Psychiatric Annals

CME Article 

Cognitive Impairment and Dementia in Parkinson's Disease

Mazen T. Elkurd, DO; Richard B. Dewey Jr, MD

Abstract

Cognitive decline is common in Parkinson's disease (PD) and is a leading cause of reduced quality of life. Cognitive difficulty seen early in the course of PD takes the form of mild cognitive impairment (MCI-PD), and Parkinson's disease dementia (PDD) is nearly universal in the late stages of the disease. Although most people with MCI-PD will progress to PDD, the two entities have significant differences in terms of underlying pathophysiology as well as cognitive profiles and management strategies. The most important contributor to MCI-PD is frontostriatal dopamine depletion, whereas the major cause of PDD is Lewy body pathology spreading to the neocortex plus, in many cases, comorbid Alzheimer's pathology. Management strategies for both MCI-PD and PDD are limited. The best approach for MCI-PD is a combination of cognitive rehabilitation and appropriate titration of dopaminergic therapy, and the medications used in treatment of Alzheimer's disease appear to have a modest benefit for patients with PDD. [Psychiatr Ann. 2020;50(3):100–106.]

Abstract

Cognitive decline is common in Parkinson's disease (PD) and is a leading cause of reduced quality of life. Cognitive difficulty seen early in the course of PD takes the form of mild cognitive impairment (MCI-PD), and Parkinson's disease dementia (PDD) is nearly universal in the late stages of the disease. Although most people with MCI-PD will progress to PDD, the two entities have significant differences in terms of underlying pathophysiology as well as cognitive profiles and management strategies. The most important contributor to MCI-PD is frontostriatal dopamine depletion, whereas the major cause of PDD is Lewy body pathology spreading to the neocortex plus, in many cases, comorbid Alzheimer's pathology. Management strategies for both MCI-PD and PDD are limited. The best approach for MCI-PD is a combination of cognitive rehabilitation and appropriate titration of dopaminergic therapy, and the medications used in treatment of Alzheimer's disease appear to have a modest benefit for patients with PDD. [Psychiatr Ann. 2020;50(3):100–106.]

Cognitive decline is well recognized as a cardinal non-motor feature of Parkinson's disease (PD) that can be seen at any stage in the disease. Although little controversy exists on the subject today, this view has evolved significantly over time. In his first description of the disease in the seminal Essay on the Shaking Palsy in 1817, James Parkinson expressed doubt about the extension of morbidity to the encephalon “by the absence of any injury to the sense and to the intellect.”1 It wasn't until more than 50 years later that Charcot and others first began to describe cognitive difficulties in PD.2 Today, cognitive impairment has grown to be a recognized source of morbidity, leading to reduced quality of life, increased caregiver burden, increased risk of nursing home placement, and increased health care costs.3

A Spectrum of Cognitive Impairment Across PD

Cognitive impairment in PD is broadly divided into two distinct categories: mild cognitive impairment (MCI-PD) and Parkinson's disease dementia (PDD). The distinction between the two is based on whether impairment in normal daily functioning is present. Cognitive impairment is extremely prevalent in PD, increasing steadily in incidence with increasing age and disease duration.4,5 An important longitudinal study showed that among PD patients observed for 20 years, the prevalence of dementia was 83%.6 Estimates on the prevalence of MCI have varied significantly, but a task force of the Movement Disorder Society (MDS) in 2012 found the prevalence of MCI in PD patients without dementia to be 26.7%,7 and as many as 18.9% of newly diagnosed, drug-naïve patients with PD were found to have MCI in a 2009 Norwegian study.8 MCI-PD likely represents an early manifestation of PDD, as studies have demonstrated that a majority of those with MCI will eventually progress to develop dementia.9

Etiology and Neuropsychological Profiles

Although MCI has been demonstrated to be a strong risk factor for the subsequent development of PDD, the underlying pathophysiology and resulting cognitive profiles in MCI are distinct from those in patients with dementia. Although the deficits that characterize PDD affect a multitude of cognitive functions resulting from global cortical dysfunction, those deficits seen with MCI-PD tend to be more limited in scope and consist mainly of dysfunction in the dopaminergically mediated frontostriatal network.10 As a result of striatal dopamine depletion, dysfunction of the frontostriatal system leads to deficits that mimic lesions of the frontal lobes, causing difficulties in planning, working memory, attention, and inhibition (Figure 1).11 Due to these deficits, patients with MCI will tend to have mental inflexibility, rigidity, and difficulties with executive functioning.12

Neuropsychological profiles of mild cognitive impairment and dementia in Parkinson's disease.

Figure 1.

Neuropsychological profiles of mild cognitive impairment and dementia in Parkinson's disease.

In contrast to the limited and relatively mild deficits in MCI-PD, PDD is associated with global cortical dysfunction as a result of the large-scale disruption of multiple neurotransmitter systems, including widespread and marked cholinergic depletion due to spreading alpha-synuclein pathology.10 The Braak hypothesis states that Lewy body pathology progresses gradually in a caudal to rostral fashion beginning in the brainstem, traversing upward into the forebrain, and ultimately spreading widely into the neocortex.13 It is in the later stages of this process that widespread Lewy body pathology begins to result in significant cognitive impairment. This hypothesis is supported by neuropathological evidence correlating cognitive status with the Braak stage of PD.13 Although there is no direct linear relationship, in general it appears that the degree of cognitive impairment correlates with the burden of cortical Lewy body pathology.13,14 With the increasing burden of cortical Lewy bodies, patients begin to experience increasing cognitive difficulties that impair activities of daily living. The early difficulties seen with executive function and attention in MCI become much more pronounced, and additional difficulties can arise, including conspicuous defects in memory, visuospatial abilities, and semantic fluency.15

In addition to the alpha-synuclein and Lewy body pathology in PDD, as many as 50% of patients with PDD have been found to have concomitant amyloid beta and tau neurofibrillary tangle pathology, which are classically associated with Alzheimer's disease (AD).16 The additive effect of AD pathology may explain some of the variability in the phenotype of dementia seen in patients with PD. Clinicopathological studies have demonstrated that people with both cortical Lewy body and AD pathology show more rapid decline in cognition than those without AD pathology,10 suggesting a possible synergistic effect between the two entities. These findings hold true not only in clinicopathological studies, but also in genetic analyses, which demonstrate a higher rate of cognitive decline in carriers of the ApoE4 allele, a well-established risk-factor for AD.10

Diagnosis of MCI-PD and PDD

Because variable definitions of MCI in PD make research difficult, a task force was created by the MDS to create a unified set of diagnostic criteria.17 The proposed diagnostic criteria for MCI-PD require (1) an existing diagnosis of PD by United Kingdom Brain Bank Criteria, (2) a gradual decline in cognition as reported by the patient or informant or as observed by the clinician, (3) cognitive deficits on either formal neuropsychological testing or a scale of global cognitive ability such as Montreal Cognitive Assessment (MoCA), a widely used screening tool for cognitive impairment, and (4) that the cognitive deficits not interfere with functional independence. Exclusion criteria for MCI-PD are a diagnosis of PDD and the presence of other explanations for cognitive impairment or poor performance on cognitive testing. Specifically, in regard to neuropsychological testing, the guidelines recommended the use of at least two tests in each cognitive domain to account for test sensitivity and variability. It is also recommended that an evaluation of premorbid intelligence be made, as it is important to be able to assess each patient on the background of their premorbid cognitive functioning. Although many studies have evaluated the use of biomarkers and imaging in the diagnosis of both MCI-PD and PDD, the task force guidelines did not recommend their use in the diagnosis of MCI-PD due to a lack of robust evidence.

Diagnostic criteria were also created by the MDS to identify probable or possible PDD.15 The core features include an existing diagnosis of PD by Queen Square criteria along with a slowly progressive, insidious-onset dementia syndrome with impairment in more than one cognitive domain. The cognitive difficulties must represent a decline from premorbid levels and include deficits severe enough to impair daily life. Associated clinical features include impaired attention, executive dysfunction, visuo-spatial impairment, and memory and language problems. Behavioral features often seen include apathy, changes in personality and mood, hallucinations, delusions, and excessive daytime sleepiness. Features that exclude a diagnosis of PDD include metabolic abnormalities, drug intoxication, major depression, and imaging evidence indicative of vascular dementia. In addition, the diagnosis of dementia with Lewy bodies (DLB) would be more appropriate than PDD if the above cognitive impairment occurs within 1 year or less of onset of parkinsonian motor features.

Treatment of Cognitive Dysfunction in PD

Dopaminergic Treatment

As might be expected, the syndrome of cognitive dysfunction seen with MCI caused by frontostriatal dopaminergic depletion responds favorably to dopa-minergic therapy through the use of levodopa or other dopamine-enhancing therapies such as dopamine agonists or monoamine oxidase B inhibitors.18 The symptoms that have been shown to most significantly improve after dopaminergic therapy are those that require improved cognitive flexibility.19 Although some improvements may be seen in the above-mentioned domains, other cognitive functions may be adversely affected with dopaminergic therapy. Specifically, tasks that involve learning and decision-making may become impaired with the use of dopaminergic medications.10 The “dopamine overdose hypothesis,” as proposed by Cools et al.20 aims to explain these observations. The hypothesis postulates that as dopaminergic therapy is titrated to ameliorate the motor symptoms of PD that result from dopaminergic depletion in the putamen, the caudate nucleus and ventral striatum, which are less affected early in PD, suffer from a dopaminergic overdose.20 The overdosing of the ventral striatum and caudate are implicated in the impairments of decision-making, leading to impulsive behavior and impairment of learning tasks. Taken together, these data suggest that dopaminergic therapy must be carefully titrated to achieve the desired motor benefit with careful attention to avoiding adverse effects on cognition. In addition, the specific choice of dopaminergic therapy is important. The dopamine agonist class of therapies (including pramipexole and ropinirole), due to their higher affinity for the D2/D3 receptors, appear more likely to cause orbitofrontal dysfunction and thus cause difficulties with impulse control and resulting behaviors such as pathological gambling.21

Cholinergic Treatment

Cholinergic therapy, which is typically used in the treatment of AD dementia, can be useful in the management of PDD (Table 1). The most robust evidence is found for rivastigmine, a dual cholinesterase inhibitor. The study was a randomized, double-blind, placebo-controlled study of 541 patients with dementia that developed at least 2 years after diagnosis of PD. Participants were randomized to rivastigmine or placebo, and change from baseline to 24 weeks in the Alzheimer's Disease Scale-Cognitive Subscale (ADAS-cog), the most widely used instrument in clinical trials of cognitive enhancers, was the primary outcome measure. The results showed a modest improvement in the ADAS-cog, compared to placebo. Adverse effects (AEs) were relatively well tolerated and included increased nausea, vomiting, and tremor.22

Summary of Pharmacologic Agents Used in the Management of Parkinson's Disease Dementia

Table 1.

Summary of Pharmacologic Agents Used in the Management of Parkinson's Disease Dementia

Donepezil, another cholinesterase inhibitor used in the treatment of AD, was evaluated in a much smaller trial.

The study was a randomized, double-blind, placebo-controlled design with 14 patients stratified to either donepezil or placebo. The primary outcome measures were Mini-Mental Status Examination (MMSE) score, the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC+) score, as well as the unified Parkinson's Disease Rating Scale Motor Sub-score. The results showed similar modest improvements on MMSE and CIBIC+ scores, and parkinsonism did not worsen. Of the 14 patients, 2 withdrew due to cholinergic side effects, although those that remained in the study reported similar rates of AEs to those taking placebo.23

Galantamine, another cholinesterase inhibitor with additional nicotinic activity, has also been evaluated in patients with PD. The most robust trial to date was conducted in an “open controlled” design. In the study, the investigators randomized 41 participants into two groups to receive either galantamine or no cholinergic treatment for 24 weeks without blinding. The results were positive, with statistically significant improvements in the prespecified outcome measures. AEs were reported in 30% of the active group and included drooling, orthostatic hypotension, increased tremor, nausea, and urinary frequency.24

Rivastigmine is currently the only drug that is approved for treatment of PDD by the US Food and Drug Administration. Conversely, anticholinergic therapies, which are used in PD for treatment of tremor, have been implicated in worsening cognitive function and even implicated in the development of AD pathology with long-term use.25

Other Pharmacotherapies

In addition to cholinergic and dopaminergic dysfunction, other neurotransmitter systems are known to be dysfunctional in PD-related cognitive impairment. As such, therapies targeting a number of other neurotransmitter systems have been explored for the management of PDD. The norepinephrine reuptake inhibitor atomoxetine has been evaluated with small-scale pilot studies and shown to have positive effects on executive dysfunction26 and impulsivity.27

Drugs targeting the N-methyl-D-aspartate (NMDA) receptor have also been evaluated for PDD. Amantadine, a drug with a number of uses in PD, was evaluated for its effects on dementia in a retrospective study of 593 patients.28 The study showed that those who had been taking amantadine had a longer latency until the onset of dementia and higher MMSE scores after dementia was diagnosed.28 Despite these results, the use of amantadine in this population is limited due to the risk of causing hallucinations or delirium.

Memantine, another NMDA receptor antagonist that is approved for use in AD, has been shown to be well tolerated and is modestly effective in ameliorating dementia symptoms in PD.29 The study was a parallel-group, randomized, controlled trial with 75 participants diagnosed with dementia on the background of PD for at least 1 year or DLB, randomized to memantine or placebo. The results met statistical significance, with a modest improvement in the primary outcome variable compared to placebo. AEs were mild and reported at rates similar to placebo.

Other Interventions

Due to the limited benefits provided by pharmacologic therapies, alternative strategies for the management of cognitive decline in PD have been explored. Cognitive training is an intervention involving structured practice of specific tasks to enhance performance in a particular cognitive domain. A meta-analysis by Leung et al.30 published in 2015 included seven studies with a total of 272 participants. The study found that there were clinically meaningful, although statistically nonsignificant, improvements on global assessments and specific batteries. They concluded that cognitive training likely leads to measurable benefits on working memory, executive functioning, and processing speed, but they suggested that future randomized controlled trials with larger samples were needed to further investigate the use of these interventions.30

Another important intervention for improving cognition is physical exercise. A systematic review of the evidence for physical exercise in improving cognition in PD by da Silva et al.31 in 2018 included nine randomized controlled trials. The studies included a range of physical exercise modalities such as treadmill training, dancing, stationary bicycle training, tai-chi, cognitive training combined with motor training, and multimodal exercise, all of which were conducted for 40 to 90 minutes, 2 to 3 times per week, and ranged from 7 to 24 weeks in length. The results showed statistically significant improvements in cognition as measured by global tools such as MMSE or MoCA, or by specific testing of cognitive domains such as processing speed, attention, cognitive flexibility, and cognition. The largest magnitude of improvement was seen in improved cognition with treadmill training at 80% to 100% of the preferred walking speed, performed 3 times a week for 60 minutes.31

Conclusion

Cognitive impairment is now recognized as an important feature of PD. Mild cognitive impairment is an early feature of PD, and in some cases can be present at the time of initial diagnosis. By contrast, dementia is typically seen later in the disease, becoming nearly universal in the late stages of the disease. Recent advances in understanding the types of cognitive difficulties seen at various stages have shed light on the underlying cause of these dysfunctions. This enhanced understanding is beginning to allow for a more personalized approach for the management of cognitive decline in each patient. Despite these recent advances in our understanding, the overall management options remain limited. Early cognitive impairment is best managed with a combination of optimal titration of dopaminergic therapy to enhance motor function and cognition with an emphasis on avoiding dopaminergic overdose, along with nonpharmacologic measures such as cognitive training and physical exercise. Later-stage dementia remains difficult to treat, with the cholinesterase inhibitor rivastigmine being the only agent with robust evidence showing a modest benefit for PDD, and other agents such as donepezil, galantamine, and memantine having some clinical utility in the appropriate scenario.

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Summary of Pharmacologic Agents Used in the Management of Parkinson's Disease Dementia

Drug Class Benefit Side Effects Best Evidence
Rivastigmine Cholinesterase inhibitor Improvement of 2.1 points in ADAS-cog score from baseline, compared to 0.7 point worsening in placebo21 Mild Randomized, double-blind, placebo-controlled trial of 541 patients
Donepezil Cholinesterase inhibitor Mean MMSE score increased by 2.1 points compared to 0.3 points for placebo22 Mild to moderate Randomized, double-blind, placebo-controlled trial of 14 patients
Galantamine Cholinesterase inhibitor Improved scores on MMSE, ADAS-cog, clock drawing, and FAB compared to control23 Moderate Open-label, placebo-controlled trial of 41 patients
Atomoxetine Norepinephrine reuptake inhibitor Improved executive dysfunction25 and impulsivity26 Mild to moderate Executive function, small, uncontrolled trial Impulsivity was a small RCT
Memantine NMDA receptor antagonist Improved CGIC with a mean difference of 0.7, improvement in tasks on AQT form28 Mild Randomized, double-blind, placebo-controlled trial of 72 patients with PDD or DLB
Amantadine NMDA receptor antagonist Increased latency until dementia diagnosis by about 3 years and slower mental decline27 Moderate to severe Retrospective observational study
Authors

Mazen T. Elkurd, DO, is an Assistant Instructor. Richard B. Dewey Jr., MD, is a Professor. Both authors are affiliated with the University of Texas Southwestern Medical Center.

Address correspondence to Mazen T. Elkurd, DO, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390; email: mazen.elkurd@utsouthwestern.edu.

Disclosure: Richard B. Dewey Jr. has been a consultant for Amneal Pharmaceuticals. The remaining author has no relevant financial relationships to disclose.

10.3928/00485713-20200206-01

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