The need for identifying neuropsychiatric symptoms and neural correlates among racially and ethnically minoritized older adults. Commentary on “Neuropsychiatric symptoms and white matter hyperintensities in older adults without dementia” by Liampas et al.

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The presence of white matter hyperintensities (WMH) has several clinical implications and are associated with cognitive decline, cerebral vascular disease, stroke and neurodegenerative disorders such as Alzheimer’s disease and related dementias (ADRD) [8]. Studies have identified associations between WMH and neuropsychiatric symptoms (NPS) in populations with ADRD [5]. However, less is known about these associations among unimpaired populations and those with and without mild cognitive impairment (MCI), and the few studies that have explored this, have inconsistent results [16,17]. NPS are common among those with MCI and ADRD, and the onset of these symptoms may likely occur years before diagnosis. The Center for Disease Control and Prevention has estimated that about 20 % of adults aged 55 and older experience psychiatric symptoms and the most common conditions include anxiety and mood disorders, and cognitive impairment [4]. Examining associations between NPS and WMH among people without ADRD has the potential to provide further understanding of different etiologies of WMH and can lead to early interventions that prevent cognitive decline and progression to ADRD.

With their study, Liampas et al. [15] addressed the crucial need to better understand the association between WMH and NPS among people 50 and older without ADRD. Interestingly, several NPS were associated with WMH among unimpaired individuals, especially when comparing those with no to mild WHM vs those with extensive WMH. However, these associations did not exist in the group with MCI, which may explain why previous studies that did not stratify by cognitive status found inconsistent results. The results of the study are consistent with much of the previous literature in that the risk of having NPS was associated with high levels of WMH [5]. NPS that were associated with extensive WMH among unimpaired individuals include elation, disinhibition, agitation, and anxiety. The study found no significant findings for the presence of depression or apathy, which is inconsistent with previous research [5].

This paper has a number of strengths. One strength includes the use of the National Alzheimer’s Coordinating Center’s (NACC) Unified Data Set (UDS), which consists of data collected across 46 Alzheimer’s disease research centers (ADRCs). The NACC UDS provides the opportunity to examine this data in a large and well characterized sample with WMH data at different severity levels. Other strengths include the stratified analyses by cognitive status (MCI or cognitively unimpaired), a validated scale that measured multiple NPS, and controlling for vascular risk factors, cognitive scores, and key sociodemographic variables. Authors argue that the lack of associations between WMH and NPS in the group with MCI may be due the association between other pathologies (e.g., amyloid) and NPS, which overwhelms WMH-NPS associations.

Liampas et al. [15] provide a comprehensive definition and background NPS and describe them to include depression, anxiety, delusions, and apathy. Other NPS present among older adults and that have been associated with increased WMH and risk of ADRD include delirium, fatigue, emotional liability, and psychosis. Apathy and fatigue have been identified as being associated with greater WMH [5] and worse clinical outcomes for individuals with MCI [6]. Late life depression has been identified as the most prevalent neuropsychiatric disorder among older adults [3], and has been independently linked to an increased risk of Alzheimer’s disease [1,10] and other dementias [9]. The authors mention mild behavioral impairment as being a condition where NPS are highly prevalent and associated with greater risk of incident ADRD. This diagnostic construct may identify patients who have an increased risk of developing ADRD but may or may not have cognitive symptoms.

Previous studies have examined associations between NPS, WMH and neuropathology among clinical and non-clinical populations. One recent study identified that the most prevalent NPS experienced by individuals with MCI include depression, irritability and sleep disturbances, and these symptoms are associated with reduced brain volumes in the orbitofrontal and posterior cingulate cortices, and posterior cingulate cortex predicted neuropsychiatric burden [7]. Another study examined WMH and gray matter atrophy as it relates to NPS among individuals with MCI and AD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and found that WMH played a greater role than gray matter atrophy in predicting neuropsychiatric subsyndromes including hyperactivity, psychosis, affective and apathy [17]. Results of this and other studies highlighted by the authors demonstrate that WMH may be a key and important contributor to NPS during early and prodromal stages of ADRD. This is relevant because NPS interfere with cognitive functioning, specifically executive control, which is related to connectivity between brain regions. It has been hypothesized that the presence of WMH may interfere with this connectivity between brain regions and have a greater effect than other neuropathological findings such as gray matter brain atrophy.

Like others, Liampas et al.’s study [15] has some limitations, many of which are noted by the authors. These include the limits to the nature of their observational research in making causal inferences. Directionality cannot be determined based on these results and future studies should examine if NPS cause WMH or vice versa. Other limitations included the non-standardized WMH assessment which may have caused variability, not correcting the findings for multiple comparisons, and potential residual confounding. Despite not being mentioned, other limitations may impact the findings of this study. The assessment of NPS is made by an informant, who may be a spouse, partner, or companion, child, sibling, other relative, friend, neighbor, or someone known through family, friends, work, or community, or a paid caregiver, health care provider, or clinician. These different informant relationships with the participant, in addition to the level of depth of their relationship may bias NPS scores. These NPS assessments are also reported and not direct observations, which may lead to memory bias. However, given the field of expertise of the two authors of the current commentary, we would like to highlight limitations related to race and ethnicity.

There is room for improvement with regards to a number of aspects from the Liampas et al. [15] study related to race and ethnicity. First, the generalizability and associations with race of these findings are limited by a non-probabilistic sampling where ethnically and racially minoritized groups are under-represented and are also generally recruited from sources that are different from non-Latino Whites [11]. Second, while including race, this was added as a covariate. It is acceptable to use race as a covariate, but only when there is no interaction between race and other independent variables or the dependent variable of interest [12]. We acknowledge that interactions by race in this study may be impacted by the small sample size of non-White participants. Third, the study used the racial category “other”. It is preferrable not to combine racial categories, and if necessary, this should be acknowledged in the limitations section [12]. Fourth, the study did not report the frequency of participants who identified as being of Latino ethnicity, which is the largest group of all ethnic and racial groups after non-Latino White individuals in the U.S. Reporting Latino ethnicity is important for understanding the composition of the sample and identifying ethnicity-related health disparities or differences.

With the increasing ethnic and racial diversity of the U.S. population, it is important to consider examining the prevalence of NPS and its neural correlates such as WMH among underrepresented ethnic and racial groups. The need is especially important, as for instance, Latinos experience a higher risk of cerebrovascular disease [2] and ADRD [13] and unimpaired Latinos and Latinos with ADRD exhibit more NPS compared to non-Latino White individuals [18]. Latinos are under-represented in the NACC UDS, and their higher prevalence of NPS could mean that better representation of this group may have helped address non-significant findings related to the small frequency of some NPS. Ethnically and racially minoritized individuals with a combination of cognitive impairment and NPS or a mild behavioral impairment diagnosis are at greater risk for progression to ADRD [14,19]. Therefore studies focused on identifying associations of these constructs to ADRD neuroimaging and biomarkers have relevant and immediate implications for prognosis. It is critical to include ethnically and racially minoritized groups in studies examining neuropathological correlates to NPS among older adults. Including these groups in less diverse studies or leveraging existing studies with a high representation of ethnically and racially minoritized groups would significantly strengthen the findings and provide a fuller picture of the role of NPS in WMH and ADRD. Future studies should also examine comparisons between these ethnic and racial groups.

Despite the limitations mentioned above, these findings are a significant step forward in understanding these associations and the role that NPS has in ADRD-related neuropathology and neuroimaging biomarkers. However, future study should examine more diverse samples. Examining NPS and WMH among unimpaired populations and those with MCI, significantly contributes to our understanding on the presence of these associations prior to ADRD development. Given that the presence of NPS, especially late life depression, increases the risk of ADRD, understanding these associations can lead to treatments and lifestyle changes that can reduce and/or prevent WMH accumulation and manifestation of NPS.

In conclusion, the study conducted by Liampas et al. [15] extends the understanding of associations between WMH and NPS among older adults without ADRD by examining the risk of cognitively unimpaired populations and those with MCI to develop NPS over time. These findings add to mixed results of previous studies which have attempted to examine and understand these associations by indicating that elation, disinhibition, agitation and anxiety were more likely to be predicted by extensive WMH. However, there findings were inconsistent with other studies who identified stronger associations to apathy and depression. There is room for improvement with regards to how race and ethnicity is dealt with in the study, and the use of the NACC UDS for this study was a strength as well as a limitation.