Biomedical subjects
Publications and source records attributed to B Barbiroli.
In children, narcolepsy may be the symptom of a brain lesion or genetic disease. The authors report two cases with severe narcolepsy-cataplexy emerging in childhood in close temporal association with obesity and precocious puberty.
The authors used 1H-MRS to investigate hypothalamic metabolism in 26 patients with cluster headache (CH) and 12 healthy subjects. Hypothalamic N-acetylaspartate/creatine was reduced in patients with CH vs controls (p < 0.01). Dividing the patients into episodic CH outside- and in-cluster periods and chronic CH, the hypothalamic N-acetylaspartate/creatine in all three subgroups of patients was reduced. The reduction of the neuronal marker N-acetylaspartate is consistent with hypothalamic neuronal dysfunction in patients with CH.
Over the last two decades magnetic resonance spectroscopy has been extensively used to investigate the role of energy metabolism impairment in the physiopathology of migraine. In this paper we review the studies performed on migraine sufferers during headache attacks as well as interictally. Overall there is currently evidence that migraine is associated with a generalised disorder of energy metabolism and that this, in association with other susceptibility factors, may be an important feature that lowers the threshold for triggering migraine attacks.
BACKGROUND: Overlapping phenotypes including LHON, MELAS, and Leigh syndrome have recently been associated with numerous mtDNA point mutations in the ND5 gene of complex I, now considered a mutational hot spot. OBJECTIVE: To identify the mtDNA defect in a family with a prevalent ocular phenotype, including LHON-like optic neuropathy, retinopathy, and cataract, but characterised also by strokes, early deaths, and miscarriages on the maternal line. RESULTS: Sequencing of the entire mitochondrial genome from the proband's muscle DNA identified the heteroplasmic 13042G-->A transition, which was previously described only once in a patient with a different mitochondrial disease. This mutation fulfils the major pathogenic criteria, inducing an amino acid change (A236T) at an invariant position in a highly conserved domain of the ND5 gene. Phosphorus magnetic resonance spectroscopy in the proband disclosed an in vivo brain and skeletal muscle energy metabolism deficit. CONCLUSIONS: These findings conclusively establish the pathogenic role of the 13042G-->A mutation and underscore its variable clinical expression.
Clinical MRI/MRS applications require radio frequency (RF) surface coils positioned at an arbitrary angle alpha with respect to B(0). In these experimental conditions the standard circular loop (CL) coil, producing an axial RF field, shows a large signal loss in the central region of interest (ROI). We demonstrate that transverse-field figure-of-eight (FO8) RF surface coils design are not subject to the same amount of signal loss in the central ROI as loop coils when their orientations are changed. The 1.5-T CL and FO8 prototypes (diameter = 10 cm) were built on Plexiglas using copper strips (width = 4 mm, thickness = 100 mum). The two linear elements of the FO8 coil were 1 cm apart. Axial spoiled gradient echo (SPGR) images of a phantom containing doped water were acquired with the coil plane at alpha=0 degrees , 45 degrees , and 90 degrees . As alpha increases, the CL images show, in the central ROI, a signal that decreases from a maximum value to zero. Whereas the FO8 images show, in the same ROI, a signal that varies little from the maximum value (20%). Optimized FO8 coils can be oriented with the coil plane positioned along any direction with respect to B(0) without significant signal loss. Transverse RF coil design should be useful for clinical MRS studies and also for parallel imaging techniques where versatile RF coils disposed along arbitrary directions are required.
A dysfunction of the orexin (hypocretin) system in the hypothalamus has recently been linked to the pathogenesis of narcolepsy. The authors used in vivo proton MR spectroscopy to assess the N-acetylaspartate (NAA) content in the hypothalamus of narcoleptic patients. Hypothalamic NAA/creatine-phosphocreatine was reduced in narcoleptic patients compared with control subjects (p < 0.01). Hypothalamic neuronal loss/damage is a central pathogenetic feature in narcolepsy.
BACKGROUND: Brain edema and increased intracranial pressure worsen prognosis in patients with end-stage chronic cirrhosis. OBJECTIVE: To use diffusion-weighted imaging (DWI) to quantify water apparent diffusion coefficient (ADC) in different brain regions of patients with chronic liver failure with or without hepatic encephalopathy. METHODS: The authors studied 14 patients with viral liver cirrhosis and 12 sex- and age-matched healthy volunteers. Seven patients had no clinical evidence of hepatic encephalopathy; six had grade I hepatic encephalopathy; and one had grade II hepatic encephalopathy. Brain DWI was obtained using a single-shot echo-planar imaging sequence, and four gradient strengths (b values = 0, 300, 600, and 900 s/mm(2)) were applied to calculate the average diffusivity maps. RESULTS: Mean ADC values in the brains of patients with cirrhosis were significantly increased in all selected regions of interest (caudate, putamen, and pallidus nuclei; occipital, parietal, and frontal lobe white matter) except in the thalamus. Venous ammonia was linearly related to ADC values in deep gray and white matter regions of interest. CONCLUSIONS: Brain water apparent diffusion coefficient is increased in patients with chronic liver disease and may be useful in monitoring patients with hepatic encephalopathy.
A mathematical model is proposed showing that the mono-exponential recovery of phosphocreatine (PCr) after exercise is an approximation of a more complex pattern, which is identified by a second-order differential equation. The model predicts the possibility of three different patterns of PCr recovery: bi-exponential, oscillatory damped, and critically damped; the mono-exponential pattern being a particular case of the functions which are solutions of the differential equation. The model was tested on a sample of recovery data from 50 volunteers, checking whether the recovery patterns predicted by the model lead to a significant improvement of fit (IF) compared with the mono-exponential pattern. Results show that the IF is linked to pH. Bi-exponential solutions showed an IF in the pH range 6.65-6.85, and the oscillatory solutions at pH>6.9. Critically damped solutions displayed a poor IF. Oscillation frequencies found in the oscillatory recoveries increase at increasing pH. These results show that pH has a pivotal role on the pattern of PCr recovery and implications on the regulation of oxidative phosphorylation are discussed.
Gliomatosis cerebri is a rare form of diffusely infiltrating glioma that is typically resistant to conventional chemotherapy and radiation therapy and carries a poor prognosis. Temozolomide has shown antineoplastic activity against malignant gliomas and more recently was beneficial in one patient with gliomatosis cerebri. To make an objective assessment of the effect of long-term temozolomide administration in a patient with gliomatosis cerebri we used brain proton magnetic resonance spectroscopy and structural MRI. A 46-year-old man with gliomatosis cerebri was treated with temozolomide (200 mg/m(2) per day for 5 days every 28 days). Twenty cycles of temozolomide resulted in a marked reduction in choline and scyllo-inositol content, as detected using brain proton MR spectroscopy, indicating reduced tumor cellularity and/or growth rate. Neurochemical improvements were associated with normalization of the signal intensity in most of the previously affected cerebral regions and regression of mass effect on MRI. A left pyramidal syndrome, present at the start of the treatment, disappeared. Our observation lends support to larger clinical trials evaluating the use of temozolomide to treat this brain tumor.
We used phosphorus magnetic resonance spectroscopy (31P-MRS) to assess in vivo the brain bioenergetics of 28 patients with liver cirrhosis. Seven had clinical hepatic encephalopathy (HE), nine hepatocellular carcinoma. 31P-MRS was performed by the DRESS localisation technique on occipital lobes. Brain phosphocreatine was significantly reduced in patients with or without overt HE, and inorganic phosphate was increased in both groups of patients. The cytosolic phosphorylation potential (PP), the relative rate of oxidative metabolism and the regulatory [ADP] were all abnormal. Brain PP was inversely correlated with serum ammonia concentration only in patients without liver cancer. The degree of bioenergetic failure was significantly higher in the presence of overt encephalopathy. We conclude that patients with liver cirrhosis had a derangement of brain energy metabolism, and that 31P-MRS offers a non-invasive method for investigating the underlying mechanisms of HE, with relevant implications in the identification and management of this condition.
Occipital lobe and calf muscle energy metabolism were studied in vivo by magnetic resonance spectroscopy (31P-MRS) in four members of a family harbouring the mitochondrial DNA G3460A mutation causing Leber's hereditary optic neuropathy (LHON). Three siblings carried 100% mutated mitochondrial DNA (homoplasmy), while their mother had coexistence of mutated and wild-type mitochondrial DNA (heteroplasmy). Indices of brain energy metabolism on 31P-MRS were abnormal in all subjects examined, but the muscle oxidative phosphorylation rate was normal. These findings indicate a tissue specific distribution of the biochemical expression of the G3460A LHON mutation and suggest that extramitochondrial factors, such as nuclear genes, may influence expression of this mutation in vivo.
We used phosphorus magnetic resonance spectroscopy to assess in vivo the brain cytosolic free magnesium concentration and the free energy released by the reaction of adenosine triphosphate (ATP) hydrolysis (DeltaG(ATPhyd)), the latter being an index of the cell's bioenergetics condition. We studied 78 patients with migraine in attack-free periods (7 with migraine stroke, 13 with migraine with prolonged aura, 37 with migraine with typical aura or basilar migraine, and 21 with migraine without aura), and 13 patients with cluster headache. In the occipital lobes of all subgroups of migraine and in cluster headache patients cytosolic free [Mg(2+)] as well as the free energy released by the reaction of ATP hydrolysis were significantly reduced. Among migraine patients, the level of free energy released by the reaction of ATP hydrolysis and the cytosolic free [Mg(2+)] showed a trend in keeping with the severity of clinical phenotype, both showing the lowest values in patients with migraine stroke and the highest in patients with migraine without aura. These results support our current hypothesis that the reduction in free [Mg(2+)] in tissues with mitochondrial dysfunction is secondary to the bioenergetics deficit, and are against a primary role of low brain cytosolic free [Mg(2+)] in causing the bioenergetics deficit in headache.
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Brain and muscle energy metabolism was assessed in vivo in five patients with progressive supranuclear palsy (PSP) using phosphorous magnetic resonance spectroscopy (31P MRS). 31P MRS disclosed a reduced phosphocreatine (PCr) and an increased calculated free adenosine diphosphate (ADP) in the occipital lobes of all patients. In our patients with PSP, inorganic phosphate (Pi) was significantly increased and Mg2+ was reduced. In the gastrocnemius muscle, Pi at rest was increased in four patients, and the three patients who were able to perform an incremental exercise showed a rate of PCr postexercise recovery slower than control subjects. Our findings show that multisystemic deficit of energy metabolism occurs in PSP and suggest that it may play a role in the pathogenesis of this disorder.
Cytosolic free [Mg(2+)] can be assessed in vivo by (31)P-MRS from the chemical shift of beta-ATP. The reliability of in vivo measurements depends on the availability of appropriate in vitro calibration curves obtained by using solutions that mimic the in vivo cytosolic conditions as far as possible. We build a semi-empiric equation that correlates the chemical shift of beta-ATP to free [Mg(2+)] taking into account the amount of Mg(2+) bound to all other ligands in solution. Our experiments resulted in a reliable ten-parameters equation directly usable to assess the cytosolic free [Mg(2+)] of human skeletal muscle at rest, during work and recovery. Our experiments also resulted in a new equation that allows the assessment of cytosolic pH from the chemical shift of Pi taking into account the measured free [Mg(2+)]. To perform simultaneous calculation of free [Mg(2+)] and pH in the skeletal muscle in different metabolic conditions we developed a specific software package available on Internet (http://www.unibo.it/bioclin) together with another program based on the equation previously obtained to calculate cytosolic free [Mg(2+)] in the human brain. The reliability and effectiveness of our equations and software were tested on the calf muscles of healthy volunteers at rest, during work and recovery.
The pathogenic role of 'secondary' mitochondrial DNA (mtDNA) point mutations, when occurring in patients with Leber's hereditary optic neuropathy (LHON) in association with 'primary' mutations, is still controversial. We used phosphorus magnetic resonance spectroscopy to establish whether two of these 'secondary' LHON mtDNA mutations, 4216/ND1 and 13708/ND5 (haplogroup J), further affect in vivo mitochondrial oxidative metabolism in subjects with the 'primary' 11778/ND4 mtDNA mutation. Brain and skeletal muscle energy metabolism was assessed in 10 subjects homoplasmic for the 11778/ND4 mtDNA mutation and 10 subjects homoplasmic for the same mutation occurring on the haplogroup J mtDNA background. Brain phosphocreatine concentration and phosphorylation potential were significantly reduced and brain inorganic phosphate concentration was significantly increased compared with controls in both groups of 11778/ND4-positive subjects. The degree of reduction in the phosphocreatine concentration and phosphorylation potential and of increase in the inorganic phosphate concentration was, however, similar in the two groups with the 11778/ND4 mtDNA mutation with or without the haplogroup J. Similarly, the rate of muscle phosphocreatine resynthesis after exercise, a sensitive index of the rate of mitochondrial ATP production, was reduced by the same extent in both groups of LHON subjects. This in vivo study does not support synergism of the 4216/ND1 and 13708/ND5 'secondary' mutations with the 11778/ND4 'primary' mutation in determining the deficit of energy metabolism in LHON.
We performed in vivo phosphorus 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.
We used in vivo phosphorus magnetic resonance spectroscopy (31P-MRS) to study the effect of CoQ10 on the efficiency of brain and skeletal muscle mitochondrial respiration in ten patients with mitochondrial cytopathies. Before CoQ, brain [PCr] was remarkably lower in patients than in controls, while [Pi] and [ADP] were higher. Brain cytosolic free [Mg2+] and delta G of ATP hydrolysis were also abnormal in all patients. MRS also revealed abnormal mitochondrial function in the skeletal muscles of all patients, as shown by a decreased rate of PCr recovery from exercise. After six-months of treatment with CoQ (150 mg/day), all brain MRS-measurable variables as well as the rate of muscle mitochondrial respiration were remarkably improved in all patients. These in vivo findings show that treatment with CoQ in patients with mitochondrial cytopathies improves mitochondrial respiration in both brain and skeletal muscles, and are consistent with Lenaz's view that increased CoQ concentration in the mitochondrial membrane increases the efficiency of oxidative phosphorylation independently of enzyme deficit.