Editor's note: Alzforum received several belated comments on some interesting studies presented at the American Neurological Association's annual meeting in New York City last fall. We thus present summaries of these studies by our reporter Hakon Heimer, along with comments by Gjumrakch Aliev, Mark A. Smith, and George Perry, as well as John Blass and Mark Mattson.

I. Heme Oxygenase-1 Suppressor Is Candidate in the AD Biomarker Sweepstakes
Hyman Schipper and his colleagues at McGill University in Montreal, Canada, presented new developments in their ongoing work to evaluate the relationship of heme oxygenase-1 (HO-1) to AD. This stress protein catalyzes the oxidative degradation of heme to biliverdin, and the Schipper lab had previously demonstrated that HO-1 levels are higher in AD hippocampal and temporal lobe neurons and astrocytes compared with normal elderly controls (Schipper et al., 1995). Conversely, HO-1 levels appear to be lower in sporadic AD plasma and CSF compared to controls, suggesting the existence of a circulating suppressor that might serve as a useful biomarker for AD in its early stages or in therapeutic trials.

In one study, led by Steven Kravitz, the researchers reported an HO-1 suppressor (HOS) at work in the plasma of early sporadic AD patients, subjects with mild cognitive impairment, but not normal elderly controls. In a second study, led by Daniel Berlin, the researchers find evidence that the activity of this suppressor might be mediated by a heat-labile, heparin-binding glycoprotein.

References:
Kravitz S, Mawal Y, Sahlas DJ, Liberman A, Chertkow HM, Bergman H, Schipper HM. Heme oxygenase suppressor activity in Alzheimer plasma. Ann Neurol. 2002;52(3S);S31. Abstract 47.

Berlin D, Mawal Y, Liberman A, Schipper HM. Partial characterization of a heme oxygenase-1 suppressor activity in Alzheimer plasma. Ann Neurol. 2002;52(3S):S30. Abstract 42.

Coenzyme Q10 Slows Parkinson's Decline in Preliminary Study
The biggest splash at the meeting, at least in terms of media attention, was made by the preliminary report by the Parkinson Study Group that a dietary supplement appears to slow the progression of Parkinson's disease. The results appeared simultaneously in the Archives of Neurology (Shults et al., 2002). If larger studies confirm these results, coenzyme Q10 (CoQ10, also called ubiquinone) would be the first therapy that slows the underlying disease process, rather than merely improving symptoms temporarily.

Study leader Clifford Shults, of the University of California, San Diego, emphasizes that the 80 subjects in the study were not sufficient to prove that the drug was effective. "It would be premature to recommend that patients with Parkinson's take high doses of coenzyme Q10," he said in a news release.

Previous work by the laboratories of Shults, Richard Haas of UCSD, and Flint Beal of Weill Medical College of Cornell University, had found that CoQ10 levels are reduced in the mitochondria of Parkinson's patients, leading to the hypothesis that supplemental CoQ10 could help protect the mitochondria.

Shults and his collaborators randomly assigned patients to regimens of CoQ10 at dosages of 300, 600, or 1200 mg/day, or to a placebo group. Patients were assessed one month after beginning the study and then every four months during the 16-month study. Both patients and study investigators were blinded.

By the eighth month, patients on the highest dose were scoring significantly better on the Unified Parkinson Disease Rating Scale (which assesses mental function and mood, activities of daily living, and motor skills) than patients in all other groups. By the time the study ended, patients in the high-dose group were scoring 44 percent better than the placebo group. The lower CoQ10 doses slowed the functional decline relative to placebo, but were less effective. There was no significant difference in side effects between the CoQ10 and placebo groups.

If the drug had merely been ameliorating symptoms while the disease continued unchecked to kill neurons, the researchers would have expected the initial, first-month check-up to reveal improvement in the CoQ10 groups. Since that was not the case, Shults hypothesizes that the drug might have slowed the underlying progression of the disease over the 16-month period of the study. He stressed, however, that the study was designed to assess function, not to examine whether groups treated with CoQ10 did, in fact, have less damage to substantia nigra neurons. He and his colleagues hope to look at such damage in a larger study with hundreds of patients, perhaps even testing a dose larger than 1,200 mg/day.—Hakon Heimer

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  1. The results of the trial of Coenzyme Q10 in Parkinson's patients are very encouraging and provide a rationale for longer-term therapy. There is a solid basis for believing that CoQ10 may also benefit patients with Alzheimer's disease, particularly those in the early stages of the disease. CoQ10 is neuroprotective in cell culture and animal models relevant to AD. Importantly, a closely related quinone called idebenone was reported to be effective in clinical trials in AD patients in Europe and Japan (Bergamasco et al, 1994). Coenzyme Q10 and idebenone both improve energy metabolism and exhibit antioxidant activity, which appears to be the basis for their neuroprotective actions. Of course Co Q10 is available at any health food store, and the findings in the Parkinson's patients will likely stimulate an increase in sales of this supplement.

    References:

    . Idebenone, a new drug in the treatment of cognitive impairment in patients with dementia of the Alzheimer type. Funct Neurol. 1994 May-Jun;9(3):161-8. PubMed.

  2. Focus on the Mitochondrion in Neurodegenerative Disease
    Mitochondrial structure and function decline with age, and especially in age-associated diseases including neurodegeneration. Mitochondrial damage appears to be a primary cause for the development of human AD and AD-like pathology in transgenic mice (Hirai et al., 2001; Aliev, 2002; Castellani RJ et al., 2002; Aliev et al., 2002; 2003a; 2003b). In addition, AD and/or other cerebrovascular pathology is characterized by significant decreases of cytochrome oxidase activity—but not immunoreactivity in different cellular compartments such as large pyramidal neurons (Hirai et al., 2001), vascular endothelium and perivascular astrocytes or pericytes (Aliev et al., 2002; 2003a; 2003b) and it coexists with chronic brain inflammation. Therefore, drug delivery to mitochondria may be a new opportunity for treatment of aged-associated diseases such as AD.

    The study by Saydoff and coworkers demonstrated that oral uridine prodrug PN401 is neuroprotective in mitochondrial and neuroinflammatory models of AD. PN401 is a prodrug that efficiently delivers uridine after oral administration in humans. The pyrimidine uridine forms the backbone of uridine diphosphate sugars that are required for the glycosylation reaction. Therefore pyrimidine derivatives are also critical for phospholipid and glycogen synthesis. De novo biosynthesis of uridine nucleotides is coupled to the respiratory chain via the mitochondrial enzyme dihydroorotate dehydrogenase. Saydoff and coworkers show in a chemical hypoxia model that PN401 significantly decreases weight loss, mortality, and apoptotic cell loss in the cerebral cortex induced by azide infusion (subcutaneous) for two weeks.

    The novelty of this study is that it shows for the first time that oral delivery of PN401 can protect mitochondria against hypoxia and suppress neuroinflammation after the infusion of lipopolysaccharides. PN401 significantly attenuated the increase in interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the plasma and brain in response to lipopolysaccharides. This study confirms our recent finding that AD needs to be considered a hypoperfusion-induced mitochondrial disease with neurological consequences (Aliev et al., 2002; 2003a; 2003b). Future research should explore a possible protective effect of PN401 in a transgenic mouse model of AD, especially after chronic hypoxia and/or ischemia/reperfusion. This new research direction may provide AD patients with an alternative treatment option.

    See also:

    Aliev G. Seyidova D., Lamb B.T., Raina A.K., Obrenovich M., Siedlak S.L., Vinters H., LaManna J.C., Smith M.A., and Perry G. Vascular Hypoperfusion, Mitochondria Failure and Oxidative Stress in Alzheimer Disease. Proceeding Indian National Science Academy, 2003b (In press).

    References:

    . Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001 May 1;21(9):3017-23. PubMed.

    . Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice. Ann N Y Acad Sci. 2002 Nov;977:45-64. PubMed.

    . Role of mitochondrial dysfunction in Alzheimer's disease. J Neurosci Res. 2002 Nov 1;70(3):357-60. PubMed.

    . Is non-genetic Alzheimer's disease a vascular disorder with neurodegenerative consequences?. J Alzheimers Dis. 2002 Dec;4(6):513-6. PubMed.

    . Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice. Neurol Res. 2003 Sep;25(6):665-74. PubMed.

  3. This interesting abstract indicates that a prodrug for uridine protects against mitochondrial and inflammatory damage in cultured cells and experimental animals. The result is not surprising, since uridine is known to protect mitochondria against free-radical damage. The Alzheimer brain is under oxidative stress, but the relevance of this approach to treating human Alzheimer’s disease is conjectural.

References

Paper Citations

  1. . Expression of heme oxygenase-1 in the senescent and Alzheimer-diseased brain. Ann Neurol. 1995 Jun;37(6):758-68. PubMed.
  2. . Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002 Oct;59(10):1541-50. PubMed.

Further Reading

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Primary Papers

  1. . Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002 Oct;59(10):1541-50. PubMed.