Some Genes May Alter Cognition in Parkinson Disease More Than Others

Different forms of genetic Parkinson disease (PD) come with varying levels of cognitive impairment, according to a recent review.

About 10% of PD is genetic, and in this review, researchers sought to understand more of the link between the complicated genetics of PD and cognitive decline. Some genetic influences appear to be more closely associated with cognitive problems than others, according to their findings.

Mild cognitive impairment (MCI) affects about a third of patients with PD, advancing to dementia in most individuals over time.

Autosomal dominant PD is linked to mutations in the α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), and vacuolar sorting protein 35 (VPS35) genes, while autosomal recessive PD genes include Parkin and PTEN-induced putative kinase 1 (PINK1). More recently, some genetic risk factors for PD have been recognized, such as mutations in the glucocerebrosidase (GBA) gene.

The cognitive profile of patients with the LRRK2 mutation came from several cross-sectional studies and 1 longitudinal study. Most of these cross-sectional studies found no significant differences between patients with the mutation and those with idiopathic PD, whereas 4 other studies found a trend toward better performance on cognitive tests.

The longitudinal study found no significant differences as well, although scores on the Montreal Cognitive Assessment were somewhat higher in those with the mutation. Overall, researchers observed a trend toward milder cognitive impact compared with idiopathic PD, but they cautioned that larger, longitudinal studies are needed to confirm these findings.

Cognitive impairment is also lower in patients with Parkin and PINK1 mutations, based on the 6 cross-sectional studies found by the authors, with the limited results available pointing to similar or even better function than in idiopathic PD.

Parkin mutations are the most common cause of autosomal recessive early-onset PD, followed by PINK1 mutations. Clinically, PINK1 is similar to Parkin and is also believed to have more mild effects on cognition, although more research is needed.

There are no data on imaging or biological biomarkers for Parkin and only 1 case describing Lewy bodies in the brainstem in an autopsy report of a patient with PINK1.

However, cognitive decline is worse among patients affected with SNCA gene mutations, the authors said, although because these mutations are rare (making up about 2% of autosomal dominant familial PD cases) there is a lack of data comparing cognitive function in this subtype to that of idiopathic PD. Patients with this mutation have dementia with psychiatric symptoms, and patients with SNCA triplications have earlier disease onset and more severe disease.

In another example of the impact of genetics on cognitive outcomes in PD, 11 studies looked at GBA mutations. Heterozygous GBA mutations are the most common genetic risk factor for PD. Various studies put the risk for cognitive impairment or dementia at about double the frequency as in idiopathic PD. These patients tended to have worse functioning in executive and visuospatial domains and, possibly, a faster progression of disease.

Reference

Planas-Ballvé A, Vilas D. Cognitive impairment in genetic Parkinson’s disease. Parkinsons Dis. Published online December 30, 2021. doi:10.1155/2021/8610285