PINK1 parkinsonism and Parkinson disease: distinguishable brain mitochondrial function and metabolomics.

Mutations in the PINK1 gene are associated with early onset autosomal recessive parkinsonism (EOP), which is characterized by a phenotypic presentation that, although variable, generally overlaps with that of idiopathic Parkinson Disease (PD). The clinical features and brain metabolomics of a patient who was compound heterozygous for the novel association of PINK1 A168P/W437X mutations have been extensively characterized. Apart from a few typical EOP findings, the clinical features and SPECT mostly overlapped with typical idiopathic PD. Brain metabolomics, as examined by magnetic resonance spectroscopy and PET, were clearly distinguishable.

Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction.

BACKGROUND: The axonal forms of Charcot-Marie-Tooth (CMT2) disease are a clinically and genetically heterogeneous group of disorders. Mitofusin 2 gene (MFN2) mutations are the most common cause of CMT2. Complex phenotypes have been described in association with MFN2 gene mutations, including CMT2 with pyramidal features (hereditary motor and sensory neuropathy [HSMN V]) and CMT2 with optic atrophy (HMSN VI). OBJECTIVE: To report on the clinical, neurophysiologic, and neuropathologic features of an Italian family with a novel MFN2 gene mutation and investigate brain functional parameters using magnetic resonance spectroscopy (MRS). METHODS: Three family members, a father and his two sons, were affected by peripheral neuropathy, cognitive impairment, and poor nocturnal vision (also optic neuropathy in one case). A member of this family also showed spastic paraparesis. The MFN2 gene sequence was analyzed. A sural nerve biopsy as well as brain (1)H-MRS and (31)P-MRS were evaluated in two patients. RESULTS: Affected family members carried a novel MFN2 missense mutation, namely R104W, located within the critical GTPase domain of the protein which affects a highly conserved amino acid position. Sural nerve biopsies showed a normal mitochondrial network, particularly at the nodes of Ranvier, upon electron microscopy examination. A significant defect of high energy phosphates (HEPs) in the visual cortex was observed at rest by (31)P-MRS in the adult proband, while his son showed a defective recovery of HEPs after stimulation of the visual cortex. CONCLUSION: Cognitive impairment may be another feature of the MFN2-related phenotype. The widespread peripheral and CNS involvement, as well as the neurosensorial defects, underline the similarities among MFN2-related and primary mitochondrial disorders.

Myoinositol content in the human brain is modified by transcranial direct current stimulation in a matter of minutes: a 1H-MRS study.

Brain content of myoinositol (mI) has been shown to be altered in several neuropsychiatric conditions. Likewise, various forms of electric currents have been applied to the human brain for therapeutic purposes in neuropsychiatric diseases. In this study we aimed to depict the effects of low-power transcranial direct current stimulation (tDCS) on brain mI by proton magnetic resonance spectroscopy ((1)H-MRS). We studied two groups of five healthy subjects by (1)H-MRS: the first group was studied before and after both anodal and sham (placebo) tDCS over the right frontal lobe, and the second group was studied at the same intervals without undergoing either sham or anodal tDCS. Anodal tDCS induced a significant increase of mI content at 30 min after stimulation offset (141.5 +/- 16.7%, P < 0.001) below the stimulating electrode but not in distant regions, such as the visual cortex, whereas sham tDCS failed to induce changes in mI. Neither N-acetyl-aspartate (NAA) nor the other metabolite contents changed after anodal or sham stimulation. (1)H-MRS represents a powerful tool to follow the regional effects of tDCS on brain mI and, possibly, on the related phosphoinositide system.

Parkinson's disease, chronic hydrocarbon exposure and striatal neuronal damage: a 1-H MRS study.

Several patients with Parkinson' s disease (PD) reveal an history of chronic exposure to hydrocarbon-solvents. Chronic exposure to hydrocarbon-solvents has been proposed as a risk factor for more severe forms of PD with earlier onset of symptoms and reduced response to dopaminergic therapy. A direct correlation between disease severity and exposure degree has been previously shown. Seven exposed PD patients (two with low degree exposure and five with high degree exposure), 10 unexposed PD patients matched for sex, age and Hoehn and Yahr scale (=3 in the "on" phase), and 10 unexposed PD patients matched for sex, age and l-dopa daily intake instead of disease severity (Hoehn and Yahr scale=3.5 in the "on" phase) were studied. Twenty normal subjects without previous exposure to hydrocarbon-solvents and matched for age and sex with HPD patients were studied for comparison. The purpose of the study was to assess neuronal degeneration in the striatum of exposed vs unexposed PD patients. The authors investigated whether neuronal damage/loss was detectable in the lentiform nucleus measuring N-acetylaspartate (NAA) levels by 1-H MRS. Multiple single voxel MRS water-suppressed spectra were obtained also from the white matter and the occipital lobe. NAA was normal in the lentiform nucleus of patients with low exposure as well as in patients with no exposure whereas it was decreased in PD patients with high degree exposure. White matter and occipital lobe NAA content was normal both in exposed and unexposed PD patients. Clinical expression is more severe in PD patients with previous high degree solvent exposure because of the associated post-synaptic damage of the nigro-striatal pathway.

Brain activation in normal subjects and in patients affected by mitochondrial disease without clinical central nervous system involvement: a phosphorus magnetic resonance spectroscopy study.

It remains unclear whether brain energetics is disturbed in patients with mitochondrial disease without clinical central nervous system involvement (MDW). The authors used the high temporal and spatial resolution phosphorus magnetic resonance spectroscopy (31P MRS) technique that they developed to study high energy phosphates (HEPs) and intracellular pH (pH) in the visual cortex of 9 normal subjects and 5 MDW patients with single mtDNA deletion at rest, during, and after visual activation. In normal subjects, HEPs remained unchanged during activation but rose significantly (by 17%) during recovery, and pH increased during visual activation with a slow return to rest values. In MDW patients, HEPs were within the normal range at rest and did not change during activation, but fell significantly (by 22%) in the recovery period; pH did not reveal a homogeneous pattern. In the brain of patients with MDW, energy balance remains normal until oxidative metabolism is intensively stressed, as during a postactivation phase. The heterogeneity of the physicochemical environment (that is, pH) suggests various degrees of subclinical brain involvement. The combined use of MRS and brain activation is fundamental for the study of brain energetics and may prove an important diagnostic tool in patients with MDW.

Energetics of 3.5 s neural activation in humans: a 31P MR spectroscopy study.

No direct information on brain energetics and energy-related compounds in the first seconds of physiological activation has been reported to date. In this study visual cortex high energy phosphate changes were monitored in 11 normal subjects during 3.5 s activation and the following 23.5 s by a simple 31P magnetic resonance spectroscopic method. An intraactivation decrease of phosphocreatine (PCr) was observed in all subjects, with changes in pH in three, one of them also presenting a change in adenosine triphosphate (ATP). In the subgroup of eight subjects without changes in pH, the mean rate of mean PCr decrease (D(PCr)) was 7.24 +/- 0.78%/s, and the postactivation mean rate of mean PCr recovery was <1/2 D(PCr). Short phasic neural activity requires a large amount of energy, i.e., at least three times basal consumption, in agreement with theoretical calculations. Additional energy demands in the visual cortex are several times those measured by positron emission tomography during prolonged stimulation studies, implying that mean energy requirements decrease with increases in duration of stimulation. During short activation, the vascular responses as detected by brain-mapping techniques (BMT) are preceded by an important reduction of the intracellular high-energy phosphate content, which returns to resting values during an interval that corresponds to the poststimulation return of BMT signals to baseline.

Central nervous system trans-synaptic effects of acute axonal injury: a 1H magnetic resonance spectroscopy study.

N-acetylaspartate (NAA) has previously been proposed as a neuronal marker. 1H magnetic resonance spectroscopy (MRS) is able to detect NAA in brain, and decreases of NAA have been documented after brain injury. The reason for this decrease is not fully understood and neuron loss damage and "dysfunction" have all been proposed. It is hypothesized that acute central nervous system (CNS) deafferentation causes a trans-synaptic NAA decrease and that high resolution 1H MRS is able to detect such a decrease. To test this hypothesis, an experimental model was used in which axonal lesions were obtained by stretch injury in guinea pig right optic nerve (95-99% crossed fibers). The trans-synaptic concentration of NAA, total creatine (Cr), and the NAA/Cr ratio in lateral geniculate bodies (LGB) and superior colliculi (SC) sample extracts were measured 72 h later by high resolution 1H MRS. In the left LGB/SC, which is where right optic nerve fibers project, reductions of NAA and NAA/Cr were found whereas Cr levels were normal. NAA, NAA/Cr, and Cr values were all normal in the right LGB/SC. Histology and EM findings revealed no abnormalities. At 7 days, left LGB/SC NAA and NAA/Cr values were in the normal range. It was concluded that 1) acute deafferentation in the CNS causes a trans-synaptic decrease of NAA levels that can be detected by 1H MRS and 2) NAA decrease may be due to changes of NAA metabolism caused by functional neuronal inactivity rather than neuronal loss, injury or "dysfunction." 1H MRS is a potential tool for the study of functional effect of CNS lesions in vivo.

Brain pH in head injury: an image-guided 31P magnetic resonance spectroscopy study.

It has been suggested that brain acidosis may follow head trauma, and therapies aimed at correcting acidosis have been proposed. Direct measurements of intracellular pH, however, have thus far not been possible in clinical situations. We have studied the intracellular brain pH in 22 patients after head injury (mean Glasgow Coma Score 6.1). Patients were investigated by a combined approach of phosphorus 31 magnetic resonance spectroscopy and magnetic resonance imaging (overall examination time 50-75 min) at a mean time of 11 days after injury (36 hours to 24 days). 31P spectra were obtained in 11 patients on assisted ventilation and in 11 patients on spontaneous ventilation. These spectra were analyzed to yield the pH in the regions studied in all the patients. All pH values were in the normal or alkalotic range when compared with 6 age-matched normal controls. No differences were found between patients on assisted ventilation and patients on spontaneous ventilation. When analyzed as a group, the brain pH in the focal lesions appeared to increase in the first days, to reach a peak in the alkalotic range in the second week, and to return toward normal within 3 weeks from acute injury. Our results suggest that there is no evidence of posttraumatic intracellular brain acidosis in recent human head injury, and therefore, therapies aimed at alkalinizing brain cells need to be reconsidered.

Validation studies of iodine-123-iodoamphetamine as a cerebral blood flow tracer using emission tomography.

We studied the radioisotope iodine-123-iodoamphetamine ([123I]IMP) and its performance in single-photon emission computed tomographic (SPECT) studies of cerebral blood flow (CBF). In seven normal volunteers, IMP/SPECT CBF measurements were calculated using a two-compartment model and were compared with the results of CBF measurements utilizing (O15)-H2O and positron emission tomography (PET). Calculated mean PET CBF was 57.6 ml/100 g/min while the SPECT CBF value was 47.3 ml/100 g/min. The response of IMP/SPECT CBF to alterations in arterial PaCO2 was studied in hypo-, eu- and hypercarbic subjects. SPECT CBF values showed a reactivity of 1.03 ml/100 g/min per mmHg PaCO2 change. These results show that the IMP/SPECT CBF technique may be used for quantitative imaging of CBF in man. They provide further support for IMP as a CBF tracer.

Relation of hyperglycemia early in ischemic brain infarction to cerebral anatomy, metabolism, and clinical outcome.

We studied the relation of serum glucose level measured in the first 12 hours of symptoms to the clinical findings, results of computed tomography (CT), and patterns of cerebral metabolism in 39 patients who had acute ischemic cerebral infarction. Structural damage was assessed by CT. Metabolic disruption was assessed using 18F-fluorodeoxyglucose and positron emission tomography (PET). Median initial serum glucose concentration was 155 mg/dl (6.7 mM). Clinical recovery was significantly poorer in patients with initial serum glucose levels higher than the median (p less than 0.05, chi square). PET tended to show normal results or minor abnormalities in patients with initial glucose levels less than the median, as opposed to lobar or multilobe abnormalities in patients with levels that were higher than the median (p less than 0.05, Kendall's Tau b). The severity of hypometabolism in the ischemic region, expressed as the percent asymmetry of local cerebral glucose metabolism between homologous brain regions, was greater in patients with initial glycemia concentrations higher than the median (p less than 0.001, t test). Relationships of serum glucose level with metabolic derangement and structural damage, but not outcome, held true in patients without a history of diabetes mellitus.

Cortical pathophysiology and clinical neurologic abnormalities in acute cerebral ischemia. A serial study with single photon emission computed tomography.

We studied brain cortical radioactive tracer activity in a consecutive series of nine patients with acute hemispheric ischemic stroke at their first cerebral ischemic stroke at their first cerebral ischemic episode. Results from N,N,N'-trimethyl-N'- (2-hydroxy-3-methyl-5-[123-I]-iodobenzyl)-1,3 propanediamine-2HCl (four patients) and technetium Tc 99m hexamethylpropyleneamine oxime (five patients) single photon emission computed tomographic studies were compared with x-ray computed tomography (CT) and clinical findings within the first 48 hours, on day 10, and on day 30 after the clinical ictus. Cortical hypoactivity agreeing with the clinical findings was found on all initial scans but not in the follow-up studies. Cortical activity on the affected side in patients with stroke was significantly lower when compared with cortical activity in sex- and age-matched controls (n = 21). Computed tomography (with contrast) was less sensitive in detecting the ischemic lesions. These studies demonstrate that in the acute phase of stroke there is a single photon emission computed tomographic cortical disturbance that agrees with clinical findings, even when computed tomography scan infarction is limited to subcortical structures.