Neuropsychiatric Symptoms Present Differently in Individuals with Different High-Risk States of Dementia

Authors: Alvin Keng, Daniel Kapustin, Clement Ma, Kathleen S. Bingham, Corinne E. Fischer, Linda Mah, Damien Gallagher, Meryl A. Butters, Christopher R. Bowie, Aristotle N. Voineskos, Ariel Graff-Guerrero, Alastair J. Flint, Nathan Herrmann, Bruce G. Pollock, Benoit H. Mulsant, Tarek K. Rajji, Sanjeev Kumar

Abstract

Introduction

Neuropsychiatric symptoms (NPS) are common in neurocognitive disorders. However, the differences in presentation of NPS in high-risk states for dementia such as mild neurocognitive disorder (Mild NCD) and remitted major depressive disorder (rMDD) remain unclear. The purpose of this study was to compare the frequency and factor structure of NPS in Mild NCD, rMDD, and Mild NCD with rMDD (Mild NCD-rMDD).

Methods

We analyzed baseline data from the multicenter Prevention of Alzheimer’s Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression trial (NCT0238667). NPS were assessed using the Neuropsychiatric Inventory Questionnaire in those with Mild NCD, rMDD, and Mild NCD-rMDD. We compared the NPS frequency and factor structure across the three groups.

Results

Among 374 participants with a mean (SD) age = 72.0 (6.3) years, the overall frequency of any NPS was highest in Mild NCD-rMDD (75.9%), as compared to Mild NCD (63.5%) or rMDD (55.7%) groups (p = 0.014). Depression/dysphoria was the most common NPS in all three groups. In factor analyses, NPS grouped into four factor structures in all three groups, but the composition of factors of individual symptoms (delusions, motor disturbances, nighttime behaviors, anxiety, and apathy) were different.

Conclusion

NPS are common in high-risk states of dementia, and the frequency of NPS is higher in Mild NCD-rMDD as compared to only Mild NCD or rMDD. Further, there are key differences in presentation of NPS in Mild NCD, rMDD, and Mild NCD-rMDD. Future studies should investigate the relevance of these differences for cognition, function, and disease biomarkers.

Introduction

Neuropsychiatric symptoms (NPS), also known as behavioral and psychological symptoms of dementia, are common in neurocognitive disorders including Alzheimer’s disease (AD) [1–3]. NPS are associated with adverse patient outcomes, such as decline in general health, quality of life, social isolation, as well as increased caregiver burden [4]. In a significant majority, NPS present well before development of dementia, and increase the risk for progression of mild cognitive impairment (MCI) to dementia [5–7]. For the purpose of this article, MCI is interchangeable with mild neurocognitive disorder (Mild NCD) as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [8]. NPS are highly heterogeneous, and include motor disturbances, disinhibition, hyperactivity, psychosis (including delusions or hallucinations), euphoria, affective symptoms (including depression, irritability, or anxiety), apathy, eating disturbances, and nighttime disturbances. Due to this heterogeneity, NPS can overlap considerably with primary psychiatric disorders. For example, affective NPS overlap with major depressive disorder (MDD), which is another well recognized high-risk state for cognitive decline and dementia [9]. In the DSM-5, MDD is an episodic psychiatric disorder; patients with active symptoms of a major depressive episode (MDE) are characterized differently from those with remitted MDD (rMDD) [8]. The heterogeneity and overlap pose challenges for the assessment and management of NPS in clinical practice, particularly in those with rMDD.

NPS rarely occur in isolation and usually have a high degree of overlap among themselves as well [2]. Exploratory factor analyses of NPS in AD and MCI have attempted to understand clustering of NPS to better characterize their phenomenology [10–12]. While certain symptoms cluster consistently together (delusions and hallucinations), there is variability in clustering of others (such as apathy, eating disturbances, and nighttime behaviors) depending on the cohort [10]. Despite this variability, identifying clusters of NPS that manifest together can help advance understanding about their biological underpinnings. Indeed, certain symptom clusters have been associated with specific brain lesion circuits [13] and with neuroimaging and disease biomarkers [14, 15]. For example, delusions, apathy, and depression as NPS have been associated with structural and functional changes in the anterior cingulate cortex [14]. Depression, as an NPS, has been associated with cerebrospinal fluid soluble intracellular cell adhesion molecule-1 (CSF sICAM-1), and changes in serum biomarkers such as interleukin-8 (IL-8), macrophage inflammatory protein 1β (MIP-1β), thymus and activation-regulated chemokine, and vascular endothelial growth factor D precursor. Anxiety, as an NPS, has been associated with changes in CSF C-reactive protein, and sICAM-1 [15]. Apathy, as an NPS, has been associated with CSF sICAM-1 [15]. Further, identifying phenomenology and grouping of NPS in high-risk states for dementia (such as Mild NCD or rMDD) could help in detection and management of these symptoms and to understand and mitigate risk of dementia. To our knowledge, phenomenology and grouping of NPS in Mild NCD with rMDD has not been studied before. In this study, we aimed to compare the frequency and factor structure of NPS among individuals with Mild NCD, rMDD, and comorbid Mild NCD and rMDD (Mild NCD-rMDD).

Methods

Overall Design and Participants

We obtained baseline data on participants enrolled in the Prevention of Alzheimer’s Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression (PACt-MD), a multicenter trial conducted across five academic sites in Toronto, Canada (clinical trial # NCT0238667). Details about PACt-MD study participant inclusion and exclusion criteria have been published previously [16]. For the current study, we analyzed 374 individuals with available NPS data. Participants belonged to one of three (1) individuals with a diagnosis of Mild NCD and no history of MDD (Mild NCD group), (2) individuals with normal cognition but with a history of MDD currently in remission (rMDD group), and (3) individuals with comorbid Mild NCD and rMDD (Mild NCD-rMDD group).

Assessments

The diagnosis of Mild NCD was made using clinical assessments and applying DSM-5 criteria [17]. Clinical assessments were conducted using the Montreal Cognitive Assessment (MoCA) [18], Mini-Mental State Examination (MMSE) [19], and a comprehensive neurocognitive battery that included tests of verbal and visual memory, language function, visuospatial ability, attention, and executive function were used to assess cognition [16]. The MoCA and the MMSE are widely used cognitive screening assessments but have different sensitivities based on participants’ level of education [20]. Regardless, all cognitive assessments were used to inform and confirm a consensus diagnosis of Mild NCD.

The diagnosis of rMDD was made using the Structured Clinical Interview for DSM-5 [21]. Study participants with rMDD have not met criteria for a major depressive episode in the last 2 months.

NPS were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q) [22]. The NPI-Q is an informant-based questionnaire made up of 12 symptom domains (apathy/indifference, delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, appetite/eating). Informants (e.g., spouse, adult child, other family member, close friend) were identified by the study participant and interviewed by research staff. Informants must select “yes” or “no” in response to a screening question for each symptom based on its presence in the last 4 weeks. The severity of each identified NPS is then assessed on a three-point scale (1-mild, 2-moderate, 3-severe). This study used the total severity score for each NPS category for factor analysis.

Other assessments included the Montgomery-Åsberg Depression Rating Scale (MADRS) [23], and Cumulative Illness Rating Scale for Geriatrics (CIRS-G) to assess medical illness severity [24], Modified Hachinski Ischemic Score (MHIS) to assess vascular risk [25], and Clinical Dementia Rating Scale (CDR) for cognitive and functional status [26].

Statistical Analyses

SPSS, version 29.0 (SPSS Inc), was used for all statistical analyses. The demographic and clinical characteristics of Mild NCD, rMDD, and Mild NCD-rMDD were compared. ANOVA was used to compare continuous variables across groups, and Pearson chi-square (Χ^2^) tests were used to compare categorical variables across groups. We employed a Fisher’s exact test for categorical variables where cell counts were less than 5. Bonferroni correction was applied for multiple comparisons. To identify the clustering of NPS, factor analysis was conducted using the total severity of each NPS on the NPI-Q. We used a principal component extraction method and conducted a varimax rotation using correlation matrices for each of the three groups. We also performed an oblique rotation for comparison and no difference was found between the varimax and oblique rotations. The number of components was identified using Kaiser’s correction of eigenvalues equal to or greater than 1, and values of less than 0.4 were suppressed from the matrix, following a similar approach [10]. The Kaiser-Meyer-Olkin (KMO) test was used to assess for sampling adequacy with the threshold value above 0.50 [27]. Bartlett’s test of sphericity was used to assess homogeneity of variances with a significance cutoff of p < 0.001.

Results

Participant Characteristics

Of 374 participants, 181 had Mild NCD, 106 had rMDD, and 87 had Mild NCD-rMDD. The details of the participant demographics and clinical characteristics are presented in Table 1. Demographics: The entire sample’s mean (SD) age was 72.0 (6.3) years. There was a significant difference in mean age between Mild NCD and rMDD (mean difference = 2.2 years, 95% CI: 0.4–3.9, p = 0.011) but not between other groups. The study population was 65.8% female, with no statistically significant differences in gender distribution across groups. The study population was 79.9% white, and there were statistically significant differences in ethnicity across groups (Fisher’s exact test = 19.95, p = 0.005). Most participants were married or in common-law relationships (50.3%), had children (75.1%), lived at home independently (98.9%), and had at least a high school education (90.1%), with no statistically significant differences across groups. There was no statistically significant difference between years of education among all three groups. The Mild NCD and Mild NCD-rMDD groups had lower mean scores on the MMSE and MOCA, and higher mean scores on the CDR when compared to the rMDD group. The rMDD and Mild NCD-rMDD groups had higher mean scores on the MADRS when compared to the Mild NCD group. There were no statistically significant differences for CIRS-G and MHIS scores between the three groups. These data are presented in online supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000547061).

Frequency of NPS

In the overall sample, 64.2% of participants had at least one NPS, and 36.1% had at least one NPS of moderate severity (score ≥2). There was a difference in frequency of any NPS between Mild NCD (63.5%), Mild NCD-rMDD (75.9%), and rMDD (55.7%) (Χ^2^ = 8.54, n = 374, p = 0.014). The frequencies for all individual NPS and their comparisons between the groups are presented in Table 2. The most frequently reported NPS among all participants was depression/dysphoria (37.2%), followed by irritability/lability (25.1%), and nighttime behaviors (17.9%). These three NPS were also the most frequently reported in the Mild NCD and rMDD groups. However, in the Mild NCD-rMDD group, depression/dysphoria was the most prevalent, followed by apathy/indifference. Hallucinations were not reported by any study participants.

Factor Analyses

The factor analyses for each group are presented in Figure 1. In summary, each group had a four-factor model based on eigenvalues and percentage of variance (see Tables 3–5 for details).

Mild Neurocognitive Disorder

The four factors explained 55.4% of the total variance in NPI-Q severity scores. Factor 1 (labeled as depression/apathy) included depression/dysphoria, nighttime behaviors, apathy/indifference, and appetite/eating, and explained 22.2% of the total variance. Factor 2 (labeled as irritability/disinhibition) included irritability/lability, disinhibition, and elation/euphoria, and explained 13.3% of the total variance. Factor 3 (labeled as delusions/agitation) included delusions and agitation/aggression and explained 10.6% of the total variance. Factor 4 (labeled anxiety/motor) included anxiety and motor disturbance, and explained 9.4% of the total variance.

Remitted Major Depressive Disorder

The four factors explained 55.7% of the total variance in NPI-Q severity scores. Factor 1 (labeled as depression/apathy) included depression/dysphoria, apathy/indifference, and appetite/eating and explained 20.0% of the total variance. Factor 2 (labeled as irritability/elation) included irritability/lability, and elation/euphoria, and explained 14.1% of the total variance. Factor 3 (labeled as anxiety/agitation) included anxiety, nighttime behaviors, disinhibition, agitation/aggression, and motor disturbance explained 11.1% of the total variance. Factor 4 (labeled as motor) included only motor disturbance, and explained 10.5% of the total variance.

Mild Neurocognitive Disorder-Remitted Major Depressive Disorder

The four factors explained 66.3% of the total variance in NPI-Q severity scores. Factor 1 (labeled as motor/disinhibition) included motor disturbance, disinhibition, and appetite/eating, and explained 31.9% of the total variance. Factor 2 (labeled as apathy/irritability) included apathy/indifference, irritability/lability, and nighttime behaviors, and explained 13.5% of the total variance. Factor 3 (labeled as delusions/elation) included delusions and elation/euphoria and explained 10.8% of the total variance. Factor 4 (labeled as anxiety/depression) included anxiety, depression/dysphoria, and agitation/aggression, explaining 10.1% of the total variance.

Discussion

The aims of our study were to compare the frequency and factor structure of NPS among different high-risk states of dementia such as Mild NCD, rMDD, and comorbid Mild NCD-rMDD. The frequency of any one NPS was 64.2% in our entire cohort; although high, this is in keeping with previously reported prevalence in adults with Mild NCD at 35–85% [2]. Our finding supports the existing literature that NPS are prevalent among individuals with Mild NCD [11, 12, 28–30]. Furthermore, our study adds to the literature by describing the frequency of NPS in patients with Mild NCD-rMDD; notably, this group had the highest frequency (75.9%) of any NPS in our study. In recent years, there has been increasing interest in the relationship between NPS and high-risk states of conversion to dementia [31]. History of MDD is a risk factor for progression to dementia [32] and a higher frequency of NPS in this group could be related to progression. Sociodemographic variables may also affect risk of progression to dementia. Although this was not established in our study, this would be an important consideration for future studies. For example, years of education, which may reflect cognitive reserve [33], could play a role in impacting the prevalence, severity, or clustering of NPS. Future studies should examine such relationships longitudinally and also determine whether effective treatment of NPS in this population reduces risk of dementia.

Depression/dysphoria was the most common NPS reported in the entire cohort and for each of the groups including the Mild NCD group. It is important to note that although participants with rMDD were included in our study, they were not in a current major depressive episode, and the participants in the Mild NCD group had no history of MDD. A depressed or dysphoric mood on the NPI-Q does not represent the full constellation of MDD. However, these depressive symptoms are a risk factor for progression to dementia [32]. Furthermore, depressive symptoms have been associated with greater atrophy in AD-affected brain regions, increased cognitive decline, and higher rates of progression to AD [34]. The significance of managing depressive symptoms in dementia prevention remains unclear and warrants future study. Prior research has supported that antidepressant treatment may have an impact on AD pathology at the molecular level and neuroprotective effects [35]. However, more research is needed on the clinical benefit of treating NPS that resemble but are subsyndromal for MDD [35]. NPS factor structures of depression/dysphoria may provide a future basis for case identification and selection for antidepressant treatment in AD. We also observed high frequencies of other NPS, such as irritability/lability, nighttime behaviors, and apathy/indifference. These NPS have also been linked to the progression to dementia [2, 31]. Furthermore, we observed a low frequency of psychotic symptoms (delusions) in the Mild NCD and Mild NCD-rMDD groups that is consistent with previous literature [12]. We observed no psychotic symptoms in rMDD group, which might suggest that psychotic symptoms, while less frequent in high-risk states for dementia, are more common in primary cognitive disorders as opposed to those with rMDD.

Lastly, we compared the factor structure of NPS in those with Mild NCD, rMDD, and Mild NCD-rMDD to investigate presentation of NPS in these groups. Delusions clustered differently across the three with agitation/aggression in Mild NCD, with elation/euphoria in Mild NCD-rMDD, and was not present in rMDD group. Our findings contrast with previous studies where delusions and hallucinations typically did not group with other NPS [11, 12]. This could have been due to the influence of rMDD on delusions or due to low frequency of delusions and hallucinations in our study participants.

Motor disturbance did not group with other NPS in rMDD; however, motor disturbance grouped with anxiety in Mild NCD and disinhibition in Mild NCD-rMDD. Furthermore, the motor/disinhibition factor explained most of the variance in NPS within the Mild NCD-rMDD group. In one prior study, motor disturbance was associated with non-amnestic MCI [28]. In another study, motor disturbance mapped with several other NPS, including depressive symptoms, anxiety, appetite and eating disturbances, and nighttime behaviors [12]. Our findings suggest a potential difference in the phenomenology of motor disturbance in Mild NCD patients with and without a history of MDD.

Nighttime behaviors also loaded differently in the factor structures for Mild NCD and rMDD. Although sleep disturbances have been known to play a role in both Mild NCD [36] and rMDD [37], it is possible that they may represent different syndromes in Mild NCD and rMDD. In a prior case-control study, sleep disturbances were strongly associated with MCI and a past diagnosis of MDD [38]; our study builds on this finding and bolsters our understanding that nighttime behaviors are important in high-risk states of dementia.

Similarly, anxiety grouped differently in Mild NCD, with motor disturbances, and Mild NCD-rMDD, with depression and agitation. In our study, we posit that differences exist with the quality and severity of anxiety in how it presents in patients with different high-risk states of dementia. Anxiety is known to be prevalent in MCI, and highly suspected to have an important relationship with cognition and other NPS; however, it remains poorly understood in comparison to other NPS [39]. The appearance of late-life anxiety symptoms warrants inquiry into the presence of Mild NCD or rMDD as risk factors for dementia.

Apathy grouped with depressive symptoms in our Mild NCD and rMDD groups but with irritability and nighttime behaviors in Mild NCD-rMDD. Apathy grouped separately from depressive symptoms in prior studies with Mild NCD [12], and interestingly, in early AD [10, 12], however, these studies did not include participants with a history of rMDD. Apathy alone and apathy comorbid with depressive symptoms have been associated with the progression of Mild NCD to AD in comparison to those without NPS [40]. Although apathy and depression can be challenging to distinguish from each other, they have been known to have independent and differential effects on function [41]. Our study adds to the current literature by distinguishing a distinct apathy/irritability cluster in the Mild NCD-rMDD group in comparison to Mild NCD and rMDD where it grouped with depression. Future studies should consider exploring the impact of this apathy cluster on functional outcomes.

Furthermore, some NPS grouped on multiple factor nighttime behaviors, apathy, and agitation/aggression for the Mild NCD group, and nighttime behaviors in the Mild NCD-rMDD group. Factors were generated based on where they loaded most strongly, and we used a similar approach as previous factor analyses [42]. Prior studies looking at NPS factor structures in Mild NCD also note that it is common for some NPS to cross-load on multiple factors, possibly indicating a shared mechanism for these NPS [12, 30].

A better understanding of NPS factor structures may improve our ability to diagnose and treat high-risk states of dementia. NPS have been associated with cognitive and functional impairment with validated tools to assess their diagnostic validity [6]. However, the importance of specific NPS or their groupings may confer different risks of progression among patients with cognitive impairment. In the literature on NPS in MCI, apathy and anxiety were more consistently associated with disease progression, in comparison to depression and sleep problems [1, 39]. We posit that a more sophisticated understanding of NPS clustering may improve risk stratification and management of MCI or early dementia. For example, depression/apathy, depression/anxiety, and depression/agitation clusters may signify different diagnoses and prognoses of neurocognitive disorders. Furthermore, therapeutic options in NPS remain limited, and while NPS resemble psychiatric disorders, they are not direct comparators. Current guidelines on treating NPS are limited in their recommendations; for example, recent practice guidelines acknowledge that outside of agitation, there are few high-quality studies to derive evidence-based recommendations [43]. We also posit that different NPS clusters may require different non-pharmacological or pharmacological approaches, as could be in depression/apathy in comparison to depression/agitation. Future studies can utilize these NPS structures and compare prognosis or response to therapeutic interventions.

This study has several limitations. First, the participants were from a research study cohort, and not from a population-based cohort, which may limit generalizability of findings. However, the frequencies of NPS observed in our study reflected those reported in population-based studies. Second, NPS were only measured with a single informant-rated questionnaire, the NPI-Q. The NPI-Q may be prone to reporting bias and having additional measures of NPS may have added further depth to our factor analysis. Nevertheless, the NPI-Q has similarly been used in other factor analyses of Mild NCI patients but not in rMDD patients [31]. Third, although rigorous criteria and neuropsychological assessment were used to ascertain diagnoses, we did not distinguish between amnestic and non-amnestic Mild NCD subtypes or include disease-specific biomarkers. Fourth, this study was a cross-sectional sample and thus, is unable to comment on stability of the estimates of frequency or factor structure of NPS over time. Finally, frequency of some NPS, specifically psychotic symptoms was low, which may have contributed to instability in factor structures.

Conclusion

This study assessed frequency and factor structure of NPS in individuals with Mild NCD, rMDD, and Mild NCD-rMDD. NPS were frequent in all groups, and especially the Mild NCD-rMDD group. Depression/dysphoria was the most common NPS. Factor analyses in each group revealed four factors with some key differences. Specifically, we observed a difference in presentation of delusions and motor disturbances in the factor structures of Mild NCD and Mild NCD-rMDD. These findings emphasize the importance of individualized assessment and treatment of NPS in patients with Mild NCD and primary psychiatric disorders such as MDD. In addition, it is important to assess for a history of MDD in primary cognitive disorders. Future studies should investigate how these varied presentations of NPS influence cognition and function in neurocognitive disorders in longitudinal population-based cohorts. Future studies should also investigate the association of NPS clusters with disease-specific biomarkers to advance understanding of mechanisms underlying NPS and facilitate the development of effective interventions.

Acknowledgments

The authors would like to thank the PACt-MD study group (online supplement 1) and all participants and caregivers involved in the study.

Statement of Ethics

This study protocol was reviewed and approved by Review and Ethics Board of the Centre for Addiction and Mental Health (CAMH), Toronto, Canada, Approval No.: CTO Project ID: 1333 Sponsor Study ID: 041-2014. All participants provided written informed consent before any research procedures were conducted. When required, written informed consent was obtained from the patient’s legal guardian/healthcare proxy for participation in this study.

Conflict of Interest Statement

A.K., D.K., C.M., D.G., A.G.-G., and N.H. have no conflicts of interest to declare. K.S.B. receives grant support from the University of Toronto. C.E.F. receives grant funding from NIA, NIH, CCNA, CIHR, ADDF, TDRA, Mito2i, the Hilary and Galen Weston Foundation, and Novo Nordisk. L.M. has received research funding from the Alzheimer’s Society of Canada, Centre for Aging and Brain Health Innovation, Ontario Ministry of Health and Long-Term Care, and Brainsway, Ltd. M.A.B. receives research support from the NIH. C.R.B. has received in-kind research accounts from Scientific Brain Training Pro and grant funding from Pfizer and Diamentis. He has been a consultant for Boehringer Ingelheim. A.N.V. receives funding from the National Institute of Mental Health (NIMH), Canadian Institutes of Health Research, Brain and Behavior Research Foundation (BBRF), Canada Foundation for Innovation, Centre for Addiction and Mental Health (CAMH) Foundation, and the University of Toronto. A.J.F. has received grant support from the US National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Canadian Institutes of Health Research, Brain Canada, the Ontario Brain Institute, the Alzheimer’s Association, AGE-WELL, the Canadian Foundation for Healthcare Improvement, and the University of Toronto. B.G.P. holds and receives support from the Peter and Shelagh Godsoe Endowed Chair in Late-Life Mental Health, Centre for Addiction and Mental Health Foundation and Discovery Fund. His research is supported by the National Institute of Aging, Brain Canada, the Canadian Institutes of Health Research, the Alzheimer’s Drug Discovery Foundation, the Ontario Brain Institute, the Centre for Aging and Brain Health Innovation, Alzheimer’s Society of Canada, the W. Garfield Weston Foundation, the Weston Brain Institute, the Canadian Consortium on Neurodegeneration in Aging and Genome Canada. He receives honoraria from the American Geriatrics Society and holds US Provisional Patent No. 16/490,680 and Canadian Provisional Patent No. 3,054,093 for a cell-based assay and kits for assessing serum anticholinergic activity. B.H.M. holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. B.H.M. has received research funding from Brain Canada, the CAMH Foundation, the Canadian Institutes of Health Research, the Patient-Centered Outcomes Research Institute (PCORI), and the US National Institutes of Health (NIH); research support from Bristol-Myers Squibb (medications for an NIH-funded clinical trial), Eli-Lilly (medications for an NIH-funded clinical trial), Pfizer (medications for an NIH-funded clinical trial), Capital Solution Design LLC (software used in a study funded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). He has been an unpaid consultant to Myriad Neuroscience. T.K.R. has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research, Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute. T.K.R. also received in-kind equipment support for an investigator-initiated study from Magstim, and in-kind research accounts from Scientific Brain Training Pro. He participated in 2021 in an advisory board for Biogen Canada Inc. T.K.R. also received for an investigator-initiated study in-kind equipment support from Newronika, and in-kind research online accounts from Scientific Brain Training Pro and participated in 2021 and 2022 in an advisory activity for Biogen Canada Inc. T.K.R. is also an inventor on the US Provisional Patent No. 17/396,030 that describes cell-based assays and kits for assessing serum cholinergic receptor activity. S.K. has received research support the Brain and Behavior Foundation, US National institute on Aging, BrightFocus Foundation, Brain Canada, Canadian Institutes of Health Research, Canadian Consortium on Neurodegeneration in Aging, Centre for Ageing and Brain Health Innovation, Centre for Addiction and Mental Health, and an Academic Scholars Award from the Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto. He has also received equipment support from Soterix Medical.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

A.K. and S.K. were responsible for the design of the study and drafting of the manuscript. K.S.B., C.E.F., L.M., D.G., M.A.B., C.R.B., A.N.V., A.G.-G., A.J.F., N.H., B.G.P., B.H.M., T.K.R., and S.K. were responsible for the acquisition of the data. A.K., D.K., C.M., and S.K. were responsible for the analysis of the data. All authors were involved in the analysis and interpretation of the data, were responsible in reviewing and providing final approval of the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.