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B Barbiroli

Publications and source records attributed to B Barbiroli.

At least 37 records · Page 2Linked to original sources
PubMed1999

Low brain intracellular free magnesium in mitochondrial cytopathies.

The authors studied, by in vivo phosphorus 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., deltaG(ATPhyd)) 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 deltaG(ATPhyd)). 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 deltaG(ATPhyd). 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.

Adolescent↗
PubMed1998

Aspects of human bioenergetics as studied in vivo by magnetic resonance spectroscopy.

We outline the relevant capabilities of in vivo phosphorus MR spectroscopy by discussing some aspects of normal human biochemistry as studied by this technique. The transport of inorganic phosphate from cytosol into mitochondria in the human skeletal muscle was studied by exploiting a new experimental protocol. We found that Pi was transported into mitochondria in the absence of ATP biosynthesis and in the presence of a pH gradient. The control of CoQ on the efficiency of oxidative phosphorylation in the skeletal muscle and brain was studied by administering CoQ to patients with mitochondrial cytopathies due to known enzyme defects. Before CoQ we had detected a relevant reduction of mitochondrial functionality in the skeletal muscle as shown by the reduced rate of phosphocreatine recovery from exercise, and in the occipital lobes by reduced [phosphocreatine] and a high [ADP] and [Pi]. After CoQ all brain variables were remarkably improved. Treatment with CoQ also improved the rate of muscle phosphocreatine recovery from exercise. Our in vivo findings support the hypothesis that the concentration of CoQ rather than the rate of its lateral diffusion in the mitochondrial membrane controls the efficiency of oxidative phosphorylation. Other experiments were undertaken to clarify the functional relationship between cytosolic free [Mg2+] and cell bioenergetics in the intact human brain. In the same group of patients with mitochondrial cytopathies we found decreased delta G of ATP hydrolysis and low cytosolic free [Mg2+]. Treatment with CoQ resulted in improved brain bioenergetics and increased free [Mg2+]. These findings strongly indicate that decreased free magnesium was secondary to defective mitochondrial respiration, and support the hypothesis that cytosolic free [Mg2+] is regulated in the intact brain cell to equilibrate, at least in part, any changes in rapidly available free energy.

Adult↗
PubMed1998

Absolute metabolite quantification by in vivo NMR spectroscopy: II. A multicentre trial of protocols for in vivo localised proton studies of human brain.

We have performed a multicentre trial to assess the performance of three techniques for absolute quantification of cerebral metabolites using in vivo proton nuclear magnetic resonance (NMR). The techniques included were 1) an internal water standard method, 2) an external standard method based on phantom replacement, and 3) a more sophisticated method incorporating elements of both the internal and external standard approaches, together with compartmental analysis of brain water. Only the internal water standard technique could be readily implemented at all participating sites and gave acceptable precision and interlaboratory reproducibility. This method was insensitive to many of the experimental factors affecting the performance of the alternative techniques, including effects related to loading, standing waves and B1 inhomogeneities; and practical issues of phantom positioning, user expertise and examination duration. However, the internal water standard method assumes a value for the concentration of NMR-visible water within the spectroscopic volume of interest. In general, it is necessary to modify this assumed concentration on the basis of the grey matter, white matter and cerebrospinal fluid (CSF) content of the volume, and the NMR-visible water content of the grey and white matter fractions. Combining data from 11 sites, the concentrations of the principal NMR-visible metabolites in the brains of healthy subjects (age range 20-35 years) determined using the internal water standard method were (mean+/-SD): [NAA]=10.0+/-3.4 mM (n=53), [tCho]=1.9+/-1.0 mM (n=51), [Cr + PCr]=6.5+/-3.7 mM (n=51). Evidence of system instability and other sources of error at some participating sites reinforces the need for rigorous quality assurance in quantitative spectroscopy.

Adult↗
PubMed1997

Failure of muscle energy metabolism in a patient with adenylosuccinate lyase deficiency. An in vivo study by phosphorus NMR spectroscopy.

31P-nuclear magnetic resonance spectroscopy was used to investigate in vivo the energy metabolism of the calf muscle in a 10-year-old patient with adenylosuccinate lyase deficiency and severe psychomotor retardation. The patient showed a markedly reduced PCr/P(i) molar ratio, known to well represent the cytosolic phosphorylation potential, due to low PCr and high P(i) content in resting muscle. Moreover, intracellular ATP concentration was significantly lower than in the control group both at rest and at the end of post-exercise recovery. The rate of patient's PCr recovery after an exercise in ischaemic conditions was also out of the reference range, suggesting a reduced ability of mitochondria to respond to metabolic needs.

Adenosine Triphosphate↗
PubMed1997

Clinical and brain bioenergetics improvement with idebenone in a patient with Leber's hereditary optic neuropathy: a clinical and 31P-MRS study.

We used phosphorus magnetic resonance spectroscopy (31P-MRS) to study in vivo brain and muscle bioenergetics in a male patient with Leber's hereditary optic neuropathy (LHON) and mtDNA mutation at 11,778 bp who developed spastic paraparesis with white matter lesions on brain MR imaging. The study was performed before and during treatment with idebenone (135 mg t.i.d.) and after withdrawal. Clinical amelioration and worsening were associated with parallel changes in brain and skeletal muscle bioenergetics following the administration or withdrawal of idebenone. Reversal of paraparesis by idebenone was paralleled by normalization of 31P-MRS, serum lactate and central motor conduction. Extra-ocular neurological dysfunction in LHON may be amenable to treatment by appropriate quinones.

Adult↗
PubMed1997

Quantitative analysis of skeletal muscle bioenergetics and proton efflux in migraine and cluster headache.

Phosphorus MR spectroscopy (31P-MRS) was used to quantify skeletal muscle bioenergetics and proton efflux in 63 patients with migraine (23 with migraine without aura, MwoA, 22 with migraine with aura, MwA, and 18 with prolonged aura or stroke, CM) and in 14 patients with cluster headache (CH), all in an attack-free period. At rest mitochondrial function was abnormal only in CM, as shown by a low phosphocreatine (PCr) concentration. At the end of a mixed glycolytic/aerobic exercise all three migraine groups showed a significantly smaller decrease of cytosolic pH compared to controls with a similar end-exercise PCr breakdown, while end-exercise pH was normal in cluster headache patients. The normal rate of proton efflux in all headache groups suggests that the reduced end-exercise acidification was due to a reduction of glycolytic flux in migraine patients. The maximum rate of mitochondrial ATP production (Qmax), calculated from the rate of post-exercise PCr recovery and the end-exercise [ADP], was low in cluster headache patients as well as in migraine patients except MwoA. In migraine the degree of the mitochondrial impairment, that apparently is associated with a reduced glycolytic flux, is related to the severity of the clinical phenotype.

Adolescent↗
PubMed1997

Influence of cytosolic pH on in vivo assessment of human muscle mitochondrial respiration by phosphorus magnetic resonance spectroscopy.

The authors present an in 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 (Q(MAX)) was evaluated. 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 contrast, both adenosine diphosphate recovery halftime and Q(MAX) were independent of cytosolic pH at the end of exercise.

Adenosine Diphosphate↗
PubMed1997

Brain and skeletal muscle bioenergetic failure in familial hypobetalipoproteinaemia.

OBJECTIVE: To determine whether a multisystemic bioenergetic deficit is an underlying feature of familial hypobetalipoproteinaemia. METHODS: Brain and skeletal muscle bioenergetics were studied by in vivo phosphorus MR spectroscopy (31P-MRS) in two neurologically affected members (mother and son) and in one asymptomatic member (daughter) of a kindred with familial hypobetalipoproteinaemia. Plasma concentrations of vitamin E and coenzyme Q10 (CoQ10) were also assessed. RESULTS: Brain 31P-MRS disclosed in all patients a reduced phosphocreatine (PCr) concentration whereas the calculated ADP concentration was increased. Brain phosphorylation potential was reduced in the members by about 40%. Skeletal muscle was studied at rest in the three members and during aerobic exercise and recovery in the son and daughter. Only the mother showed an impaired mitochondrial function at rest. Both son and daughter showed an increased end exercise ADP concentration whereas the rates of postexercise recovery of PCr and ADP were slow in the daughter. The rate of inorganic phosphate recovery was reduced in both cases. Plasma concentration of vitamin E and CoQ10 was below the normal range in all members. CONCLUSIONS: Structural changes in mitochondrial membranes and deficit of vitamin E together with reduced availability of CoQ10 can be responsible for the multisystemic bioenergetic deficit. Present findings suggest that CoQ10 supplementation may be important in familial hypobetalipoproteinaemia.

Brain↗
PubMed1997

Deficit of brain and skeletal muscle bioenergetics and low brain magnesium in juvenile migraine: an in vivo 31P magnetic resonance spectroscopy interictal study.

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.

Adolescent↗
PubMed1997

Phosphorus magnetic resonance spectroscopy in cluster headache.

We performed in vivo MR spectroscopy phosphorus (31P-MRS) on the brain and skeletal muscles of 14 patients affected with cluster headache (CH). We examined patients in interictal periods, and also examined nine of them during the cluster period, although not during the attack. Brain 31P-MRS showed reduced phosphocreatine (PCr) levels, an increased ADP concentration (calculated from the creatine kinase equilibrium), a reduced phosphorylation potential, and a high relative rate of ATP biosynthesis (V/Vmax %). The inorganic phosphate (P(i)) content was increased during the cluster period. Ten of 13 patients also showed a slow rate of PCr recovery in muscle after the exercise. 31P-MRS in CH patients showed abnormalities of brain and skeletal muscle energy metabolism comparable with those seen in various types of migraine, thus leading us to suggest a similarity in biochemical pathogenic mechanisms between CH and migraine.

Adenosine Diphosphate↗
PubMed1997

Coenzyme Q10 improves mitochondrial respiration in patients with mitochondrial cytopathies. An in vivo study on brain and skeletal muscle by phosphorous magnetic resonance spectroscopy.

With phosphorus magnetic resonance spectroscopy (31P-MRS) we studied in vivo the effect of six-month coenzyme Q10 treatment on the efficiency of brain and skeletal muscle mitochondrial respiration in six patients with different mitochondrial cytopathies. Before CoQ we found a low phosphocreatine content (average of 25% decrease from controls) in the occipital lobes of all patients. Calculated [ADP] and the relative rate of ATP synthesis were high (as an average, 57% and 16% above control group respectively), whereas the cytosolic phosphorylation potential was low (as an average, 60% of control value). 31P-MRS also revealed an average of 29% reduction of the mitochondrial function in the skeletal muscle of patients compared with controls. After a six-month treatment with 150 mg CoQ10/day all brain variables were remarkably improved in all patients, returning within the control range in all cases. Treatment with CoQ also improved the muscle mitochondrial functionality enough to reduce the average deficit to 56% of the control group. These in vivo findings show the beneficial effect of CoQ in patients with mitochondrial cytopathies, and are consistent with the view that increased CoQ concentration in the mitochondrial membrane increases the efficiency of oxidative phosphorylation independently of enzyme deficit.

Adult↗
PubMed1997

In vivo assessment of human skeletal muscle mitochondria respiration in health and disease.

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 have 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.

Electron Transport↗
PubMed1996

Inorganic phosphate is transported into mitochondria in the absence of ATP biosynthesis: an in vivo 31P NMR study in the human skeletal muscle.

We used 31-phosphorus magnetic resonance spectroscopy to study in vivo the transport of inorganic phosphate (Pi) from cytosol into mitochondria as assessed by the kinetics of Pi recovery during ischemia after aerobic exercise in human skeletal muscle. In all subjects during the first 30 s of ischemia inorganic phosphate showed a marked decrease from the value measured at the end of exercise, whilst phosphocreatine maintained the same value reached at the end of exercise. Our results show that Pi transport from cytosol into mitochondria is active in the absence of ATP biosynthesis and lasts 30 s possibly as a consequence of a decreased pH gradient, due to symport of Pi and H+ associated with an inactive electron transport chain during ischemia.

Adolescent↗
PubMed1996

In vivo assessment of free magnesium concentration in human brain by 31P MRS. A new calibration curve based on a mathematical algorithm.

Free cytosolic [Mg2+] can be assessed in vivo by 31P MRS from the chemical shift of beta-ATP which in turn depends on the fraction of total ATP complexed to Mg2+ ions. The reliability of these in vivo measurements depends on the availability of an appropriate in vitro calibration to determine the limits of chemical shifts of unbound ATP and Mg-ATP complexes, using solutions that mimic the in vivo cytosolic conditions as far as possible. We used an algorithm and software to allow a quantitative definition of the Mg(2+)-binding molecules to build a semi-empirical equation that correlates the chemical shift of the beta-ATP signal to the [Mg2+] taking into account the amount of Mg2+ bound to all other constituents in solution. Our experiments resulted in a simple and reliable equation directly usable to assess in vivo the free cytosolic magnesium concentration of human brain by 31P MRS. Our method is also flexible enough to make it suitable for in vivo measurements of [Mg2+] in other organs and tissues.

Adenosine Triphosphate↗
PubMed1996

Partial block of glycolysis in late-onset phosphofructokinase deficiency myopathy.

A late-onset, myopathic variant of phosphofructokinase (PFK) deficiency has been previously described in two patients of Ashkenazic descent. We report here on a non-Ashkenazic woman with the onset, at the age of 48 years, of a progressive limb girdle myopathy that was not preceded by a history of exercise intolerance. Muscle biopsy findings at the age of 58 years showed deposition of amylopectin-like material in muscle fibers and the absence of histochemical PFK activity. Enzymatic PFK activity in vitro was only 4% of normal. Since the forearm ischemic exercise test induced a sub-normal production of serum lactate, the patient underwent phosphorus magnetic resonance spectroscopy (31P-MRS), a non-invasive method that allows in vivo assessment of the functional status of the glycolytic pathway and mitochondrial oxidative metabolism by measuring the high-energy phosphates and cytosolic pH. In vivo, 31P-MRS disclosed a residual glycolytic flux and a normal rate of ATP production both at rest and during exercise. These results suggest that, in some patients, muscle PFK deficiency may be partial in vivo, and more severe in vitro, possibly due to protein or mRNA instability rather than absence. The presence of these findings in a patient with the late-onset myopathic form is compatible with a distinct pathogenetic mechanism, relying on progressive polysaccharide accumulation, rather than on acute energetic shortage in muscle fibers.

Female↗