Rivastigmine for Dementia Associated with Parkinson's Disease

University of Bergen, Bergen, Hordaland, Norway
New England Journal of Medicine (Impact Factor: 55.87). 12/2004; 351(24):2509-18. DOI: 10.1056/NEJMoa041470
Source: PubMed


Cholinergic deficits are prominent in patients who have dementia associated with Parkinson's disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients.
Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test.
A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer's disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01).
In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson's disease but also with higher rates of nausea, vomiting, and tremor.

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    • "Among the many non-motor problems affecting patients with PD, psychosis is particularly relevant, as it represents a great burden to caregivers and increases the risk that a patient can no longer be looked after at home, but will move to a nursing home. While the cholinesterase inhibitor rivastigmine may relieve psychotic symptoms in PD patients, (Emre 2004) it is not licensed for this indication, and neuroleptics often become necessary. Among the available antipsychotics, only clozapin has been classified as being effective in PD patients [23]; however, specialised monitoring is required due to the risk of agranulocytosis. "
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    ABSTRACT: While a curative treatment for Parkinson's disease remains elusive, our understanding of disease mechanisms as well as preclinical and pre-motor early manifestations has improved greatly over the past years. An agent with proven disease modifying properties has not yet been identified but symptomatic treatment options for affected patients have improved. For patients with motor complications, this includes invasive approaches such as deep brain stimulation and continuous device-aided drug delivery. The many facets of non-motor problems patients are faced with have finally been fully recognized and have become the target of treatment trials, as have been non-pharmacological approaches.
    Journal of Neurology 04/2014; 261(5). DOI:10.1007/s00415-014-7308-9 · 3.38 Impact Factor
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    • "However, the role of acetylcholine in PD cognition is not straightforward. On one hand there are previous studies indicating that medications that prevent the breakdown of acetylcholine (i.e., cholinesterase inhibitors) improve cognition in demented patients with PD (Emre et al., 2004; Bosboom et al., 2009; Possin et al., 2013). On the other hand we argue here that increased activity in cholinergic interneuron leads to a deficit in procedural-based category learning. "
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    ABSTRACT: Previously we found that Parkinson's disease (PD) patients are impaired in procedural-based category learning when category membership is defined by a nonlinear relationship between stimulus dimensions, but these same patients are normal when the rule is defined by a linear relationship (Maddox and Filoteo, 2001; Filoteo et al., 2005a,b). We suggested that PD patients' impairment was due to a deficit in recruiting "striatal units" to represent complex nonlinear rules. In the present study, we further examined the nature of PD patients' procedural-based deficit in two experiments designed to examine the impact of (1) the number of categories, and (2) category discontinuity on learning. Results indicated that PD patients were impaired only under discontinuous category conditions but were normal when the number of categories was increased from two to four. The lack of impairment in the four-category condition suggests normal integrity of striatal medium spiny cells involved in procedural-based category learning. In contrast, and consistent with our previous observation of a nonlinear deficit, the finding that PD patients were impaired in the discontinuous condition suggests that these patients are impaired when they have to associate perceptually distinct exemplars with the same category. Theoretically, this deficit might be related to dysfunctional communication among medium spiny neurons within the striatum, particularly given that these are cholinergic neurons and a cholinergic deficiency could underlie some of PD patients' cognitive impairment.
    Frontiers in Systems Neuroscience 02/2014; 8:14. DOI:10.3389/fnsys.2014.00014
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    • "Moreover, anticholinergic medication is used commonly in PD patients to alleviate motor symptoms presumably by counteracting hyperactivity of striatal cholinergic interneurons, but may have adverse effects on cognition [12] [13]. Conversely, cognitive dysfunction is known to improve in PDD and DLB when these patients are given acetylcholinesterase inhibitors (AChEIs), although mild adverse effects on motor symptoms have been described [14] [15]. Although the interaction between the dopaminergic and cholinergic system has been studied extensively, the exact mechanism remains controversial. "
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    ABSTRACT: Dysfunction of the cholinergic neurotransmitter system is present in Parkinson's disease, Parkinson's disease related dementia and dementia with Lewy bodies, and is thought to contribute to cognitive deficits in these patients. In vivo imaging of the cholinergic system in these diseases may be of value to monitor central cholinergic disturbances and to select cases in which treatment with cholinesterase inhibitors could be beneficial. The muscarinic receptor tracer [(123)I]iododexetimide, predominantly reflecting M1 receptor binding, may be an appropriate tool for imaging of the cholinergic system by means of SPECT. In this study, we used [(123)I]iododexetimide to study the effects of a 6-hydroxydopamine lesion (an animal model of Parkinson's disease) on the muscarinic receptor availability in the rat brain. Rats (n=5) were injected in vivo at 10-13days after a confirmed unilateral 6-hydroxydopamine lesion. Muscarinic receptor availability was measured bilaterally in multiple brain areas on storage phosphor images by region of interest analysis. Autoradiography revealed a consistent and statistically significant lower [(123)I]iododexetimide binding in all examined neocortical areas on the ipsilateral side of the lesion as compared to the contralateral side. In hippocampal and subcortical areas, such asymmetry was not detected. This study suggests that evaluation of muscarinic receptor availability in dopamine depleted brains using [(123)I]iododexetimide is feasible. We conclude that 6-hydroxydopamine lesions induce a decrease of neocortical muscarinic receptor availability. We hypothesize that this arises from down regulation of muscarinic postsynaptic M1 receptors due to hyperactivation of the cortical cholinergic system in response to dopamine depletion. In rats, dopamine depletion provokes a decrease in neocortical muscarinic receptor availability, which is evaluable by [(123)I]iododexetimide imaging. This study may further underline the role of a dysregulated muscarinic system in patients with Lewy body disorders.
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