UvA-DARE (Digital Academic Repository) Cognitive change in Parkinson's disease Broeders, M. Link to publication

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1 UvA-DARE (Digital Academic Repository) Cognitive change in Parkinson's disease Broeders, M. Link to publication Citation for published version (APA): Broeders, M. (2015). Cognitive change in Parkinson's disease General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 03 Dec 2018

2 CHAPTER 1 General introduction 7

3 Chapter 1 Parkinson s disease Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The earliest description of PD was made by James Parkinson (Parkinson, 1817). His now famous Essay on the shaking palsy consisted of six descriptions of patients (three of whom he examined himself) who presumably suffered from what we now call PD. The description of their symptoms clearly illustrates the classic, characteristic motor features of PD, such as tremor, disturbances of gait and posture, slowness of movements (bradykinesia), and the stiffness of the muscles (rigidity). In addition to these features, Parkinson also mentions the slow onset of the disease: "So slight and nearly imperceptible are the first inroads of this malady, and so extremely slow its progress, that it rarely happens, that the patient can form any recollection of the precise period of its commencement." (Page 3). Parkinson s essay primarily focused on the motor features, while non-motor features were not seen as part of the disease: By the nature of the symptoms we are taught, that the disease depends on some irregularity in the direction of the nervous influence; [ ]; and by the absence of any injury to the senses and to the intellect, that the morbid state does not extend to the encephalon. (Page 17). For example, in his description of one of his patients (A.B.), Parkinson specifically mentions the patient s unaffected cognitive skills: Milk was almost his only food; his body was rather loose, his urine natural, his sleep good, his senses, and the powers of his mind, unimpaired; he was attentive to, and sensible of every thing which was said in conversation, and shewed himself very desirous of joining in it; but was continually checked by the impediment in his speech, and the difficulty which his hearers were put to. (Page 18). Although the diagnosis of PD is based primarily on motor symptoms, we now know that patients also suffer from various non-motor features. In 1967, Hoehn and Yahr published a review in which they described five stages of PD (Hoehn & Yahr, 1967). In their review, the authors already mentioned the presence of, for instance, sleep disturbances, personality changes, and autonomic changes. During the past decades, knowledge of non-motor features of PD such as depression, apathy, sleep deficits, autonomic dysfunction, and cognitive impairments has increased exponentially (Bowen, Hoehn, & Yahr, 1972; Dubois & Pillon, 1997; Kudlicka, Clare, & Hindle, 2011; Litvan et al., 2011). These symptoms can be very invalidating for patients. For instance, cognitive dysfunction and PD related dementia are associated with placement in nursing homes and result in higher costs to society (Aarsland, Larsen, Tandberg, & Laake, 2000; Goetz & Stebbins, 1993). These non-motor symptoms may present themselves early in the course of the disease. Neuropsychological studies have shown that as early as the time of diagnosis, approximately a quarter of patients already show cognitive deficits (Foltynie, Brayne, Robbins, & Barker, 2004; Muslimovic, Post, Speelman, & Schmand, 2005; Pedersen, 8

4 General Introduction Larsen, Tysnes, & Alves, 2013). The number of patients with cognitive dysfunction increases further as the disease progresses. Three years into the disease, half of the patients may have developed cognitive impairment (Muslimovic, Post, Speelman, De Haan, & Schmand, 2009; Williams-Gray, Foltynie, Brayne, Robbins, & Barker, 2007). Also, in the course of the disease the types of cognitive impairments become more diverse. Whereas in the early disease stages cognitive deficits are mostly restricted to domains of executive function and attention, presumably due to dopamine depletion in the basal ganglia, in later stages memory and visuospatial functions may become affected. Evidence for cognitive impairment in PD is also supported by findings of cognitive neuroscience studies. Patients often show impairments in response inhibition, decision-making, and reward-based probabilistic learning (Cools, Barker, Sahakian, & Robbins, 2001; Ridderinkhof et al., 2012; van den Wildenberg et al., 2010; van Wouwe, Ridderinkhof, Band, van den Wildenberg, & Wylie, 2012; Wylie et al., 2012). These impairments are generally attributed to a disruption of the cognitive circuits of the basal ganglia. This thesis focuses on cognitive changes in patients with PD. We examined the natural course of cognitive decline in a sample of patients with newly-diagnosed PD. Furthermore, we obtained information from a subset of this group on response inhibition and reward-based learning, based on experimental studies. Before I discuss these studies, I will first describe PD and its pathology. Next, I focus on what we already know about cognitive decline, describe response inhibition and reward-based learning in PD, and finally, I will discuss the relevance of these issues. The pathology of Parkinson's disease The main pathology in PD is degeneration of dopamine neurons in the substantia nigra pars compacta. This structure is part of the basal ganglia, a subset of interconnected nuclei located in the forebrain and midbrain involved in both motor functioning and cognition (Wolters, van Laar, & Berendse, 2008). Its main components are the striatum (caudate, putamen and the nucleus accumbens), the pallidum (globus pallidus pars externa [GPe] and globus pallidus pars interna [GPi]), the subthalamic nucleus (STN), and the substantia nigra (substantia nigra pars compacta and substantia nigra pars reticulata) (Smith & Kieval, 2000). Based on intrinsic and extrinsic connections in the basal ganglia and the surrounding cortex, Alexander and colleagues (1986) identified five segregated parallel cortical-subcortical circuits, namely the motor, oculomotor, dorsolateral prefrontal, lateral orbitofrontal, and anterior cingulated circuits. Although there is debate as to whether these circuits are closed (as put forward by Alexander and colleagues) or whether there is convergence, it is generally acknowledged that the basal ganglia encompass multiple circuits (S. Haber, 2008; S. N. Haber & Calzavara, 2009; Joel & Weiner, 1994; Joel & Weiner, 1997). 9

5 Chapter 1 Figure 1.1 Illustration of the direct and indirect pathways in the basal ganglia Note: GPe=globus pallidus pars externa, GPi=globus pallidus pars interna, SNc=substantia nigra pars compacta, SNr=substantia nigra pars reticulate, STN=subthalamicus nucleus, VTA=ventral tegmental area. Figure adopted from Yin and Knowlton (2006). The motor features of PD are linked to a disruption in the functioning of the motor circuit. In the motor circuit, the dorsal striatum (consisting of the putamen and nucleus caudatus) gives rise to two pathways in the basal ganglia, the direct and indirect pathway (see Figure 1.1). The direct pathway, which connects the dorsal striatum directly to the GPi, facilitates movement. Striatal Go cells receive excitatory input via D1 receptors from the cortex. The striatum then inhibits the GPi via the transmitter GABA. The GPi is normally tonic active and inhibits the thalamus. Striatal inhibition of the GPi leads to disinhibition of the thalamus. This disinhibition enables the thalamus to excite the cortex, thereby facilitating movement (hence, the term Go cells ). In contrast, the indirect pathway, which connects the dorsal striatum to the GPi via the GPe and STN, inhibits movement. When striatal NoGo cells receive input from the cortex via D2 receptors, they send inhibitory signals to the GPe. The GPe in turn, inhibits the STN. The STN normally sends excitatory signals to the GPi. This disinhibition of the STN thus leads to more excitatory signals from the STN to the GPi. The GPi inhibits the thalamus thereby reducing the facilitation of movements (hence, the term NoGo cells ). These two pathways selectively act to facilitate the appropriate movements while at the same time inhibiting other movements (Mink, 1996). In healthy individuals, there is a balance between these two pathways; however, PD leads to misbalance between the pathways. According to the classic model of PD (see Obeso, Rodriguez-Oroz, Rodriguez et al., 2000), the main feature in PD is increased neuronal activity in the STN/GPi output nuclei of the basal ganglia. It is hypothesized that dopamine deficiency results in a decrease in dopaminergic activation which results in 1) reduced inhibition of neurons along the indirect pathway, and 2) decreased 10

6 General Introduction excitation of neurons along the direct pathway. Thus, along the indirect pathway decreased sensitivity in dopamine receptors leads to less inhibition of the GPe, which in turn does not properly inhibit the STN. The STN sends out more excitatory signals to the GPi, which then strongly inhibits the thalamus. While along the direct pathway the decreased excitation of dopamine neurons directly leads to less inhibition of the GPi, which then leads to greater inhibition of the thalamus. This imbalance between the two pathways leads to the classic features of PD. The classic model also explains the levodopa-induced dyskinesia seen in medicated PD patients. The basic notion is that the dyskinesia arises as a result of reduced activity in the STN, GPi and GPi/STN neurons. This could either be due to lesions in the putamen, lesions in the STN itself, or because of high dosages of levodopa (Obeso, Rodriguez-Oroz, Chana et al., 2000). Cognitive dysfunction in patients with Parkinson's disease In addition to the motor features that define PD, cognitive dysfunction is frequently seen in PD. Approximately a quarter of patients show cognitive deficits at the moment when they are diagnosed with PD. These early disease stages are primarily characterized by executive dysfunction and attentional deficits (Foltynie et al., 2004; Muslimovic et al., 2005). Such impairments are hypothesized to be a direct result of dopamine depletion within the substantia nigra pars compacta, which leads to impaired striatalfrontocortical dysfunction. Between three to eight years after the diagnosis, up to 80% of patients are identified with cognitive impairment (Aarsland, Bronnick, Larsen, Tysnes, & Alves, 2009; Muslimovic et al., 2009; Williams-Gray et al., 2007). Whereas executive dysfunction is most common in the earlier disease stages, cognitive deficits are more diverse in the later stages. For instance, there is an increase in memory impairment and visuospatial dysfunction in later disease stages. There are several hypotheses to explain the increase in these types of impairments. First, memory impairment and visuospatial dysfunction may be secondary to executive dysfunction. While patients with PD often show problems with the retrieval of information, recognition is usually intact. Recognition is a cognitive process that depends more on posterior functioning, in particular the temporal lobe. Thus, executive components might be the cause of impaired memory performance. A different explanation refers to the pathology of PD. Besides dopamine depletion, PD is additionally characterized by accumulation of Lewy bodies throughout the cortex, and by other histological changes (Jellinger, 2001; Jellinger, 2012). Such cortical pathology may lead to impairments in memory and visuospatial functioning. Of course, it could also be a combination of these two explanations. One of the problems in explaining the neuropsychological impairments of PD is the heterogeneity of the disease. There usually is great variation in cognitive performance between patients with PD. Attempts have been made to parse the 11

7 Chapter 1 heterogeneity of PD into meaningful concepts. For instance, a current topic in the PD literature is the concept of mild cognitive impairment (MCI). MCI is traditionally defined as the transitional stage between normal aging and Alzheimer's dementia (Petersen, 2004). All PD patients with dementia (PDD) most likely passed a similar transitional stage. However, Alzheimer's dementia and PDD are not directly comparable. For instance, whereas early Alzheimer's dementia is mainly characterized by deficits in the domain of memory, patients with PD more often experience executive impairment and attention deficits. Despite these differences, modified MCI criteria (i.e., adapted to PD) have been applied in studies that focused on PD. One study found that 62% of PD patients who fulfilled modified MCI criteria progressed to dementia within 4 years (Janvin, Larsen, Aarsland, & Hugdahl, 2006). Although MCI appears to have good prognostic value and may therefore be useful in explaining the heterogeneity within PD, many studies suffered from methodological difficulties, such as using different criteria for MCI. Recently, the Movement Disorder Society taskforce published consensus criteria for MCI in PD (PD-MCI Litvan et al., 2012). Application of these criteria may be useful to identify patients who are at risk for developing dementia; however, the criteria need to be validated. Recently, Kehagia, Barker, and Robbins (2012) postulated a dual-syndrome hypothesis that may account for some of the heterogeneity within PD. In short, the dual-syndrome hypothesis differentiates two broad syndromes: (1) a syndrome characterized by frontal-striatal dysfunction and (2) a syndrome with distinctive early visuospatial deficits that are indicative of the involvement of temporal and other posterior cortical areas. Patients with more profound executive impairment at baseline, suggestive of fronto-striatal dysfunction, generally progress slower than those with more profound memory and visuospatial impairments. Despite the increase in studies that examine cognitive change in PD, much still remains unclear. This is mostly due to methodological difficulties with previous research. For instance, the earliest studies that examined cognitive decline in PD usually comprised small study samples and many used convenience samples, consisting of patients at varying disease stages (e.g., Biggins et al., 1992; Fischer et al., 1990; Hobson & Meara, 2004). Given the great heterogeneity within the PD population, neuropsychological studies need to include large(r) samples. In addition to these small and mixed samples, a control group was often lacking. During the past decade however, more thorough studies appeared that included newly-diagnosed patients and control groups (Aarsland, Andersen, Larsen, Lolk, & Kragh-Sorensen, 2003; Foltynie et al., 2004; Kandiah et al., 2009; Muslimovic et al., 2005; Reid, Hely, Morris, Loy, & Halliday, 2011). Unfortunately, most studies did not include an extensive neuropsychological examination. Given the variety of cognitive impairments, rather large test batteries are needed to adequately describe the impairments. 12

8 General Introduction Inhibition and reward-based learning in Parkinson's disease In addition to impairments of these relatively molar neuropsychological functions, there is also evidence that PD affects more fine-grained mental abilities, such as response inhibition and reward-based learning. These two abilities strongly depend on proper frontostriatal functioning, and therefore dopamine depletion in the striatum may result in their impaired performance. Response inhibition refers to the suppression of response impulses and depends strongly on basal ganglia-prefrontal interactions (Chudasama & Robbins, 2006). Inhibition is an important aspect of cognitive control. A distinction can be made between two theoretically separable modes of cognitive control: 1) reactive control refers to the detection and resolution of conflict between a response impulse and the actual response that is needed, whereas 2) proactive control refers to the anticipation Box 1.1 The Simon task In a typical Simon task, participants have to respond to stimuli based on a certain stimulus dimension, namely color, while ignoring the irrelevant stimulus feature, namely location. The stimuli, which usually consist of colored circles, are presented either to the left or to the right of the center of the computer screen. In case of a compatible trial, the location of the stimulus and the location of the response are similar, while incompatible trials are trials where the location of the stimulus does not match the location of the correct response. Compatible trials usually are associated with faster RTs and higher accuracy rates than incompatible trials. Figure 1.2 shows a compatible and incompatible trial the typical Simon task. Figure 1.2 Compatible and Incompatible Trials in the Simon Task. Figure adapted from van den Wildenberg et al.,

9 Chapter 1 and prevention of this response conflict (Braver, 2012). A frequently used task to examine inhibition is the so-called Simon task (Simon & Small, 1969). In the Simon task (see Box 1.1), the spatial location of the stimuli elicits a strong impulse to respond with the corresponding hand. In case of spatial compatibility (i.e. the location in which the stimulus appears is identical to the side of the response), this strong response impulse leads to faster RTs. However, in case of spatial incompatibility (e.g. a color-designated response with the right hand to a stimulus that is presented on the left side), the strong response impulse needs to be inhibited. As such, RTs are usually slower for conflict trials. The difference in RT between compatible and incompatible trials is referred to as the Simon effect (Simon & Small, 1969). Although in general no differences in the overall Simon effect have been observed between patients and controls, there appear to be differences in the proficiency of reactive and proactive control. Reward-based learning is a kind of instrumental conditioning. It refers to the formation of an association between an action and an outcome. According to Thorndike s law of effect (Thorndike, 1911), behavior or actions that lead to positive outcomes are more likely to reoccur in future events than actions that lead to negative reinforcement. In a typical reinforcement learning paradigm, a subject has to learn the association between a response (e.g. a right- or left hand button press) and stimulus (e.g. a Chinese letter). Immediately after the presentation of the stimulus, the subject has to make a response after which feedback is followed (e.g. a monetary reward after a correct response or monetary loss after an incorrect response). According to Thorndike s law of effect, a response that is followed by a positive outcome is more likely to reoccur the next time the same stimulus is presented. Thus, the subject learns which response is associated with a stimulus based on the feedback he or she is given. One model that has been developed to describe the learning of future rewards is the so-termed Q-learning model (Watkins, 1989). The Q-learning model (see Box 1.2) makes a distinction between outcome evaluation (reward prediction error [RPE]) and reward prediction (stimulus-action dependent reward prediction [SADRP]). PD seems to have a negative impact on reward prediction (SADRP), while outcome evaluation (RPE) may be relatively unimpaired (Ridderinkhof et al., 2012). However, some studies found interesting individual differences among patients with regard to outcome evaluation. The RPE showed improvements with larger daily dosages of dopaminergic medication, and was positively affected by deep brain stimulation of the subthalamic nucleus in patients with relatively short disease duration (van Wouwe et al., 2011; van Wouwe et al., 2012). Thus, PD may have a detrimental effect on reward-based learning, but there are differences between patients. While these findings begin to portray a coherent picture, they await independent replication, and extension to further factors that might be clinically relevant in modulating reactive and/or proactive control in PD. In particular, apart from factors related to motor impairment (such as UPDRS scores), 14

10 General Introduction variables related to cognitive impairment might also influence the proficiency of action control among PD patients. Studies on response inhibition and reward-based learning may be helpful in identifying early cognitive changes in PD and could overcome some of the limitations of neuropsychological examinations. For instance, one of the limitations of neuropsychological tests is the fact that they may fail to capture specific aspects of cognitive performance that are influenced differentially by dopamine depletion, such as action control and reward-based learning. Furthermore, neuropsychological examinations and the PD-MCI criteria do not take the influence of dopaminergic medication into account. It has therefore been suggested that combining neuropsychological and experimental cognitive measures might be helpful in optimizing the detection of early cognitive changes in PD (Claassen & Wylie, 2012). Box 1.2 Q-learning paradigm There are several models that describe action-outcome learning, but we focus here on the Q-learning model (Watkins, 1989). The Q-learning model distinguishes between outcome evaluation and reward prediction. Outcome evaluation refers to the reward prediction error (RPE), which represents the difference between the expected outcome of an action and the actual outcome of the action. In case of a positive RPE, i.e., a greater reward than what was expected, the association between the action and outcome is strengthened and is likely to occur more often in the future. A negative RPE however, which indicates a smaller reward than what was expected, leads to a reduction in associative strength between the action and outcome. Thus, in early learning stages RPE values will be high, whereas in later stages RPE values will decrease as a result of learning. Reward prediction in the Q- learning model, is computed as the stimulus-action dependent reward prediction (SADRP). The SADRP is updated according to RPE values. In early learning stages, SADRP values will be low because an individual cannot adequately predict the reward; however, during learning SADRP values will increase. Imaging studies have provided evidence for the role of the striatum in learning. For instance, positive RPE values have been associated with an increase in firing in dopaminergic neurons, while negative RPE values were associated with a dip in dopaminergic firing (Frank, Seeberger, & O'reilly, 2004; Schultz, 2007). Moreover, the nucleus accumbens and caudate nucleus have been identified as regions related to the RPE, whereas the putamen is related to the SADRP (Haruno et al., 2004; Haruno & Kawato, 2006). 15

11 Chapter 1 Aims of this thesis In 2002, the Academic Medical Center in Amsterdam started a large study to examine the progression of cognitive decline in a large cohort of PD patients. This study was embedded in the larger CARPA project (Comorbidity and Aging in Rehabilitation Patients with sequalae of poliomyelitis, osteoarthritis, and PD: the influence on Activities). Between 2002 and 2005, 133 newly-diagnosed PD patients and 69 patients with more advanced PD were recruited to participate in our study. At baseline testing, newly-diagnosed PD patients had just received the PD diagnosis, while the advanced PD cohort had a longer disease duration of approximately five years. In this thesis, I will present findings from the five-year follow-up study of this sample in which we tried to overcome the limitations that were mentioned above. Our study aimed: 1) to examine cognitive decline, using statistical and consensus criteria and functional status in patients five years after the PD diagnosis, and to identify predictors of cognitive and functional decline, 2) to disentangle the relation between executive functioning, memory, and visuospatial skills using structural equation modeling, and 3) to examine the ability to inhibit responses and to learn through reward-based feedback, and to explore the association between inhibition and reward-based feedback learning on the one hand, and clinical and cognitive status on the other. Outline of the thesis In Chapter 2 we examined the cognitive status of newly-diagnosed PD patients five years after the initial diagnosis. Neuropsychological performance of 59 newly-diagnosed PD patients was compared with that of 40 healthy controls. We analyzed cognitive abilities in both groups at the group level and at the individual level. Furthermore, we aimed to identify prognostic factors of cognitive decline. We also analyzed data from patients who were lost to follow-up, to gain a better insight into the influence of attrition. Chapter 3 describes the functional status of newly-diagnosed PD patients five years after the diagnosis. We examined the progression of newly-diagnosed PD in terms of motor impairments, disability and quality of life in a cohort of 129 newly-diagnosed PD patients. Additionally we aimed to identify prognostic factors of functional decline. In an attempt to better identify patients who are at risk for cognitive decline and dementia, the concept of mild cognitive impairment in PD (PD-MCI) has been introduced. Recently, the MDS taskforce published consensus criteria to define PD- MCI. In Chapter 4 we apply these new PD-MCI criteria to our sample of newlydiagnosed PD patients. We aimed to examine the inter- and intra-rater reliabilities of the criteria. Furthermore, we explored the progression of PD-MCI over the course of five years. There is debate as to whether memory and visuospatial deficits are secondary to executive dysfunction. In Chapter 5 we used structural equations modeling to aim to 16

12 General Introduction examine the causal relations between disease severity on the one hand and executive functions, memory, and visuospatial abilities on the other. The causal relations were tested using data from the newly-diagnosed PD cohort at baseline. Moreover, to examine these causal relations after longer disease duration, we combined five year follow-up data from newly-diagnosed PD patients with baseline data from advanced PD patients. In Chapter 6 we examined the influence of PD on response inhibition using a variant of the classical Simon task. We compared Simon task data from 33 patients (combined newly-diagnosed PD and advanced PD patients) with that of 27 controls. Our first aim was to systematically replicate the effects of PD on measures of reactive and proactive control. We further examined to which extent cognitive impairments and motor deficits affect reactive and proactive control. Chapter 7 focuses on reward-based learning in PD. We compared the performance of 30 PD patients (combined newly-diagnosed PD and advanced PD patients) and 27 healthy controls on a probabilistic learning task. Our first aim was to study differences between patients and controls in their ability to learn which actions yield reward (SADRP) and outcome evaluation (RPE). Second, we explored individual differences by looking at the association between SADRP and RPE values, clinical characteristics (e.g., motor symptom severity, disease stage, disease duration, and levodopa use) and cognitive performance (neuropsychological functioning and PD- MCI). Finally, Chapter 8 presents an overview and discussion of the main findings. Furthermore, we discuss the clinical relevance of this thesis. 17