Surprising results, not sure what to make of this but it raises serious questions about mitochondrial abnormalities being the driving force in PD. However, note the last paragraph, too tentative at this point. In fact they found the opposite of what was expected. However, particularly given the sensitivity of dopaminergic neurons to oxidative stress, the increased oxygen utilisation may be the problem as it will drive oxidation events.
Article:
Cerebral mitochondrial metabolism in early
Parkinson’s disease
Authors:
William J Powers, Tom O Videen, Joanne Markham, Kevin J Black, Nima Golchin
and JoeL S Perlmutter
Journal:
Journal of Cerebral Blood Flow & Metabolism (2008) 28, 1754–1760
& 2008 ISCBFM
Location: Neuroscience\NI\Title
Date obtained: 1/10/2008
Date Read: 21/10/2008
Date to Review:
Web Page: www.jcbfm.com
Keywords:
Printed:
Notes:
Abstract
Abnormal cerebral energy metabolism owing to dysfunction of mitochondrial electron transport has been implicated in the pathogenesis of Parkinson’s disease (PD). However, in vivo data of mitochondrial dysfunction have been inconsistent. We directly investigated mitochondrial oxidative metabolism in vivo in 12 patients with early, never-medicated PD and 12 age-matched normal controls by combined measurements of the cerebral metabolic rate of oxygen (CMRO2) and the cerebral metabolic rate of glucose (CMRglc) with positron emission tomography. The primary analysis showed a statistically significant 24% increase in bihemispheric CMRO2 and no change in CMRO2/CMRglc. These findings are inconsistent with a defect in mitochondrial oxidative phosphorylation owing to reduced activity of the mitochondrial electron transport system (ETS). Because PD symptoms were already manifest, deficient energy production owing to a reduced activity of the mitochondrial ETS cannot be a primary mechanism of neuronal death in early PD. Alternatively, this general increase in CMRO2 could be due not to an increased metabolic demand but to an uncoupling of ATP production from oxidation in the terminal stage of oxidative phosphorylation. Whether this is the case in early PD and whether it is important in the pathogenesis of PD will require further study.
--
Although PD is characterized neuropathologically by alpha-synuclein-immunopositive Lewy bodies in the substantia nigra and other brainstem structures, there is an increasing recognition that PD is a diffuse brain disease involving both cortical and subcortical structures (Braak et al, 2003).
--
If a defect in mitochondrial electron transport is important in the pathogenesis of PD, it will be present early in the course of the disease and before the possibly confounding effects of drug therapy.
--
Cerebral Mitochondrial Metabolism
The primary analysis showed a statistically significant 24% increase in bihemispheric CMRO2 in PD (P = 0.037) (Table 1). This increase is the opposite direction expected for defects in mitochondrial electron transport. Bihemispheric CMRglc was increased by 15% and CMRO2/CMRglc was increased by 10%. Both of these changes are also in the opposite direction expected with defects in mitochondrial electron transport. Examination of the confidence intervals for the differences between the two groups for these latter two measurements shows that there is less than a 6% chance that CMRglc is lower in PD by any amount and only a 10% chance that CMRglc/CMRO2 is reduced by 10% or more.
Similar results, although with more measurement imprecision as expected, were found in the substantia nigra. Examination of the confidence intervals for the differences between the two groups shows that there is less than a 20% chance that substantia nigra CMRO2 in PD is lower by more than 10%, that CMRglc is lower by more than 16%, and that there is only a 10% chance that CMRglc/CMRO2 is reduced by any amount.
Measurements from the putamen and globus pallidus also showed increases in regional CMRO2 and CMRglc (Table 2). Analysis of regional/bihemispheric ratios showed no difference between controls and participants with PD indicating that the increases in regional metabolism were primarily a reflection of overall bihemispheric changes There were no differences in CMRO2 or CMRglc between the structures ipsilateral and contralateral to the side of the body with the greatest signs (data not shown).
--
Discussion
Increased CMRO2 with a normal CMRO2/CMRglc is inconsistent with a defect in mitochondrial oxidative phosphorylation owing to reduced activity of the mitochondrial ETS (Brierley et al, 1977; Frackowiak et al, 1988). Although a finding of normal CMRO2 in PD would not exclude the possibility of dysfunction of mitochondrial ETS because complex I, III, and IV activity can be substantially reduced before there is a reduction in CMRO2, dysfunction of the ETS cannot be the explanation for increased CMRO2 in PD (Davey et al, 1998). Because PD symptoms were already manifest in these 12 patients, we can exclude deficient energy production owing to a reduced activity of the mitochondrial ETS as a pathogenic mechanism of their disease. Thus, although defects in mitochondrial ETS may be present in some patients with PD, the absence of such defects in these 12 patients with early PD indicates that they cannot be esLL000000sential to the pathogenesis of neuronal death in early PD.
--
Previous studies of CMRglc in PD have yielded mixed results. In five studies of global CMRglc, four have reported reductions of approximately 20% and one reported no significant difference compared with age-matched controls (Kuhl et al, 1984; Leenders et al, 1985; Eidelberg et al, 1993, 1994; Piert et al, 1996). In one of these studies, reductions in global CMRglc were seen only after L-DOPA was administered, suggesting that the reduction in metabolism may be at least, in part, because of medication effects (Piert et al, 1996). Berding et al have suggested that hypometabolism parallels disease duration (Piert et al, 1996). Thus, these reported changes in CMRglc likely reflect a consequence of the PD process. We deliberately chose to study patients with very early disease to try to determine if there was metabolic dysfunction that caused PD. The mean disease duration of 22 months in our study was substantially shorter than in these previous studies where it ranged from 4 to 15 years. Our analysis using absolute and relative measurements showing a trend toward increased global CMRglc in very early PD supports the theory that the reported reductions in metabolism are a consequence, not a cause, of the disease.
--
Nevertheless, loss of inhibitory dopaminergic input seems an unlikely explanation for the general increase in hemispheric CMRO2 that we measured. Alternatively, this general increase in CMRO2 could be due not to an increased metabolic demand but to an uncoupling of ATP production from oxidation in the terminal stage of oxidative phosphorylation. Uncoupling (dysfunction of Complex V ATP synthase) produces an increase in both CMRO2 and CMRglc similar to what we observed (Patel and Brewer, 2003; Tretter and Adam-Vizi, 2007). Whether uncoupling of oxidative phosphorylation occurs in early PD and whether it is important in the pathogenesis of PD will require further study.
