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Biweekly fluctuations of neuropsychiatric symptoms according to the Neuropsychiatric Inventory: Erratic symptoms or scores?

Abstract Objectives This study investigates the stability of neuropsychiatric symptoms (NPS) assessed biweekly using the Neuropsychiatric Inventory (NPI) in a memory clinic population during a 6 week period. Methods Twenty‐three spousal caregivers (mean [SD] age = 69.7 [8.8], 82.6% female) of 23 patients (43.5% had dementia) completed all assessments. The NPI was assessed four times during 6 weeks. We examined whether NPI domains were present during all four assessments, studied within‐person variation for each NPI domain, and calculated Spearman's correlations between subsequent time‐points. Furthermore, we associated repeated NPI assessments with repeated measures of caregiver burden to examine the clinical impact of changes in NPI scores over time. Results The course of NPS was highly irregular according to the NPI, with only 35.8% of the NPI domains that were present at baseline persisted during all 6 weeks. We observed large within‐person variation in the presence of individual NPI domains (61.3%, range 37.5%–83.9%) and inconsistent correlations between NPI assessments (e.g., range r s = 0.20–0.57 for agitation, range r s = 0.29–0.59 for anxiety). Higher NPI total scores were related to higher caregiver burden (r s = 0.60, p < 0.001), but changes in NPI total scores were unrelated to changes in caregiver burden (r s = 0.16, p = 0.20). Conclusions We observed strong fluctuations in NPI scores within very short time windows raising the question whether this represents erratic symptoms and/or scores. Further studies are needed to investigate the origins of these fluctuations.


| INTRODUCTION
Neuropsychiatric symptoms (NPS) such as depression, apathy, agitation, and sleep disturbances are frequently observed in individuals who visit the memory clinic. 1,2 These symptoms have a major impact on the lives of patients and their caregivers and are associated with increased caregiver burden. [3][4][5] The Neuropsychiatric Inventory (NPI) is considered the gold standard to assess NPS in neurocognitive disorders. 6 Previous studies that examined the course of NPS using the NPI have shown large within-person variability in the progression of NPI scores when administering the NPI every 6-12 months. 1,[7][8][9] It remains unclear whether there is also such within-person heterogeneity in longitudinal NPI scores when measured during shorter time intervals, for example, within weeks instead of months. 7 Although several studies have administered the NPI twice within a timeframe of 2-3 weeks to establish the test-retest reliability of the NPI, 10 knowledge on short-term trajectories of NPS according to repeated NPI assessments is lacking.
Here, we describe the stability of NPI scores over a period of 6 weeks in a memory clinic population. During this 6 week period, the NPI was administered biweekly in order to compare our findings with previous test-retest studies that have assessed the NPI within a similar timeframe. [11][12][13] Furthermore, we compared the trajectories of NPI scores with repeated measures of caregiver burden. NPS is a well-known contributor to caregiver burden. [3][4][5] Therefore, we included a measure of caregiver burden to examine the clinical impact of short-term changes in NPI scores. Based on previous testretest studies, 10 we hypothesized stable NPI scores over time for apathy and psychotic symptoms, while we expected less stable NPI scores for affective symptoms, agitation-related behaviors, and sleep disturbances.

| Study design and participants
We invited all caregivers of patients who visited the memory clinic of the Erasmus MC in Rotterdam, the Netherlands, between June 2020 and July 2020, and between November 2020 and January 2021, to participate in this study. We included participants regardless of clinical diagnosis and presence/severity of NPS at baseline, with the only requirement that caregivers had to live with the patient. All patients underwent a standard diagnostic workup including medical history taking, neurological examination, neuropsychological assessment, and brain MRI. Clinical diagnoses were established using conventional diagnostic criteria during a multidisciplinary meeting.

| Measures
The Dutch NPI and Dutch Caregiver Strain Index (CSI)-Expanded were administered in person to caregivers during the initial the memory clinic visit. 14,15 During the 6 weeks that followed, the NPI and CSI-Expanded assessments were repeated every 2 weeks by telephone. Caregivers evaluated the presence, frequency (0-4), severity (0-3), and distress (0-5) of NPS in the previous 2 weeks. NPI domain scores were calculated by multiplying the frequency and severity scores (0-12). The presence of specific NPI domains was defined as an NPI domain score of ≥1. We summed the 12 NPI domain scores to obtain the NPI total score (0-144). 14 The Dutch CSI-Expanded was used to assess caregiver burden. This instrument covers aspects of caregiver strain (13 items) and aspects of caregiving that may decrease burden (5 items), resulting in a total score ranging between −5 and 13. 15

| Data analysis
We examined the prevalence of specific NPI domains at baseline and its persistence. NPI domains were persistent if they were present on all four assessments. For each NPI domain, we described the between-person variation (i.e., how many individuals had an NPI domain score of ≥1 at least once) and the within-person variation (i.e., total number of assessments in which NPS were present in individuals who had an NPI domain score of ≥1 at least once, with both 0% and 100% indicating no variation). 8 For each NPI domain, we conducted Spearman's correlations to examine the relationship between NPI domain scores on subsequent time-points (baseline-t1, t1-t2, t2-t3). Individual trajectories of NPI domain scores over time were plotted for descriptive purposes, but not analyzed at grouplevel.
We correlated NPI total scores with CSI-Expanded total scores across all time-points. Next, we calculated delta scores for NPI total scores and CSI-Expanded total scores for each time-point and associated these delta scores using Spearman's correlations.
To examine the effects of cognitive status, we conducted exploratory analysis in which prevalence, persistence, betweenperson variation, within-person variation, and Spearman's correlations between NPI domain scores were performed for patients with dementia and patients with cognitive impairment no dementia (CIND) separately.

| Ethics
This study received ethical approval from the Medical Ethics Committee of the Erasmus University Medical Center (MEC-2020-0341).
All participants gave informed consent.

| Study participants
A total of 26 caregivers agreed to participate in this study. There were three drop-outs during the study due to perceived burden (n = 1), acute health problems of the caregiver (n = 1), and loss of contact (n = 1). All analyses were conducted in the 23 caregivers who completed all assessments (Table 1). Caregivers had a mean age of 69.7 (SD = 8.8), 82.6% were female, and all were spouses. The patients had a mean age of 72.8 (SD = 8.2) and 21.7% were women.
Most patients were diagnosed with dementia (n = 10, 43.5%), eight individuals had CIND (34.8%), and four patients had no evidence of cognitive impairment (17.4%). A clinical diagnosis could not be determined in one individual (4.3%). Two patients (8.7%) were on a stable dose of psychotropic medications, while Escitalopram was prescribed during study period in only one patient (4.3%). A cognitive enhancer was prescribed during the 6 week period for two patients (8.7%).

| Prevalence and course of NPS according to the NPI
At baseline, all caregivers indicated the presence of at least one NPS [mean number of NPI domains was 3.0 (range 1-6)], with a mean NPI total score of 12.3 (SD = 9.5). Irritability (56.5%), sleep disturbances (47.8%), and depression (42.3%) were most common at baseline (  Table S2).  Table S1). NPI total scores correlated significantly between time-points (range r s = 0.55-0.67,  and several NPI domain scores (see Table S3).
We considered the presence of sleep disturbances, irritability, and aberrant motor behavior to be most stable, while the presence of hallucinations, disinhibition, and anxiety were the least stable within persons ( Table 2). When present, we considered the severity/frequency of apathy, sleep disturbances, and euphoria most stable, while depression, anxiety, and hallucinations were the least stable ( Figure 1 and Table S1).

| Data associations between NPI scores and caregiver burden
Across all time-points, higher NPI total scores were related to higher caregiver burden (r s = 0.60, p < 0.001). However, changes in NPI total scores were unrelated to changes in caregiver burden (r s = 0.16, p = 0.20).

| DISCUSSION
This study shows that NPI scores at one time-point in a memory clinic sample are poorly related to NPI scores administered only 2 weeks later. Our findings provide further evidence for the large variability of NPI scores within individuals with neurocognitive disorders. 1,[7][8][9] When looking at specific NPI domains, we found lowest stability over time for anxiety, hallucinations, depression, and disinhibition, which is in line with prior test-retest studies. [10][11][12][13] Our findings extend previous studies by looking at trajectories over a period over several weeks compared to the commonly examined (bi)annual NPI assessments. 1,[7][8][9] The large within-person variation in NPI scores could reflect substantial fluctuations in the manifestation of NPS in patients visiting the memory clinic. Previous studies that have used diaries to daily assess NPS in dementia suggested a rather erratic nature of NPS. [16][17][18] This is in line with the growing body of evidence emphasizing the role of proximal causes of NPS including psychosocial factors (e.g., caregiver burden, caregiver communication style), environmental factors (e.g., light, temperature), and somatic conditions (e.g., pain, thirst). 17,19 Alternatively, the irregular course of NPI scores could also arise from methodologic issues related to the NPI.

| Strengths and limitations
Strengths of this study are the inclusion of a representative tertiary memory clinic sample consisting of various clinical diagnoses and the

| Conclusions
This study suggest highly unstable NPI scores when assessed at 2- week intervals. These findings question the reliability of NPI scores when administered at short-term intervals at the memory clinic, but also as outcome measure in trails that evaluate the effectiveness of (non)pharmacological interventions, especially for those who do not meet diagnostic criteria for dementia (i.e., CIND). Further studies are needed to investigate whether the large within-person variability of NPI scores reflect the erratic nature of NPS in neurocognitive disorders or arise from methodological issues. Although the origin of these fluctuations remains unclear, memory clinic clinicians should be aware that NPI scores at one time point are poorly related to future NPI scores within a timeframe of weeks.

AUTHOR CONTRIBUTIONS
Willem S. Eikelboom designed the study, analyzed the data, and wrote the paper. Amy den Teuling collected the data and assisted with writing the paper. Daphne E. Pol collected the data and assisted with writing the paper. Michiel Coesmans assisted with writing the paper. Sanne Franzen collected the data and assisted with writing the paper. Lize C. Jiskoot collected the data and assisted with writing the paper. Judy van Hemmen collected the data and assisted with writing the paper. Ellen Singleton assisted with writing the paper. Rik Ossenkoppele assisted with writing the paper. Frank Jan de Jong assisted with writing the paper. Esther van den Berg designed the study and assisted with writing the paper. Janne M. Papma designed the study, supervised the study, and assisted with writing the paper.