICAs at screening neuroimaging in a population of genetically confirmed MFS patients and present the results of a meta-analysis including our cohort of patients and those of previous studies.Patients and methods: We enrolled 100 consecutive MFS patients, who underwent screening with brain magnetic resonance angiography at our tertiary center between August 2018 and May 2022. We did a PubMed and Web of Science search to retrieve all studies on the prevalence of ICAs in patients with MFS published before November, 2022.Results: Of the 100 patients included in this study (94% Caucasians, 40% females, mean age 38.6 ± 14.6 years), three had an ICA. We pooled the current study with five previously published studies, including a total of 465 patients, 43 of which harbored at least one unruptured ICA, leading to an overall ICA prevalence of 8.9% (95% CI 5.8%–13.3%).Discussion and conclusion: In our cohort of genetically confirmed MFS patients, the prevalence of ICAs was 3%, which is substantially lower compared to previous studies based on neuroimaging. The high frequency of ICA found in previous studies could be explained by selection bias and lack of genetic testing, which may have led to the inclusion of patients with different connective tissue disorders. Further studies, including several centers and a large number of patients with genetically confirmed MFS, are needed to confirm our results.

Purpose: Medulloblastoma is a rare tumor in adults and the use of adjuvant chemotherapy in average risk patients is debated.Methods: Patients included in our study were ⩾16 years of age, had histologically confirmed medulloblastoma, and underwent adjuvant radiotherapy with or without chemotherapy. Average risk was defined according to the Chang classification.Results: We included 48 average-risk patients. Median follow-up was 151.5 months (95% confidence interval, 124.5–178.5). Both progression-free survival (PFS) and overall survival (OS) were significantly influenced by adjuvant chemotherapy (PFS: hazard ratio [HR], 0.334, p= 0.05; OS: HR, 0.187, p= 0.017) and by receiving the treatment in a referral center (PFS: HR, 0.250, p= 0.008; OS: HR, 0.295, p= 0.038).Conclusions: Treating patients with average-risk medulloblastoma in a referral center improves both PFS and OS, does adding adjuvant chemotherapy.

Major cerebral vessels have been proposed as a target of defective mitochondrial metabolism in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS). Cerebral angiographic techniques are not routinely performed in MELAS patients. A systematic literature review was performed to identify studies describing major vessel caliber alterations in MELAS. Twenty-three studies reporting on 46 MELAS patients were included. Alterations in major caliber vessels were present in 59% (27/46) of patients. Dilation occurred in 37% (17/46) of patients, and in 88% (15/17) of them during a stroke-like episode (SLE). Stenosis was reported in 24% (11/46) of patients: 36% (4/11) related to an SLE and 64% (7/11) to dissections or degenerative changes.

IMPORTANCE: Early diagnosis is a requirement for future treatment of prion diseases. Magnetic resonance imaging (MRI) with diffusion-weighted images and improved real-time quaking-induced conversion (RT-QuIC) in cerebrospinal fluid (CSF) have emerged as reliable tests. OBJECTIVES: To assess the sensitivity and specificity of diffusion MRI for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) with a new criterion (index test) of at least 1 positive brain region among the cortex of the frontal, parietal, temporal, and occipital lobes; the caudate; the putamen; and the thalamus. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study with a prospective and a retrospective arm was performed from January 1, 2003, to October 31, 2018. MRIs were collected from 1387 patients with suspected sCJD consecutively referred to the National Prion Disease Pathology Surveillance Center as part of a consultation service. INTERVENTION: Magnetic resonance imaging. Four neuroradiologists blinded to the diagnosis scored the MRIs of 200 randomly selected patients. One neuroradiologist scored the MRIs of all patients. MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of the index test compared with currently used criteria and CSF diagnostic (improved RT-QuIC, 14-3-3, and tau CSF tests). RESULTS: A total of 872 patients matched the inclusion criteria (diffusion MRI and autopsy-confirmed diagnosis), with 619 having sCJD, 102 having other prion diseases, and 151 having nonprion disease. The primary analysis included 200 patients (mean [SD] age, 63.6 [12.9] years; 100 [50.0%] male). Sensitivity of the index test of 4 neuroradiologists was 90% to 95% and superior to sensitivity of current MRI criteria (69%-76%), whereas specificity was 90% to 100% and unchanged. Interrater reliability of the 4 neuroradiologists was high (κ = 0.81), and individual intrarater reliability was excellent (κ ≥0.87). The sensitivity of the index test of 1 neuroradiologist for 770 patients was 92.1% (95% CI, 89.7%-94.1%) and the specificity was 97.4% (95% CI, 93.4%-99.3%) compared with a sensitivity of 69.8% (95% CI, 66.0%-73.4%; P &lt; .001) and a specificity of 98.0% (95% CI, 94.3%-99.6%; P > .99) according to the current criteria. For 88 patients, index test sensitivity (94.9%; 95% CI, 87.5%-98.6%) and specificity (100%; 95% CI, 66.4%-100%) were similar to those of improved RT-QuIC (86.1% [95% CI, 76.5%-92.8%] and 100% [95% CI, 66.4%-100%], respectively). Lower specificities were found for 14-3-3 and tau CSF tests in 452 patients. CONCLUSIONS AND RELEVANCE: In this study, the diagnostic performance of diffusion MRI with the new criterion was superior to that of current standard criteria and similar to that of improved RT-QuIC. These results may have important clinical implications because MRI is noninvasive and typically prescribed at disease presentation.

Primary diffuse large B-cell lymphoma of the primary central nervous system (CNS-DLBCL) is an aggressive disease, with dismal prognosis despite the use of high-dose methotrexate-based polychemotherapy. Our study aimed to expand the biologic profiles of CNS-DLBCL and to correlate them with clinical/imaging findings to gain diagnostic insight and possibly identify new therapeutic targets. We selected 61 CNS-DLBCL whose formalin-fixed paraffin-embedded samples were available at first diagnosis. These were investigated by immunohistochemistry, cMYC rearrangements were explored by fluorescence in situ hybridization, and CNS-DLBCL mutated genes were evaluated by next-generation sequencing. CD10, BCL6, and IRF4 were observed in 16%, 83.6%, and 93% of cases, respectively. As typical of CNS lymphoma, 10 (16.4%) of 61 cases were classified as germinal center (GCB) type and 51 (83.6%) of 61 as non-germinal center (non-GCB) type according to the Hans algorithm. Double-expression status for BCL2 and cMYC was detected in 36 (59%) of 61 cases whereas 25 (41%) of 61 were non-DE. Rearrangement of the cMYCgene was detected in 2 cases, associated with BCL6translocation only in 1 case MYD88, PIM1, CD79B, and TP53were mutated in 54.5%, 53.5%, 30.2%, and 18.4% cases, respectively. Novel mutations not previously reported in CNS-DLBCL were found: AIPin 23.1%, PI3KCAin 15%, NOTCH1in 11.4%, GNASin 8.1%, CASP8in 7.9%, EGFRin 6.4%, PTENin 5.1, and KRASin 2.6% of cases. Survival was significantly longer for patients with mutated MYD88(8.7 months vs 1.7 months; log-rank test = 5.43; P = .020) and for patients with mutated CD79B(10.8 months vs 2.5 months; log-rank test = 4.64; P = .031). MYD88and CD79Bpredicted a longer survival in patients affected by CNS-DLBCL. Notably, we identified novel mutations that enrich the mutational landscape of CNS-DLBCL, suggest a role of PTEN-PI3K-AKT and receptor tyrosine kinase-RAS-mitogen-activated protein kinase signaling in a subset of CNS-DLBCL, and provide new potential therapeutic targets.

•EAA is an innovative, promising, safe and effective approach for 3VCPs.•Key of success is surgeon learning curve in endoscopy and patients selection.•With correct indications, EEA gives GTR and morbidity rate similar to other routes.•Clinical, tumoral and anatomical features should be considered for EEA selection.

•EEA represents an ideal approach for loco-regional recurrent CCs.•EEA is well tolerated, with preservation of patients QoL.•EEA can be considered for patients with perspectives of adjuvant therapies.•Otherwise, EEA can be considered only in selected cases with a palliative aim.

Background: Friedreich's ataxia is an autosomal recessive neurodegenerative disease where impaired mitochondrial function and excessive production of free radicals play a central pathogenetic role. Idebenone, a synthetic analogue of coenzyme Q, is a powerful antioxidant that was first administrated to Friedreich's ataxia patients less than 10 years ago. Objective: The aim of this study was to evaluate the efficacy of idebenone administration and define the optimal dosage. Methods: A critical evaluation of all open and double-blinded idebenone trials in Friedreich's ataxia patients was undertaken. Results/conclusions: Idebenone is well tolerated in paediatric and adult patients. Most trials demonstrated a positive effect on cardiac hypertrophy. The neurological function is in general not modified in adult patients, but a dose-dependent effect was demonstrated in young Friedreich's ataxia patients. Further double-blinded high-dose trials should evaluate idebenone in Friedreich's ataxia early in the disease course.

Obstructive sleep apnoea syndrome (OSAS) causes sleep related oxygen desaturation, excessive daytime sleepiness (EDS), and cognitive impairment. The role of hypoxic brain damage, sleep fragmentation, and the associated comorbidities (hypertension, vascular disorders) in the pathogenesis of cognitive deficits remains controversial. The aim of this study was to evaluate the cerebral metabolism of OSAS patients in vivo before and after CPAP treatment.

Clinical differentiation of parkinsonian syndromes such as the Parkinson variant of multiple system atrophy (MSA-P) and progressive supranuclear palsy (PSP) from Parkinson's disease is difficult in the early stage of the disease. In order to identify objective markers for differential diagnosis, we studied these three groups of patients with diffusion-weighted MRI (DWI). Sixteen MSA-P patients, 16 with PSP, 16 with Parkinson's disease and 15 healthy volunteers were studied. Regional apparent diffusion coefficients (rADC) were determined in different brain regions including basal ganglia, thalamus, white matter, pons and middle cerebellar peduncles (MCPs). rADC calculated in the MCP completely differentiated MSA-P patients (median: 0.93 × 10−3 mm2/s) from PSP patients (median: 0.82 × 10−3 mm2/s, P < 0.001), Parkinson's disease patients (median: 0.79 × 10−3 mm2/s, P < 0.001) and healthy volunteers (median: 0.81 × 10−3 mm2/s, P < 0.001). Other regions considered showed an overlapping among groups. DWI discriminates MSA-P from PSP and Parkinson's disease and healthy volunteers on the basis of MCP rADC values. These in vivo results confirm the pathological findings that the majority of MSA-P patients have moderate or severe degenerative changes not only in the nigrostriatal but also in the olivopontocerebellar systems. Our findings indicate that, in order to substantially contribute to the in vivo differential diagnosis of MSA-P, PSP and Parkinson's disease, rADC measurements should not be limited to the basal ganglia but should also include the MCP.

Friedreich's ataxia (FRDA) is the most common inherited ataxia. FRDA is an autosomal recessive degenerative disorder caused by a GAA triplet expansion or point mutations in the FRDA gene on chromosome 9q13. The FRDA gene product, frataxin, is a widely expressed mitochondrial protein that is severely reduced in FRDApatients. The function of frataxin has not been established yet. Studies of the yeast and animal model of the disease as well as of tissues from FRDA patients have demonstrated that deficit of frataxin is associated with mitochondrial iron accumulation, increased sensitivity to oxidative stress, deficit of respiratory chain complex activities and in vivo impairment of tissue energy metabolism. Pilot studies have shown the potential effect of antioxidant therapy in this condition and provide a strong rationale for designing larger clinical randomized trials.

Dominant optic atrophy has been associated with mutations in the OPA1gene, which encodes for a dynamin‐related GTPase, a mitochondrial protein implicated in the formation and maintenance of mitochondrial network and morphology. We used phosphorus magnetic resonance spectroscopy to assess calf muscle oxidative metabolism in six patients from two unrelated families carrying the c.2708‐2711delTTAG deletion in exon 27 of the OPA1gene. The rate of postexercise phosphocreatine resynthesis, a measure of mitochondrial adenosine triphosphate production rate, was significantly delayed in the patients. Our in vivo results show for the first time to our knowledge a deficit of oxidative phosphorylation in OPA1‐related DOA. Ann Neurol 2004;56:719–723

A novel mitochondrial DNA (mtDNA) transition (3733G→A) inducing the E143 K amino acid change at a very conserved site of the NADH dehydrogenase subunit 1 (ND1) was identified in a family with six maternally related individuals with Leber's hereditary optic neuropathy (LHON) and in an unrelated sporadic case, all negative for known mutations and presenting with the canonical phenotype. The transition was not detected in 1,082 control mtDNAs and was heteroplasmic in several individuals from both pedigrees. In addition, the mtDNAs of the two families were found to belong to different haplogroups (H and X), thus confirming that the 3733G→A mutation occurred twice independently. Phosphorus magnetic resonance spectroscopy disclosed an in vivo brain and skeletal muscle energy metabolism deficit in the four examined patients. Muscle biopsy from two patients showed slight mitochondrial proliferation with abnormal mitochondria. Biochemical investigations in platelets showed partially insensitive complex I to rotenone inhibition. We conclude that the 3733G→A transition is a novel cause of LHON and, after those at positions 3460 and 4171, is the third ND1 mutation to be identified in multiple unrelated families. This finding shows that, in addition to ND6, the ND1 subunit gene is also a mutational hot spot for LHON. Ann Neurol 2004;56:631–641

Quantitative MRI and phosphorus magnetic resonance spectroscopy (31P‐MRS) were used to investigate skeletal muscle metabolism in vivo in patients with dermatomyositis (DM) and polymyositis (PM) in order to evaluate the role of mitochondrial abnormalities in the pathogenesis and clinical expression of these conditions. Nine patients with DM (mean age ± SD, 57 ± 14 years) and five with PM (42 ± 12 years) and with age at disease onset 53 ± 16 and 38 ± 12 years, respectively, were included in the study together with 18 age‐matched controls. Post‐exercise 31P‐MRS indices of muscle oxidative metabolism were all impaired in DM and PM. In both groups of patients, the phosphocreatine and adenosine diphosphate recovery half‐times were almost twice as long as in controls (P < 0.05 for each variable) and the maximum rate of mitochondrial ATP production was half that found in normal subjects (P < 0.001). The rate of proton efflux from muscle fibres was significantly reduced in DM (P < 0.001) and PM (P = 0.02). The impairment of 31P‐MRS recovery indices in DM and PM patients was similar to that found in a group of 10 patients with a primary mitochondrial disorder that showed a normal proton efflux rate. There was no correlation between the MRS‐detectable abnormalities and the degree of inflammation or fatty infiltration of the muscle, as measured by MRI. The in vivo findings in DM and PM patients indicate impaired muscle aerobic function, which, considering the reduced proton efflux, is likely to be secondary to an impaired blood supply. Our results suggest that the abnormal mitochondria seen in some muscle biopsies are unlikely to be the primary cause of the oxidative insufficiency in these patients.

Quantitative MRI and phosphorus magnetic resonance spectroscopy ((31)P-MRS) were used to investigate skeletal muscle metabolism in vivo in patients with dermatomyositis (DM) and polymyositis (PM) in order to evaluate the role of mitochondrial abnormalities in the pathogenesis and clinical expression of these conditions. Nine patients with DM (mean age +/- SD, 57 +/- 14 years) and five with PM (42 +/- 12 years) and with age at disease onset 53 +/- 16 and 38 +/- 12 years, respectively, were included in the study together with 18 age-matched controls. Post-exercise (31)P-MRS indices of muscle oxidative metabolism were all impaired in DM and PM. In both groups of patients, the phosphocreatine and adenosine diphosphate recovery half-times were almost twice as long as in controls (P < 0.05 for each variable) and the maximum rate of mitochondrial ATP production was half that found in normal subjects (P < 0.001). The rate of proton efflux from muscle fibres was significantly reduced in DM (P < 0.001) and PM (P = 0.02). The impairment of (31)P-MRS recovery indices in DM and PM patients was similar to that found in a group of 10 patients with a primary mitochondrial disorder that showed a normal proton efflux rate. There was no correlation between the MRS-detectable abnormalities and the degree of inflammation or fatty infiltration of the muscle, as measured by MRI. The in vivo findings in DM and PM patients indicate impaired muscle aerobic function, which, considering the reduced proton efflux, is likely to be secondary to an impaired blood supply. Our results suggest that the abnormal mitochondria seen in some muscle biopsies are unlikely to be the primary cause of the oxidative insufficiency in these patients.

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 YFH1knockout 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 Q10400 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.

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. Ann Neurol 2000;47:381–384

Meningiomas are the most common primary intracranial tumors. The majority of meningiomas are benign, but they can present different grades of dedifferentiation from grade I to grade III (anaplastic/malignant) that are associated with different outcomes. Radiological surveillance is a valid option for low-grade asymptomatic meningiomas. In other cases, the treatment is usually surgical, aimed at achieving a complete resection. The use of adjuvant radiotherapy is the gold standard for grade III, is debated for grade II and is not generally indicated for radically resected grade I meningiomas. The use of systemic treatments is not standardized. Here we report a review of the literature on the clinical, radiological and molecular characteristics of meningiomas, available treatment strategies and ongoing clinical trials.

Meningiomas are the most common primary intracranial tumors. The majority of meningiomas are benign, but they can present different grades of dedifferentiation from grade I to grade III (anaplastic/malignant) that are associated with different outcomes. Radiological surveillance is a valid option for low-grade asymptomatic meningiomas. In other cases, the treatment is usually surgical, aimed at achieving a complete resection. The use of adjuvant radiotherapy is the gold standard for grade III, is debated for grade II and is not generally indicated for radically resected grade I meningiomas. The use of systemic treatments is not standardized. Here we report a review of the literature on the clinical, radiological and molecular characteristics of meningiomas, available treatment strategies and ongoing clinical trials.

The authors studied, by in vivophosphorus magnetic resonance spectroscopy (31P-MRS), the occipital lobes of 19 patients with mitochondrial cytopathies to clarify the functional relation between energy metabolism and concentration of cytosolic free magnesium. All patients displayed defective mitochondrial respiration with low phosphocreatine concentration [PCr] and high inorganic phosphate concentration [Pi] and [ADP]. Cytosolic free [Mg2+] and the readily available free energy (defined as the actual free energy released by the exoergonic reaction of ATP hydrolysis, i.e., ΔGATPhyd) were abnormally low in all patients. Nine patients were treated with coenzyme Q10(CoQ), which improved the efficiency of the respiratory chain, as shown by an increased [PCr], decreased [Pi] and [ADP], and increased availability of free energy (more negative value of ΔGATPhyd). Treatment with CoQ also increased cytosolic free [Mg2+] in all treated patients. The authors findings demonstrate low brain free [Mg2+] in our patients and indicate that it resulted from failure of the respiratory chain. Free Mg2+contributes to the absolute value of ΔGATPhyd. The results also are consistent with the view that cytosolic [Mg2+] is regulated in the intact brain cell to equilibrate, at least in part, any changes in rapidly available free energy.

We performed in vivophosphorus magnetic resonance spectroscopy on the occipital lobes of 15 patients with multiple system atrophy (MSA; eight with olivopontocerebellar atrophy [OPCA] and seven with the striatonigral degeneration variant [SND]), 13 patients with idiopathic Parkinson's disease (PD), and 16 age‐matched healthy subjects. The MSA group showed significantly reduced phosphocreatine (PCr), increased inorganic phosphate (Pi), and unchanged cytosolic free [Mg2+], and pH. We did not find any significant difference between the OPCA and SND variants. However, patients with PD showed significantly increased content of Pi, decreased cytosolic free [Mg2+], and unchanged [PCr] and pH. Comparing the MSA and PD groups, [PCr] was significantly lower in MSA than in PD, whereas cytosolic free [Mg2+] was significantly lower in PD. Despite a certain degree of overlap of [PCr] and [Mg2+] values between the two groups, by considering both variables at the same time it was possible to classify correctly 93% of cases by discriminant analysis. We conclude that phosphorus magnetic resonance spectroscopy discloses abnormal phosphate metabolite and ion contents in both MSA and PD, respectively, and may provide noninvasive diagnostic help to differentiate MSA from PD.

Abstract: The authors present anin vivo phosphorus magnetic resonance spectroscopy systematic study on the effects of cytosolic pH on skeletal muscle mitochondrial respiration in human calf muscle. In 49 normal subjects, the effect of cytosolic pH on kinetics of phosphocreatine and adenosine diphosphate recovery and on maximum rate of mitochondrial adenosine triphosphate production (Qmax) was evaluation. The results show a strong relationship between the rate of postexercise phosphocreatine recovery and the lowest value of cytosolic pH reached during recovery from exercise (termed minimum pH;r=0.89); in constrast, both adenosine diphosphate recovery halftime andQ max were independent of cytosolic pH at the end of exercise.

We used phosphorus magnetic resonance spectroscopy (31P MRS) to investigate in vivo the brain and skeletal muscle energy metabolism of 15 children with migraine with aura in interictal periods. Brain 31P MRS disclosed low phosphocreatine and high inorganic phosphate contents, and high intracellular pH in all patients. Calculated [ADP] and the relative rate of mitochondrial oxidation were higher in the brain of patients than in control subjects, whereas the phosphorylation potential was lower. Brain intracellular free Mg2+concentration was reduced by 25% in patients. Abnormal skeletal muscle mitochondrial respiration was also disclosed in 7 of 15 patients as shown by the slow rate of phosphocreatine postexercise recovery. The multisystem bioenergetic failure found in patients with juvenile migraine is comparable to that found in adults with different types of migraine.

We studied brain energy metabolism by phosphorus magnetic resonance spectroscopy (31P MRS) in 28 patients with mitochondrial cytopathies, and 20 normal control subjects. Fourteen patients had myopathy alone, six had only mild brain symptoms, and eight showed different degrees of brain involvement. Brain 31P MRS showed a low phosphocreatine content in all patients, accompanied by a high inorganic phosphate in 14 of 28 patients. The average value of the Piconcentration in the patient group was significantly (p = 0.009) different from the control group. The cytosolic pH was normal. From these data were derived a high concentration of ADP (calculated from the creatine kinase equilibrium), a high percent value of V/Vmaxfor ATP biosynthesis, and a low phosphorylation potential, all features showing a derangement of brain energy metabolism, in all patients with mitochondrial cytopathies. 31P MRS proved to be sensitive enough to disclose a deficit of mitochondrial functionality not only in the affected patients, but also in those without clinically evident brain symptoms.

We used phosphorus magnetic resonance spectroscopy (31P MRS) to investigate in vivothe brain and skeletal muscle energy metabolism of 15 children with migraine with aura in interictal periods. Brain 31P MRS disclosed low phosphocreatine and high inorganic phosphate contents, and high intracellular pH in all patients. Calculated [ADP] and the relative rate of mitochondrial oxidation were higher in the brain of patients than in control subjects, whereas the phosphorylation potential was lower. Brain intracellular free Mg2+concentration was reduced by 25% in patients. Abnormal skeletal muscle mitochondrial respiration was also disclosed in 7 of 15 patients as shown by the slow rate of phosphocreatine postexercise recovery. The multisystem bioenergetic failure found in patients with juvenile migraine is comparable to that found in adults with different types of migraine.

One of many problems to be faced when assessing in vivo human muscle mitochondria respiration by phosphorus magnetic resonance spectroscopy (31P-MRS) is the definition of the correct reference population and the values of reference range. To take into account most factors that influence muscle activity as age, sex, physical activity; nutritional state etc., an exceedingly high number of different reference groups are needed. To overcome this problem we developed specific tests to assess separately in vivo the activity and the functionality of muscle mitochondria by 31P-MRS in clinical settings. By activity we refer to muscle whole metabolic activity, i.e. the total oxidative capacity of muscle mitochondria which is influenced by many factors (age, sex, physical activity, nutritional state etc.). By functionality we refer to the qualitative aspects of mitochondrial respiration which depends on the integrity of mitochondrial multienzyme systems and on substrate availability. Our tests ha ve been experienced on some 1200 patients and are currently used to detect deficits of mitochondrial respiration and ion transport in patients with suspected primary or secondary muscle mitochondrial malfunctioning. (Mol Cell Biochem 174: 11–15, 1997)

Huntington disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disorder characterized by extrapyramidal motor signs often preceded by cognitive and behavioral disturbances, with a prevalence of 5–10 cases per 100,000 people worldwide1; expanded CAG repeats within the coding sequence of the HTTgene on chromosome 4p2are the cause. The gene encodes huntingtin (HTT), a ubiquitously expressed protein associated with most intracellular organelles. CAG repeats of 40 or more are associated with nearly full penetrance by age 65 years with a mean age at onset of 40 years and death 15–20 years later.3Although the function of HTT remains incompletely understood, HD likely arises from gain of function caused by the abnormal conformation of the mutant protein.3

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Objective: Friedreich ataxia (FRDA), the commonest form of inherited ataxia, is often associated with cardiac hypertrophy and cardiac dysfunction is the most frequent cause of death. In 97%, FRDA is caused by a homoplasmic GAA triplet expansion in the FRDA gene on chromosome 9q13 that results in deficiency of frataxin, a mitochondrial protein of unknown function. There is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration associated with abnormal mitochondrial iron accumulation. To determine whether bioenergetics deficit underlies the cardiac involvement in Friedreich ataxia (FRDA) we measured cardiac phosphocreatine to ATP ratio non-invasively in FRDA patients. Methods and results: Eighteen FRDA patients and 18 sex- and age-matched controls were studied using phosphorus MR spectroscopy and echocardiography. Left ventricular hypertrophy was present in eight FRDA patients while fractional shortening was normal in all. Cardiac PCr/ATP in FRDA patients as a group was reduced to 60% of the normal mean (P<0.0001). In the sub-group of patients with no cardiac hypertrophy PCr/ATP was also significantly reduced (P<0.0001). Conclusion: Cardiac bioenergetics, measured in vivo, is abnormal in FRDA patients in the absence of any discernible deterioration in cardiac contractile performance. The altered bioenergetics found in FRDA patients without left ventricle hypertrophy implies that cardiac metabolic dysfunction in FRDA precedes hypertrophy and is likely to play a role in its development.