Activity of complexes II, III, and IV of the mitochondrial electron transport system (ETS) is reduced in postmortem Huntington's disease (HD) striatum, suggesting that reduced cerebral oxidative phosphorylation may be important in the pathogenesis of neuronal death. We investigated mitochondrial oxidative metabolism in vivo in the striatum of 20 participants with early, genetically proven HD and 15 age-matched normal controls by direct measurements of the molar ratio of cerebral oxygen metabolism to cerebral glucose metabolism (CMRO2/CMRglc) with positron emission tomography. There was a significant increase in striatal CMRO2/CMRglc in HD rather than the decrease characteristic of defects in mitochondrial oxidative metabolism (6.0 ؎ 1.6 vs. 5.1 ؎ 0.9, P ‫؍‬ 0.04). CMRO2 was not different from controls (126 ؎ 37 vs. 134 ؎ 31 mol 100 g ؊1 min ؊1 , P ‫؍‬ 0.49), whereas CMRglc was decreased (21.6 ؎ 6.1 vs. 26.4 ؎ 4.6 mol 100 g ؊1 min ؊1 , P ‫؍‬ 0.01). Striatal volume was decreased as well (13.9 ؎ 3.5 vs. 17.6 ؎ 2.0 ml, P ‫؍‬ 0.001). Increased striatal CMRO2/CMRglc with unchanged CMRO2 is inconsistent with a defect in mitochondrial oxidative phosphorylation due to reduced activity of the mitochondrial ETS. Because HD pathology was already manifest by striatal atrophy, deficient energy production due to a reduced activity of the mitochondrial ETS is not important in the mechanism of neuronal death in early HD. Because glycolytic metabolism is predominantly astrocytic, the selective reduction in striatal CMRglc raises the possibility that astrocyte dysfunction may be involved in the pathogenesis of HD.cerebral metabolism ͉ mitochondria ͉ oxidative phosphorylation ͉ basal ganglia H untington's disease (HD) is a degenerative neurological disease that is manifested by abnormal involuntary movements, psychiatric disorders, and dementia. It has a variable age at onset and progresses slowly to death 15-25 years after symptoms develop. HD is neuropathologically characterized by early selective loss of medium spiny neurons in striatum (caudate and putamen) with later neuronal loss in cortex, globus pallidus, and other structures. Although it is now known that an expansion of the triple repeat CAG in the IT15 gene on chromosome 4 leads to production of an abnormal polyglutamine string on the huntingtin protein, it is still unclear how this leads to selective neuronal cell death (1). In postmortem specimens from the striatum of patients with HD, reduced activity of the mitochondrial electron transport system (ETS) (29-76% decreases in complexes II and III and 30-62% decreases in complex IV) has been measured in vitro, although these findings have not been universal (2-6). These findings and the correlative effects of mitochondrial toxins in producing striatal neuronal loss in animal models suggest that excitotoxicity triggered by reduced ATP production as a consequence of impaired mitochondrial oxidative phosphorylation may be an important mechanism for neuronal death in HD (7). Alternatively, these mitochondrial changes may be ...

These data suggest that STN stimulation increases firing of STN output neurons, which increases inhibition of thalamocortical projections, ultimately decreasing blood flow in cortical targets. STN stimulation appears to drive, rather than inhibit, STN output neurons.

In this study we have investigated the pathophysiology of two idiopathic focal dystonias: hand cramp with excessive cocontractions of agonist and antagonist hand or forearm muscles during specific tasks, such as writing, and facial dystonia manifested by involuntary eyelid spasms (blepharospasm) and lower facial and jaw spasms (oromandibular dystonia). We used positron emission tomography (PET) to measure the in vivo binding of the dopaminergic radioligand [18F]spiperone in putamen in 21 patients with these two focal dystonias and compared the findings with those from 13 normals. We measured regional cerebral blood flow and blood volume in each subject as well as the radiolabeled metabolites of [18F]spiperone in arterial blood. A stereotactic method of localization, independent of the appearance of the images, was used to identify the putamen in all of the PET images. We analyzed the PET and arterial blood data with a validated nonsteady-state tracer kinetic model representing the in vivo behavior of the radioligand. An index of binding called the combined forward rate constant was decreased by 29% in dystonics, as compared with normals (p < 0.05). There were no significant differences between dystonics and normals in regional blood flow, blood volume, nonspecific binding, permeability-surface area product of [18F]spiperone or the dissociation rate constant. These findings are consistent with a decrease of dopamine D2-like binding in putamen and are the first demonstration of a receptor abnormality in idiopathic dystonia. These results have important implications for the pathophysiology of dystonia as well as for function of the basal ganglia.

Article abstract-Objective: To determine whether welding-related parkinsonism differs from idiopathic PD. Background: Welding is considered a cause of parkinsonism, but little information is available about the clinical features exhibited by patients or whether this is a distinct disorder. Methods: The authors performed a case-control study that compared the clinical features of 15 career welders, who were ascertained through an academic movement disorders center and compared to two control groups with idiopathic PD. One control group was ascertained sequentially to compare the frequency of clinical features, and the second control group was sex-and age-matched to compare the frequency of motor fluctuations. Results: Welders were exposed to a mean of 47,144 welding hours. Welders had a younger age at onset (46 years) of PD compared with sequentially ascertained controls (63 years; p Ͻ 0.0001). There was no difference in frequency of tremor, bradykinesia, rigidity, asymmetric onset, postural instability, family history, clinical depression, dementia, or drug-induced psychosis between the welders and the two control groups. All treated welders responded to levodopa. Motor fluctuations and dyskinesias occurred at a similar frequency in welders and the two control groups. PET with 6-[18 F]fluorodopa obtained in two of the welders showed findings typical of idiopathic PD, with greatest loss in posterior putamen. Conclusions: Parkinsonism in welders is distinguished clinically only by age at onset, suggesting welding may be a risk factor for PD. These preliminary data cannot exclude a genetic contribution to susceptibility in these exposed individuals.

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