Background on cognitive impairment in Parkinson’s disease

Cognitive impairment is a very common problem in Parkinson’s disease (PD). Parkinson’s disease dementia (PDD) has a point prevalence estimated at about 40% [1], and prospective longitudinal studies find that up to 78% of PD patients can develop dementia over an 8-year period [2]. Parkinson’s disease dementia can have a significant impact on the quality of life of both patients and caregivers, and is associated with greater risk of nursing home placement and mortality [3, 4]. Parkinson’s disease patients also experience more subtle cognitive deficits not severe enough to warrant a diagnosis of dementia early in the course of the disease, with 25–30% of patients demonstrating some cognitive impairment even at the time of PD diagnosis [5]. Mild cognitive impairment in Parkinson’s disease (PD-MCI), defined as mild cognitive decline that is not normal for age and with essentially normal functional activities, has been increasingly recognized as a distinct clinical entity that may represent a transitional state between normal cognition and PDD [6]. Approximately 20–50% of nondemented PD patients meet the criteria for PD-MCI [7].

The profile of cognitive impairment in PD-MCI is heterogeneous and often characterized as either amnestic (i.e. memory deficit) or nonamnestic (impaired cognition other than memory) and as single domain or multiple domain (i.e. impairments in more than one cognitive area). Nonamnestic single-domain MCI is the most common subtype, representing approximately 42–62% of all individuals with PD-MCI [8–10]. Of PD-MCI patients with nonamnestic domain MCI, approximately 13–26% exhibit executive dysfunction and 18% were found to have visuospatial deficits [9, 10]. Overall, 16–24% of PD-MCI patients are characterized as amnestic single-domain MCI, while 24–40% of individuals are characterized as multiple-domain MCI (19% amnestic multiple domain; 5% nonamnestic multiple domain) [8–10].

Executive dysfunction is the most common cognitive disturbance and is usually evident early in the course of PD as well as sometime being an early sign of incident PDD [11]. Studies suggest that executive function deficits in PD result from a disruption in frontostriatal circuitry, particularly the dorsolateral prefrontal circuit [12–14]. Executive function deficits found in PD include impaired complex attention, verbal fluency, cognitive set-shifting, abstract thinking and planning [15–18]. Although there can be heterogeneity in the memory performance of PD patients [19, 20], the memory profile in general can be characterized by mild retrieval deficits with relatively spared retention of information. Episodic memory deficits in PD are thought to be a result of frontostriatal dysfunction that leads to impairments in higher-level strategy or organization of information during encoding and retrieval [21, 22]. Visuospatial deficits found in PD include impairments in perception of line orientation, visuomotor construction, facial recognition and memory for spatial location [23, 24].

The cognitive deficits in PDD are generally qualitatively similar to those with PD-MCI but are more severe and pervasive, affecting subjects’ functions [25]. The majority of individuals with PDD exhibit a subcortical profile, characterized by prominent executive dysfunction along with impaired attention, slowness of thought, and visuospatial and episodic memory deficits [26]. Compared with patients with Alzheimer’s disease (AD), PDD patients show more severe impairments in executive function and visuospatial processes, and less severe deficits in learning and memory [27–29]. However, some individuals with PDD may present with a “cortical” profile, which is characterized by memory (impaired retention of information) and language impairments that are found in cortical dementias such as AD [9]. The extent to which this represents a mixed pathology is unknown.

Given the frequency and progressive nature of cognitive deficits in PD and the impact that cognitive impairment has on patients and their families, it is critically important to identify treatments for cognitive impairment. Treatments that could improve cognitive functioning or delay or stop progression from PD-MCI to PDD are vitally important for this population. The following sections review the research conducted examining pharmacological and nonpharmacological treatments for cognitive impairment in PD.

Pharmacological interventions

There are no standard pharmacological treatments for the cognitive impairment of patients with PD-MCI; however, there are good clinical practice guidelines that advocate the discontinuation of medications that have the potential of deteriorating cognition when the symptoms of cognitive disturbances start to manifest. Medications that can worsen cognition include anticholinergic agents (commonly used to treat tremor or urinary disturbances), amantadine; dopamine agonists and benzodiazepines (reviewed in [30]). Good clinical practice guidelines include ruling out metabolic disorders (e.g. thyroid or hepatic dysfunction), infections (e.g. usually urinary) and vitamin deficits (e.g. hypovitaminosis of vitamin D, hypovitaminosis D, B or folic acid B or folic acid).

Moreover, there have been no therapeutic trials to improve the cognitive aspects of patients with PD-MCI except for a pilot study with rasagiline, a monoamine oxidase B (MAO-B) inhibitor, which showed improvements in working memory and verbal fluency [31] [Table 11.1]. The results of this study have led to an ongoing 24-week, multicenter, double-blind, placebo-controlled study to determine whether 1mg/day of rasagaline is more effective than placebo in improving the cognitive dysfunction of PD-MCI patients.

To improve the cognitive dysfunction of patients with PDD on the other hand, in addition to the above good clinical practice guidelines, the use of cholinesterase inhibitors such as rivastigmine, donepezil and galantamine provide modest benefit [34, 31]). There is good evidence (level A evidence) from a double-blind, randomized, placebo-controlled study that rivastigmine has moderate beneficial effects on cognition in PDD [32] (Table 11.1). One large and two small donepezil randomized, double-blind, placebo-controlled studies [33, 60, 61] also showed cognitive benefits (level A evidence) (Table 11.1). Despite these promising findings, cholinesterase inhibitors have side effects that include worsening of motor symptoms (tremor), nausea, vomiting, diarrhea and urinary disturbances.

Memantine, a N-methyl-d-aspartate (NMDA) receptor antagonist, which is also used in moderately advanced AD, does not or minimally benefits patients with PDD [34, 35] (Table 11.1), and it is at present not recommended. Neuroleptics are used to treat the neuropsychiatric disturbances (i.e. hallucinations, agitation, delusions), but do not influence cognition and may worsen the parkinsonism as well as leading to a neuroleptic malignant syndrome. Similarly, antidepressants useful for depression or anxiety do not appear to improve cognition in this population. Moreover, the use of serotoninergic antidepressants and selegiline in high doses may lead to a serotoninergic syndrome, which manifests with cognitive, somatic and autonomic disturbances.

Nonpharmacological interventions

Related posts:

Management of disease-related behavioral disturbances in Parkinson’s disease Experimental pharmacological agents in the management of Parkinson’s disease Emerging targets and other stimulation-related procedures in the management of Parkinson’s disease Functional imaging markers as outcome measures in clinical trials for Parkinson’s disease Lessons and challenges of trials for other nonmotor complications of Parkinson’s disease Lessons and challenges of trials involving ancillary therapies for the management of Parkinson’s disease

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