Neurodegenerative Deficits of Executive Function in Parkinson’s Disease

Parkinson’s disease (PD) is an illness that comes accompanied by a host of progressive neurologic, motor, and cognitive deficits. The first problems a person with PD is likely to notice are motor symptoms such as tremors or rigidity in a limb or another extremity. These motor issues often begin with a single lateral side of the body, and progress to both sides (Karádi et al., 2015). Motor symptoms, however, are only part of the symptomology. In addition to motor issues, the vast majority of PD patients will suffer cognitive impairments. One such affected area of cognition includes executive function (EF). Executive function consists of several components, including working memory, planning, impulse control, and motivation. Problems with EF can occur even at the earliest stages, and usually become as debilitating in the later stages as the motor issues (Siepel et al., 2014). For a significant portion of PD patients, the cognitive impairments will lead to the onset of dementia, severely impacting quality of life and rendering an individual unable to care for themselves. While much of the research on PD focuses on the substantia nigra’s (SN) role in motor dysfunction, much of the cognitive and EF-related research focus on the striatum and neocortex. The current research seeks to identify and explain the affected components of EF in PD and the neural processes underlying them.

The onset of PD is most often signaled by aberrant motor problems. An individual may begin by noticing a tremor in their hand, or a stiffness and rigidity to a leg (Kudlicka, Clare, & Hindle, 2014). Such symptoms will continue to worsen until the individual has such difficulty that they may stumble and hurt themselves. Indeed some 81% will suffer falls, and around 23% may sustain fractures (Hely, Morris, Reid, Trafficante, 2005). What is less obvious than the motor symptomology, however, is the onset of cognitive deficits.

Cognitive problems frequently occur even in the early stages (Siepel et al., 2014). Symptoms may begin in ways that one could possibly misinterpret as the normal effects of aging. Many sufferers report a slowness of thinking and noticeable forgetfulness (Poliakoff, Ellen, Smith-Spark, & James, 2008). A person with PD may have a harder time recalling a name or a word that they are trying to remember. Additionally, individuals may not be as interested in seeking novel stimulation as they previously were, even to the point of apathy (Pagonabarraga, Kulisevsky, Strafella, & Krack, 2015). Early stage mild cognitive impairment (MCI) will occur in between 20 and 25 percent of patients with PD who don’t have dementia (Aarsland et al., 2010). Mild cognitive impairment usually occurs in two varieties; the amnestic form which primarily affects memory, and the non-amnestic form which negatively impacts areas like perception and EF. Eventually though, the cognitive symptoms will multiply in magnitude and in number of areas affected. In one study, the authors found that, of the one-third of their original sample who survived the 15-18 year span of their study, 84% exhibited a cognitive decline, and 48% met criteria for dementia (Hely, Morris, Reid, Trafficante, 2005).

Cognition usually begins to deteriorate in a similarly lateral pattern as indicated by the side of the body which motor symptomology first appeared (Karádi et al., 2015). This is potentially important because the two hemispheres of the brain are associated with different properties. The left hemisphere in humans is traditionally associated with language and speaking; Broca’s area being the cortical region primarily related to speech production, and Wernicke’s area being the region primarily related to understanding language (Hartman, David, Hutter, Richard, Boland, & Kevin, 2011). Strangely, this speech and language asymmetry seems to highly correlate with handedness; with left-lobe language dominance occurring most often with right hand dominance. Language lateralization isn’t absolute however. Many subdivisions of Broca and Wernicke’s are less lateralized to various degrees, but there is a trend irrespective of these nuances (Ramachandran, 2002). The right hemisphere is considered to be strongly related to visual and spatial function. Though again, lateralization isn’t absolute; the right hemisphere is now known to have a crucial role in language as well.

Nonetheless, evidence for lateralization in PD patients is abundant. Individuals with PD who show right (RPD) and left symptom dominance (LPD) patterns as defined by the side of motor symptom onset, have shown differential cognitive impairments. Those who are RPD tend to have a more difficult time with vocabulary recall, naming, and verbal expression (Verreyt et al., 2011). Conversely, LPD patients demonstrated more of a decline in mental imagery, spatial attention, orientation, and visual memory (Blonder, Gur, Gur, Saykin, & Hurtig, 1989; Amick, Grace, & Chou, 2006). Since each hemisphere of the brain controls the part of the body contralateral to it, LPD individuals are more likely to display neuropathology particularly in the right hemisphere, and RPD individuals would display more in the left hemisphere. Thus, the lateralized pattern of impairment in PD appears to support the traditional understanding of the lateralization of the brain. Knowing the areas of the brain where dysfunction is most intense, and what cognitive abilities are affected, may help identify and understand which areas of the brain are responsible for cognitive—and more specifically EF—decline.

Several neurological structures have been associated with cognitive impairment. One study utilizing a mixed sample of PD patients with and without dementia reported a correlation between global measures of cognitive function and volume of the caudate, ventricles, and the hippocampus (Filoteo, Reed, Litvan, & Harrington, 2014). The caudate nucleus is often first thought of as a member of the basal ganglia, the role of which is highly related to movement and coordination. However, recent findings have linked the caudate nucleus to some important cognitive functions as well. Indeed, through its communication with areas in the frontal and medial cerebral cortex, it seems to play a critical role in EF, such as goal-directed behavior via schema activation (Grahn, Parkinson, & Owen, 2008). This confirms the findings of Lewis, Shine, Duffy, Halliday, and Naismith (2012) that EF is closely related to frontostriatal mechanisms.

It is less surprising that the hippocampus showed volume loss. The hippocampus is known to affect spatial memory and—particularly relevant to EF—working memory (Bannerman, Deacon, Offen, Friswell, Grubb, & Rawlins, 2002). Filoteo et al. (2014) further noted that those PD patients with the most verbal memory impairment also were generally those with the largest decrease of volume in all medial temporal regions. Specifically included were the amygdala, entorhinal cortex, hippocampus, and parahippocampus; all regions of the brain related to declarative conscious memory and memory of events and facts (Squire, Stark, & Clark, 2004).

Neurotransmitters too are important when investigating neural functioning. Siepel et al. (2014) reported that deficits in nigrostriatal dopamine correlated with both cognitive EF and age. The correlation of the two, however, was more strongly related to age rather than one-another. This does not mean the relationship with dopamine and EF is weak, only that the connection must be further investigated. The nigrostriatal pathway itself is highly related to Parkinsonian motor deficits, which get worse with age. So it not astonishing that one of the central components of PD neurodegeneration in general may likewise be connected to cognitive and EF impairment as well.

Executive function consists of several components which collectively are considered to deal with higher level cognition and goal-directed behaviors. Working memory (WM) is often simplistically referred to as short-term memory, though there are many subtleties and ancillary components to it which make that appellation seem somewhat simplistic (Baddeley, 1986, 2007). Strategic planning is related to WM because one must be able keep their focus on a target and not forget it for something else before that target is reached. Additionally, working memory has a relationship with visuospatial and visuo-constructional abilities because a person must be able to hold an image in their consciousness in order to manipulate it for the purpose of accomplishing a goal (Karádi et al., 2015). Other important components include motivation, which involves rewards, punishments, and novelty seeking—and impulse control, which allows you to inhibit behaviors that may hinder reaching a desired outcome. Thus, EF describes the way in which a collection of many diverse cognitive abilities are utilized by motivational factors to achieve a goal. Because there are so many components to the system, there are many ways in which neurodegenerative diseases like PD can impact them.

Working memory was theorized by Baddeley (1986) to be short-term memory split into at least three components: the central executive, the visuospatial sketchpad, and the phonological loop. The central executive was the component that controlled and directed the other systems. It was thought to apportion data to its subordinates as well as be responsible for problem solving and mental arithmetic. The visuospatial sketchpad was thought to hold visual data—as well as spatial and orientation-related information—in consciousness in order to be manipulated and used. Lastly, the phonological loop may be conceptualized as the voice in one’s head that puts thoughts in the form of words which can consciously be utilized. The theory of WM has evolved somewhat over the years, but the basic concepts are still largely the same. Thus, the mechanisms of WM continue to be conceptualized in terms of visual WM (often called nonverbal WM), verbal WM (often thought of as self-guidance or an inner voice), and an executive component that may coordinate and participate in planning and allocating cognitive resources (Barkley & Murphy, 2011; Knouse, Barkley, & Murphy, 2012; Barkley, 2013)

One WM-related aspect that is affected by Parkinsonian neurodegeneration is storage capacity. Individuals with PD often cannot hold as much information in their short-term conscious memory as normal individuals. This lack of storage capacity affects one’s ability to keep in mind all the information relevant to accomplish a task. It also either causes or exposes another deficit regarding the ability to choose what information is most pertinent to the task and what information can safely be ignored or discarded. Kudlicka, Clare, and Hindle (2014) conducted a series of tests and inventories on sixty-five PD patients and fifty of their caretakers in order to assess EF. They found that patients were noticeably impaired in several areas of EF related to limited WM storage capacity, including setswitching, cognitive flexibility, selective attention, and planning. Consistent with the perspective of limited WM, patients seemed not to be able to remember all the rules of the tests long enough to complete them effectively, and when the rules on the stroop tests were reversed, they couldn’t prioritize the most pertinent information. Indeed, task-switching appears particularly compromised for sufferers of PD.

The basal ganglia play a prominent role in PD specific task-switching pathology (Ravizza, Goudreau, Delgado, & Ruiz, 2012). Using an fMRI to investigate this connection, researchers discovered that the frontostriatal system in particular was correlated with deficiencies in task-switching. Specifically, impairment seemed to be closely correlated with a reduction in the connectivity between the striatum and the medial frontal cortex (Helmich, Aarts, de Lange, Bloem, & Toni, 2009). This is in line with other studies that identified the frontostriatum and its communication to the cortex as key factors in EF dysfunction in general. It is still uncertain whether frontostriatal function directly affects the WM storage aspect of EF, or if it merely has an indirect role, but it does have an impact in final product of task-oriented impairment.

Task-switching and attentional deficits are not the only aspects where storage capacity deficiency has an impact. It also has a bearing on visuospatial memory. This was demonstrated by a study involving PD patients who were instructed to remember the orientation of red triangles while ignoring green triangles (Lee, Cowan, Vogel, Rolan, Valle-Inclan, & Hackley, 2010). The study found that the PD patients could hold fewer relevant red triangles and their orientations in memory relative to the controls. Also notable was that the individuals with PD had a marked difficulty with focusing on relevant items (the red triangles and their orientation) while ignoring distractors (the green triangles). So not only was their visuospatial memory more limited, they weren’t able to utilize the memory they did have very efficiently. These results are in line with those reported by Kudlicka et al. (2014).

In light of such findings, visuospatial memory appears to be one of the more profoundly affected EF components in PD. Indeed, further support for this comes from an investigation which record PD patients engaging in an aberrant visuospatial-related phenomenon called closing in (CI) (De Lucia, Grossi, Mauro, & Trojano, 2015). In a figure copying test where participants were instructed to start from a dot and copy the figure above it, the participants with PD tended to approach the figure to the point where they were often literally drawing on top of the figure by the end. This was found to correlate significantly with general EF dysfunction rather than a general deterioration of cognitive faculties, contrary to what has typically been observed in dementing diseases. Accordingly, it appears that EF is uniquely affected in PD, and it is not merely part of the general global decline in brain functioning.

Task-switching impairment, as mentioned earlier, hinted at another problem area of EF in PD: strategic planning. The concept of strategic planning involves developing a specific sequence of behaviors which when followed will help the planner achieve a goal in the future. Rather than just a simple cause and effect cycle, strategic planning is used in order to reach a goal which is more distal rather than proximal. A person may not be particularly successful at this relatively higher level of cognition if they are suffering from deficiencies in impulse control, or if they have a hard time problem-solving and thinking in abstract terms of something that could occur at some later point in time. For the purpose of EF study, however, strategic planning refers more to problems with the latter rather than impulse control. In one investigation, Taylor, Saint-Cyr, and Lang (1986) observed marked deficiencies in PD patients regarding the ability to generate efficient strategies. These individuals had problems thinking spontaneously of ways to accomplish a task, especially on task-specific planning when self-directed. Deficits were further investigated by comparing strategic planning to IQ and age, all of which showed a relationship. Strangely, unlike the multitude of more recent peer-reviewed reports, Taylor et al. (1986) did not record a decline in memory or visiospatial abilities. The explanation for this discrepancy may be related to the scarcity of tests specifically designed to measure memory and visiospatial abilities at the time that study was done. Irrespective of those uncertainties, it still agreed with modern discoveries regarding strategic planning.

Recent research has identified specific areas of the brain related to strategic planning issues, even going as far as theorizing on how the interaction works. It is no surprise that once again, the caudate nucleus has been implicated. Grahn et al. (2008) concluded that through the activation of schemas relating to the task at hand, the caudate nucleus is a critical component of planning and goal-oriented action. They state that the caudate accomplishes this by stimulating schemas and selecting appropriate sub-goals following the evaluation of possible outcomes. This contrasts with what they observed of the putamen, which seems to be more limited to spontaneous reactions to stimuli, habit development, and learning rather than planning multiple future-oriented actions. Elaborating on the overall theory, the authors assert that based on a hierarchical model, the ventral striatum is associated with identifying the necessary behaviors to accomplish a task. That is followed by the caudate which plans the behavior sequence, then the putamen which implements the behaviors through sensorimotor coordination. Lastly, all of this is accomplished through cortico-striatal communication; many of the components that the striatum is working with may be stored or packaged in the cortex. Further study will be needed to develop the understanding on how the cortico-striatal communication works, but existing data is promising nonetheless.

Planning of any sort, however, is not accomplishable until one feels motivated to plan. Indeed, motivation is a very important aspect of accomplishing goals, and thus is highly related to EF. Many sufferers of PD are afflicted with deficits in motivation, especially in the later stages, and this leads to a variety of disabilities. Apathy is one of the more severe manifestations of this deficit in motivation. Pagonabarraga et al. (2015) describe apathy as being a syndrome with several contributing elements. One such element is autoactivation failure, which can be described as a failure for a person to initiate thoughts. People with an autoactivation failure report feeling a striking absence of thought. The same people, however, often act almost completely normal when directed or stimulated by another person.

In addition to autoactivation problems, the authors mentioned that apathetic PD patients display a reward deficiency issue where dopamine, the key neurotransmitter related to rewards, shows diminished effectiveness. This leads people to not feel as much neuropsychological stimulation for any given behavior, resulting in fewer total behaviors. These conclusions support previous work by Mazzoni, Hristova, and Krakauer (2007) which also linked motivational deficits in PD to an abnormal response to rewards. Further in line with previous research, Pagonabarraga et al. (2015) identified frontostriatal pathways as one of the central components of pathology (Ravizza, Goudreau, Delgado, & Ruiz, 2012). Clearly motivation is highly impacted by the neurodegenerative pathology affecting EF. Conversely though, if EF problems can cause a deficiency in motivated actions, can there also be EF issues were someone has trouble stopping their actions? Indeed, impulse control is another EF region of dysfunction with Parkinson’s disease.

Impulse control disorders (ICD) can be characterized as behavioral problems that arise from the inability or difficulty for one to inhibit a particular behavior (Evans, Strafella, Weintraub, & Stacy, 2009). Most healthy individuals have the capacity to mentally veto many of the impulses that occur to them. People can recognize that something may not be in their best interest and resist the impulse, but this often seems to be difficult for many with PD. The lifetime prevalence of ICD among those with PD is approximately 14 percent (Weintraub et al. 2010). Based on recent research, this very common PD problem seems to be associated with the dopaminergic drugs used to treat it.

A study by Pineau et al. (2016) compared 17 PD patients with ICD to 20 control PD patients. They were subjected to multiple tests: Conner’s Performance test, Trail Making Test, the Wisconsin Card Sorting Test, and several others. In addition to this, the subjects were treated to an experimental gambling test with cards in the hope of isolating PD-specific impulsiveness. The results were that the experimental and control groups exhibited similar levels of actual impulsive behavior, but those with ICD noticeably overestimated the actual reward value that would result from their choices. This outcome, while measurable, seems modest. A reason for the lack of a strong outcome could be because of the fairly small sample size; a larger group of PD patients may yield more compelling results. Moreover, the study’s control group was other individuals with PD rather than the general populous. It is quite possible that had the experimental group been compared to healthy individuals, recorded outcomes may have shown more of a correlation with PD and problems involving impulse control. Irrespective of this, there is further research to support a trend of ICD among the PD community and ICD’s connection with dopamine.

Dopamine’s role in ICD seems to specifically involve D2 and D3 receptors. Those particular receptors are known to be abundant particularly in the ventral striatum, an area understood to play a part in substance abuse disorders and addiction (Gurevich and Joyce 1999). When certain recreational drugs are taken, the user often then gets a spike in dopamine levels, rewarding the user with euphoria. In addition to this, other dopaminergic pathology is related to fronto-striatal denervation of neurons. Vriend et al. (2014) found that of 31 PD patients who underwent dopamine replacement therapy, 11 developed ICD problems. Of those 11, 8 of them were taking dopamine agonists. The authors also noted that the severity of ICD symptomology was negatively correlated with baseline dopamine transporter availability, specifically in the anterior-dorsal and right ventral striatum. They concluded that in addition to ICD partly caused by adverse side effects from PD treatment, existing predispositions regarding striatal dopamine transporters make individuals vulnerable to ICD beforehand. This data appears to all converge on the conclusion that ICD is closely related to dopamine issues in PD patients. Some of the problems are related to treatment, and other aspects are related to destruction to dopaminergic neurons in the ventral striatum.

While most of the research on EF dysfunction in PD points to the striatum, there may be other areas of at least secondary importance. For example, the anterior cingulate cortex (ACC) is an area of the brain that is critical for many cognitive and executive operations, and it may be involved in detection of errors, detection of conflicts, and reward based learning (Bush, Luu, Posner, 2000). It has also been proposed that the ACC assists with stimuli responses by reducing the competing impulses down to the most likely relevant options (Carter et al., 2000). This may help ease cognitive load and increase the speed at which someone can respond. Lewis, Shine, Duffy, Halliday, and Naismith (2012) found that lower N-acetyl aspartate/creatine (NAA/Cr) ratios in the ACC correlated strongly with many tasks related to EF. These tasks tested areas such as response inhibition, attention set-shifting, and even some psychotic aspects.

With so many often crippling EF deficits in PD, patients frequently have trouble living their lives, especially in the later stages of degeneration. Issues with EF in patients have specific consequences in how they are affected in real life. In order to study EF in entirety in PD, it is important to identify and measure the ways in which a sufferer’s life is impacted. Instrumental activities of daily living (IADL) are one way of assessing how cognitive EF has deteriorated in PD patients (Puente, Cohen, Aita, & Brandt, 2016). Instrumental tasks are the behaviors that someone will engage in on a relatively daily basis in order to accomplish specific short-term goals. Examples of IADLs are using the telephone, doing the laundry, preparing a meal, doing housework, and managing your medication and finances (Royall et al., 2007). One area that may have implications for IADLs is working memory. Because WM storage capacity is often limited, an individual with PD may have difficulty with tasks that require very many steps to complete. Moreover, because of the lack of short term memory, sufferers may fail to return to tasks when distracted, and end up forgetting them altogether. This could be potentially dangerous if it causes them to forget to take medication.

Nevertheless, forgetfulness isn’t the only risk; visuospatial issues could also cause problems. Many IADLs require at least some coordination, so if a person has difficulty in this area they may fall down their stairs and injure themselves, drop their food on the floor, or any of numerous other things. To address these problems, it may be beneficial to assess a patient’s laterally more affected side in order to predict who will have the most visiospatial problems. Karádi et al., (2015) found that within their sample of PD patients, laterality showed a highly significant correlation between visuospatial symptoms and onset of motor symptoms. If someone with PD first showed motor symptoms on their left side, they would be more at risk for spatial comprehension deficits. Patients that are RPD would instead need more assistance with communication and expressing their needs.

In addition to using IDALs to assess the everyday function of patients, questionnaires also provide insight into what issues they are having related to EF. Direct observation is highly useful to gain certain types of information on patients, but there may be subjective experiential aspects to PD that may be most effectively unearthed directly by a patient’s self-report. This approach would likely yield more useful information in non-demented patients because demented individuals may not be capable of accurately communicating their symptoms, or they may not even understand the questions properly. Using questionnaires, one study sought to learn about cognitive deficits among sufferers of PD without dementia (Poliakoff, Ellen, Smith-Spark, & James, 2008). Specifically, the study wanted to find out how cognitive and executive impairment impacted day to day tasks. The questionnaire asked the patients how often they made cognitive errors in various areas, such as forgetting what they were about to say. Based on these reports, the authors found that the questionnaire participants experienced specific types of errors related to cognition and EF. Some had more dysfunction regarding attentional processes (exhibited as being more distractible) while other patients reported more problems relating to retrieval process, such as not being able to remember important details from the prior day. This study supports the understanding that that EF affects a PD patient’s daily living, particularly through WM and attentional issues.

Problems with EF can also manifest in individuals with PD in other ways. Behavioral problems can arise as a result of EF dysfunction, and this has an impact on caregivers in addition to the patients themselves (Kudlicka, Clare, & Hindle, 2014). The impulsivity that often occurs in PD patient—partly as a result of dopaminergic treatment—can lead even to destructive or bad behavior like it does in otherwise healthy individuals. A patient may spend more money than they should on impulse, or they may react negatively with less restraint in a confrontation with a loved one or caregiver. This aggression may become even worse if they become demented.

Dementia doesn’t necessarily occur in all people with PD, but it occurs in a large portion; up to 48% (Hely, Morris, Reid, Trafficante, 2005). In dementia, most of the cognitive and executive problems that an individual exhibited before will be even more dysfunctional. Memory will be worse, eventually to the point where they may not remember close family members. They could even become more impulsively aggressive, and will have more difficulty inhibiting behaviors. Some though, may experience the opposite. For the patients who exhibited marked apathetic issues preceding dementia, they may have even more difficulty with autoactivation and other symptoms (Pagonabarraga et al., 2015). It is also likely that—contrary to more benign stages involving autoactivation—they may not respond much better even when directed by another person. In general though, apathy seems to herald dementia and predict a lower standard of living in the later stages of PD.

The overall convergence of evidence strongly indicates that people with PD do indeed very often have problems with cognition, especially in the area of executive function. Not all patients will exhibit uniformly dysfunctional symptoms; some may become impulsive while others become apathetic; and some may have relatively intact memory and visuospatial abilities while losing the ability to effectively problem solve (Siepel et al., 2014). Despite this variability, most PD patients do show some level of cognitive EF deterioration. Most EF dysfunction is strongly related to dopamine and fronto-striatal issues, but some, such as memory, have been shown to be impacted by the cholinergic system as well (Siepel et al., 2014; Vriend et al. 2014). Moreover, the ACC plays an important role through its communication with striatal areas, suggesting that it is critical to executive functioning that the two systems work together (Lewis, Shine, Duffy, Halliday, & Naismith, 2012). It will be important for future research to identify more precisely the ways in which the ACC and striatum work together in EF, and it will be necessary to experiment with more selective dopaminergic medication in order to prevent impulsivity as a side-effect of treatment.

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