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Cognitive profiles of patients with mild cognitive impairment due to Alzheimer's versus Parkinson's disease defined using a base rate approach: Implications for neuropsychological assessments

Abstract Introduction Large studies on cognitive profiles of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD‐MCI) compared to Parkinson's disease (PD‐MCI) are rare. Methods Data from two multicenter cohort studies in AD and PD were merged using a unified base rate approach for the MCI diagnosis. Cognitive profiles were compared using scores derived from the Consortium to Establish a Registry for Alzheimer's Disease battery. Results Patients with AD‐MCI showed lower standardized scores on all memory test scores and a language test. Patients with PD‐MCI showed lower standardized scores in a set‐shifting measure as an executive task. A cross‐validated logistic regression with test scores as predictors was able to classify 72% of patients correctly to AD‐MCI versus PD‐MCI. Discussion The applied test battery successfully discriminated between AD‐MCI and PD‐MCI. Neuropsychological test batteries in clinical practice should always include a broad spectrum of cognitive domains to capture any cognitive changes.


INTRODUCTION
Cognitive decline is common in both Alzheimer's disease (AD) 1

and
Parkinson's disease (PD), 2 representing the two most frequently occurring neurodegenerative disorders associated with older age. Several studies have revealed differential patterns of cognitive deficits between patients with AD compared to patients with PD, which is thought to reflect differential neuropathological processes. Memory deficits rather depend on cortical dysfunctions, which are typically associated with the AD pathology, 3 whereas fronto-striatal dysfunctions resulting in the impairment of executive function, working memory, and attention rather depend on dopaminergic imbalances, which are typically associated with PD. 4,5 However, according to the dual syndrome hypothesis regarding cognitive impairment in PD, 4,5 cognitive deficits in PD are highly heterogeneous. Some patients may display an "Alzheimer-typical" pattern, associated with prominent amnestic dysfunctions, and possibly associated with a higher risk of the progression of cognitive decline to dementia. 6 To date, only a few studies have provided direct comparisons between AD and PD samples across different levels of cognitive impairment. [7][8][9][10][11][12][13] Overall, the expected cognitive patterns have been confirmed, with more severe levels of cognitive impairment identified in AD compared to PD, and memory and language deficits were particularly more pronounced in patients with AD compared to those in patients with PD. In PD, the observed deficits were more severe in executive, attentional, and visuo-cognitive tasks. [7][8][9][10][11][12][13] One limitation of these prior publications has been the rarity of biomarker-based etiological AD diagnoses. Furthermore, existing studies comparing the two etiologies during the mild cognitive impairment (MCI) stage (AD-MCI vs. PD-MCI) have been based on relatively small or strongly imbalanced sample sizes. [11][12][13] Particularly, the PD-MCI samples tended to be very small (13 ≤ n ≤ 41). [11][12][13] Another limitation associated with existing comparisons during the MCI stage has been the use of inhomogeneous MCI criteria across AD-MCI and PD-MCI samples within one study; 12 for example, differences in the cutoff scores applied for impaired cognitive test performance (e.g., ≤ −1 standard deviation [SD] vs. ≤ −1. 5 SD) and differences in the numbers of impaired tests required to diagnose objective cognitive impairment (e.g., 2 vs. 1) have been reported. Therefore, the observed differences might be at least partially due to divergent MCI criteria rather than differences in etiologies.
One method for overcoming this problem may be the application of a base rate approach to the neuropsychological definition of MCI. [14][15][16][17][18][19] This approach recognizes that cognitive variability among healthy older adults can result in low test scores when multiple tests are administered, even in the absence of any clinically relevant objective cognitive impairment. 14 The most common base rate approach described in the literature is to diagnose MCI, when the number of cognitive tests on which impaired performance is shown equals or exceeds the number of cognitive tests on which impaired performance is shown by the worst-performing 10% of a non-impaired control group, as defined by established diagnostic criteria. [14][15][16][17][18][19] So far, to the authors' best knowledge, the base rate approach has only been applied in the AD context but has never been used across different etiologies.
Differential cognitive profiles associated with the two different etiologies might strongly influence diagnostic accuracy when applying neuropsychological screening instruments or test batteries. For example, the well-established Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery 20 may fail to capture relevant changes in PD-specific fronto-striatal cognitive functions. Those functions tend to be underrepresented in the CERAD test battery, which features a substantial majority of subscores designed to represent amnestic functions (e.g., Word List Learning, Recall, and Recognition; Figure Recall and Savings). In German-speaking countries, the augmentation of the original CERAD test battery 20 has been suggested through the inclusion of additional subtests designed to assess processing speed and executive functions. The resulting CERAD-Plus test battery 21,22 has been demonstrated to display strongly improved diagnostic accuracy for identifying dementia associated with non-AD etiologies. 21

Patients
Baseline data of patients with AD-MCI were obtained from the DCN study, 23 14 severely cognitively impaired patients did not complete the TMT subtests. Therefore, we substituted missing values for the TMT-A and TMT-B using the lowest possible value (TMT-A: 180 seconds, TMT-B: 300 seconds) to ensure a non-random penalty for the non-completion of these subtests.

Clinical and neuropsychological assessment
The details regarding the diagnostic procedures of the DCN 23 and the DEMPARK/LANDSCAPE study 24 have been described previously. For both studies, in addition to other tests, the CERAD test battery 20,22 extended by TMT-A and TMT-B was applied, resulting in 12 test scores obtained from nine tests: the Boston Naming Test (BNT), Figure

Definition of MCI
In the initial datasets, MCI was diagnosed according to the established diagnostic criteria for MCI at the time of each respective study design. 25,28 However, the neuropsychological tests used, the definition of cognitive domains considered relevant for MCI diagnosis, the cutoff scores that were used to define impaired test performance (≤ -1 SD vs. ≤ −1.5 SD), and the numbers of impaired tests that were considered necessary to diagnose objective cognitive impairment (2 vs. 1) differed between the two studies.

Standard protocol approvals, registrations, and patient consents
The underlying study protocols were conducted in compliance with the World Medical Association Declaration of Helsinki. The study protocol for the DCN study 23   a Presence of at least mild depressive symptoms as indicated by a MADRS sum score > 6 in the AD-MCI sample and a GDS score > 5 in the PD-MCI sample.

Statistical analysis
for age, sex, and education using published normative data for the CERAD. 22

Demographic and clinical characteristics
Patients with AD-MCI and patients with PD-MCI did not significantly differ in terms of age or total years of education. Whereas the sex ratio was balanced in the AD-MCI sample, there were significantly more men than women in the PD-MCI sample. The prevalence of depressive symptoms according to the respective cutoff criteria for the applied screening tools was higher among patients with AD-MCI than among patients with PD-MCI. Compared to patients with AD-MCI, patients with PD-MCI showed higher scores for the MMSE and CERAD total score. For further details, see Table 2.

Cognitive profile comparison
Descriptively, the scores for patients with AD-MCI were lower than those for patients with PD-MCI for all subscores except for Figure   Copy Table 3 and Figure 2.   Comparing the frequencies of patients with impaired test performance, as defined by a performance of ≤ −1.5 SD below the mean of published normative data for each test score, significant differences were only observed for Figure Savings and Word List Recall, indicating that significantly more patients with AD-MCI were impaired than patients with PD-MCI. Further details can be obtained from Table 3.

Logistic regression
The logistic regression analysis for predicting the etiological diagnosis using the 12 CERAD subscores as predictors is displayed in

DISCUSSION
The present analyses aimed to outline the differential cognitive profiles AD-MCI and PD-MCI using a large dataset of patients and applying a uniform MCI definition. We found that (1)  Notes: Based on using the z-scores (lower score = less performance) and dummy-coding of the dependent variable (AD = 0, PD = 1), results can be interpreted as follows: For scores with a significant odds ratio > 1, lower z-score performance is predictive (i.e., associated with an increased likelihood) for belonging to the AD group, for scores with a significant odds ratio < 1 lower z-score performance is predictive for belonging to the PD group. In the initial datasets, the neuropsychological MCI diagnosis was based on several different parameters. 23,24 In this context, cutoff scores for impaired test performance and the numbers of impaired tests required to diagnose objective cognitive impairment strongly influenced the identified prevalence of MCI in each cohort. To ensure a valid profile comparison that is not built on diverging MCI criteria, we aligned the neuropsychological MCI definition across the AD-MCI and PD-MCI samples by applying a novel albeit more conservative base rate approach. [14][15][16][17][18][19] The applied cutoff of ≥ three tests with scores ≤ −1.5 SD was stricter than the criteria for objective cognitive impairment in established criteria for the MCI diagnosis. 25 Overall, we were able to confirm our hypotheses regarding the existence of differential cognitive profiles between AD-MCI and PD-MCI.
The cross-validated logistic regression model was able to classify 72% of patients correctly in the testing datasets, which were not used to train the model. This indicates that the neuropsychological profiles based on cognitive test scores that were included in the model substantially differed between AD-MCI and PD-MCI, suggesting that our model might be valid beyond the training datasets. The 28% misclassification rate may be due to the significant overlap in amnestic dysfunctions between patients with AD-MCI and PD-MCI that may occur during the transition from PD-MCI to PD dementia. Furthermore, due to the heterogeneity of cognitive decline reported among PD patients, some patients with PD-MCI may display rather "AD-typical" cognitive profiles during early disease stages. 6 As expected, [11][12][13]   for global cognition, and the cross-validation procedure used for the logistic regression analysis. Additionally, this study only included those patients with AD-MCI that were supported by a biomarker-based AD profile. 26 Another strength of this profile comparison was that all test scores were standardized using published normative data correcting for age, sex, and education. 22 Accordingly, the results of the reported cognitive profile comparison can be considered to be valid despite etiology-dependent observed (and expected) differences in sex distribution that may otherwise bias cognitive outcomes.
In conclusion, patients with AD-MCI were more impaired in measures of memory and language, whereas patients with PD-MCI were more impaired in a measure of executive function. Furthermore, we found some evidence that similar levels of impairment in one cognitive test might be attributable to differential underlying mechanisms, reflecting the differential influence of contributing cognitive functions.
Future data-driven approaches may be able to shed further light on this aspect. Finally, neuropsychological test batteries in clinical practice should include a broad spectrum of cognitive domains to capture any cognitive changes.

ACKNOWLEDGMENTS
The authors thank all patients participating in the two studies and all staff members in the recruiting centers who contributed to the study.

DATA AVAILABILITY STATEMENT
The data are available from the corresponding author upon reasonable request. Desitin GmbH, outside the submitted work.