Dr. Bassett is associate professor and director of the Division of Psychiatric Neuroimaging in the Department of Psychiatry at the Johns Hopkins Medical Institutions of the Johns Hopkins University in Baltimore, Maryland. 

Disclosure: Dr. Bassett receives grant and/or research support from Eli Lilly, Forest, and the National Institutes of Health.

Funding/support: This work was supported by a grant from the National Institute of Child Health and Human Development (grant no. RO1 HD39822), and by a grant from the National Institutes of Health (grant no. P50 N8 38377), awarded to Dr. Bassett.

Please direct all correspondence to: Susan Spear Bassett, PhD, Department of Psychiatry, Johns Hopkins Hospital, Phipps 300, 600 N Wolfe St, Baltimore, MD 21287; Tel: 410-614-2813; Fax: 410-614-3676; E-mail: sbassett@jhmi.edu.


 

Abstract

Parkinson’s disease (PD), a neurodegenerative disorder characterized by motor impairments, including bradykinesia, cogwheel rigidity, and resting tremor, also impairs intellectual functioning. Almost all patients with PD suffer from selective cognitive impairments, including difficulties with attention, concentration, problem solving, set-shifting, and memory, which are thought to reflect dysfunction of cortical circuits subserving frontal brain regions. These impairments are most frequently reported by patients in terms of the disabilities they cause, such as difficulties in paying attention at work; problems handling more than one project at a time; inability to sequence, plan, and organize tasks at work and home; and problems completing tasks that have been started. These disabilities present serious complications for patients in the management of their everyday lives, particularly with regard to occupational functioning. In addition, perhaps one-quarter of PD patients will go on to develop dementia, initially developing significant memory problems. At the present time, treatment of cognitive dysfunction relies primarily on patient and family education, behavioral interventions, and the use of cholinesterase inhibitors.

 

Introduction

Parkinson’s disease (PD), a neurodegenerative disorder reflecting selective neuronal loss, is characterized by motor impairments, including bradykinesia, tremor, and rigidity. These motor abnormalities may also be accompanied by changes in cognition for a significant proportion of patients. While a minority of PD patients will develop frank dementia, most patients with PD will experience changes in cognitive function, frequently early in the course of their illness. These cognitive impairments manifest themselves primarily as difficulties in executive function, and their effect on daily life can be profound. Such impairments significantly interfere with occupational and social functioning, frequently leading to loss of employment and family conflict. This picture is complicated by the fact that some medications can exacerbate existing cognitive difficulties or precipitate their development.

This review provides a description of these cognitive impairments, as well as their underlying pathology, clinical evaluation, and the current treatments available. While psychiatrists are not often initially focused on cognitive aspects of PD, treatment of the psychiatric complications requires an understanding of the role cognitive status plays in the patient’s presentation. In addition, where it might be expected that successful treatment of depression would restore cognitive function, this is frequently not the case in PD. However, since cognitive deficits are restricted to executive functions for most PD patients, individual strategies can be developed to circumvent many of the life problems that result from these impairments.

 

Selective Cognitive Impairments

Although Dr. James Parkinson’s original essay on PD, “The Shaking Palsy,”1 reported that intellect remains intact in PD patients, with some degree of cognitive impairment does, in fact, occur in the majority of those affected with PD.2-4 Typically, the impairment is evident early in the course of the illness and is more selective and less severe than that found in PD patients who develop overt dementia.5,6

PD patients—even those with mild disease—exhibit patterns of cognitive deficits that include decrements in planning, sequencing, concept formation, and working memory,7-11 which are all tasks associated with frontal lobe dysfunction. However, it is not clear whether cognitive deficits are restricted solely to those associated with frontal lobe dysfunction. Reports from studies that have examined performance on memory tests,2,10,11 including both immediate and delayed recall of material, differ. Sullivan and colleagues11 suggested that memory deficits were directly related to overall disease severity, with mildly impaired patients showing no decrements in memory performance, while Goldman and colleagues2 found increasing memory deficits with increasing disease severity, including deficits among those very mildly affected. A recent study by Locascio and colleagues12 found decrements in verbal memory for all patients; however, decrements in visual memory occured later and varied with age of disease onset. Reports of cognitive slowing13,14 are also inconsistent, as are reports of decrements in verbal fluency and confrontational naming.2,15 It is unclear whether these impairments correlate with age of disease onset or the eventual development of dementia.12,16 In global terms, many of these deficits reflect an inability to spontaneously self-generate efficient task-specific strategies.

 

Dementia

A significant percentage of PD patients develop dementia. Earlier estimates of the prevalence of dementia in PD have been highly varied, ranging from 20%17 to 81%.18-20 Part of this variability no doubt reflected differences among studies in sample characteristics, operational criteria for dementia, and the variation in cognitive function over the disease course and between individuals. A more recent survey21 indicated that 20% to 40% of PD patients ultimately become demented, with an incidence of 10% per year. However, the risk factors and underlying pathology related to the development of dementia remain unclear and controversial. While the probability of dementia increases with age, several studies22-24 now indicate that impairment of memory function may also be a harbinger of eventual dementia. In contrast, motor impairment itself does not appear to be a reliable predictor of subsequent dementia.24,25

 

Pathophysiology of Cognitive Impairments in Parkinson’s Disease

While basal ganglia pathology and degeneration of dopaminergic neurons in the substantia nigra is regarded as central to the pathogenesis of PD, theories suggest that the diverse disturbances present in this disease likely involve disruption in functionally segregated neuronal circuits in different components of the basal ganglia, thalamus, and cerebral cortex.26,27 This model of basal ganglia function involves five segregated circuits, of which three—the orbitofrontal, dorsolateral prefrontal, and anterior cingulate—appear integral to cognitive function.

Recent functional brain imaging studies28,29 have examined responses to cognitive tasks in an effort to understand the effects of basal ganglia pathology on cognition. Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have shown that specific cognitive tasks produce different metabolic or activation patterns, distinguishing these circuits. For example, a PET study28 using a gambling task requiring judgment and set-shifting found decreased metabolism in the orbitofrontal circuit, whereas the connections between the dorsolateral prefrontal cortex and thalamus via left caudate were unchanged. An fMRI study29 using an implicit rule-learning paradigm found decreased activation in the inferior frontal region, while activation in the medial frontal cortex and cingulate, areas related to memory function, did not differ. This differential involvement of the cortical loops may reflect the progressive nature of the disease and prove useful for targeting therapies.

While dysfunction in the cortico-circuits may underlie cognitive deficits apparent on executive and other frontal tasks, the dopaminergic system is likely not the only neurotransmittter disruption in this disease. Among newly diagnosed and previously unmedicated PD patients, for example, dopaminergic and anticholinergic medications improved motor control, dopaminergic treatment improved performance on a working memory and cognitive sequencing task, and anticholinergic agents adversely affected immediate recall.5 Other cognitive processes were not affected, however, suggesting that some cognitive functions (eg, short-term memory) may be served both by dopamine and cholinergic subcortical frontal systems, while others may be independent of nigrostriatal pathology and perhaps related to primary cortical dysfunction. While the primary degeneration seen in PD may contribute to the development of dementia, it is likely that Alzheimer’s type pathology and/or cortical limbic Lewy body degeneration are significant factors.30 Support for the involvement of Alzheimer’s-type pathology includes reports of decreased hippocampal volumes in PD related to memory performance rather than frontal tasks, and a decrease in posterior cingulate gyrus metabolites.31,32

 

Changes in Cognition in Response to PD Treatments

Surgical Interventions

Pallidotomy, an ablation procedure performed for patients with severe motor symptoms that have not responded to standard treatment, in general appears to have little long-term effect on cognition. Studies have reported initial changes in working memory, visuospatial learning, and visuoconstruction. At 3–12-month follow-up, most cognitive functions returned to baseline, although there are reports of sustained impairment in verbal learning for those with a left-sided procedure.33 Longer-term follow-up (≤4 years) has found that for most patients, cognitive functions have returned to pre-surgery levels.34,35

Deep brain stimulation (DBS), another procedure for treatment-refractory PD patients, is successful in reducing the range of motor symptoms that afflict patients. It does not appear to produce global cognitive decline; however, there is general agreement that specific language dysfunction, namely verbal fluency, commonly occurs.36-38

In addition, there have been reports37,38 of impairments of attention, verbal memory, and executive function; conversely, improvement in memory and executive function has been reported.38

Imaging studies of patients following DBS have noted a correspondence between improvements in learning performance and increases in brain networks thought to be involved in these functions.39 A recent 3-year follow-up of 70 patients36 employed an extensive neuropsychological battery, abd found that the majority of patients showed no change from baseline on all cognitive areas tested. For each test, there were selected individuals that improved and declined. Only verbal fluency showed a significant number of patients declining from baseline, with no improvement over the 3-year period.

 

Medications for Motor Impairments

Levodopa (ι-DOPA) is the standard treatment for motor complications of PD. There is evidence that ι-DOPA also effects cognition, improving a number of aspects of executive function and verbal fluency, as well as sentence comprehension and short-term memory,40-44 while possibly impairing inhibitory control.45 However, it is possible that the impact of ι-DOPA therapy on cognition may reflect individual drug responsiveness, with de novo patients showing an improvement in cognition, patients who stabilize on therapy showing no change, and patients whose status fluctuates continuing to show cognitive impairment.43 The effects of ι-DOPA on cognition may also reflect differential dopamine depletion on individual corticostriatal circuits.45 Recently, clinicians have been prescribing dopamine agonists initially instead of ι-DOPA because of the reported lower incidence of dyskinesias in patients whose initial therapy is a dopamine agonist.46 While studies of dopamine agonists employing coarse measures of cognition have not reported changes in cognition, a recent comparison of ι-DOPA and the dopamine agonist pramipexole, which included testing of specific cognitive functions, showed that the agonist impaired executive functions, verbal fluency, and memory performance.47

 

Clinical Presentation

The cognitive impairments discussed above produce significant disability for those with PD and affect normal physical, social, intellectual, and occupational activities, thereby producing significant distress. The level of disability can be expected to increase as the disease progresses.48-50 Although it is known that declines in physical functioning, which include tasks for self-care and maintenance of independent living, are associated with intellectual decline,51 difficulty with these tasks are rarely attributed to cognitive problems. As a consequence, patients rarely mention changes in cognition when discussing difficulty with conducting daily tasks.

The most common complaints include a decline or change in the ability to organize and complete activities both at home and at work. This appears to be related to a decrease in organizational skills, attention. and concentration, with increased distractibility. Reports to physicians include responses such as this recent communication from a 55-year-old female patient to the author:

When I woke up at 7:45 this morning, my priority was to finish making a card for a sick friend and then work on finishing my Christmas 2003 cards…but first I needed to get my shower and get dressed. Before I got out of bed, though, I wanted to go through a pile of catalogs and yesterday’s mail. At 9:30, I was interrupted by a phone call that made me come downstairs. And I never went back up to get ready for the day.

The selective cognitive impairments that affect most patients have the greatest impact on social and occupational functioning. There has been little study of the impact of cognitive impairment on areas of social functioning, including family relationships or social interaction, yet patient interviews indicate that these are significant. Furthermore, quality-of-life studies52-55 have found a direct association between poorer cognitive function and compromised life quality. Indirect evidence for the link between cognition and social function comes from several treatment-outcome studies following ι-DOPA, pallidotomy, and implants,56-58 in which improvements in cognition and social functioning were reported.

The impact of cognitive dysfunction on occupational functioning obviously varies with the demands of specific jobs, but can be significant. Patients frequently complain of being unable to complete tasks on time, organize and plan assigned tasks, organize office supplies and materials, and focus on tasks.

 

Assessment, Management, and Treatment of Cognitive Impairments in Parkinson’s Disease

Management and treatment of cognitive dysfunction in PD requires a multifaceted approach. Patient and family education are crucial. The patient is frequently not told that cognitive impairment can be a part of th disease. The patients are generally relieved to learn that they are “not losing my mind” and that problems with  thinking are not unexpected. For family members, understanding that the cognitive capacity of their relative is compromised helps them to understand behaviors and develop plans to accommodate these dysfunctions. Each patient requires individual strategies to compensate for these impairments; one important strategy is to utilize external cues that are effective for improving organizing and planning. In addition, regularizing sleep and exercise can maximize functioning.

 

Assessment of Cognitive Impairments

A thorough and targeted neuropsychological evaluation is required to quantitatively document and track the selective cognitive impairments that affect most patients. Such a targeted evaluation is outlined by Zgaljardic and colleagues7 and includes tests that are related to the integrity of each of the three cortico-striatal loops important for cognition. Unfortunately, while this test would provide detailed information, ordering an extensive neuropsychological evaluation is not feasible for most patients. Instead, information regarding cognitive dysfunction is most often gathered through interviews with the patient and family members, as well as through brief assessment measures. Most PD patients are well aware of the cognitive difficulties they are experiencing and usually report these in terms of their impact on occupational and social functioning.

A brief cognitive assessment tool, developed specifically for PD from the Mini-Mental State Examination (MMSE), may be useful to document and track cognitive problems.59 The Informant Questionnaire on Cognitive Decline in the Elderly provides a means for rating changes in cognition by family members and can also be used to track changes over time.60,61

 

Cholinesterase Inhibitors

Pharmacologic treatment of cognitive impairments in PD has been focused primarily on the use of cholinesterase inhibitors in patients with dementia. A retrospective study62 of 160 consecutive patients treated for dementia with cholinesterase inhibitors found that those with a diagnosis of PD dementia showed improvement in global cognitive function and global clinical assessment. Two double-blind trials of donepezil63-64 have also been completed, and both show improvement in cognition. The first63 included 16 PD patients on donepezil 5–10 mg/day for 10 weeks and found significant improvement in global cognition, with the effect being larger than that seen in Alzheimer’s disease (AD). The second,64 an 18-week study of donepezil 2.5–10 mg/day that included 16 PD patients with dementia or serious cognitive impairment, found improvements in memory, processing speed, and attention. While not all patients were able to tolerate the medication, all adverse side effects were rapidly reversible.64

Rivastigmine, a drug that inhibits both acetylcholinesterase and butyrylcholinesterase and has been shown to be effective in delaying cognitive decline in AD patients, appears promising for use in PD.65 An open-label study of 12 patients66 showed improvement with cognition and neuropsychiatric complications. A case series67 of patients with cognitive and behavioral problems also showed improvement both in cognition and functional abilities, as well as in resolution of visual hallucinations. A second open-label study of rivastigmine68 in 28 PD patients with mild-to-moderate dementia (scores of 13–25 on the MMSE) treated for 26 weeks found significant improvements in attention, concentration, memory, and word-finding, with no worsening of motor symptoms.

There have also been recent studies of cholinesterase inhibitors that include nicotinic activity, as well as nicotine itself. This is of interest because stimulation of nicotinic receptors may assist with dopamine release. A recent study69 of 16 patients with galantamine, a cholinesterase inhibitor with additional nicotinic activity, found that two-thirds of patients showed an improvement in global cognitive function. However, a study70 utilizing transdermal nicotine treatment did not find any effect on cognition.

 

Other Medications

There are other medications that have potential use in PD. These include the drug modafinil, a novel wake-promoting agent currently used for narcolepsy that has been shown to significantly improve performance on tests of memory, planning, and stop-inhibition.71 A second medication, atomoxetine, a norepinephrine reuptake inhibitor currently used for attention-deficit/hyperactivity disorder, may be particularly useful for improving attention and concentration, as it increases extracellular levels of both norepinephrine and dopamine.72,73 Finally, memantine, an N-methyl-d-aspartate receptor blocker that neutralizes the effects of glutamate and has been used to treat dyskinesia in PD patients,74,75 has recently been shown to improve cognition in patients with both AD and vascular dementia.76,77

 

Cognitive Rehabilitation

While there have been several studies of comprehensive, multidisciplinary rehabilitation programs for individuals with PD, none have included any cognitive assessments nor interventions aimed at cognitive rehabilitation.78,79 Therfore, studies in AD must be examined to explore the potential of cognitive therapy and its possible application in PD. A recent study80 of mildly impaired AD patients on stable doses of cholinesterase inhibitors evaluated three techniques that have been shown to enhance learning in these patients: spaced retrieval, dual-cognitive support, and procedural memory training. The 12-week study compared these cognitive rehabilitation programs with a program of mental stimulation and found gains in orientation, associate learning, processing speed, and functional tasks that were evident at the conclusion of the program and at 3-month follow-up.80 While this type of program would need to be evaluated and tailored for PD patients with selective cognitive deficits, the program as outlined may be useful for PD patients, particularly because the use of explicit cues has been shown to improve performance on tests of learning in PD.81

 

Conclusion

Cognitive impairment is common in PD. While only a minority of patients go on to develop frank dementia, the majority is beset by more selective cognitive changes early in the course of the illness. These impairments compromise complex tasks, such as planning, sequencing, and organizing, and are an important predictor of disability in these patients. The resulting disabilities affect all realms of patients’ lives, including physical, social, occupational, and emotional functioning. Behavioral therapy, as well as pharmacotherapy, may be beneficial for many patients.  PP

 

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