DOI: 10.5061/dryad.hqbzkh1g2
title: Supplemental Materials Eikelboom et al. Neuropsychiatric and cognitive symptoms across the Alzheimer's disease clinical spectrum

description: The objective of this study was to investigate the
 prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation
 to cognitive functioning in a cohort of amyloid-β positive individuals
 across the Alzheimer’s disease (AD) clinical spectrum. In this
 single-center observational study, we included all individuals who visited
 the Alzheimer Center Amsterdam and had 1) a clinical diagnosis of
 subjective cognitive decline (SCD), mild cognitive impairment (MCI), or
 probable AD dementia, and 2) were amyloid-β positive (A+). We measured NPS
 with the Neuropsychiatric Inventory (NPI), examining total scores and the
 presence of specific NPI domains. Cognition was assessed across five
 cognitive domains and with the MMSE. We examined trajectories including
 model based trends for NPS and cognitive functioning over time. We used
 linear mixed models to relate baseline NPI scores to cognitive functioning
 at baseline (whole-sample) and longitudinal time-points (subsample n=520,
 Mean=1.8 [SD=0.7] years follow-up). We included 1,524 amyloid-β positive
 individuals from the Amsterdam Dementia Cohort with A+ SCD (n=113), A+ MCI
 (n=321), or A+ AD dementia (n=1,090). NPS were prevalent across all
 clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia;
 ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia).
 Cognitive functioning showed an uniform gradual decline; while in
 contrast, large intra-individual heterogeneity of NPS was observed over
 time across all AD groups. At baseline, we found associations between NPS
 and cognition in dementia that were most pronounced for NPI total scores
 and MMSE (range β=0.18 to 0.11, FDR-adjusted p&lt;0.05), while there
 were no cross-sectional relationships in SCD and MCI (range β=-0.32 to
 0.36, all FDR-adjusted p&gt;0.05). There were no associations between
 baseline NPS and cognitive functioning over time in any clinical stage
 (range β=-0.13 to 0.44, all FDR-adjusted p&gt;0.05). NPS and
 cognitive symptoms are both prevalent across the AD continuum, but show a
 different evolution during the course of the disease.
description: We included all patients who visited Alzheimer Center Amsterdam
 between June 2002 and December 2017 and had 1) a clinical diagnosis of
 subjective cognitive decline (SCD), mild cognitive impairment (MCI), or
 probable Alzheimer's disease (AD) dementia, 2) were
 amyloid-<em>β</em> positive, and 3) had NPI and
 neuropsychological assessment available at baseline. This resulted in a
 total of 1,524 individuals of which 113 participants had a 64 clinical
 diagnosis of SCD, 321 participants with MCI, and 1,090 participants with
 AD 65 dementia at baseline. A subsample of the participants had follow-up
 assessments available: n=53 (46.9%) with 68 A+ SCD at baseline, n=142
 (44.2%) with A+ MCI at baseline, and n=325 69 (29.8%) with A+ AD dementia
 at baseline. We compared baseline clinical
 characteristics, neuropsychiatric symptoms (NPS) prevalence, and cognitive
 performance across the diagnostic groups using ANOVA (with Tukey’s HSD
 post hoc test) or Chi-squared tests where appropriate.<br> We
 plotted individual trajectories of NPS and cognitive functioning over time
 according to disease stage and added model based trends with 95%
 confidence intervals to the graphs for descriptive purposes. In addition,
 we investigated the extent to which NPS and cognitive functioning changed
 over time within individuals (intra-individual variance) and between
 individuals (inter-individual variance). To quantify the variation within
 and between individuals, we conducted multilevel null models to obtain the
 percentage variance explained by intra-variance and inter-variance for
 neuropsychiatric measures and cognitive measures over time. For these
 analyses, the continuous severity x frequency scores (0-12) of specific
 Neuropsychiatric Inventory (NPI) domains were used.<br> To study
 associations between baseline NPS and cognitive functioning at baseline
 and over time, we performed linear mixed models (LMMs) including random
 intercepts and fixed slopes that were corrected for age, sex, and
 education. Determinants included the NPI total score and the presence of
 specific NPI domains. Outcomes were performance on the MMSE and the five
 predefined cognitive domains. LMMs were run separately for the clinical
 stages at baseline (i.e. SCD, MCI, dementia). We tested non-linear
 associations using LMMs with quadratic and cubic splines and selected
 linear LMM for all models based on the Likelihood-Ratio Chi-Squared Test
 and Akaike information criterion.<br> We checked assumptions by
 visual inspection of standardized residuals scatterplots and Q-Q plots. As
 normality of cognitive scores slightly deviated in language and
 visuospatial abilities most pronounced in A+ SCD, we conducted sensitivity
 analyses using a bootstrap procedure with 200 bootstrap samples to
 calculate confidence intervals. This approach did not change the initial
 findings.<br> Level of significance was set
 at <em>p</em>&lt;0.05. Yet, the post-hoc analyses on the
 NPS prevalence rates and the LMMs to study associations between NPS and
 cognitive performance were corrected for multiple testing using the
 Benjamin-Hochberg adjusted false discovery rate (FDR) of 0.05. Analyses
 were performed using <em>SPSS</em> version 26.0
 and <em>R</em> version 4.0 (<em>lme4, splines, lmerTest,
 effectsize</em>, and <em>boot</em> packages).
description: Data not provided in the article and additional information on
 methods and materials can be shared upon reasonable request.