With Reckless Abandon We Contaminate Our Home

Yet another study has emerged indicating that reckless disregard towards the consequences of environmental pollution is a health hazard for all of us. Libertarians and their ilk may argue that property rights will afford protection against pollution but this is unmitigated piffle. Pollution does not recognise boundaries or property rights and it can take decades for the full consequences of a pollutant to become apparent. Methylmercury is an excellent example of that.

Wines and Heavy Metals

For years we have been advised that a glass or two of wine is good for us and then this pops up. The basic message is: some European wines have such extraordinarily levels of heavy metals that even a single glass could be bad for our health.

There is an important nutritional lesson here and it is this: we're ignorant. For all the research that goes on we are a very long way of knowing what exactly constitutes good living. The research must proceed but please be very careful with health reporting. It is so very difficult to draw conclusions from a group of studies let alone a single study. Whatever you do with regard to your health always stick to the essentials. Experiment with diet and supplements, where possible do this in the context of regular blood tests so as to determine the effects. Remember, studies are statistical, the results of a particular study may be completely you irrelevant for someone living your life and with your physiology.

At the end of the day, all of us have to find out what works for us healthwise.

SAM-e can be Dangerous

SAM-e is being widely promoted as a "natural antidepressant". Quite by accident I recently stumbled upon some data which indicated that sustained use of SAM-e is potentially very dangerous.

SAM-e is S-adenosylmethionine. Part of its known actions is to act as a methyl donor. If you are using SAM-e you must make sure your vitamin B levels are adequate. The use of SAM-e has been associated with hyperhomocysteinemia, excess SAM-e is associated with Parkinson's Disease like disorders, excess methyl donation is a risk factor for some cancers, and the hyperhomocysteinemia that can arise from unwise use of SAM-e can induce atherosclerosis. It has also been found that in the brains of schizophrenic patients there is an over expression of SAM-e. Excessive SAM-e also induces oxidative stress and lipid peroxidation.

If you are taking S-adenosylmethionine be absolutely certain you have a very good intake of the B vitamin group, particularly folate, and you have a good antioxidant intake as well.

NEVER take SAM-e in conjunction with any antidepressants, "natural" or otherwise. It is probably advisable that before taking SAM-e you should have your homocysteine levels checked. If these levels are high then do not take it and immediately boost your intake of B vitamins and folate.

If you are using SAM-e for depression you might want to consider an "unnatural antidepressant" prescribed by your doctor. Antidepressant drugs are amongst the most widely prescribed drugs and have been subject to extensive trials and analysis. They have an excellent safety profile but it can take quite some experimentation to find the antidepressant that works for you. As recent studies have indicated the efficacy of antidepressants appears contingent on the induction of neurogenesis. This is probably a downstream effect from antidepressant use. At present I am taking an antidepressant. No, I'm not depressed, I just prefer the occasional dosing of an antidepressant because the one I am using has a number of favourable qualities.

Ideally if you are suffering from depression you should first try strategies that do not require taking anything. Check your diet, get some regular exercise, spend time with positive people, stabilise your sleep patterns if need be, get out in the sun occasionally(yes, sunshine, probably via circadian regulation and vitamin D, can give a slight boost to serotonin levels), and find ways to reduce your stress levels.

A brief overview of SAM-e is available at Wikipedia.

Brain Aging in Relation to Genes, Diet, and Behavior

Over recent years there has been tremendous progress in our understanding of brain aging and neurodegeneration. Whereas in times past it was presumed that little could be done to forestall the onset of age associated cognitive impairment it is now obvious that there is a welter of strategies we can utilise to markedly slow down the rate of age associated cognitive impairment.

This review article from Mark P. Mattson et. al. is a good starting point for enhancing your understanding of brain aging and the strategies that can help in slowing that trend. Some even claim that one can completely forestall brain aging. I remain very cynical of that possibility but hey it is worth a try so give it a go!

In brief, the following strategies are advisable:

• Regular light aerobic exercise.
• Moderate fasting a couple of times a week appears to be beneficial. Caloric Restriction, however, is ill advised as there is some suggestion that over the long term it can damage the brain.
• A good diet, obviously.
• Avoiding saturated fats and trans fats. Do not eliminate saturated fat, just reduce it.
• Maintaining an appropriate balance of omega 3 to omega 6 fats.
• Regular sleeping patterns.
• Avoiding excessive stress.
• Treat depression quickly. Numerous studies now indicate that depression damages the brain and the body. In fact sustained major depression is a significant risk factor for Alzheimers and a minor risk factor for heart disease.
• Avoid knocks to the head. Even mild brain injury can pave the way for latter dementia.

The abstract:

Mattson, Mark P., Sic L. Chan, and Wenzhen Duan. Modification of Brain Aging and Neurodegenerative Disorders by Genes, Diet, and Behavior. Physiol. Rev. 82: 637-672, 2002; 10.1152/physrev.00004.2002.Multiple molecular, cellular, structural, and functional changes occur in the brain during aging. Neural cells may respond to these changes adaptively, or they may succumb to neurodegenerative cascades that result in disorders such as Alzheimer's and Parkinson's diseases. Multiple mechanisms are employed to maintain the integrity of nerve cell circuits and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g., protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), preservation of genomic integrity by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of Alzheimer's disease (amyloid precursor protein and presenilins), Parkinson's disease (-synuclein and Parkin), and trinucleotide repeat disorders (huntingtin, androgen receptor, ataxin, and others) overwhelm endogenous neuroprotective mechanisms; other genes, such as those encoding apolipoprotein E₄, have more subtle effects on brain aging. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction and folate and antioxidant supplementation) and behavioral (intellectual and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response in which neurons increase production of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modern methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.

Placebo Power

Henry Beecher would have been pleased with these findings. He pioneered the concept of the placebo effect. A surgeon in World War 2, he found that simply giving wounded soldiers a sugar pill alleviated their pain. Fascinated by this after World War 2 he began research into the Placebo Effect.

Sadly the Placebo Effect is often perceived as a statistical artefact rather than a real phenomenon. However it can be very powerful. Even classical conditioning has been shown to induce altered immune responses in humans and rats. In fact in humans one can induce immunosuppression through behavioral conditioning. Now before you start thinking something spooky is going on here, you should read this article which indicates that there is a physical basis for this phenomenon.

There needs to be greater attention to the potential of the Placebo Effect in clinical practice. As this news item indicates, many doctors are not adverse to using the Placebo Effect in their daily practice.

For an introduction to the work of Henry Beecher, read this Wikipedia entry.

Eat Smart, Be Smart

They like to say that we cannot improve our intelligence. Recent studies have contradicted this as has my personal experience. There are a great many things we can do to improve our intelligence but to achieve maximum benefit requires careful management and a holistic approach to health. By "holistic" I do not mean that New Age crap or the continual popping of pills, but rather an integrated approach where we address many aspects of our lives. This includes:

• Being happy. If you are lacking happiness then this is the first challenge you must address.
• Sound sleep. There used to be the boast of how little sleep one could get by on. Great, welcome to future dementia.
• Aerobic fitness. Absolutely essential.
• Don't just exercise your brain, push it. Make it work. Read material that you find challenging, that makes you think, that challenges your preconceptions. One of my favourite quotes is:*Gelett Burgess: "If in the last few years you haven't discarded a major opinion or acquired a new one, check your pulse. You may be dead."
• Remember that exercising the brain is not just about conceptual work, bodily exercises that require co-ordination and timing can also be very important. This is further highlighted by recent research indicating that simple physical training in co-ordination appears to be beneficial for some children with ADHD. This appears to be related to the cerebellum(little brain). This part of the CNS has been neglected for too long.
  
• Eat well.

This study from the FASEB journal involved the administration of some supplements to gerbils. It was found that these readily available compounds enhanced their cognition. The nutshell goes like this:

DHA: an important omega 3 fat that is a substrate for NPD1, a neuroprotective compound that prevents apoptosis(programmed cell death).
Choline: an important component in cell walls and also a substrate for acetylcholine, the "memory neurotransmitter".

A news item on the study can be read here.

FASEB, July 2008

Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils

Abstract:

This study examined the effects on cognitive behaviors of giving normal adult gerbils three compounds, normally in the circulation, which interact to increase brain phosphatides, synaptic proteins, dendritic spines, and neurotransmitter release. Animals received supplemental uridine (as its monophosphate, UMP; 0.5%) and choline (0.1%) via the diet, and docosahexaenoic acid (DHA; 300 mg/kg/day) by gavage, for 4 wk, and then throughout the subsequent period of behavioral training and testing. As shown previously, giving all three compounds caused highly significant (P<0.001)>

The Mediterranean Diet

You may have heard about the Mediterranean Diet and its implications for health. This meta-analysis confirms previous findings, including reductions in mortality from cardiovacular disease(9%), cancer(6%), Parkinson's Disease, and Alzheimers(13%).

In short, the diet focuses on high intakes of legumes vegetables, high cereals, relative absence of red and processed meats, a high ratio for Monunsaturated vs. Saturated Fat, low milk and dairy products.

I have concerns about a high cereal diet and suggest that this is not a necessary component in relation to the health benefits derived from the Mediterranean diet. Cereals tend to contain high levels of omega 6 and this may create an unbalance in relation to omega 3 levels. Additionally, cereals are often high in carbohydrates, thus potentially leading to excess caloric intake.

However I do agree that in general we consume too much processed and red meat. As recent studies have indicated simply reducing protein intake, as opposed to adopting a torturous caloric restriction regime, can confer substantial benefits. We need to be cautious here, in reducing protein intake we may also be depriving ourselves of some essential amino acids.

An important component of the Mediterranean diet is the large amounts of olive oil used. Monounsaturated fats tend to be ignored these days, in my view there is too much emphasis on omega 3's and I have some concerns about high levels of omega 3's in the diet. After all, eskimos may be relatively free of conditions associated with an imbalance of the omega 3 and omega 6 fats, but they also tend to suffer from cerebral hemorrhages in their 60's and 70's. This propensity to bleeding first came to my attention is a wonderful text on lipids: The Fats of Life by Caroline M Pond. You can preview this text at this site. Thanks Google! The Australian Cardiologist, Ross Walker, also makes reference to this in his text The Cell Factor. I highly recommend this text, it contains abundant useful advice and for anyone with a cardiovascular condition it should be recommended reading.

Another reason I am interested in the role of monounsaturated fats is a study I read wherein they induced a cortical lesion in animals and then gave a massive intravenous infusion of monounsaturated fats. The results were remarkable, a huge reduction in lesion size. Unfortunately I cannot find it in my archives. It seems my memory is still better than my damned database.



Adherence to Mediterranean diet and health status: meta-analysis

Updated information and services can be found at:
http://bmj.com/cgi/content/full/337/sep11_2/a1344

ABSTRACT
Objective To systematically review all the prospective cohort studies that have analysed the relation between adherence to a Mediterranean diet, mortality, and incidence of chronic diseases in a primary prevention setting.

Design

Meta-analysis of prospective cohort studies. Data sources English and non-English publications in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials from 1966 to 30 June 2008.

Studies reviewed Studies that analysed prospectively the association between adherence to a Mediterranean diet, mortality, and incidence of diseases; 12 studies, with a total of 1 574 299 subjects followed for a time ranging from three to 18 years were included.

Results

The cumulative analysis among eight cohorts (514 816 subjects and 33 576 deaths) evaluating overall mortality in relation to adherence to a Mediterranean diet showed that a two point increase in the adherence score was significantly associated with a reduced risk of
mortality (pooled relative risk 0.91, 95% confidence interval 0.89 to 0.94). Likewise, the analyses showed a beneficial role for greater adherence to a Mediterranean
diet on cardiovascular mortality (pooled relative risk 0.91, 0.87 to 0.95), incidence of or mortality from cancer (0.94,0.92 to 0.96), and incidence of Parkinson’s disease and
Alzheimer’s disease (0.87, 0.80 to 0.96).

Conclusions

Greater adherence to a Mediterranean diet is associated with a significant improvement in health status, as seen by a significant reduction in overall mortality (9%), mortality from cardiovascular diseases (9%), incidence of or mortality from cancer (6%), and
incidence of Parkinson’s disease and Alzheimer’s disease (13%). These results seem to be clinically relevant for public health, in particular for encouraging a Mediterranean-like dietary pattern for primary prevention of major chronic diseases.

Power Napping

Sleep deprivation is chronic in our society and this has important implications for our health. Chronic sleep deprivation typically increases the production of proinflammatory cytokines. Chronic sleep deprivation will induce increased production of cortisol and interleukin 6. Both have a number of functions in physiology.

Cortisol is a key stress hormone that is important in suppressing excessive inflammatory responses and helping us to maintain alertness. Throughout the 24 hour period both cortisol and interleukin 6, along with a host of other physiological mediators, vary in accordance with our circadian rhythms. Cortisol rises in the early hours of the morning, helping us to wake up, climbs through the morning, then starts a gradual decline through the evening and night. At basal physiological levels it plays important roles.

Interleukin 6 is a perplexing cytokine, it has been associated both with inflammatory and growth processes, my guess is that its function is contingent on the expression of inflammatory mediators like tumour necrosis factor. That is, in the presence of tumour necrosis factor at elevated levels, in can promote inflammation. It is worth noting that in this study at least the levels of tumour necrosis factor were largely unaffected.

In this study the human subjects were sleep deprived for a number of days and then allowed to nap for 2 hours. The effects were minor, statistically significant yes but physiologically significant? Not so sure about that. Napping does help but it cannot make up for maintaining good sleeping patterns.

The Lesson

Don't fall for the idea that you can catch up on sleep and no harm done. Sleep deprivation is a stressor and will impact your performance. Chronic sleep deprivation will do you no good at all. It will do the exact opposite. During the deepest phases of our sleep cycle growth hormone levels are elevated, and various repair processes come into play. As high cortisol is often found in depression, chronic sleep deprivation can pave the way for depression. Indeed it can be the final straw that breaks the camel's back. So if you are experiencing chronic sleep deprivation try to find ways to change that.

I take good quality sleep so seriously that I wear a sleep mask and ear plugs. This has a wonderful effect on my sleep cycle and I typically wake up wonderfully refreshed. A great change from years gone by when I would wake up feeling like death. I am a night owl who likes to stay up late, typically reading, studying, or just playing computer games. However I do make sure I get a good night's sleep and this has substantially improved my productivity and cognition.

If you're interested in learning about sleep and the importance of maintaining regular sleeping patterns I highly recommend The Promise of Sleep by William C. Dement and Christopher Vaughan. Dr. Dement commenced the Stanford Sleep Centre and is a leading authority on sleep. The text is very accessible. Here is a link to it.

You can download the full paper here.

Am J Physiol Endocrinol Metab 292: E253–E261, 2007.
Daytime napping after a night of sleep loss decreases sleepiness,improves performance, and causes beneficial changes in cortisol and interleukin-6 secretion

A. N. Vgontzas,S. Pejovic, E. Zoumakis, H. M. Lin, E. O. Bixler, M. Basta, J. Fang, A. Sarrigiannidis, and G. P. Chrousos

Daytime napping after a
night of sleep loss decreases sleepiness, improves performance, and
causes beneficial changes in cortisol and interleukin-6 secretion. Am J
Physiol Endocrinol Metab 292: E253–E261, 2007. First published August
29, 2006; doi:10.1152/ajpendo.00651.2005.—Sleep loss has been
associated with increased sleepiness, decreased performance, elevations
in inflammatory cytokines, and insulin resistance. Daytime napping has
been promoted as a countermeasure to sleep loss. To assess the effects of
a 2-h midafternoon nap following a night of sleep loss on postnap
sleepiness, performance, cortisol, and IL-6, 41 young healthy individuals
(20 men, 21 women) participated in a 7-day sleep deprivation experiment
(4 consecutive nights followed by a night of sleep loss and 2 recovery
nights). One-half of the subjects were randomly assigned to take a
midafternoon nap (1400–1600) the day following the night of total sleep
loss. Serial 24-h blood sampling, multiple sleep latency test (MSLT),
subjective levels of sleepiness, and psychomotor vigilance task (PVT)
were completed on the fourth (predeprivation) and sixth days (postdeprivation).
During the nap, subjects had a significant drop in cortisol and
IL-6 levels (P < 0.05). After the nap they experienced significantly less
sleepiness (MSLT and subjective, P < 0.05) and a smaller improvement
on the PVT (P < 0.1). At that time, they had a significant transient
increase in their cortisol levels (P < 0.05). In contrast, the levels of IL-6
tended to remain decreased for ~8 h (P < 0.1). We conclude that a 2-h
midafternoon nap improves alertness, and to a lesser degree performance,
and reverses the effects of one night of sleep loss on cortisol and IL-6.
The redistribution of cortisol secretion and the prolonged suppression of
IL-6 secretion are beneficial, as they improve alertness and performance.

Eat slowly, eat well, with friends and\or family

In our fast paced world eating has taken on a utilitarian aspect that is not doing us any good at all. We read the labels for nutrients, we pop pills for health, we eat on the run, we avoid unhealthy foods, we have turned eating into a chore when it should be a pleasure.

Even supermarkets are now selling various supplements, foods are fortified with this and that, purportedly claiming superior health from eating these fortified foods. The evidence for this is scant. What epidemiological studies show is that you don't need a "scientifically" determined eating plan but rather observing some simple rules for eating healthily.

The French Paradox remains unresolved. Basically it goes like this: the French eat a great many unhealthy foods yet have markedly lower rates of the types of diseases that pervade many Western countries. The French enjoy their food, eat as a social event not as an intrusion on a busy life. They take time to enjoy their food, eat much more slowly than us, and enjoy their meals.

Now consider how many of us eat: we agonise of the right balance of foods to optimise health, we eat lunch quickly so that we have more time to enjoy our lunch break before going back to the grind, we get home from work and are so tired we slap dash something together and gulp it down while watching TV or on the internet instead of using meal time as a chance to socialise and unwind.

This latest study from the BMJ highlights a problem with our eating style. It found that eating quickly and until we are full is a risk factor for obesity. No surprises there. The feeling of being full arises when food reaches the stomach, hormones are released which signal that we have had enough to eat. However if we eat quickly the hormonal message doesn't begin to function until we have over eating. This is because it takes time for food to reach the stomach. The other problem with eating quickly is that we tend to insufficiently chew our food. This prevents nutrient absorption.

We need to change our eating habits. We need to return to the habits of enjoying eating rather than treating it as a scientific exercise. We need to eat with others, take our time, enjoy our meals, and stop obsessing about food and nutrients.

Cerebral mitochondrial metabolism in early Parkinson's Disease

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.