Association between physical frailty and incident depression: a prospective study

477 

Abstract Submission 

Rongtao Jiang¹, Stephanie Noble², Matthew Rosenblatt¹, Jean Ye¹, Vince Calhoun³, Jing Sui⁴, Dustin Scheinost¹

¹Yale University, New Haven, CT, ²Northeastern University, Boston, MA, ³Georgia State University, Atlanta, GA, ⁴State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China

Rongtao Jiang  
Yale University
New Haven, CT

Stephanie Noble  
Northeastern University
Boston, MA

Matthew Rosenblatt  
Yale University
New Haven, CT

Jean Ye  
Yale University
New Haven, CT

Vince Calhoun  
Georgia State University
Atlanta, GA

Jing Sui  
State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University
Beijing, China

Dustin Scheinost  
Yale University
New Haven, CT

Identifying modifiable risk factors that prevent depression constitutes a public health priority[1]. Cross-sectional studies have demonstrated strong associations between physical frailty and depression, pointing towards physical frailty as one potential target[2]. However, the evidence from prospective, longitudinal studies is limited. This study investigates the prospective association between physical frailty and incident depression and the potential mechanisms driven by inflammatory markers and brain structure.

This study included 352,277 participants (37-73 years, who were free of depression at baseline and within the 2-year follow-up period) from UK Biobank, of whom 11,269 developed depression during the 12.25-year follow-up. Physical frailty was defined using the following five criteria: weight loss, exhaustion, weakness (low grip strength), physical inactivity, and slow walking speed[2-4]. Participants were deemed pre-frail if they fulfilled one or two criteria or frail if they fulfilled three or more[5,6]. Cox proportional hazard models were used to estimate the association between frailty status and depression incidence. Mediation analyses were performed to examine the role of regional grey matter volume (GMV) and nine inflammatory markers in mediating the relationships.

Compared with non-frail individuals, pre-frail (hazard ratio (HR)=1.60, [95% CI 1.53-1.66]) and frail (HR=3.20, [2.98-3.43]) individuals had increased risk for incident depression independent of sociodemographic, lifestyle, and metabolic factors during the 12.25-year follow-up period (Figure 1A). Altogether, pre-frail and frail individuals accounted for 20.58% and 13.16% of depression cases by population attributable fraction analyses[7]. The HR of depression increased from 1.45 to 4.37 for participants fulfilling one to five frailty components, and no evidence of non-linearity was observed (Figure 1B). Age and sex showed significant interactions with physical frailty on depression. Specifically, higher risks were observed in males and individuals younger than 65 years than their counterparts (Figure 1C). All five components defining frailty showed individual and independent associations with incident depression, with exhaustion showing the strongest effect (Figure 1D). Associations were also observed between eight of the nine inflammatory markers and incident depression (Bonferroni corrected P<0.05, Figure 2A), whereas significant non-linear associations were only observed for leukocytes (P<0.001), platelets (P=0.03), and neutrophils (P=0.04), with plateauing slopes at lower exposure and linear trends at higher levels. Six out of the nine inflammatory markers significantly mediated the prospective association between physical frailty and depression incidence while adjusting for covariates and multiple comparisons (Figure 2B). Further, the neuroimaging analyses revealed 46 and 7 brain regions significantly associated with physical frailty and depression symptoms (measured by PHQ-9 scores), respectively (Figure 2C). Five brain regions were consistently identified by both physical frailty and depressive symptom scores, and the association map of frailty was significantly similar to that of depression symptoms, indicating a shared neurobiological basis (r=0.568, P=9.25×10-11). Further analysis indicated that the mean GMV of these 5 brain regions significantly mediated the association between physical frailty and depressive symptoms (P<0.001).

The present findings suggest that frailty may be a risk factor for depression, and the associations can be explained by brain structure and systemic inflammation. Given the scarcity of curative treatment for depression and the high disease burden[8], routine surveillance and assessment of physical frailty from middle age may provide cost-effective targets for monitoring and potentially mitigating the onset of depression.

Psychiatric (eg. Depression, Anxiety, Schizophrenia) ¹

Aging ²

Aging

Psychiatric Disorders