Mild cognitive impairment (MCI) is increasingly accepted as part of the spectrum of cognitive impairment in Parkinson’s disease (PD). The presence of a subjective cognitive complaint (SCC), in order to diagnose MCI, is a requirement as per the well-referenced Petersen criteria,1,2 and constitutes 1 of 2 ways in which gradual cognitive decline can be established within the recent criteria proposed by the Movement Disorders Society Task Force on PD-MCI.3 There are no current guidelines for eliciting a cognitive complaint, or with regard to what constitutes a cognitive complaint. For example, different studies may elicit the presence of a cognitive complaint from subjects, caregivers, or both. In addition, different methods are used to elicit cognitive complaints, ranging from single questions to structured interviews to formal scales, with the sensitivity of different approaches being unknown. The limitations in understanding how to formalize the presence of a cognitive complaint are recognized in the proposed PD-MCI criteria.3
The topic of eliciting a SCC is critical in the context of MCI for several reasons. First, inclusion of a SCC in MCI criteria affects the calculated prevalence of MCI in PD. In 1 PD study, of 62 nondemented subjects with impaired cognitive testing, only 23 (37%) self-reported cognitive decline, thus fulfilling the diagnostic criteria for PD-MCI.4
In addition, there is evidence that the presence of a SCC may be a risk factor for subsequent cognitive impairment. In a study of 76 newly diagnosed, untreated PD patients, 23 (30.3%) patients had a memory complaint and these individuals were more likely to develop MCI at follow-up.5 Outside of PD, a recent meta-analysis found that the presence of a cognitive complaint in older people is associated with a higher risk of developing dementia.6 The source of the cognitive complaint may be important. For example, a recent study of nondemented older adults found that mutual cognitive complaints (from patients and informants) was the most predictive of diagnostic outcome and informant complaints alone were the second most predictive.7 Given that the presence or absence of a SCC influences whether a person is diagnosed with MCI and potentially their prognosis for progressing to dementia, understanding from whom the complaint should be solicited (the patient, an informant, or both) and how that complaint should be solicited is important. In this context, we investigated different methods of eliciting cognitive complaints in a cohort of nondemented PD patients. We also investigated the relationship between SCCs elicited in several different ways and cognitive performance at baseline and follow-up.
Consecutive English-speaking nondemented PD patients were enrolled at 6 North American movement disorders centers as part of an ongoing prospective longitudinal study of PD-MCI screening measures. All subjects were enrolled with a consenting close contact, defined as a person in touch with the participant at least twice weekly. Recruitment started in December 2008 and continued through June 2011. Full methods including inclusion and exclusion were reported previously.8 Enrolled subjects received an annual clinical evaluation followed 1 to 3 weeks later by formal neuropsychological testing performed blinded to clinical results. Each participating institution received local research ethics board approval before study enrollment. Written informed consent was obtained from all study subjects and participating close contacts before formal screening and study visits.
Eliciting Cognitive Complaints
SCC were elicited in 3 different ways. (1) A modified Neurobehavioral Inventory (NBI) (Professional Resources and Technologies, Westtown, PA; a list of 19 cognitively based problems with everyday life) was administered by the investigator or research coordinator with patients and close contacts separately identifying if a problem was present, and if so, if it was new or present during the subject’s whole life. Each problem was given a score of one point with the range being between 0 and 19. Patients free of cognitive complaints would have a score of 0, while 19 would be the worst. The NBI was the method chosen a priori for determining a cognitive complaint for the purposes of the study; the presence of at least one new complaint by either the subject or the close contact was considered a positive subjective complaint for the purposes of diagnosing MCI. (2) Subjects answered “yes” or “no” to the General Complaint Question, “Do you have any concerns about your memory or thinking?” and (3) Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)9 item question 1.1 “Over the past week have you had problems remembering things, following conversations, paying attention, thinking clearly, or finding your way around the house or in town?” The close contacts were not present during administration of these instruments; thus, the responses reflected the subject’s view alone.
Functional impairment related to cognitive problems was assessed by the Disability Assessment for Dementia,10 modified to specify whether or not each activity was impaired related to cognitive problems or to physical limitations from the PD. The MDS-UPDRS was administered by a movement disorder neurologist.
Diagnosis of Cognitive Impairment
Cognitive impairment at baseline was defined as a score of ≥1.5 SD below the normative mean on at least 2 neuropsychological tests. We selected this definition to align as much as possible with MDS Task Force level II criteria for diagnosis of PD-MCI. However, in order to avoid circularity in our analyses examining prognostic value of SCCs, we did not include SCCs in the application of the PD-MCI criteria.
Two neuropsychological tests were applied for each of the 5 different cognitive domains. Attention was tested with the Delis Kaplan Executive Function System (DKEFS) Color Word Interference Color Naming test11 and the Wechsler Memory Scale-III letter-number sequencing test,12 while Language was tested with the DKEFS Verbal Fluency Category Fluency test11,13 and the 30-item Boston Naming Test.14 Executive function was tested with the Trail Making Test B minus A15 and the Visual Verbal Test abbreviated 10-item version.16 Memory was tested using the Rey Complex Figure Test and Recognition Trial (RCFT) Delayed Recall and the California Verbal Learning Test-II Long Delay Free Recall test,17 while visuospatial function was tested with the Benton Judgment of Line Orientation test18 and the Copy Trial of the RCFT.19 Clinical and neuropsychological evaluations were performed at a similar time of day and participants were evaluated in the ON state as judged by the patient’s self-report of the effectiveness of their PD medication at the time of testing.
Our analysis was divided in 5 parts. First, we measured the agreement (according to presence or absence) among different ways of eliciting complaints using a kappa coefficient (κ). For these analyses, complaints were defined as follows: (1) MDS-UPDRS question 1.1: a score of ≥1, (2) an NBI score of ≥1 was considered positive for a SCC for purposes of analysis, (3) a yes response to the general complaint question.
Second, we measured the correlation between cognitive complaints and cognitive testing scores including the MDS-UPDRS question 1.1 (ranges, 0 to 4), NBI-subject score, and NBI-close contact count of complaints using Spearman correlation coefficients (ρ). Cognitive test z-scores were averaged within domains to generate domain-specific measurements and across all 10 tests to generate a global cognitive score.
Third, in order to assess the association between cognitive impairment at baseline and presence or absence of cognitive complaints with the different measurements, we used a χ2 test and quantified the association using odds ratios (ORs). Because we hypothesized that SCC may be more closely related to decline from premorbid abilities rather than to differences from the normative mean, we performed a secondary analysis where cognitive impairment was defined as 1.5 SD below expected performance based on estimated premorbid IQ. Premorbid IQ was estimated using the Wechsler Test of Adult Reading.
Fourth, to assess the prognostic value of a cognitive complaint we used a χ2 test to test the association between cognitive complaints measures and development of cognitive impairment at year 1 and 2 of follow-up among individuals who had no impairment of any of the 10 core cognitive tests at baseline.
Fifth, we compared the average change in z-score on the 2 tests within each cognitive domain over 1 year (ΔZ score), across groups defined by the presence or absence of cognitive complaints. We used t tests or analysis of variance for variables with a normal distribution and Mann-Whitney or Kruskal-Wallis test otherwise.
Within each of the 5 parts of this study, we defined the threshold for statistical significance as 0.05 divided by the number of statistical tests performed. Statistical analyses were performed with SPSS 20 software (IBM, Armonk, NY).
Data on 139 patients were available for this analysis. At year 1, 119 patients were assessed for follow-up and 104 after 2 years. At baseline, the median age was 71 (range: 60 to 84) and median time from diagnosis was 4 (range, 1 to 29) years. At baseline, 58 (42%) patients had impairment on ≥2 tests of the core battery and thus met criteria for cognitive impairment. Table 1 lists the clinical features of the patients at baseline and follow-up. At baseline, 6 of 139 patients were taking cognitive enhancing medications and 5 of 139 patients were taking potentially cognitive impairing meds. Neither were significantly associated with MCI status at baseline (P=0.21 and P=1.00, respectively).
The majority of close contacts were spouses (71%), followed by children (15%), friend/neighbor (9%) and sibling, partner/girlfriend (2% each). There were isolated cases of daughter-in-law and roommate as close contacts. Female individuals accounted for 79% of the close contacts.
Agreement Between Different Cognitive Complaint Assessments
Agreement for the presence of a cognitive complaint occurred more frequently than by chance between MDS-UPDRS question 1.1 and the dichotomized NBI score from the subject, between the MDS-UPDRS question 1.1 and general complaint question, and between the dichotomized NBI score from the subject and general complaint question, but agreement was generally poor (κ≤0.29) (Table 2). There was absence of significance when comparing the close contact SSC to patients SSC.
Correlation Between Cognitive Complaint Assessments and Baseline Cognitive Testing
We found a weak negative correlation between MDS-UPDRS question 1.1 and global (ρ: −0.282, P=0.001) and memory (ρ: −0.221, P=0.009) z-score values (Table 3). There was a weak negative correlation with global (ρ: −0.208, P=0.014) and language z-score (ρ: −0.279, P=0.001) and the NBI count of complaints. No other significant correlations were found.
Association Between Cognitive Complaints and Cognitive Diagnosis at Baseline
Cognitive impairment relative to estimated premorbid cognitive abilities: MDS-UPDRS question 1.1 was associated with cognitive impairment (P=0.001, OR: 8.67). There was no significant association between cognitive diagnosis and dichotomized NBI score from subject, dichotomized NBI score from close contact, or the general complaint question.
Cognitive impairment relative to normative values: there was no significant association between cognitive diagnosis and MDS-UPDRS question 1.1, NBI score from subject, NBI score from close contact, or the general complaint question.
Association Between Cognitive Complaint in PD Cognitively Normal (PD-CN) at Baseline and Conversion to Cognitively Impaired at Years 1 and 2
At 1 year of follow-up, 18 of 70 (26%) baseline PD-CN patients who continued in the study had developed cognitive impairment and 13 of 64 (20.3%) had developed cognitive impairment after 2 years (Tables 4, 5). There were 4 patients who converted to PD-MCI/Parkinson’s disease dementia (PDD) from year 1 to year 2, while 5 reverted from MCI/PDD to CN from year 1 to year 2. Furthermore, 6 patients (4 PD-MCI/PDD and 2 PD-CN) were lost follow-up from year 1 to year 2. There were no differences in the frequency of patients expressing cognitive complaints by any method among those PD-CN patients who developed cognitive impairment after 1 or 2 years of follow-up.
Relationship Between Cognitive Complaint Assessments and Change in Cognitive Domains Performance Over 1 Year
There were no differences between the mean change of global or domain-specific z-score among those with our without cognitive complaints according to either the MDS-UPDRS question 1.1 or the general complaint question (Table 6). Similarly, there was no significant difference in mean change of z-score within any cognitive domain or the global z-score across groups defined by scores of 0, 1, or ≥2 reflecting the number of complaints for the NBI-subject and NBI-close contact at baseline. A detailed relationship between cognitive complaint assessments and change of z-score within cognitive tests at 1-year follow-up has been provided (Supplementary Table, Supplemental Digital Content 1, http://links.lww.com/WAD/A217).
Relationship Between Apathy and Conversion to PD-MCI/PDD at 1 Year
The ORs for conversion to PD-MCI/PDD at 1 year was 1.71 and at 2 years was 2.92. Neither of these was statistically significant as the P-value were 0.34 and 0.11, respectively. The ORs are suggestive of a relationship that would be in agreement with prior reports. The lack of statistical significance may be related to sample size/power.
In contrast, there was a weak positive correlation between the number of cognitive complaints (according to MDS-UPDRS Q1.1 and NBI-subject) and the apathy score (r 0.224 and 0.306, respectively).
In the present study, we reviewed different methods of eliciting cognitive complaints and changes in cognitive performance over a period of 2 years. We found that agreement between 4 methods of eliciting SCCs was low. The close contact report of subjective complaints had no significant agreement with any of the patient-reported measures. Although this alone cannot suggest whether the close contact’s report is more or less accurate than the subject’s, it may suggest that a close contact’s report is substantially different from that of the subject. It also suggests that physicians should not rely solely on a patient’s report of SCCs, but rather should also consider interviewing a close contact to the patient about cognitive changes.
Although we found little agreement between methods of eliciting a cognitive complaint, we were unable to identify the “best” method of eliciting a SCC. When comparing types of SCC to cognitive testing, MDS-UPDRS Question 1.1 and the NBI-close contact both had statistically significant correlations with at least some neuropsychological testing domains, but correlations were generally weak. Only the MDS-UPDRS Question 1.1 had a statistically significant association with PD-MCI diagnosis at baseline (where MCI was diagnosed without the criterion of a SCC). When considering the prognostic value of SCC for development of cognitive impairment, no method of eliciting a SCC was significantly associated with such progression over time.
Our finding that SCC in PD-CN and PD-MCI subjects is not predictive of cognitive progression over time has also been observed in various other studies.20–23 Although prior studies have suggested that poor predictive value of SCCs could relate to the confounding effect of depression,24–25 our study excluded patients with significant depression at baseline (as measured by the GDS-15).8 Some studies suggest that MCI patients may not complain because they are unaware of their deficits26 and that these subjects are more likely to convert to dementia than patients who are aware of their deficits.27 Had our patients lacked self-awareness and therefore, underreported SCC, one might consider that the close contact should be aware of cognitive changes if they were indeed present. However, SCC from close contacts were not associated with cognitive progression in our patient sample. Although we and others have found no clear relationship between SCC and cognitive progression, there are other reports that have demonstrated a strong correlation between subjective memory complaints and future cognitive decline in PD and non-PD populations.28–30 In fact, a recent study showed that subjective memory complaints among women can indicate impaired higher-level functional capacity and may suggest higher 1 year mortality rates.31 Given our finding of poor correlation between different methods of eliciting SCCs, it is possible that the conflicting reports in the literature may relate in part to the methods used for eliciting cognitive complaints. However, we found no clear difference across methods ranging from a yes/no question to a more structured rating scale. Our study was one of the few in which a detailed neuropsychological assessment was performed for the participants. This further strengthened the results and the conclusions of our study. With increasing recognition of different subtypes of MCI, these subtypes may also be important.
Limitations of our study include the fact that to date, we only have 2 years of follow-up and that the number of patients following up has decreased over time. This is particularly important as it is likely that patients have dropped out for nonrandom reasons including both motor and cognitive progression of their PD. Another interesting avenue of investigation to understand the biological relevance of cognitive complaints could be to correlate them with structural and/or functional imaging.
Although these are important considerations, the use of 4 different methods of eliciting SCCs concurrently is unique, and long-term follow-up with a comprehensive neuropsychological battery, are clear strengths of our study. Our findings provide insight into a poorly understood area that has considerable significance for the diagnosis of MCI. We demonstrated that many subjects had cognitive deficits in the absence of cognitive complaints, which supports the new established diagnostic criteria for MCI in PD patients that do not require a complaint on the part of the caregiver or patient, if observed by the clinician. Our findings also have clinical implications, as there was no correlation found between SCCs and cognitive impairment, PD-MCI can be missed if relying on complaints to trigger a cognitive assessment. Administering a cognitive tool on an annual basis might be beneficial to screen for MCI regardless of the presence or absence SCCs. Recently the Montreal Cognitive Assessment (MoCA)32 has been shown to be a reliable tool in evaluating cognitive decline in early PD.
The low level of agreement between different methods of eliciting a SCC from both subjects and close contacts, and the lack of association between these complaints and both current and future measures of cognitive impairment, call into question the value of SCCs in definitions of PD-MCI or PDD.
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cognitive complaint; mild cognitive impairment; Parkinson’s disease
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