We found that mild cognitive impairment, either in single or multiple cognitive domains, occurs in almost one-third of PD patients with intact global cognition as defined by a normal score on the MMSE. In addition, memory deficits, including retrieval deficits, are as common as executive function and attention deficits at the initial stage of cognitive impairment. Finally, anti-anxiety medication use and excessive daytime sleepiness may be reversible or treatable contributors to mild cognitive impairment in PD.
Recent research focusing on mild cognitive changes in PD typically has defined the study populations as being either newly diagnosed [3
], relatively recently diagnosed [31
], or as not meeting clinical criteria for dementia [1
]. However, newly or recently diagnosed patients have significant variability in actual disease duration and cognitive abilities. Moreover, PD patients not meeting clinical criteria for dementia have a wide range of global cognitive abilities, from being completely intact to being on the cusp of meeting criteria for dementia. By using a well-standardized cognitive screening instrument and a conservative cut-off point (i.e., excluding patients in the bottom 25th percentile based on their age- and education-adjusted MMSE score), we helped ensure that our population did not have global cognitive impairment beyond the earliest stage.
In spite of these operationalized criteria to exclude patients with significant global cognitive impairment, almost one-third of our patients met criteria for MCI. This suggests that the MMSE is insensitive for detecting the earliest stage of cognitive impairment in PD. Although the MMSE has been criticized as being too insensitive and narrow when used in PD, to our knowledge this is the first report documenting the frequency and range of cognitive impairment in patients with normal age- and education-adjusted MMSE scores. As more extensive neurocognitive testing is typically not feasible in the day-to-day clinical practice of most movement disorder physicians, the use of a screening measure is often the only choice to assess cognition in a time-efficient manner. Recent research suggests that other screening instruments, such as the Montreal Cognitive Assessment (MoCA) [33
], may be more sensitive than the MMSE in detecting MCI in PD [10
We, like others before us, found that mild cognitive impairment is common in PD and occurs in a range of domains, including memory [1
], executive function [1
], and attention [34
]. Reviewing recent studies, Janvin et al. [1
] reported that 55% of non-demented PD patients had MCI, with half of those showing widespread cognitive deficits in visual memory, executive abilities, and visuospatial skills. Caviness et al. [5
], using more stringent criteria similar to those applied by us, found that 25.4% of non-demented patients in a brain bank sample met criteria for MCI, with the most common deficits being in executive functioning and memory. Unlike some previous research in non-demented PD patients [6
], we found that memory impairment is more common than executive impairment early in the course of cognitive decline, with impairment in recognition memory nearly as common as in free recall. This latter finding is different from what is commonly reported in the literature, although there is research reporting deficits in both encoding and retrieval in PD [35
]. Memory deficits in PD, even early in the course of cognitive decline, are not surprising given the prominent diffuse cholinergic deficits that occur in PD [36
] and the presence of neuropathology in both the basal forebrain and hippocampal formation relatively early in the disease course [37
Impaired attention was as common as memory impairment. Impairment was almost exclusively on the backward digit span, which requires working memory as well as attention, while almost no impairment was seen on the forward digit span, which is thought to be more of a test of immediate recall [27
Certain demographic (increasing age), PD-related (increasing Hoehn & Yahr stage and UPDRS motor score), and psychiatric (anti-anxiety medication use and increasing daytime sleepiness) variables were associated with MCI on univariate analyses. All of the aforementioned variables maintained at least a trend association with cognitive impairment on multivariate analysis. Interestingly, some of these variables have also been reported to be risk factors for the development of dementia in PD [38
Anti-anxiety medications, particularly benzodiazepines, can be a cause of or contributor to cognitive impairment in the elderly [39
], and use of non-benzodiazepine anti-anxiety agents (e.g., selective serotonin reuptake inhibitors (SSRIs)) or nonpharmacologic treatment approaches may lead to cognitive improvement in impaired patients. Likewise, better recognition and treatment of excessive daytime sleepiness (EDS) potentially could lead to an improvement in cognitive abilities. The etiology of EDS is complex [40
], and management strategies include reducing overall exposure to dopaminergic replacement therapy as well as treatment with stimulants or modafinil.
There are limitations to our study. First, we did not have a non-PD control group, so it is not known if similar levels of cognitive impairment would be found in persons in the general population with normal MMSE scores. The MMSE has also been found to be insensitive in the detection of pre-AD MCI, leading to the development of more sensitive instruments such as the MoCA. Second, our results may not be generalizable, as the majority of our patients were white and all were from specialty care centers. Third, we did not use formal criteria to diagnose MCI or exclude patients with dementia, so it is possible that a small percentage of our patients, in spite of having a high MMSE score, might have met clinical criteria for dementia. However, the mean MMSE score of our patients was similar to that reported in PD studies that only included patients who did not meet clinical criteria for dementia [1
]. Fourth, our neuropsychological battery included memory, executive function and attention tests, but did not specifically assess visuospatial, language, or praxis abilities. Thus, we likely underestimated the frequency of cognitive impairment in our patients. Finally, the study was cross-sectional, and additional, longitudinal studies are needed to determine if particular cognitive deficits or clinical correlates of MCI also predict future development of PD dementia (PDD).
There is increasing evidence that PDD is common in advancing disease, affecting up to 78% of patients followed long term [43
]. As MCI precedes the development of PDD, the cumulative prevalence of MCI in PD must be at least as high. In order to detect initial cognitive deficits in PD, all patients should undergo routine cognitive screening with a sensitive instrument that assesses a range of cognitive domains. Recognition of cognitive impairment at this stage will enable the treating doctor to educate the patient and family about prognosis and to make decisions about appropriate therapy.