Genetic influences on cognition in PD
Genetic association studies can provide opportunities to assess the pathophysiological mechanisms underlying different aspects of cognitive impairment in PD. So far, genome-wide association studies have not included sufficiently detailed clinical data to investigate loci associated with particular cognitive phenotypes, but some useful insights have been gained from adopting a candidate gene approach. Four genes in particular have been implicated in cognition in PD: COMT, MAPT, APOE, and GBA.
The enzyme catechol-O-methyltransferase (COMT) is involved in the degradation of catecholamines and acts as the principal regulator of synaptic dopamine within the cortex, especially the prefrontal cortex. The common Val158Met polymorphism in the COMT gene results in a trimodal distribution of high (Val/Val), intermediate (Val/Met), and low (Met/Met) enzyme activity
. These differences in activity have demonstrable effects on executive function in health and disease and have been exploited in attempts to understand the role of dopaminergic dysfunction in cognitive impairment in PD and its development.
In individuals without PD, low-activity COMT genotypes—implying higher prefrontal dopamine levels—have been associated with enhanced performance in problem-solving tasks that are known to engage prefrontal networks . Interestingly, the opposite trend has been observed in cross-sectional studies of patients with early PD. In a large cohort of 288 newly diagnosed patients, low-activity COMT genotypes (associated with putatively higher dopaminergic activity) were associated with inferior performance on the CANTAB one-touch Tower of London test of spatial planning . This association was replicated in an early PD cohort, although with a small effect size . However, subsequent studies of patients with more established disease have reported either no overall association between COMT genotype and executive function  or the same pattern as in controls, with low-activity genotypes predicting superior performance .
These seemingly disparate observations have been accommodated through an inverted U- shaped model, in which dopamine levels are related non-linearly to cognitive performance . It is hypothesized that there is an optimal level of dopamine within the prefrontal cortex and both increases and decreases relative to that level become detrimental to neural efficiency. The effects of the COMT enzyme will therefore be contingent on its dopaminergic environment, which in turn is influenced by disease progression and exogenous dopaminergic therapy. It is speculated that the high-activity Val/Val variant is advantageous in early PD because of the existence of abnormally elevated dopamine in the prefrontal cortex ; the Val/Val variant helps to negate these high dopamine levels while, under these circumstances, the low-activity Met/ Met variant is detrimental as it contributes to dopamine ‘overload’. As disease progresses, it is expected that the relative disadvantage of the Met/Met genotype is lost as the hyperdopaminergic state subsides, offering a rationale for the observation that patients with the COMT Met/ Met genotype improve on executive tasks over time while those with the Val/Val genotype do not (Fig. 17.1) .
The inverted U-shaped model predicts that increasing dopaminergic stimulation further with medication contributes to even greater executive impairments in PD patients with the low- activity Met/Met COMT genotype, presumably due to dopamine overload, but not in those with Val/Val genotypes [36, 37]. These hypothetical effects of medication have been demonstrated at a single subject level, emphasizing the concept that COMT works within a dynamic system. In line with the inverted U-shaped model, increasing dopamine through COMT inhibition in healthy
Fig. 17.1 Hypothesized inverted U-shaped relationship between working memory (WM) and dopaminergic activity in the prefrontal cortex (pfc). predetermined factors influencing dopaminergic activity including disease state and COMT val158Met genotype determine an individual's position on the curve, and hence predict their cognitive response to exogenous (drug-induced) changes in dopamine levels, as well as disease progression.
williams-Gray cH, Evans JR, Goris A, et al, The distinct cognitive syndromes of parkinson's disease: 5 year follow-up of the CamPaiGN cohort, Brain 2009, 132, 2958-69, by permission of Oxford University Press.
controls enhances executive function in individuals with the COMT Val/Val genotype but impairs performance in those with the Met/Met variant ; a similar direction of effect has been demonstrated using the Tower of London task in PD (authors’ unpublished data). Hence it seems that increases as well as decreases in frontostriatal dopamine contribute to executive dysfunction in PD, and the cognitive response to medication is likely to vary as a function of individual differences in baseline dopaminergic state.
However, a consistent finding from longitudinal studies is that differences associated with variation in COMT are not linked to progressive global cognitive decline and dementia [28, 38]. This supports the hypothesis that although dopaminergic disturbances account for a proportion of the cognitive dysfunction in PD, other coexisting pathologies underlie progression to dementia.