The most commonly reported neuropsychiatric complications in Parkinson’s disease (PD) are symptoms of depression, anxiety, and psychosis. However, some of the most interesting advances recently have been in the areas of cognitive impairment and behavioural disturbances in the form of disorders of reward and motivation, such as apathy and impulse control disorders (ICDs). These cognitive and behavioural complications, which may interlink with each other, will be the focus of this article.
Cognitive impairment in PD
Cognitive impairment, particularly in the form of executive dysfunction is common and may manifest at the same time as the onset of the motor symptoms. More extensive cognitive manifestations such as dementia in PD (PDD) may also appear and since people are living with the disease longer, the prevalence of PDD is increasing. Furthermore, a relatively new area of inquiry in cognition in PD is gaining increasing attention, namely, changes in emotionally-dependent decision-making, which may be driven by changes in limbic-based neural pathways.
Executive dysfunction or mild cognitive impairment in PD
Even in the early stages of PD, impairments in various cognitive domains may be evident in a significant minority. In one study, 42% of an incident cohort of PD sufferers had cognitive impairment on presentation [1]. In particular, executive functions (abstract reasoning, planning, working memory, attention, and temporal sequencing), recall, language, memory, and visuoperceptual ability may be affected. In general, these deficits may initially only be evident on detailed neuropsychological testing, however, in some they may become more severe or widespread and begin to impact on non-routine daily activities. At this point, the deficits may be considered as a “mild cognitive impairment” (MCI) syndrome, although there is debate about the utility of using such a label [2]. MCI may be a precursor to a more severe cognitive syndrome that meets criteria for dementia (PDD), however, it is more likely that the neurotransmitter deficits underlying these mild cognitive deficits are due to disruptions in dopaminergic pathways, whereas the deficits underlying a more obvious dementia syndrome are cholinergic [3].
Dementia in PD
It is now accepted that if someone lives with PD long enough, they are likely to develop dementia. The Sydney Multicentre Study, which followed-up a cohort of 136 PD sufferers over several years, found that 83% of the 20-year survivors had developed dementia, together with a constellation of other symptoms of advanced PD including excessive daytime sleepiness (EDS), falls, freezing and hallucinations.4 Based on this study, the mean age at diagnosis of dementia was about 70 years old and the mean time to onset after diagnosis of PD was about 11 years. Clinically, PDD is characterised by an insidious onset and slowly progressive global cognitive decline, usually accompanied by a variety of behavioural symptoms such as apathy, hallucinations, depression, anxiety, and EDS. PDD differs clinically from dementia with Lewy Bodies (DLB) in that the dementia syndrome in PDD does not generally predate or occur at the same time as the onset of motor impairments, and perceptual abnormalities such as visual hallucinations are usually more common in DLB. Several factors may predict the conversion from PD to PDD, suggesting the presence of a “dementia-prone” subtype of PD.
For example, impaired verbal fluency and visuoperceptual functioning at diagnosis, older age at disease onset, akinetic-rigid type of PD, depression or psychosis early on in the course of the illness, orthostatic hypotension, and weight loss may all be predictors of later conversion to PDD [3,5,6]. The underlying pathology of PDD is heterogeneous and may reflect
Alzheimer’s disease-like changes with amyloid plaques and neurofibrillary tangles, the presence of cortical Lewy bodies, as well as vascular changes [4]. The extent of cholinergic deficit appears to correlate with the degree of cognitive impairment [7]. and this may relate to subcortical loss of cholinergic neurones and the associated loss of ascending cortical projections, rather than intrinsic cortical neuronal loss. This cholinergic deficit is the basis for the use of cholinesterase inhibitor therapy for the pharmacological management of PDD [8,9]. The use of the uncompetitive antagonist of N-methyl-D-aspartate (NMDA), memantine, may also have a role in managing PDD symptoms [10,11].
Decision-making abnormalities in PD
Emotionally-dependent decision-making is of increasing interest in PD due to recent studies which have shown deficits in such decision-making in people with PD. Moreover, with the relatively recent focus on ICDs in PD, this type of decision-making may be of importance as a potential basis for the development of the impulsive behaviours in the setting of dopamine replacement therapy (DRT). Broadly, such aspects of cognitive functioning have been labelled as “hot” decision-making, mediated by limbic areas (including aspects of self-control and impulsive decision-making) such as the ventral medial prefrontal cortex (VMPC) and orbitofrontal cortex (OFC), as opposed to the more “cool” or rationally-based aspects of executive function, mediated by the dorso-lateral prefrontal cortex (DLFC), all areas which may be affected by PD-related pathology. This may result in a reduced ability to interpret negative consequences or negative feedback, or take past experience into account when making deci- sions. Dopamine replacement therapy (DRT) may further impact on this type of cognitive functioning and it has been shown that when “on” DRT, those with PD were unable to learn to avoid undesirable or negative choices, as well as over-interpreting positive outcomes, compared to being “off” DRT [12].
Behavioural disturbances in PD
Behavioural disturbances in PD may manifest as either apathy, or loss of motivation and drive, or the ICDs. These disorders may co-occur with depression and anxiety and other neuropsychiatric symptoms and variable degrees of cognitive change.
Apathy in PD
Apathy in neurodegenerative conditions can be defined as “a lack of interest, emotion and motivation” [13] and is one of the most common neuropsychiatric complications in PD, occurring in over 40% of sufferers.14 Clinical correlates of apathy also include high rates of depression. Cognitive correlates include more impaired executive dysfunction, particularly working memory and verbal fluency, as well as more impaired global cognitive functioning [14]. The pathophysiology of PD that might lead to apathy is linked to impairments in pathways that underlie pleasure and reward seeking [15]. This is supported by studies in PD which have demonstrated blunted anticipatory responses to motivationally significant events or rewards [16], as well as striatal hypoactivation at the prospect of reward [17].
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Impulse control disorders in PD
“Impulse control disorders” (ICDs) in PD is a loosely defined group of behavioural conditions in PD, which was first described in the 1980s when case descriptions of an addiction to DRT were published. Later, in 2003, Driver-Dunckley described nine cases in a retrospective review of 1884 PD sufferers who developed pathological gambling (PG) following exposure to dopamine agonists (DAs) [18]. Since then, DRT has been considered to play a key, if not causal, role for the development of PG and possible other ICDs. Now, in the UK, all DAs have warnings about the risk of developing PG and other ICDs listed in their Summary of Product Characteristics. ICDs may occur in up to 14% of PD sufferers and include PG, hypersexuality, compulsive shopping and binge eating [19].
Pathological gambling (PG) is one of the most commonly reported and clinically dramatic of the behavioural disturbances associated with PD. It characteristically arises after the introduction of a DA and manifests in a change in behaviour that involve seeking out opportunities to gamble, including scratch card or lottery addiction, betting, internet or casino gambling and stock market trading. Such PG behaviour is typically difficult to control by the affected individual, progresses to involve larger amounts of money and greater risks, and continues despite adverse consequences. A recent review examined reports of 177 PD sufferers who developed PG and concluded those affected are more commonly male, young and have psychiatric co-morbidityand use DAs [20].
Hypersexuality (HS) in PD, which also usually occurs with a change in DRT, may appear in isolation, or in association with other ICDs. It may take the form of an enhanced libido, greater frequency of male erections, new sexual orientations, practices and even fetishes and may be accompanied by changes in mental state such as hypomania or disinhibited behaviour. Finally, dopamine addiction, also known as “dopamine dysregulation syndrome” (DDS) involves a progressive dependence on DRT, accompanied by marked dyskinesia, demands for more DRT despite being “on” motorically, hoarding behaviours associated with wanting more DRT, a reluctance to cut back on the medication, and marked irritability and withdrawal symptoms when denied access to DRT. DDS is often accompanied by purposeless, repetitive and stereotyped behaviours (“punding”), other ICDs and mood changes, and may be more closely linked to the use of levo-dopa than DAs. There is debate about whether DDS is a separate phenomenon from the ICDs since it is more closely related to excessive dopaminergic doses compared to mthe ICDs.
Are cognitive changes and behaviours linked in PD?
Since both apathy and the ICDs appear to involve reward and decision-making pathways, the question of whether they may overlap and how they may be linked to cognitive changes arises. Our own data suggest that rates of attentional impulsivity may be higher in those with PD-related apathy compared to PD-controls, and that ICD sufferers in PD have higher rates of apathy compared to PD-controls [21]. In apathy in PD, the predominant cognitive dysfunction involves executive dysfunction, particularly in set-shifting and verbal fluency [14], supporting the notion that cognitive deficits might be driving behaviours. In the ICDs, on the other hand, executive function may often be intact but here the key “cognitive lesion” may be disruption to emotionally-based decision-making, leading to a pattern of “cognitive impulsivity” that may in part drive impulsive behaviours in the context of DRT [22,23].
While the field of ICD studies in PD is relatively young, a few studies of an experimental nature have started to emerge and involve examining PD study participants both “on” and “off” medication while doing specific cognitive tasks. The key overall finding from these studies is that neural reward pathways, including the ventral striatum (VS), appear to be implicated in ICD pathophysiology and this may be impacted upon by DRT, and that dopamine is more readily released from the VS during reward-related tasks [24]. With this model, DRT may precipitate the development of impulsivity due to modulation of reward sensitivity by altering the “hot”-limbic/”cool”-executive system balance in favour of the “hot”- limbic loop [25]. This, in turn, leads to goal directed, impulsive behaviour, which may become addictive, and, once again, cognition appears to drive behaviour.
Conclusion
The changes in various levels of cognitive functioning in PD, as described above, and the putative links to behavioural changes, result in a challenging clinical scenario. In examining either behaviour or cognition in neurodegenerative conditions such as PD, it is important to consider how they may be interlinked and how their combined effect may manifest in the PD sufferer.
Dr Leroi has just finished a three year research project in this area funded by Parkinson’s UK.
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