Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich ataxia, decreased iron-sulphur cluster and heme formation leads to mitochondrial iron accumulation and ensuing oxidative damage that primarily affects sensory neurons, the myocardium, and endocrine glands. We assessed the possibility of reducing brain iron accumulation in Friedreich ataxia patients with a membranepermeant chelator capable of shuttling chelated iron from cells to transferrin, using regimens suitable for patients with no systemic iron overload. Brain magnetic resonance imaging (MRI) of Friedreich ataxia patients compared with agematched controls revealed smaller and irregularly shaped dentate nuclei with significantly (P < .027) higher H-relaxation rates R2*, indicating regional iron accumulation. A 6-month treatment with 20 to 30 mg/kg/d deferiprone of 9 adolescent patients with no overt cardiomyopathy reduced R2* from 18.3 s ؊1 (؎ 1.6 s ؊1 ) to 15.7 s ؊1 (؎ 0.7 s ؊1 ; P < .002), specifically in dentate nuclei and proportionally to the initial R2* (r ‫؍‬ 0.90). Chelator treatment caused no apparent hematologic or neurologic side effects while reducing neu- IntroductionTissue iron overload and ensuing organ damage have generally been identified with transfusional hemosiderosis and genetic hemochromatosis. 1 Liver, heart, and endocrine glands are among the most affected organs in these forms of systemic iron overload. 1 The source of tissue iron overload has been traced to plasma iron originating from enteric hyperabsorption of the metal and/or enhanced red cell destruction. The labile forms of plasma iron (LPI) that appear as transferrin become saturated, permeate into particular cell types by unregulated mechanisms, and cause labile iron pools to raise and challenge cellular antioxidant capacities. 2 However, in chronic inflammation 3 and in various genetic disorders, 4 iron accumulates in particular cell types attaining toxic levels, even in the absence of circulating LPI and often even in iron-deficient plasma. In Friedreich ataxia (FA), an expansion of a GAA repeat in the first intron of the nuclear encoded frataxin gene 5,6 results in underexpression of a mitochondrial protein involved in the assembly of iron-sulphur cluster proteins (ISPs) and/or in protecting mitochondria from iron-mediated oxidative damage. 7 The defective ISP formation that causes a combined aconitase and respiratory chain deficiency (complex I-III) leads in turn to mitochondrial accumulation of labile iron 8,9 and ensuing oxidative damage in brain, heart, and endocrine glands. However, the pathophysiologic role of mitochondrial iron accumulation in oxidative damage found in FA 5,9 and other neurologic disorders [10][11][12][13] has not been resolved.In analogy to transfusional iron overload, histopathologic and magnetic resonance imaging (MRI) studies of FA patients have shown that iron accumulates not only in the heart but also in the spinocerebellar tracts (dentate nuclei) and spinal cord. 10 Those and othe...

Although the gene defect responsible for Huntington disease (HD) has recently been identified, the pathogenesis of the disease remains obscure. One potential mechanism is that the gene defect may lead to an impairment of energy metabolism followed by slow excitotoxic neuronal injury. In the present study we examined whether chronic administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, can replicate the neuropathologic and clinical features of HD in nonhuman primates. After 3-6 weeks of 3-NP administration, apomorphine treatment induced a significant increase in motor activity as compared with saline-treated controls. Animals showed both choreiform movements, as well as foot and limb dystonia, which are characteristic of HD. More prolonged 3-NP treatment in two additional primates resulted in spontaneous dystonia and dyskinesia accompanied by lesions in the caudate and putamen seen by magnetic resonance imaging. Histologic evaluation showed that there was a depletion of calbindin neurons, astrogliosis, sparing of NADPH-diaphorase neurons, and growth-related proliferative changes in dendrites of spiny neurons similar to changes in HD. The striosomal organization of the striatum and the nucleus accumbens were spared. These findings show that chronic administration of3-NP to nonhuman primates can replicate many of the characteristic motor and histologic features of HD, further strengthening the possibility that a subtle impairment of energy metabolism may play a role in its pathogenesis.Huntington disease (HD) is an inherited neurodegenerative disease characterized by choreiform movements, cognitive impairment, and emotional disturbance. Although the gene defect in HD has recently been identified, the mechanism by which it leads to neuronal degeneration remains obscure (1). A leading hypothesis is that excitotoxicity may contribute to the pathogenesis of HD (2, 3). Studies in both rodents and primates show striking similarities between striatal lesions produced by N-methyl-D-aspartate (NMDA) agonists and the neurochemical and histologic features of HD (4-6). Further evidence in support of an NMDA excitotoxic mechanism is the finding of a preferential loss of striatal NMDA receptors, which may occur early in the disease process (7,8). One means by which slow excitotoxic neuronal death may occur is as a consequence of a defect in energy metabolism (2, 3). Disruption of ATP synthesis may lead to partial neuronal depolarization with activation of voltage-dependent NMDA receptors and secondary excitotoxic neuronal damage (9-12). UnderThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.these circumstances ambient levels of glutamate are sufficient to induce neuronal death. Several studies have reported decreased glucose metabolism and abnormalities in electron transport enzymes in HD (2). We recently obtained in ...

The cortical processing of vestibular information is not hierarchically organized as the processing of signals in the visual and auditory modalities. Anatomic and electrophysiological studies in the monkey revealed the existence of multiple interconnected areas in which vestibular signals converge with visual and/or somatosensory inputs. Although recent functional imaging studies using caloric vestibular stimulation (CVS) suggest that vestibular signals in the human cerebral cortex may be similarly distributed, some areas that apparently form essential constituents of the monkey cortical vestibular system have not yet been identified in humans. Galvanic vestibular stimulation (GVS) has been used for almost 200 years for the exploration of the vestibular system. By contrast with CVS, which mediates its effects mainly via the semicircular canals (SCC), GVS has been shown to act equally on SCC and otolith afferents. Because galvanic stimuli can be controlled precisely, GVS is suited ideally for the investigation of the vestibular cortex by means of functional imaging techniques. We studied the brain areas activated by sinusoidal GVS using functional magnetic resonance imaging (fMRI). An adapted set-up including LC filters tuned for resonance at the Larmor frequency protected the volunteers against burns through radio-frequency pickup by the stimulation electrodes. Control experiments ensured that potentially harmful effects or degradation of the functional images did not occur. Six male, right-handed volunteers participated in the study. In all of them, GVS induced clear perceptions of body movement and moderate cutaneous sensations at the electrode sites. Comparison with anatomic data on the primate cortical vestibular system and with imaging studies using somatosensory stimulation indicated that most activation foci could be related to the vestibular component of the stimulus. Activation appeared in the region of the temporo-parietal junction, the central sulcus, and the intraparietal sulcus. These areas may be analogous to areas PIVC, 3aV, and 2v, respectively, which form in the monkey brain, the "inner vestibular circle". Activation also occurred in premotor regions of the frontal lobe. Although undetected in previous imaging-studies using CVS, involvement of these areas could be predicted from anatomic data showing projections from the anterior ventral part of area 6 to the inner vestibular circle and the vestibular nuclei. Using a simple paradigm, we showed that GVS can be implemented safely in the fMRI environment. Manipulating stimulus waveforms and thus the GVS-induced subjective vestibular sensations in future imaging studies may yield further insights into the cortical processing of vestibular signals.