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Genetic Variant Predetermines Risk of Cognitive Decline in Parkinson’s, Research Suggests

genetic variant

Researchers have found that Parkinson’s patients whose cognitive ability is intact, but who have a specific genetic variant, have significantly less gray matter in the regions of their brain that are related to dementia.

The study with that finding, “Reduced gray matter volume in cognitively preserved COMT 158Val/Val Parkinson’s disease patients and its association with cognitive decline,” was published in Brain Imaging and Behavior.

Several mutations in the COMT gene have been associated with the risk of developing Parkinson’s disease. This gene provides instructions for making catechol-O-methyltransferase (COMT), an enzyme that helps break down certain chemical messengers like dopamine.

The most common alteration in the DNA sequence that makes up the COMT gene is the Val158Met mutation in which a valine (Val) is replaced by a methionine (Met) at position 158. Val and Met are both amino acids, also known as the protein’s building blocks.

Every individual has two copies of each gene, one inherited from each parent. Therefore, a person can have two Val’s in the same position at both COMT gene copies (also known as the Val/Val genotype), a Val in one gene and a Met in the other (Val/Met genotype), or two Met’s (Met/Met genotype). Scientists use the word “genotype” to describe a person’s genetic constitution.

Changes in COMT’s molecular structure, lead to high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzymatic activity.

The Val158Met mutation in the COMT gene has been associated with an increased risk of cognitive decline in Parkinson’s disease, particularly in people with greater COMT activity. When this happens, there is too much neurotransmitter degradation, thus leading to reduced levels of dopamine and affecting basic brain functions such as motor coordination and memory.

Evidence suggests a correlation between cognitive impairment, one of Parkinson’s non-motor features, and reduced gray matter volume.

The brain is composed of gray and white matter. The first consists of cell bodies — the control center of neurons — while the latter is made up of nerve cell projections, known as axons or fibers, connecting distinct parts of gray matter.

A Spanish team of researchers used magnetic resonance imaging (MRI), a non-invasive imaging technology, to investigate a possible structural brain compromise in Parkinson’s patients with highly active COMT activity that could explain their increased risk for subsequent cognitive impairment.

The study included 120 newly diagnosed Parkinson’s patients with normal cognition (who were not previously treated for the disease) and 48 healthy controls from the Parkinson’s Progression Markers Initiative database.

Results showed that there was a widespread, significant reduction in cerebral gray matter volume in patients with the Val/Val genotype. They observed alterations in the fronto-subcortical and posterior-cortical brain regions, where motor and cognitive functions originate.

Gray matter volume at some of the identified regions was associated with cognitive decline in a four-year follow-up period, suggesting that gray matter volume reduction during the early stages of disease predisposes Val/Val patients to cognitive impairment.

Nonetheless, gray matter volume analysis at one-year follow-up was not increased in Val/Val subjects, in comparison to Val/Met and Met/Met participants, indicating a somewhat stable atrophy in the Val/Val subset and that those brain changes might already be present prior to diagnosis.

The team believes their research “sparks the need to further characterize the association between a modified COMT enzymatic effect and a structural brain compromise in the early stages of [Parkinson’s disease].”

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Parkinson’s Patients Carrying Distinct Genetic Polymorphisms Less likely to Experience Levodopa–induced Dyskinesia, Study Shows

Polymorphisms

Parkinson’s patients carrying two types of genetic polymorphisms — a gene that has more than one variant in a given population — in the dopamine transporter gene are less likely to suffer from involuntary muscle movements associated with levodopa therapy, a study shows.

The study, “DAT gene polymorphisms (rs28363170, rs393795) and levodopa-induced dyskinesias in Parkinson’s disease,” was published in Neuroscience Letters.

Levodopa is one of the main therapies used to treat Parkinson’s disease. It works by replacing dopamine, a brain chemical produced by dopaminergic neurons that are destroyed gradually in the course of Parkinson’s.

Although levodopa therapy is often recommended to facilitate Parkinson’s symptoms’ management, the compound can have substantial side effects associated with its long-term use, including wearing-off effect (the medicine wears off before the patient can take the next dose), involuntary muscle movements, also known as levodopa-induced dyskinesia (LID), and changes in behavior (impulsive and compulsive behavior).

LID is one of the most common motor side effects of levodopa therapy — estimated to affect up to 95% of all patients taking levodopa for 15 years — and, at the same time, one of the most disabling.

Previous studies have proposed that Parkinson’s patients who are younger when they experience their first symptoms, have faster disease progression, and take higher doses of levodopa, are more likely to develop LID. However, given patients’ clinical variability to develop LID, these risk factors seem insufficient to explain its incidence, suggesting that genetic factors also may be involved.

Several studies have attempted to identify genetic factors that could increase patients’ susceptibility to LID, but results have been inconsistent so far. One particular gene, called dopamine transporter gene (DAT, also known as SLC6A3), might be an interesting candidate, because different genetic variants have been linked to different effects on dopamine uptake by neurons.

In fact, in Parkinson’s patients, homozygosity (same two copies of a given gene) for a specific form, or allele, of the DAT gene (called 9R) has been associated with an increased risk to develop the disease, whereas homozygosity for another allele, called 10R, has been associated with Parkinson’s protection.

Alleles are variant forms of the same gene (one copy of the gene inherited from each parent) that arise by mutation and are found at the same place on a given chromosome.

In this study, researchers aimed to determine whether different genetic variants of the DAT gene could be associated with patients’ risk to develop LID.

A total of 181 Italian Parkinson’s patients who had been taking at least 300 mg of levodopa daily for three years or more, were recruited. All patients were screened for two different genetic polymorphisms within the DAT gene: the rs28363170 (9R and 10R alleles) and the rs393795 (A and C alleles).

Data failed to reveal any significant difference in LID prevalence among patients who carried the two DAT genetic polymorphisms.

However, patients who possessed two copies of the 10R allele in the rs28363170 region and also carried the A allele in the rs393795 region, were less likely to develop LID in the course of long-term levodopa therapy, compared to patients who did not have these alleles.

“Despite this interesting result, our finding was obtained in an exploratory manner and thus need to be confirmed and replicated in different ethnic background populations and in larger cohorts of patients,” researchers wrote.

“Nevertheless, we believe that the identification of genomic biomarkers involved in drug response variability represents an important step in PD [Parkinson’s disease] treatment and it could be useful to identify patients more prone to better respond to treatments or to develop frequent and disabling conditions as adverse events like LID,” they concluded.

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