Caregiver Vulnerability and Brain Structural Markers: Compounding Risk

Caregiving strain confers an increased risk for all-cause mortality.¹ Intensive caregiving can produce a range of adverse mental and physical health consequences, best documented among dementia family caregivers. The provocative population-based study of the elderly by Smagula and colleagues,² drawn from a random, stratified sample, showed that more than 82% of those spouses who helped their partner with four or more of the 12 activities of daily living (ADLs) or instrumental activities of daily living (IADLs) reported strain, consistent with other literature. Caregivers who helped their partner with three or fewer IADLs, however, were 55% more likely to report strain if they had magnetic resonance imaging–assessed white matter grades of 4 or greater. This latter finding is quite novel and raises the question of whether brain structural pathology may augment caregiver strain for some individuals.

The findings are particularly notable in view of the very broad definition used for caregiving: These researchers only required that the impaired spouse have difficulty with at least one ADL or IADL, “due to physical or health problems or problems with confusion.”² Accordingly, it is likely that their sample was considerably less burdened and less distressed than the caregivers who have received the most attention: spousal caregivers for dementia sufferers, the population most heavily represented in the studies they cite. Furthermore, their research participants only needed to meet criteria as caregivers at a single time point, so that spouses who were only functioning as temporary or transient caregivers following a partner’s acute medical problems would nonetheless be classified as caregivers in their data. As a consequence of these factors, their data are likely to underestimate the actual impact of caregiving for a severely physically or cognitively disabled spouse among individuals with brain structural pathology.

STRAIN AND WHITE MATTER CHANGES: A BIDIRECTIONAL LINK?

The authors emphasize that their study’s cross-sectional design does not provide a way to establish whether white matter changes or caregiving strain occurred first.² They speculate, however, that the extensive white matter pathology developed over a more extended time interval than the spousal caregiving demands—a reasonable assumption. The risks for white matter damage include cardiovascular risk factors such as unhealthy diets, sedentary lifestyles, high blood pressure and cholesterol, and smoking, all factors that can be augmented by the elevated levels of stress and depression that are common issues among caregivers.^1,2

In addition, if brain structural pathology augments caregiver strain, then the substantial adverse health consequences that can accompany caregiving would also be magnified among caregivers with white matter damage. Caregiving’s immune-related risks include enhanced susceptibility to infectious agents and greater severity of infectious disease, diminished immune responses to vaccines, a greater risk for reactivation of latent herpes viruses, and slower wound healing.³ Perhaps most consequential, caregiving-associated distress can also substantially enhance the production of proinflammatory cytokines that are associated with a spectrum of age-related diseases. Accordingly, caregiving-related immune dysregulation could boost risk in a diverse set of health problems including cardiovascular disease, Alzheimer disease, osteoporosis, arthritis, Type 2 diabetes, cancer, and frailty and functional decline.³

Furthermore, preliminary evidence suggests that peripheral inflammation, an immunological correlate of stress and depression, is relevant for brain structure and function. Among healthy middle-aged adults who were 30 to 54 years old, those with higher inflammation had lower white matter volume as well as poorer memory and executive function than those with lower peripheral inflammation.⁴ Thus, caregiving strain could serve to exacerbate and accelerate white matter damage in a vicious spiral over longer periods.

WHITE MATTER DAMAGE AND PUTATIVE INFLAMMATORY MECHANISMS

As the authors suggest, higher white matter grades may reflect impaired executive function. If this is the case, caregivers with such structural abnormalities would struggle to regulate their negative emotions in the face of caregiving demands, resulting in exaggerated and prolonged inflammatory responses—similar to the dysregulating effects of depression.⁵ The co-occurrence of white matter hyperintensities with depression and mortality² further corroborates inflammatory responsiveness to stress as a plausible mediator of downstream health consequences.

Animal models of neural insult—namely, aging and traumatic brain injury—have demonstrated the principle that brain compromise may prime the body for more severe responses to later stressors. After a social stressor, the sensitized microglia in older brains trigger prolonged elevations in proinflammatory cytokines and longer periods of anhedonia and social withdrawal.⁶ Moreover, a peripheral immune insult triggered similarly exaggerated inflammation and depression-like behavior in mice who had previously recovered from mild, diffuse brain injury compared with mice with no prior brain injury.⁷ Thus, the authors’ observational evidence broadly coheres with conclusions from experimental animal models: Neural insult may cause exaggerated responses to subsequent stressors. Determining whether neuroinflammatory processes such as microglial activation operate in the same causal pathway in humans represents an important direction for future work.

Smagula and colleagues² report intriguing links between structural brain abnormalities and caregiver strain, and provide the compelling argument that white matter damage may lower the threshold for experiencing strain. This increased vulnerability to strain sets the stage for a multitude of ensuing inflammation-related risks, including depression, disease, and further structural damage. Caregivers under duress are likely to struggle with caregiving responsibilities on a more frequent basis and, thus, exhibit a greater number of inflammatory responses. Immune hyperactivation primed by structural brain pathology may prolong inflammation surges, preventing the normal return to baseline. Depression resulting from white matter damage and elevated inflammation can also feed back to perpetuate inflammatory signaling and demotivate protective health behaviors such as diet and exercise. Together, these risks increase the likelihood of accelerating pathologic changes in brain morphology and developing diverse age-related illnesses, including, but not limited to, Alzheimer disease, diabetes, cancer, arthritis, and cardiovascular disease. In total, it is easy to envision how the vigorous dialogue between the brain and immune system may quickly escalate the risks of even minor caregiving, and how two keystones—structural brain abnormalities and inflammation—can hasten caregivers’ mortality.¹