Abstract
We evaluated the effect of anticholinergic burden on 219 participants with incident Parkinson’s disease (PD) and 99 controls at study baseline and 18 months. Anticholinergic burden for each individual was calculated and summed according to the Anticholinergic Drug Scale (ADS). Medication with anticholinergic activity was more commonly prescribed in PD compared to controls, although mean ADS scores were not significantly different. Cognitive scores did not differ in PD participants taking medications with anticholinergic activity compared to those who were not. Low overall ADS scores due to increased awareness of adverse effects of medications and brevity of follow-up are potential explanations.
INTRODUCTION
Cognitive impairment occurs frequently inParkinson’s disease (PD), with up to 80% of patients developing dementia (PDD) within 20 years of diagnosis [1]. Mild cognitive impairment in PD (PD-MCI) is present in a significant proportion of patients even in early disease [2], and may represent a risk factor for the future development of PDD [3–5]. The underlying pathophysiology of cognitive decline in PD is complex and may vary between individuals, but is likely to involve cortical Lewy body deposition and amyloid-β plus tau accumulation [6]. Furthermore, there is evidence from imaging, neuropathological and neurophysiological studies that cholinergic dysfunction may contribute [7, 8].
The use of anticholinergic drugs to treat bladder dysfunction, mood, and pain is widespread in older adults, and over-the-counter medications that antagonise muscarinic receptors are also freely available. Several other drugs not classically categorised as antimuscarinics also exhibit a degree of anticholinergic activity [9], with increasing evidence that greater anticholinergic burden is associated with both future cognitive decline and mortality [10]. Moreover, recent work demonstrated a greater risk of dementia, largely Alzheimer’s disease (AD), with higher cumulative use of anticholinergics [11]. Many PD patients with non-motor symptoms may be treated with these drugs, and evidence suggests that they may accelerate their cognitive decline [12] due to concomitant Alzheimer-type pathology [13].
ICICLE-PD is a twin centre longitudinal observational study, the aim of which is to better understand the anatomical, biochemical and genotypic mechanisms underlying the evolution of PDD from disease onset [2]. Baseline cognitive outcomes and methodologies have been published elsewhere [2]. Here we sought to determine whether use of medications with anticholinergic activity was associated with cognitive abnormalities in early PD over the first 18 months of longitudinal follow-up.
MATERIALS AND METHODS
Participants
Newly diagnosed PD patients from community and outpatient clinics plus unrelated controls of similar age and sex to patients were recruited from two centres in the UK [2]. The study was approved by the local ethics committees and performed according to the Declaration of Helsinki, with all subjects providing written informed consent.
Clinical data
Clinical and demographic data were recorded including disease duration; level of education; co-morbidities and family history. Clinical assessments (detailed in [2]) included a standardised neurological examination, the Movement Disorder Society (MDS)-revised Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) [14] and the Geriatric Depression Scale (GDS-15) score [15]. A detailed cognitive assessment was also performed and is described elsewhere [2]. In brief, this covered global cognitive function using the Mini Mental State Examination (MMSE) [16] and Montreal Cognitive Assessment (MoCA) [17], in addition to tests of attention, visual memory, executive, language and visuospatial function. PD-MCI was determined using the MDS criteria [18] and presented here as 1.5 standard deviations below normative means.
Following a detailed medication history, including over-the-counter medications, anticholinergic burden for each participant was determined according to the published Anticholinergic Drug Scale (ADS) [19]. Each drug was classified on a scale from 0 to 3 according to no (0), mild (1), moderate (2) or high (3) anticholinergic activity [19]; for each participant the individual agent scores were then summed at baseline and 18 months to produce a score of total burden. For medications not specified on the ADS, the authors (AJY, TKK) independently reviewed the literature and utilised other scales to allocate an accurate score.
Statistics
Statistical analyses were performed using SPSS 21.0. Data were examined for normality and means compared using unpaired t-tests or ANOVAs(parametric) and Mann-Whitney or Kruskal-Wallis tests (non-parametric data). Pearson or Spearman’s rank correlation coefficients were calculated to assess bivariate associations between cognitive and clinical parameters. Pearson Chi-square tests were used to compare between-group distribution of proportions. Repeated measures ANOVA or Wilcoxon Sign-Rank tests were used to compare baseline and follow up assessments. PD subjects were then dichotomised into those who were (ADS score ≥1; PD+ADS) and were not (ADS score = 0; PD-ADS) on medications with anticholinergic activity at 18 months and comparisons were performed between these groups. Finally, hierarchical regression was used to determine whether long term use of anticholinergic medication predicted neuropsychological assessment scores. To remove non-significant predictors, backward stepwise regression was first performed for each cognitive test using the following variables to produce an initial model: age, gender, years of education, disease duration, MDS-UPDRS III, levodopa equivalent daily dose and GDS-15. The ADS score was then entered to produce a final model for each test. A p-value of <0.05 was considered significant.
RESULTS
At baseline, 219 people with PD and 99 healthy controls completed assessments, with 89% of PD and 84% of the controls seen at 18 month follow up. Reasons for lack of longitudinal data included change of diagnosis; death; and declined further assessment. Groups remained well matched for age and years in education, although male gender was over-represented in the PD group at 18 months (Table 1). Similar to baseline, PD participants demonstrated significantly higher depression scores, poorer scores of global cognition and were more likely to be classified as having MCI than controls. The proportion of subjects with PD using medication with any anticholinergic activity was significantly higher than controls; however, mean anticholinergic burden as measured by the ADS score did not differ between groups.
Comparison of the PD+ADS (n = 83) and PD-ADS (n = 112) groups revealed no differences with respect to global cognition or assessments of attention, memory and executive function at 18 months (Table 2). The proportion of PD-MCI was similar in those with and without anticholinergic drug use. The PD+ADS group showed no significant changes in either MoCA or MMSE. In contrast, the PD-ADS group demonstrated a slight but significant increase in MoCA (mean = 25.1 vs. 26.3 from baseline to 18 months, p < 0.001) and a decline in MMSE (mean = 28.8 vs. 28.3, p < 0.001). Other neuropsychological assessments showed no significant changes from baseline to follow up for either group, with the exception of verbal fluency. PD-ADS had a significant improvement in verbal fluency scores (mean = 11.9 vs. 13.0, p = 0.01); with no changes observed in the PD+ADS group. There was no correlation between total ADS and global cognition.
The use of anticholinergic medication accounted for less than 1.2% of the variance (ΔR2) for each neuropsychological test when added to the final model, indicating that anticholinergic burden over 18 months was not a significant predictor of cognitiveperformance.
DISCUSSION
This is the first study to explore an association between anticholinergic burden and MCI in PD participants, and is timely given recent research demonstrating cumulative anticholinergic burden and risk of AD in the general population [11]. We found a greater proportion of PD subjects than controls were taking medications with anticholinergic activity, although total anticholinergic burden did not differ between the groups. Overall, anticholinergic activity did not contribute to MCI in early PD and was not a significant predictor of cognition.
The lack of positive findings is in contrast to other groups [10–12], which may be due to a number of factors. Firstly, our follow-up was shorter than others [10–12]; thus, we postulate that with ongoing longitudinal assessments we may see an anticholinergic effect on cognitive outcomes. Our participants were also younger in comparison to other studies [10–12] and had incident rather than prevalent disease. Moreover, total ADS scores in this cohort were low, which may represent an increased clinician awareness of the adverse outcomes associated with anticholinergic burden in PD, although recent work in the general population has shown temporal trends of an increase in those prescribed anticholinergic medications aged over 65 [20].
The exact underlying pathophysiology of PD-MCI remains the subject of debate, largely due to the scarcity of neuropathological data. Cortical Lewy body deposition, amyloid deposition and neurotransmitter deficits are all likely to contribute, although to a lesser degree than those changes seen in PDD. Cholinergic loss is an established feature of PDD [8] and may contribute to PD-MCI [7]. There is also evidence that muscarinic receptor blockade increases amyloid-β deposition [13], hence providing a mechanism for the cognitive decline seen with long-term anticholinergic use.
The principal strengths of this hypothesis-driven prospective study are its longitudinal design, recruitment of a large community-representative incident cohort, and matched control group. Through this, we will determine whether those prescribed medications with anticholinergic activity have a higher incidence of progressing to PDD. Limitations include the fact that we were unable to ascertain previous use of anticholinergic drugs and we did not account for medication doses, although this is in keeping with other published studies [10, 12]. Medication use was collected at only two time points, and it is possible that there could have been changes over that time.
In conclusion, anticholinergic burden did not contribute to MCI and was not associated with cognitive scores over 18 months in our cohort of incident PD subjects. Longitudinal assessment will help determine whether those subjects prescribed medication with anticholinergic activity are more likely to develop PDD, and hence allow early targeted intervention to reduce future risk.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
Footnotes
ACKNOWLEDGMENTS
The ICICLE-PD study was funded by a Parkinson’s UK grant (J-0802), who played no role in the design, execution, analysis and interpretation of the data, or writing of the study. The Research was supported by the National Institute for Health Research Newcastle Biomedical Research Unit and Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The research was also supported by a National Institute of Health Research Biomedical Research Award (to Addenbrooke’s Hospital/University of Cambridge) and Raymond and Beverly Sackler Studentship (to DPB).