Examining the Link Between Cardiovascular Risk Factors and Neuropsychiatric Symptoms in Mild Cognitive Impairment and Major Depressive Disorder in Remission

INTRODUCTION

Neuropsychiatric symptoms (NPS) are common in Alzheimer’s disease (AD), estimated to occur in approximately 80% of patients at some point over the course of the disease [1]. Their frequency in mild cognitive impairment (MCI) has been estimated to be lower although the range may be anywhere from 35% to 75% [2, 3], though studies of NPS in patients with MCI to date have been limited. These symptoms typically consist of a broad spectrum of behavioral changes and include anxiety, depression, agitation, aggression, motor behaviors, delusions, and hallucinations. In recent years, there has been a greater focus on NPS as early indicators of emergent dementia in at risk patients [2, 4]. Mild behavioral impairment, a relatively new construct, suggests that NPS in some cases may be the only symptom of an emerging dementia syndrome and may predate the onset of cognitive decline by many years [5]. In addition, studies suggest that depression may be a harbinger of subsequent cognitive decline and eventual development of AD [6, 7], though the role of remitted lifetime history of depression is less clear. Furthermore, there has been limited characterization of NPS burden in patients with remitted MDD. Therefore, to the extent that remitted MDD may represent a risk factor of an evolving dementia, it is possible that patients with MDD in remission may exhibit additional NPS, potentially with a similar profile to that observed in patients with MCI.

The Prevention of Alzheimer’s Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study is a large Toronto based intervention study focused on prevention of cognitive decline in patients with MCI, and MDD in remission with and without MCI. Our study examined the association of total Neuropsychiatric Inventory (NPI) [8] scores with demographic factors, cognition, diagnosis, and CVRF. As prior studies have demonstrated an association between NPS and later progression to dementia [9], we hypothesized that NPI scores would be associated with correlates of future dementia including decreased cognitive test performance. In addition, we predicted that depression and MCI, both possible correlates of future dementia, would combined be associated with higher NPI scores compared to each condition individually.

Our study also attempted to delineate the relationship of cardiovascular disease burden with NPS burden. Cardiovascular disease and CVRF have been identified as a risk factor for both AD [10, 11] and MDD [12]. Additionally, fluctuations in blood pressure have recently been demonstrated to be associated with cognitive decline in patients with AD. Possible mechanisms of this may include a compromised blood-brain barrier and endothelial blood vessel wall damage [13–15]. However, there has been limited study of the relationship of CVRF and NPS. A potential mechanism by which cardiovascular disease could impact NPS may be through increased small vessel disease burden, which may disrupt brain network connectivity, potentially leading to NPS [16]. There is very little evidence to date, though Moon et al. found a correlation between hypertension and severity of apathy and depression in AD [17]. Similarly, Fischer et al. found a correlation between psychosis and vascular risk factors in AD patients with psychosis [18]. We thus predicted that the overall NPS burden would be associated with greater cardiovascular risk. Finally, given that specific NPS may arise from different neural mechanisms, we hypothesized CVRF would associate differentially with specific NPS domains.

MATERIALS AND METHODS

RESULTS

Baseline sample characteristics of the sample are provided in Table 1. The mean age was 73.66±6.25 years, 87 subjects were female, and 94 subjects had completed high school or greater. Seventy subjects had MCI, 38 had MDD in remission, and 32 had combined MCI plus MDD in remission (see Table 1). The mean MOCA score was 24.25±3.04 and the mean MMSE score was 27.85±1.80. The mean total NPI score was 1.60±1.70, the mean severity score was 2.24±2.71, and the mean distress score was 2.24±2.71. The mean Framingham score was 18.84±8.94 and hypertension and hypercholesterolemia were the most common vascular risk factors. Ninety-three subjects scored positive for one NPS or greater and there was no significant relationship with age, education, cognition, Framingham scores, psychoactive medication use or diagnostic group on the presence of NPS (see Table 2). Night-time behaviors were noted to be more common in MCI+MDD in remission relative to MDD in remission alone (p = 0.039), although this was no longer significant following correction for multiple comparisons (p = 0.058). However, when MCI and MCI + MDD diagnosis groups were combined, the prevalence of night-time behaviors in the expanded MCI group became significant in comparison to that of the MDD group alone (p = 0.014). Depression was the most common symptom in all groups followed by night-time behaviors and appetite disturbance (see Table 3).

We conducted a sub-analysis to further determine the effect of CVRF on different NPI sub-scores and found that disinhibition and irritability correlated positively with low HDL cholesterol (p = 0.028) and high Framingham risk scores (p = 0.039). Night-time behaviors were positively associated with hypertension (p = 0.03) and high Framingham scores (p = 0.017). Anxiety symptoms correlated positively with Hachinski ischemia scores (p = 0.031) while agitation and aggression were negatively associated with hyperlipidemia (p = 0.044). Night-time behaviors correlated with decreased global cognitive function including MMSE (p = 0.011) and MOCA (p = 0.001). Appetite disturbance correlated with low MOCA scores (p = 0.041) and delusions correlated with poor performance on MOCA (p = 0.016) and MMSE (p = 0.047). No other relationships were significant.

DISCUSSION

Our study examined the distribution of NPI scores across three groups in the PACt-MD study—patients with MCI alone, patients with MDD in remission alone, and patients with combined MDD in remission and MCI. Contrary to our predictions, the distribution of NPI scores and sub-scores was similar across all groups, with the one exception of night-time behaviors being more prevalent in patients with MCI with and without MDD relative to MDD alone. The lack of variation of NPS across the diagnostic subgroups suggests that lifetime history of MDD in remission may not play a major role in NPS burden, at least when combined with MCI. Not surprisingly, depression was the most frequent NPS, followed by night-time behaviors and appetite disturbance. These results are consistent with previous studies demonstrating that mood, anxiety and depressive symptoms are the most common NPS in MCI [2].

We also examined the association between NPS and CVRF in a combined sample. Prior studies have identified cardiovascular disease burden as an important predictor of cognitive decline [10, 11], and CVRF to be associated with late life psychiatric disorders such as MDD [12]. Moreover, fluctuations in blood pressure have recently been identified as an important risk factor for cognitive decline in patients with AD. Proposed mechanisms include damage to the endothelial blood vessel walls as well as compromised blood-brain barrier. As our study focused only on baseline data we are unable to comment on the effect this may have had on our results [13–15]. Contrary to our predictions, the presence of CVRF, including the Framingham risk score and individual risk factors, was not associated with the presence of NPS as measured by the total NPI. In addition, age and level of cognitive decline did not have an effect on the presence or absence of NPS. Night-time behaviors were the only factor to associate positively with vascular risk factors of dementia including hypertension and Framingham score and with decreased memory, possible correlates of future dementia. Agitation was the only behavior to associate inversely with vascular risk factors while anxiety, disinhibition and irritability associated positively.

Collectively, there was no correlation between cognitive test scores and total NPI scores, though there was an association with specific sub-scores. Appetite disturbance and delusions correlated with worse cognitive performance but not increased CVRF, suggesting that alternate disease mechanisms possibly linked to neurodegenerative pathology may explain these symptoms. Delusions and other psychotic symptoms are associated with increased risk of dementia and accelerated rates of cognitive decline [26]. The one behavior that showed the greatest variation across the groups, the strongest association with cardiovascular disease burden and cognitive decline was night-time behaviors. Sleep disorders and abnormal night-time behaviors may play an important role in promoting dementia based on recent research [27]. Night-time behaviors may be both a manifestation of cardiovascular disease and a cause. Many symptoms had no association with cardiovascular disease burden (including elation, anxiety, delusions, hallucinations, and increased motor behavior) while frontal behaviors (disinhibition, anxiety and irritability) tended to correlate most strongly with CVRF including Framingham scores, Hachinski scores, and low HDL cholesterol levels. A potential mechanism for this observed frontal lobe dysfunction may be small vessel disease, which may be associated with abnormal cholesterol levels [28].

While the results of this study are of interest, there are some limitations that should be highlighted. This was a cross-sectional study that looked at baseline data and thus we are not able to speculate on the trajectory of cognitive decline over time. We were unable to obtain full data on all participants. We used the Framingham Risk Score which evaluates cardiovascular disease risk as opposed to the Framingham stroke score. In addition, the MCI sample was somewhat heterogeneous in nature and this may have confounded the results. We also combined patients with MCI and remitted MDD, two distinct diagnoses, which may have also affected our results, though the NPI score distribution did not vary among groups. As well, we looked at vascular risk factors but did not incorporate any imaging markers of cerebrovascular disease. Finally, we did not look at longitudinal variables, such as fluctuation in blood pressure measurements, which has recently been identified as a risk factor for AD progression, given we looked exclusively at baseline data.

In spite of the above-mentioned limitations, our study demonstrated a number of conclusions worthy of further investigation. We were able to demonstrate that both the prevalence and profile of NPS in MCI is similar to that of MDD in remission. We showed low HDL cholesterol, high Hachinski scores, and high Framingham scores may mediate NPI sub-scores such as anxiety, irritability, and disinhibition, suggesting a potential mechanism of increased small vessel disease. In addition, we showed a link among hypertension, overall Framingham score, and night-time behaviors which also correlated with cognitive decline, thus suggesting that night-time behaviors may be symptomatic of emergent dementia. Future longitudinal studies examining the impact of CVRF and blood pressure variation on individual NPS sub-scores and incorporating imaging and disease biomarkers are required.