Authors: James F. Morley, MD, PhD, Sharon X. Xie, PhD, Howard I. Hurtig, MD, Matthew B. Stern, MD, Amy Colcher, MD, Stacy Horn, DO, Nabila Dahodwala, MD, John E. Duda, MD, Daniel Weintraub, MD, Alice S. Chen-Plotkin, MD, Vivianna Van Deerlin, MD, PhD, Dana Falcone, MS, and Andrew Siderowf, MD, MSCE
Article first published online: 16 FEB 2012
Volume 27, Issue 4, April 2012, pages 512-518
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The role of genetic factors in cognitive decline associated with Parkinson's disease (PD) is unclear. We examined whether variations in apolipoprotein E (APOE), microtubule-associated protein tau (MAPT), or catechol-O-methytransferase (COMT) genotypes are associated with cognitive decline in PD. We performed a prospective cohort study of 212 patients with a clinical diagnosis of PD. The primary outcome was change in Mattis Dementia Rating Scale version 2 score. Linear mixed-effects models and survival analysis were used to test for associations between genotypes and change in cognitive function over time. The ε4 allele of APOE was associated with more rapid decline (loss of 2.9; 95% confidence interval [CI]: 1.7-4.1) of more points per year; P < 0.001) in total score and an increased risk of a ≥10 point drop during the follow-up period (hazard ratio, 2.8; 95% CI: 1.4-5.4; P = 0.003). MAPT haplotype and COMT genotype were associated with measures of memory and attention, respectively, over the entire follow-up period, but not with the overall rate of cognitive decline. These results confirm and extend previously described genetic associations with cognitive decline in PD and imply that individual genes may exert effects on specific cognitive domains or at different disease stages. Carrying at least one APOE ε4 allele is associated with more rapid cognitive decline in PD, supporting the idea of a component of shared etiology between PD dementia and Alzheimer's disease. Clinically, these results suggest that genotyping can provide information about the risk of future cognitive decline for PD patients.
© 2012 Movement Disorder Society
Summary and review by Dr. Laura Silveira Moriyama, MD, PhD, UCL Institute of Neurology, Queen Square, London
The article chosen by the Website Editorial Board this month is called "Genetic Influences on Cognitive Decline in Parkinson's Disease". This prospective study from James Morley and associates looked at the effect of variations on 3 genes on cognitive decline in a cohort of 212 PD patients. Cognitive decline can affect up to 20% of newly diagnosed PD patients, and dementia occurs in up to 80% of patients, usually in more advanced disease.
The authors studied three genes which are implicated in the pathophysiology of cognitive impairment in PD. The first encodes catechol-O-methyltransferase, also known as COMT, an enzyme responsible for the metabolism of dopamine and had been shown to be associated with cognitive impairment in PD in another report. For this gene subjects were separated into those who had the Met/Met genotype or not.
The second gene encodes apolipoprotein E (often called APOE) and is well known to be associated with increased risk of Alzheimer's disease. For this gene, subjects were dichotomized by the presence or absence of the ?4 allele and also by the presence or absence of the ?2 allele. And the third gene encodes for the microtubule-associated protein tau (referred to as MAPT gene) and is associated with various neurodegenerative diseases in which there is cognitive decline and pathological deposition of tau protein aggregates, that includes Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and parkinsonism-dementia complex of Guam.
For this gene subjects were divided into those who had the H1/H1 haplotype or not. Clinical and neuropsychological assessment used the Mattis Dementia Rating Scale (version 2), which has already been validated for use in PD and is referred to as DRS-2. This scale is widely used to measure general cognitive ability and gives in addition to a total score, sub-scores for specific cognitive domains. These include: memory, attention, initiation and perseveration, construction and conceptualization. The highest possible score is 144. Standardized motor assessment was done using the Hoehn and Yahr scale and the UPDRS part III. Based on the inclusion criteria of 60 or more years of age, fulfillment of the Queen Square Brain Bank criteria and at least one annual follow-up visit, a total of 212 patients were included with a range of cognitive function. At baseline, the mean age of subjects was 70 years, and 68% were male. Mean disease duration was 6.7 years and the mean UPDRS score was 23.
Using linear mixed-effects models the authors tested for associations between different genotypes and changes in cognitive function over time. The mixed-effects models account for the variable length of follow-up in different subjects and also variations of intervals between assessments. In addition, Cox's proportional hazards regression model was used to examine which factors were associated with a significant drop of 10 points from the baseline DRS-2 score. This 10-point drop is considered a clinically relevant difference. The model accounted for differences in baseline DRS-2 score, disease duration, disease severity and other demographic factors. The authors found that the presence of the APOE ε4 allele was associated with a significantly higher annual rate of decline in DRS-2 score and also of reaching the 10-point decline during follow-up. Of the 212 subjects, 37 experienced such decline.
The decline associated with the APOE ε4 allele was not domain-specific, but affected a range of cognitive subscales. The COMT and MAPT genotypes were not associated with cognitive decline; nevertheless, COMT Met/Met status was associated with higher attention scores overall and MAPT H1/H1 was associated with lower memory scores. These interesting prospective findings add to the growing body of evidence about the association between APOE ε4 and cognitive decline in PD. APOE ε4 has been previously shown to be associated with higher risk of dementia in several cross-sectional studies, although negative findings in some other studies have prompted controversy.
The main take-home message of this featured article is that the genotype might have an influence on cognitive decline in PD. The presence of APOE ε4 allele is associated with faster cognitive decline in PD patients. Further studies are warranted to study if this is specific to PD, or due to the effect of APOE in cognitive status in general, and also to provide robust estimates of effect size over longer periods of follow-up.
About Dr. Laura Silveira-Moriyama
Dr. Laura Silveira-Moriyama, MD, PhD, graduated and trained in Neurology at the University of São Paulo, Brazil. She worked with Prof. Egberto Barbosa until 2004, when she moved to London to work in Queen Square with Prof. Andrew Lees. After completing a PhD on the subject of olfaction in Parkinson's disease she remained as a Senior Clinical Research Fellow in Queen Square, while at the same time she works as a visiting professor at University of Campinas (UNICAMP) in Brazil, where she develops clinical research on Pediatric Movement Disorders with Prof. Marilisa Guerreiro and Prof Maria Augusta Montenegro. She continues to work with Prof. Andrew Lees teaming up with various international collaborators.