LRRK2-related Parkinson’s Linked to Greater Risk of Stroke

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by Marta Figueiredo PhD |

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People with Parkinson’s disease caused by mutations in the LRRK2 gene have a higher risk of stroke relative to other groups of Parkinson’s patients and healthy individuals, according to a study from Spain.

These findings add to previous studies reporting a link between Parkinson’s and increased stroke risk, and further highlight the contribution of circumstances other than classical cardiovascular risk factors in this patient population, particularly in those with LRRK2 mutations.

More research is needed to better understand the role of Parkinson’s-associated mutations in cardiovascular disease risk, the researchers noted.

The study, “Increased Stroke Risk in Patients with Parkinson’s Disease with LRRK2 Mutations,” was published in the journal Movement Disorders.

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Whether Parkinson’s disease, the second-most prevalent neurodegenerative disease, is associated with a greater risk of cardiovascular events has been the subject of interest of a number of studies that have yielded conflicting results.

While some studies reported no such link, a 2019 review study found a significantly increased risk of ischemic stroke, but not of heart disease, among people with Parkinson’s. Ischemic stroke, caused by a blood clot, is the most common type of stroke.

This suggests that Parkinson’s-related mechanisms may contribute to a higher risk of stroke, regardless of classical cardiovascular risk factors.

In addition, previous research also showed that Parkinson’s and ischemic stroke patients share significant changes in the activity of certain genes, compared with neurologically healthy people, “supporting the idea of common molecular pathways between the two diseases,” the researchers wrote.

However, “little is known about the influence of [Parkinson’s]-related genes, such as the leucine-rich repeat kinase 2 (LRRK2), the parkin (PRKN) and the glucocerebrosidase (GBA) genes, in the vascular risk of these patients,” the researchers added.

To address this, a team of researchers at the Hospital Universitario Virgen del Rocio’s Movement Disorder Clinic, in Spain, retrospectively analyzed the frequency of ischemic stroke and coronary artery disease in 355 patients with sporadic Parkinson’s, 97 patients with familial Parkinson’s, and 620 healthy individuals (used as controls).

Coronary artery disease, the most common type of heart disease, develops when the heart’s blood supply is blocked or interrupted by a buildup of fatty molecules in the heart arteries.

Among familial Parkinson’s patients, 38 had GBA mutations (GBA-PD group), 36 carried LRRK2 mutations (LRRK2-PD group), and 23 had PRKN mutations (PRKN-PD group).

Participants’ demographic, clinical, and cardiovascular risk factors data also were analyzed.

Sporadic Parkinson’s patients were significantly older than controls and GBA-PD patients, who had a particularly younger disease onset than those with sporadic disease. People with PRKN-associated Parkinson’s had a significantly younger disease onset, longer disease duration, and lower rate of arterial hypertension than the other groups.

No other differences in cardiovascular risk factors were detected across the groups.

After adjusting for potential influencing factors (sex, age, and cardiovascular risk factors), results showed that a significantly greater proportion of LRRK2-PD patients had an ischemic stroke relative to controls (13.8% vs. 3.4%) — reflecting a fivefold increased risk.

Similar stroke rates were detected between controls and people with sporadic Parkinson’s (5.6%) and those with GBA-PD (2.6%), while the PRKN-PD group showed a higher stroke frequency (8.6%), but this difference did not reach statistical significance.

In addition, patients with LRRK2-PD had significantly younger age at stroke and shorter survival compared with the control group. PRKN-PD patients also showed a significantly poorer survival relative to controls.

Similar findings were obtained when the researchers  considered only patients with radiologically-confirmed stroke regardless of the presence of symptoms, with the addition of a near-significant higher stroke risk in sporadic Parkinson’s patients, compared with controls.

Notably, LRRK2-PD patients who had a stroke were significantly older at Parkinson’s onset and all of them carried p.G2019S, the most common Parkinson’s-associated LRRK2 mutation.

While both sporadic Parkinson’s patients and controls who experienced a stroke had higher rates of arterial hypertension and hyperlipidemia than those without stroke, no significant differences in cardiovascular risk factors were detected within the LRRK2-PD group.

Arterial hypertension is abnormally high pressure in blood arteries, while hyperlipidemia refers to excessive levels of fatty molecules in the blood.

These findings “support the idea that mechanisms other than classical vascular risk factors might influence the described increased risk of stroke in [Parkinson’s patients],” the researchers wrote.

Given that disease-associated LRRK2 mutations have been suggested previously to contribute to neuroinflammation, “a plausible explanation for the increased risk of stroke in our patients with LRRK2-PD could be related to a pro-inflammatory state that might contribute to [small blood vessel obstruction],” the team wrote.

No significant differences were found between groups in terms of frequency of coronary artery disease and associated survival.

Larger, prospective studies are needed to confirm these findings.

Further studies including people carrying such mutations, but not showing Parkinson’s symptoms, also will help determine their cardiovascular disease risk, regardless of Parkinson’s neurodegeneration, the team noted.

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