The RAW Brain - The Effect of Rumination, Anxiety and Worry on Aging and Dementia Risk

Anxiety and its disorders are a risk factor for several major diseases of aging including cardiovascular and auto-
immune diseases, Alzheimer's Disease and related dementias (ADRD). As anxiety disorders have the highest
lifetime prevalence of any psychiatric illness, anxiety and its phenotypes potentially represent a highly preva-
lent and modifiable risk factor for diseases of aging. However, little is known about the mechanisms underly-
ing the association between anxiety and ADRD risk. Moreover, the term "anxiety" is often used as an umbrella
covering multiple different categorical disorders or heterogenous symptom clusters. Overall, there is a severe
paucity of data regarding 1) the pathways through which specific anxiety phenotypes impact brain and body
aging; 2) the neurobiological markers contributing to increased ADRD risk among individuals with specific
anxiety phenotypes. A better understanding of specific neurobiological underpinning is critical to identify tar-
gets for interventions designed to prevent or limit the pernicious effect of anxiety on brain and body. Rumina-
tion, global anxiety, and worry (RAW) are three distinct and highly prevalent anxiety phenotypes, that have a
cummulative effect on chronic stress. We reported that worry and rumination (but not global anxiety) are as-
sociated with accelerated brain aging in late-life. Additional preliminary analyses indicate that worry and rumi-
nation severity are associated with other markers of brain aging such as hippocampal atrophy in subfields most
vulnerable to early AD while global anxiety is associated with regional accumulation of b amyloid in critical re-
gions such as precuneus and posterior cingulate, an association moderated by inflammatory markers. In this
proposal, we will identify the pathways through which the RAW phenotypes contribute to accelerated aging
and increased ADRD risk. We will operationalize RAW severity and examine the overall effect of RAW as well
as the individual effect of each phenotype. We will test the effect of RAW by using measures of 1) hippocampal
atrophy and glutamate excitotoxicity; 2) cerebrovascular burden; 3) plasma amyloid; 4) peripheral markers of
chronic stress [cortisol level, proinflammatory markers, carotid intima-media thickness] and 5) markers of ac-
celerated aging [senescence-associated secretory phenotype proteomic panel, telomere length and free-cell mi-
tochondrial DNA]. While continuing to follow our current cohort (N=150), we will add 150 new participants,
similarly recruited on dimensional measures of rumination, anxiety and worry. We will repeat the assessments
at two-year followup, giving us three time points for the original cohort and two time-points for the new cohort.
This study will render the largest cohort of older adults extensively characterized using clinical, neuropsycho-
logical, multimodal imaging measures as well as comprehensive measures of peripheral markers of stress and
aging. The blend of well-established and novel approaches (including computational methods and state of the
art imaging aquisitions) will allow us to frame and answer the questions imbedded in the above aims, with the
overall goal of identifying the most effective interventional and preventative targets anxious older adults.

Grant Number: 5R01MH108509-09
NIH Institute/Center: NIH
Principal Investigator: Carmen Andreescu