Daily Stress and Vascular Function in Midlife as a Risk Factor for Cognitive Decline

Because of global demographic trends toward increasingly older populations, there is an urgent need to identify the mechanistic underpinnings of modifiable risk factors for age-related chronic disease risk starting in midlife in order to establish novel biological targets for therapeutic intervention strategies that can be implemented earlier in the aging trajectory and prior to clinically detectable declines in function. Major depressive disorder (MDD) is the leading cause of disability and disease burden in midlife. Accordingly, the long-term goal is to determine whether and to what extent mitochondrial reactive oxygen species (mtROS)-induced impairments in peripheral endothelium-dependent dilation (EDD) explain how daily stress impacts 'real-world' cognitive function in middle-aged adults with MDD. As a necessary first step, the objective of this pilot trial is to examine the degree to which mtROS contributes to nitric oxide-dependent EDD in middle-aged adults with major depressive disorder.

A small community sample of cognitively unimpaired middle-aged males and females with and without MDD (n=20; 40-55 yrs) will be recruited. Participants will be recruited from New Castle County, Delaware (DE) and surrounding regions and will be representative of the sex/ethnic/racial population of DE. After providing verbal and written consent, all participants will undergo a clinical exam for signs and symptoms of chronic disease by clinical nursing staff. This will include a complete health history (females will also complete a gynecological history, including a 3-mo menstrual cycle recall), physical exam (anthropometry, resting hemodynamics, and a 12-lead electrocardiogram), and basic blood biochemistry (complete blood count, lipid profile, renal function, electrolytes, HbA1c, fasting glucose and insulin).

Ambulatory Assessment Protocol (Days 1-14): Daily stress processes will be assessed each day during the last daily assessment using an adapted version of the Daily Inventory of Stressful Events (DISE; ~8 min). Daily cognitive function will be assessed in multiple domains (subjective and objective).

Laboratory Assessment of Peripheral Endothelial Function (Day 15): Microvascular endothelial function will be assessed using intradermal microdialysis coupled with laser Doppler flowmetry. Two intradermal microdialysis probes (CMA Linear 31 probe, 55 kDa) will be inserted into the dermal layer of the ventral forearm and perfused with either lactated Ringer's solution (control) or MitoTempol (0.5 mM) to scavenge mitochondrial-derived superoxide. Red cell flux will be continuously measured via integrated laser Doppler flowmeters. Mean arterial pressure will be measured via brachial auscultation every 4 min. A standard local heating protocol will be used to elicit EDD and the NO-dependent portion of this response will be determined pharmacologically, as previously described.

Inclusion criteria

• Males and females aged 40-55 yrs
• Absence of objective cognitive impairment (≥26 on the Montreal Cognitive Assessment)
• Absence of diagnosed or unstable neurocognitive, cardiovascular, metabolic, renal, hepatic, autonomic, autoimmune, or dermatological diseases, as determined by medical history, physical examination, blood chemistries, and 12-lead resting electrocardiogram
• Participants must have a level of understanding of the English language sufficient to provide informed consent and to agree to all tests and procedures, as well as the capacity and willingness to attend all study related visits and to comply with the study protocol

Exclusion criteria

Subjects will be excluded at the discretion of the PI/collaborating clinicians or for any of the following reasons:

• <40 or >55 yrs
• Psychiatric illness aside from MDD (e.g., bipolar disorder, schizophrenia, eating disorders), assessed by the MINI and self-report
• Objective cognitive impairment (<26 on the Montreal Cognitive Assessment)
• Diagnosed or unstable neurocognitive, cardiovascular, metabolic, renal, hepatic, autonomic, autoimmune, or dermatological diseases
• Current or recent use (within 8 wks) of medications that alter cardiovascular function or psychoactive/psychopharmacological drugs
• Body mass index ≥35 kg/m2
• Resting systolic BP ≥140 mmHg
• HbA1c ≥5.7%
• Direct low-density lipoprotein ≥160mg/dl
• Tobacco use (including electronic cigarettes)
• Females who are pregnant, breastfeeding, or planning to become pregnant; female subjects of child-bearing age must have a negative urine pregnancy test on the day of all experimental visits
• Current or past use of hormone replacement therapy
• Allergy to study drugs or pharmacological agents