Metabolomics: Seeking Biomarkers for ALS, Parkinson’s, Huntington’s

Series - Metabolomics Comes of Age:

Metabolomics—the sum of every small molecule linked to health or illness—is a young field (see Part 1 and Part 2), but it has already given researchers studying Alzheimer’s disease plenty to think about (see Part 3). Scientists studying other neurodegenerative diseases are also trawling metabolomes for biomarkers that would help make early diagnoses or assess drug effects. The Amyotrophic Lateral Sclerosis Association (ALSA) expects to release metabolomic data this year. In Parkinson’s disease, metabolomics has pointed to purine metabolism as a possible avenue of study. And early studies with Huntington’s link the disease to a broad catabolic phenotype. However, scientists need longitudinal results to really understand disease progression.

Analyzing ALS
The hunt for biomarkers in ALS has been ongoing for some time (see ARF related news story). Could as-yet-unknown metabolites help solve the problem? Rima Kaddurah-Daouk and colleagues at Metabolon, Inc., a company she founded in Research Triangle Park, North Carolina, went fishing for ALS-linked metabolites in a 2005 paper (Rozen et al., 2005). Kaddurah-Daouk is now running a Center for Metabolomics at Duke University in Durham, also in North Carolina.

The researchers used high-performance liquid chromatography (HPLC) to profile the plasma metabolomes of 28 people with motor neuron disease (MND) including ALS, and 30 healthy controls. The study authors found that 50 metabolites went up in people with MND, and even more were decreased, compared to control subjects. But many of those changes were apparently due to the drug riluzole—the only medicine specifically approved for ALS. When the scientists limited their study to people not taking riluzole, they found that six compounds went up with disease, and 70 down. Either way, the metabolome clearly differentiated people with MND from those without, suggesting metabolomic patterns are good markers for disease.

The researchers did not identify the metabolites associated with ALS. Metabolon is continuing this research, in collaboration with the ALSA, in a larger study of fluid samples from 650 people with MND. The study is ongoing, with some results expected this year, ALSA told ARF.

Probing Parkinson’s
In Parkinson’s, too, biomarkers are highly desirable. Mikhail Bogdanov of Weill Cornell Medical College in New York, who also participated in the ALS study, is leading similar efforts for PD in his lab. He and his colleagues knew oxidative stress could be important for Parkinson’s disease when they used liquid chromatography and electrochemical methods to examine plasma samples from 66 people with PD and 25 controls (Bogdanov et al., 2008). Thus, they took care to watch out for metabolites such as 8-OHdG, a marker for oxidative damage to DNA, and the antioxidants uric acid and glutathione. They observed that 8-OHdG and glutathione levels were high in people with PD, and uric acid concentrations were low, compared to controls. These results match with other studies showing that high uric acid correlates with decreased PD risk and slow disease progression (de Lau et al., 2005; also ARF related news story on Schwarzschild et al., 2008), and that glutathione levels are high in the substantia nigra of people who died of PD (Yohnes-Mhenni et al., 2007).

Previous reports also indicated that 8-OHdG is increased in the serum or urine of people with PD, but not enough to clearly distinguish patients and controls (Kikuchi et al., 2002 and Sato et al., 2005). In Bogdanov’s 2008 study, 8-OHdG levels alone were not enough to differentiate people with and without PD. But by mapping 1,860 metabolites—many unidentified—the researchers could clearly identify controls versus people with Parkinson’s. Currently, Bogdanov said, the researchers are working on the structures of some of those metabolites.

In a subsequent study, Bogdanov and colleagues were able to distinguish different types of Parkinson’s (Johansen et al., 2009). They compared plasma profiles from people with idiopathic PD and those whose disease was due to a mutation in LRRK2. Although the two PD categories shared much in common, the profile of a dozen mostly unknown metabolites was sufficient to distinguish them. Both kinds of PD were again linked to reductions in uric acid, the final product of protein metabolism, and several purine metabolites such as hypoxanthine and xanthine. Thus, the work suggests purines are involved in Parkinson’s. Indeed, the reduction in hypoxanthine was seen both in unmedicated people with PD and healthy carriers of LRRK2 mutations, but not in people undergoing treatment for Parkinson’s—suggesting that the medicines correct this anomaly. Bogdanov’s group is tracking their subjects longitudinally.

Hints to Huntington’s
Although the genetic cause of Huntington’s disease is easily assessed, clinicians need biomarkers to track progress. David Rubinzstein and colleagues at the Cambridge, U.K., Institute for Medical Research used gas chromatography and mass spectrometry to analyze serum from 20 control subjects and 30 people with the HD mutation—10 pre-symptomatic and 20 at an early stage of disease. They also worked with 10 non-transgenic and 19 HD model mice—10 sacrificed before symptoms started and nine sacrificed later to mimic the human study population (Underwood et al., 2006).

The scientists found that serum metabolomic profiles clearly differentiate HD model mice and their wild-type littermates; the trend in people is similar, though weaker. In particular, HD was linked to changes in concentrations of glycerol, monosaccharides, and the amino acid valine, indicating that the body’s metabolism of fats, carbohydrates, and proteins changes in HD. In the human samples, α-hydroxybutyric acid was also affected, hinting at changes to nucleic acid metabolism, too. Overall, the alterations suggest HD is associated with a catabolic phenotype; the work thus confirmed longstanding reports that catabolic changes in amino acid metabolism happen before symptoms start (Reilmann et al., 1995). The catabolic processes may help explain why people with Huntington’s are often underweight (Djouse et al., 2002). In a further study, Cambridge scientists used calorimetric experiments to show that people and mice with HD do indeed have a negative energy balance (Goodman et al., 2008).

These markers could help doctors evaluate treatments meant to slow symptom onset. The researchers are still working in the validation stage, Rubinzstein told ARF. In addition, he said, they are following the subjects longitudinally to examine the rate of change on metabolomic markers.—Amber Dance.

This concludes a four-part series. See also Part 1, Part 2, Part 3. View a PDF of the entire series.

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References

News Citations

  1. Metabolomics: The Fourth Great Ome
  2. Metabolomics: All the Fish in the Sea
  3. Metabolomics: Metabolism and Omics in Alzheimer’s Disease
  4. Antioxidant Levels Mark Progression of PD, Clinical Trial to Follow

Paper Citations

  1. Greenberg N, Grassano A, Thambisetty M, Lovestone S, Legido-Quigley C. A proposed metabolic strategy for monitoring disease progression in Alzheimer's disease. Electrophoresis. 2009 Apr;30(7):1235-9. PubMed.
  2. Bogdanov M, Matson WR, Wang L, Matson T, Saunders-Pullman R, Bressman SS, Flint Beal M. Metabolomic profiling to develop blood biomarkers for Parkinson's disease. Brain. 2008 Feb;131(Pt 2):389-96. PubMed.
  3. de Lau LM, Koudstaal PJ, Hofman A, Breteler MM. Serum uric acid levels and the risk of Parkinson disease. Ann Neurol. 2005 Nov;58(5):797-800. PubMed.
  4. Schwarzschild MA, Schwid SR, Marek K, Watts A, Lang AE, Oakes D, Shoulson I, Ascherio A, , Hyson C, Gorbold E, Rudolph A, Kieburtz K, Fahn S, Gauger L, Goetz C, Seibyl J, Forrest M, Ondrasik J. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch Neurol. 2008 Jun;65(6):716-23. PubMed.
  5. Younes-Mhenni S, Frih-Ayed M, Kerkeni A, Bost M, Chazot G. Peripheral blood markers of oxidative stress in Parkinson's disease. Eur Neurol. 2007;58(2):78-83. PubMed.
  6. Sato S, Mizuno Y, Hattori N. Urinary 8-hydroxydeoxyguanosine levels as a biomarker for progression of Parkinson disease. Neurology. 2005 Mar 22;64(6):1081-3. PubMed.
  7. Johansen KK, Wang L, Aasly JO, White LR, Matson WR, Henchcliffe C, Beal MF, Bogdanov M. Metabolomic profiling in LRRK2-related Parkinson's disease. PLoS One. 2009;4(10):e7551. PubMed.
  8. Underwood BR, Broadhurst D, Dunn WB, Ellis DI, Michell AW, Vacher C, Mosedale DE, Kell DB, Barker RA, Grainger DJ, Rubinsztein DC. Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles. Brain. 2006 Apr;129(Pt 4):877-86. PubMed.
  9. Reilmann R, Rolf LH, Lange HW. Decreased plasma alanine and isoleucine in Huntington's disease. Acta Neurol Scand. 1995 Mar;91(3):222-4. PubMed.
  10. Djoussé L, Knowlton B, Cupples LA, Marder K, Shoulson I, Myers RH. Weight loss in early stage of Huntington's disease. Neurology. 2002 Nov 12;59(9):1325-30. PubMed.
  11. Goodman AO, Murgatroyd PR, Medina-Gomez G, Wood NI, Finer N, Vidal-Puig AJ, Morton AJ, Barker RA. The metabolic profile of early Huntington's disease--a combined human and transgenic mouse study. Exp Neurol. 2008 Apr;210(2):691-8. PubMed.

Other Citations

  1. ARF related news story

External Citations

  1. Amyotrophic Lateral Sclerosis Association
  2. Metabolon, Inc.
  3. larger study

Further Reading

Papers

  1. Bowser R, Cudkowicz M, Kaddurah-Daouk R. Biomarkers for amyotrophic lateral sclerosis. Expert Rev Mol Diagn. 2006 May;6(3):387-98. PubMed.
  2. Pradat PF, Dib M. Biomarkers in amyotrophic lateral sclerosis: facts and future horizons. Mol Diagn Ther. 2009;13(2):115-25. PubMed.
  3. Tsang TM, Haselden JN, Holmes E. Metabonomic characterization of the 3-nitropropionic acid rat model of Huntington's disease. Neurochem Res. 2009 Jul;34(7):1261-71. PubMed.
  4. Caudle WM, Bammler TK, Lin Y, Pan S, Zhang J. Using 'omics' to define pathogenesis and biomarkers of Parkinson's disease. Expert Rev Neurother. 2010 Jun;10(6):925-42. PubMed.
  5. Morgan JC, Mehta SH, Sethi KD. Biomarkers in Parkinson's disease. Curr Neurol Neurosci Rep. 2010 Nov;10(6):423-30. PubMed.

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