Participants
A retrospective, longitudinal, and observational study was conducted at Seoul National University Bundang Hospital in the Republic of Korea. We included participants from January 2013 and August 2020 who met the following inclusion criteria: (1) a diagnosis of MCI according to Petersen’s criteria [5], (2) a Clinical Dementia Rating (CDR) score of 0.5 at baseline assessment [6], (3) patients with a 1-year follow-up including a neuropsychological assessment, and (4) those who underwent amyloid positron emission tomography (PET) within 6 months before or after the baseline cognitive assessment. Those who had a positive amyloid PET scan more than 6 months before the baseline cognitive assessment and those who had a negative amyloid PET scan more than 6 months after the 1-year follow-up cognitive assessment were also included. Among a total of 50 patients included for the analysis, 27 participants underwent amyloid PET outside the 6-month window. The time window of the 27 participants ranged from 24 months before to 10 months after the baseline cognitive assessment. The median value was 13 months before the baseline cognitive assessment.
This study design was approved by the Institutional Review Board of Seoul National University Bundang Hospital (B-2006/618-109).
Data collection
Demographic information such as age, sex, educational level, and APOE genotype was collected from the participants. Neuropsychological assessment results at baseline and a 1-year follow-up visit and amyloid PET results were obtained. Use or non-use of ChEIs during the follow-up period after baseline cognitive assessment and the types and dosages of ChEIs prescribed to each user were investigated.
Cognitive evaluation
We assessed the global cognitive status with the Mini-Mental State Examination (MMSE) [7], dementia severity with CDR Sum of Boxes (CDR SOB), and depressive symptoms with the short form of the Geriatric Depression Scale (GDpS) [8]. Additionally, extensive neuropsychological assessments were performed to evaluate attention, language, verbal and visual memory, visuoconstructive function, and frontal executive function. We used the Digit Span Test for attention [9], the Korean version of the Boston Naming Test for language [10], the Seoul Verbal Learning Test for verbal memory [11], the Rey Complex Figure Test (RCFT) for visuoconstructive function and visual memory [12], the categorical and phonemic fluency test of the Controlled Oral Word Association Test [13], and the Stroop color reading test for executive function [14]. For statistical analysis, MMSE, CDR SOB, and GDpS scores were used as raw scores. The scores for specified neuropsychological tests were converted to standardized scores (z-scores), which were adjusted for age, sex, and educational level.
Amyloid burden
Amyloid burden was evaluated by amyloid PET. [18F]Florbetaben (n = 105), [18F]flutemetamol (n = 4), and [18F]florbetapir (n = 2) were used as ligands. Amyloid status was dichotomized as positive (abnormal) or negative (normal) after visual assessment by one experienced nuclear medicine physician and two neurologists.
Statistical analysis
To minimize treatment selection bias and the difference in baseline characteristics between ChEI users and non-users, propensity score matching analysis was conducted. Propensity scores were calculated through logistic regression [15] with covariates such as the baseline MMSE score, age, educational level, amyloid PET positivity, and CDR SOB using the Matchit packages in R. ChEI users and non-users were paired 1:1 based on these propensity scores with a caliper size of 0.2.
Demographics and clinical characteristics between groups of unmatched and matched sets were compared with Student’s t test, the Mann-Whitney U test, or the chi-squared test as appropriate. Cognitive assessment at baseline between groups of matched sets was compared using Student’s t test or the Mann-Whitney U test.
Linear regression analysis was performed to assess the influence of ChEI use or non-use on cognitive change for 1 year. The independent variable was group (ChEI user vs ChEI non-user), and the dependent variable was the difference between the 1-year cognitive test score and the baseline cognitive test score. The GDpS scores were reported as raw scores. For the MMSE analysis, age, sex, and educational level were adjusted. The z-scores of the remaining cognitive tests were already adjusted for age, sex, and educational level. Additionally, the multiple linear regression analysis included the amyloid PET scan result as a covariate to evaluate the effect of amyloid burden on the interaction between ChEI use/non-use and cognitive change for 1 year.
Univariate and multivariate logistic regression analyses were performed to investigate the associations among ChEI use/non-use, amyloid burden, and disease progression to CDR 1 at a 1-year follow-up visit.
All statistical analysis was performed using R (version 4.0.0). Statistical significance was set at < 0.05.