A neurobehavioralist approach to the management of cognitive impairment in Parkinson’s disease

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Chapter 12 A neurobehavioralist approach to the management of cognitive impairment in Parkinson’s disease


Po-Heng Tsai



Introduction


Parkinson’s disease (PD) is traditionally characterized by its motor symptoms of tremors, rigidity, bradykinesia and postural instability [1]. However, it has been increasingly recognized that nonmotor symptoms are frequently present in PD. Their onset sometimes predates the motor symptoms, and these nonmotor symptoms could lead to significant dysfunction [2, 3]. Cognitive impairment associated with PD is a common nonmotor symptom that should be recognized and managed appropriately to improve PD patients’ quality of life.



Epidemiology


The spectrum of cognitive impairment in PD ranges from mild cognitive impairment (PD-MCI) to dementia (PDD). The term MCI is used to describe the intermediate stage between age-related cognitive changes and dementia. The main distinction between PD-MCI and PDD is that the deficits in PDD are severe enough to impair activities of daily living (ADLs). Instrumental ADLs such as management of finances, medication and transportation are usually affected before basic ADLs, which consist of self-care tasks such as eating, dressing, bathing and toileting.


The most frequently cited point prevalence of PDD is approximately 30%, with a cumulative prevalence of at least 75% for PD patients with a disease duration of more than 10 years. The incidence rate is such that approximately 10% of a PD population will develop dementia per year. The main risk factors for the development of PDD include higher age, more severe parkinsonism (in particular rigidity, postural instability and gait disturbance) and mild cognitive impairment at baseline [4].


Based on pooled data from various studies, the prevalence rate of PD-MCI is approximately 26–27%. The following features have been identified to be associated with the presence of MCI: older age at time of assessment and at disease onset, lower educational level, male gender, depression, advanced stage of PD and more severe motor symptoms [5, 6].


Recent efforts have been devoted to better defining PD-MCI because it may be the precursor to PDD, and early identification provides the opportunity to intervene before progression to dementia.



Cognitive profile and bedside assessment


The neuropsychological profile of PD has traditionally been viewed as being in a “frontal-subcortical” pattern (slow processing speed, impaired executive function and memory retrieval deficit) along with visuospatial dysfunction. Executive function difficulties, which include impairments in planning, initiating, sequencing, monitoring, set-shifting, adapting to novel situations and abstract reasoning, could be the earliest signs of impairment. However, studies have demonstrated variable patterns of impairments and the involvement of various cognitive domains [6, 7].


Mild cognitive impairment can be further divided into four subtypes according to a proposed classification: (i) amnestic single-domain MCI: only memory domain is impaired; (ii) amnestic multiple-domain MCI: memory plus one or more other domains are impaired; (iii) nonamnestic single-domain MCI: one nonmemory domain such as attention, executive function, visuospatial ability or language is impaired; and (iv) nonamnestic multiple-domain MCI: one or more nonmemory domains are impaired [8]. Based on this scheme, the majority of PD-MCI presents as nonamnestic single -domain MCI [6, 9].


Formal comprehensive neuropsychological assessment is considered the “gold standard” for the diagnosis of PD-MCI. However, sometimes obtaining a neuropsychological evaluation might not be feasible due to time demands, cost or the availability of a qualified neuropsychologist. Therefore, bedside cognitive screening tools have been recommended that can be administered quickly with relatively good sensitivity to detect PD-MCI. The Movement Disorder Society Task Force listed four such scales in their recent proposed diagnostic criteria for PD-MCI: the Montreal Cognitive Assessment (MoCA), the Parkinson’s Disease Cognitive Rating Scale (PD-CRS), Scales of Outcomes of Parkinson’s disease–Cognition (SCOPA-COG) and the Mattis Dementia Rating Scale (MDRS) [10]. MoCA appears to be one of the most recommended screening scales [11, 12]. It is freely available online at http://www.mocatest.org for clinical use for healthcare professionals and is available in multiple languages.



Pharmacological treatments


None of the current medications used for the treatment of cognitive impairments in PD have demonstrated effects in modifying the underling pathophysiology that leads to cell death. The available medications are considered symptomatic agents that aim to improve cognitive decline in patients with PD without modifying disease progression. Most of the agents focus on neurotransmitter systems that have been implicated to be altered in PD such as dopamine, norepinephrine, serotonin and acetylcholine.



Cholinesterase inhibitors


Rivastigmine, a cholinesterase inhibitor, is the only medication specifically approved by the US Food and Drug Administration (FDA) for the treatment of cognitive symptoms in PDD. The approval was based on a 24-week, randomized, placebo-controlled study that enrolled 541 patients and demonstrated moderate improvement in PDD but with higher rates of nausea, vomiting and tremor [13]. Cholinesterase inhibitors enhance cholinergic function through the reversible inhibition of acetylcholinesterase. The rationale of their use is based on biochemical and pathological studies that have demonstrated that cognitive impairment in PD is associated with cortical acetylcholine deficiency [14].


Besides rivastigmine, there are currently two other cholinesterase inhibitors available: donepezil and galantamine. In addition to inhibition of acetylcholinesterase, rivastigmine inhibits butyrylcholinesterase, whereas galantamine acts as an allosteric potentiating ligand of neuronal nicotinic receptors for acetylcholine. A recent Cochrane review of six clinical trials concluded that the use of cholinesterase inhibitors is beneficial in patients with PDD, with a positive impact on global assessment, cognitive function, behavioral disturbance and ADL rating scales [15].


Donepezil is available in tablets in three strengths (5, 10 and 23mg) and in orally disintegrating tablets in two strengths (5 and 10mg). Galantamine is available in extended-release capsules in three strengths (8, 16 and 24mg) and as immediate-release tablets in three strengths (4, 8 and 12mg). It is also available as a 4mg/ml oral solution. Rivastigmine is available as a 24-h transdermal system (“patch”) in three strengths (4.6, 9.5 and 13.3mg), in capsules in four strengths (1.5, 3, 4.5 and 6mg) and is available as a 2mg/ml oral solution (Table 12.1). The most common adverse reactions of cholinesterase inhibitors are cholinergic-related gastrointestinal side effects, including nausea, vomiting and diarrhea. These side effects can be reduced by increasing the dose-titration duration, giving the medication with food or reducing the dose. Tremors may worsen but are usually mild and transient.



Table 12.1

Administration, pharmacology and common adverse reactions of cholinesterase inhibitors












































Donepezil Galantamine Rivastigmine
Dosage and titration Start at 5mg daily and increase to 10mg after 4–6 weeks. The dosage could then be increased to 23mg daily after at least 3 months Start at 4mg twice daily (or 8mg daily for extended-release [ER] formulation) and increase by 4mg twice daily (or 8mg ER daily) every 4 weeks at the minimum to maximum dosage of 12mg twice daily (or 24mg ER daily) Oral formulation: start at 1.5mg twice daily and increase by 1.5mg twice daily every 2 weeks at the minimum to a maximum dosage of 6mg twice daily Transdermal system: start at 4.6mg daily and increase to 9.5mg after a minimum of 4 weeks. The dosage could then be increased to 13.3mg after at least 4 weeks
Conversion between formulations Not applicable Conversion from immediate-release to extended-release formulation occurs on the same total daily dosage (e.g. 8mg twice daily to 16mg ER daily) A total daily dose of <6mg of oral rivastigmine can be switched to the 4.6mg/24h rivastigmine patch, and a total daily dose of 6–12mg of oral rivastigmine can be switched to the 9.5mg/24h patch
Elimination half-life 70h 7h 1.5h 3h (peripheral); 8h in central nervous system; 24h for patch formulation
Absorption Can be given with or without food Give with food Give with food Highest when applied to upper back, chest or upper arm
Most common adverse reactions Nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue and anorexia Nausea, vomiting, diarrhea, anorexia and weight decrease, and mild, transient increase in tremors Nausea, vomiting, anorexia, dyspepsia and asthenia Nausea, vomiting, diarrhea, depression, headache, anxiety, and application site reaction


Memantine


Excitotoxicity has been hypothesized to be involved in neurodegenerative processes including PD. In this pathological process, neurons are damaged by excessive stimulation by excitatory neurotransmitters such as glutamate. This occurs when N-methyl-d-aspartate (NMDA) receptors are persistently activated. Memantine is a low- to moderate-affinity, noncompetitive NMDA receptor antagonist that binds preferentially to the NMDA receptor-operated cation channels and blocks excessive NDMA receptor activity [16]. Four placebo-controlled trials of memantine on cognition in PD have been reported, but the results were mixed, with only one study showing a significant effect on a predefined primary outcome of cognitive change [17].


Memantine is available in extended-release capsule formulation in four strengths (7, 14, 21 and 28mg), in tablets in two strengths (5 and 10mg) and as a 2mg/ml oral solution (Table 12.2). The principal side effects of memantine are dizziness, headaches and somnolence.


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Feb 16, 2017 | Posted by in NEUROLOGY | Comments Off on A neurobehavioralist approach to the management of cognitive impairment in Parkinson’s disease

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