biomarker
Metabolomics: A New Approach to Understanding Glaucoma
Posted on by Michael F. Chiang, M.D., National Eye Institute
Glaucoma remains one of the most common causes of vision loss and blindness in the U.S. and much of the world, disproportionately affecting older people, African Americans, and Hispanics and Latinos. Early signs of glaucoma can vary, from eye pressure to changes in the appearance of the optic nerve, and the disease can progress for years undetected while causing irreversible vision loss. More research is needed to understand the complex processes that underpin how glaucoma develops and progresses. If detected early enough, doctors can intervene and stop or slow its progression, thus preventing or minimizing vision loss.
While more than 120 genetic factors have been linked to glaucoma, these genes account for less than 10% of glaucoma cases. Scientists are exploring other ways to predict glaucoma, including studying metabolites to see if they hold any clues. These small molecules are produced by metabolism, including the breakdown of nutrients when we digest food or byproducts from the medicine we take. Identifying at-risk individuals based on their metabolic profile might present an opportunity to intercept disease before vision loss.
Researchers already use metabolites as biomarkers or indicators to help diagnose disease or assess disease risk. There’s a standard blood test called a comprehensive metabolic blood panel that doctors use to measure levels of metabolites circulating in your blood—sugars like glucose, minerals such as calcium, and proteins such as creatinine.
Your metabolome is the complete set of metabolites not in just your blood but in your entire body. National Eye Institute-funded researchers led by Louis Pasquale, Icahn School of Medicine at Mount Sinai, New York, in collaboration with Oana A. Zeleznik and Jae Hee Kang of Brigham and Women’s Hospital, Boston, recently explored 369 blood metabolites in relation to glaucoma in a large study.1
The research team examined blood that had been stored frozen from two long-term studies of health professionals: the Nurses’ Health Studies and the Health Professionals’ Follow-Up Study. They compared about 600 participants who had developed glaucoma after study enrollment to a group of similar participants who didn’t. On average, the participants who developed glaucoma did so about 10 years after their initial blood draw in the study.
The researchers found a particularly strong association between glaucoma and two classes of lipids (fats): triglycerides and diglycerides. Patients with elevated triglycerides and diglycerides were more likely to develop glaucoma, and the association was strongest in a subtype of glaucoma that causes early loss of central vision. They confirmed their findings in a cross-sectional analysis of data from the UK Biobank.
High levels of triglycerides have been linked to a variety of health problems, notably heart disease and stroke. The good news is that effective treatments to control triglyceride levels already exist. Statin drugs, for example, lower blood lipid levels. While studies looking at statin use and glaucoma risk have shown mixed results, we may learn that specific subtypes of glaucoma can be effectively controlled with statins. More research is needed to know if existing drugs might prevent glaucoma.
Pasquale’s work adds to a growing body of evidence that links health status to metabolism. Similar associations have been made between various metabolites and kidney cancer,2 pregnancy complications,3 type 2 diabetes,4 and Alzheimer’s disease.5 For researchers interested in exploring associations between metabolites and disease risk, the NIH Common Fund offers scientists a national and international repository for metabolomics data and metadata called the Metabolomics Workbench Metabolite Database, which contained more than 167,000 entries in 2022.
These findings and others offer the potential to prevent more and treat less. We urge anyone in an at-risk group, including people with a family history of glaucoma, to get regular, comprehensive eye exams.
References:
[1] OA Zeleznik, et al. Plasma metabolite profile for primary open-angle glaucoma in three US cohorts and the UK Biobank. Nature Communications DOI:10.1038/s41467-023-38466-x (2023)
[2] OO Bifarin, et al. Urine-Based Metabolomics and Machine Learning Reveals Metabolites Associated with Renal Cell Carcinoma Stage. Cancers (Basel) DOI:10.3390/cancers13246253 (2021)
[3] EW Harville, et al. Untargeted analysis of first trimester serum to reveal biomarkers of pregnancy complications: a case-control discovery phase study. Scientific Reports DOI:10.1038/s41598-021-82804-1 (2021)
[4] Nightingale Health Biobank Collaborative Group, et al. Metabolomic and genomic prediction of common diseases in 477,706 participants in three national biobanks. medRxiv DOI: 10.1101/2023.06.09.23291213 (2023). *note this article is a pre-print and is not peer-reviewed
[5] DK Barupal, et al. Sets of coregulated serum lipids are associated with Alzheimer’s disease pathophysiology. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. DOI:10.1016/j.dadm.2019.07.002 (2019)
NIH Support: National Eye Institute, National Cancer Institute
Editor’s note: This blog post was updated on Jan. 18, 2024, to include Oana A. Zeleznik as one of the collaborators.
New Study Points to Targetable Protective Factor in Alzheimer’s Disease
Posted on by Dr. Francis Collins
If you’ve spent time with individuals affected with Alzheimer’s disease (AD), you might have noticed that some people lose their memory and other cognitive skills more slowly than others. Why is that? New findings indicate that at least part of the answer may lie in differences in their immune responses.
Researchers have now found that slower loss of cognitive skills in people with AD correlates with higher levels of a protein that helps immune cells clear plaque-like cellular debris from the brain [1]. The efficiency of this clean-up process in the brain can be measured via fragments of the protein that shed into the cerebrospinal fluid (CSF). This suggests that the protein, called TREM2, and the immune system as a whole, may be promising targets to help fight Alzheimer’s disease.
The findings come from an international research team led by Michael Ewers, Institute for Stroke and Dementia Research, Ludwig-Maximilians-Universität München, Germany, and Christian Haass, Ludwig-Maximilians-Universität München, Germany and German Center for Neurodegenerative Diseases. The researchers got interested in TREM2 following the discovery several years ago that people carrying rare genetic variants for the protein were two to three times more likely to develop AD late in life.
Not much was previously known about TREM2, so this finding from a genome wide association study (GWAS) was a surprise. In the brain, it turns out that TREM2 proteins are primarily made by microglia. These scavenging immune cells help to keep the brain healthy, acting as a clean-up crew that clears cellular debris, including the plaque-like amyloid-beta that is a hallmark of AD.
In subsequent studies, Haass and colleagues showed in mouse models of AD that TREM2 helps to shift microglia into high gear for clearing amyloid plaques [2]. This animal work and that of others helped to strengthen the case that TREM2 may play an important role in AD. But what did these data mean for people with this devastating condition?
There had been some hints of a connection between TREM2 and the progression of AD in humans. In the study published in Science Translational Medicine, the researchers took a deeper look by taking advantage of the NIH-funded Alzheimer’s Disease Neuroimaging Initiative (ADNI).
ADNI began more than a decade ago to develop methods for early AD detection, intervention, and treatment. The initiative makes all its data freely available to AD researchers all around the world. That allowed Ewers, Haass, and colleagues to focus their attention on 385 older ADNI participants, both with and without AD, who had been followed for an average of four years.
Their primary hypothesis was that individuals with AD and evidence of higher TREM2 levels at the outset of the study would show over the years less change in their cognitive abilities and in the volume of their hippocampus, a portion of the brain important for learning and memory. And, indeed, that’s exactly what they found.
In individuals with comparable AD, whether mild cognitive impairment or dementia, those having higher levels of a TREM2 fragment in their CSF showed a slower decline in memory. Those with evidence of a higher ratio of TREM2 relative to the tau protein in their CSF also progressed more slowly from normal cognition to early signs of AD or from mild cognitive impairment to full-blown dementia.
While it’s important to note that correlation isn’t causation, the findings suggest that treatments designed to boost TREM2 and the activation of microglia in the brain might hold promise for slowing the progression of AD in people. The challenge will be to determine when and how to target TREM2, and a great deal of research is now underway to make these discoveries.
Since its launch more than a decade ago, ADNI has made many important contributions to AD research. This new study is yet another fine example that should come as encouraging news to people with AD and their families.
References:
[1] Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MAA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, Trojanowski JQ, Shaw LM, Weiner MW, Haass C; Alzheimer’s Disease Neuroimaging Initiative. Sci Transl Med. 2019 Aug 28;11(507).
[2] Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, Krasemann S, Lichtenthaler SF, Müller SA, Colombo A, Monasor LS, Tahirovic S, Herms J, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Grathwohl SA, Neher JJ, Holtzman DM, Meyer-Luehmann M, Haass C. Nat Neurosci. 2019 Feb;22(2):191-204.
Links:
Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)
Alzheimer’s Disease Neuroimaging Initiative (University of Southern California, Los Angeles)
Ewers Lab (University Hospital Munich, Germany)
Haass Lab (Ludwig-Maximilians-Universität München, Germany)
German Center for Neurodegenerative Diseases (Bonn)
Institute for Stroke and Dementia Research (Munich, Germany)
NIH Support: National Institute on Aging
Personalizing Depression Treatment with Brain Scans
Posted on by Dr. Francis Collins
Caption: Depressed patients with higher activity in the anterior insula (where the green lines intersect) did better with medication than cognitive behavior therapy.
Source: Helen Mayberg, Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences
Today, figuring out who will benefit from which antidepressant medication is hit or miss—physicians prescribe a medication to treat major depression for two to three months, and then gauge the results. This trial and error is frustrating and expensive; typically only about 40% get well after this first treatment or see an improvement in symptoms. The other 60% must try a different drug or some other approach. In a new NIH funded study, researchers showed how brain scans could predict which individuals would benefit from a medication and which might respond better to psychotherapy [1].
