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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Anti-Parkinson’s, Other Anticholinergic Therapies Increase Risk of Dementia, Study Shows

dementia risk

Anticholinergic medications used to treat depression, urinary incontinence, or Parkinson’s disease increase the risk of dementia, even if the therapy was taken 20 years before diagnosis of cognitive impairment, a study has found.

The study, “Anticholinergic drugs and risk of dementia: case-control study,” was published in The BMJ.

Anticholinergic medications are designed to prevent the activation of nerve cells by the signaling molecule acetylcholine. Depending on the site where the treatment acts, it can be used to prevent several responses such as tremors in Parkinson’s or respiratory reactions. This class of medicines is also widely used to treat depression and gastrointestinal disorders, among others illnesses and conditions.

Their potential to affect cognition has been previously reported, and guidelines suggest avoiding use in frail older people. However, until now, the long-term effects of anticholinergic medications on cognitive function was not fully realized.

Researchers at the University of East Anglia in the U.K. conducted a large-scale, retrospective study to compare the use of anticholinergic medications among 40,770 people who were diagnosed with dementia and 283,933 individuals without cognitive impairment (EUPAS8705).

Patients’ clinical information was collected from the Clinical Practice Research Datalink, which covers more than 11.3 million patients from across 674 primary care practices in the U.K. The study included patients 65 years or older, who had been diagnosed with dementia between April 2006 and July 2015.

Of the five most common anticholinergic therapies used by participants in the study, 29% took amitriptyline (brand names Endep, Lentizol, Saroten, Tryptanol, and Tryptizol), 16% dosulepin (brand name Prothiaden), 8% paroxetine (brand names Paxil and Seroxat), 7% oxybutynin (brand names Ditropan, Lyrinel XL, Lenditro, Driptane, and Uripan), and 7% tolterodine (brand names Detrol and Detrusitol).

The team found that the use of anticholinergic treatments was linked to a 10-11% increased risk of dementia. When they analyzed the data according to drug indication, they found that dementia was more common among patients who had been prescribed antidepressants, anti-Parkinson’s therapies, and urological medications. No association was found with antispasmodic, antipsychotic, antihistamine, or other treatments.

This increased risk was found to persist even if the medications had been prescribed several years before the dementia diagnosis. In fact, patients who had been treated with anti-Parkinson’s therapies 10 to 15 years before diagnosis had a 54% increased risk of having dementia. For antidepressants, the risk was 19% and for urological therapies, 27%, when taken 15 to 20 years before diagnosis.

“These findings make it clear that clinicians need to carefully consider the anticholinergic burden of their patients and weigh other options,” Malaz Boustani, MD, co-author of the study and a researcher at Indiana University Center for Aging Research in the U.S., said in a press release. “Physicians should review all the anticholinergic medications — including over-the-counter drugs — that patients of all ages are taking and determine safe ways to take individuals off anticholinergic medications in the interest of preserving brain health.”

It is still unclear why these medications have such an adverse effect, and additional studies are needed to fully address the risks linked to their use. Still, these findings highlight not only the short-term effects of anticholinergic therapies but also long-term adverse effects on cognitive function.

“With many medicines having some anticholinergic activity, one key focus should be de-prescribing. Clinical staff, patients and carers need to work together collaboratively to limit the potential harm associated with anticholinergics,” said study co-author Ian Maidment, PhD, a senior lecturer in clinical pharmacy at Aston University in the U.K.

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Source: Parkinson's News Today