# Impact of Comorbidities on Stroke Outcomes and Treatments

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2020 · —

## Abstract

The complement system has an important role in the pathogenesis of inflammatory injury and subsequent
recovery following ischemic stroke. In the previous award, we identified complement-dependent mechanisms
of post-stroke injury and recovery, and we characterized a set of complement inhibitors that are targeted to
neoepitopes expressed in the injured brain following stroke. We also determined that complement inhibition
significantly improved the outcomes of rehabilitative therapy and thrombolytic therapy, two standards of care.
The work proposed here is a continuation of these mechanistic and therapeutic studies, but with a deeper
investigation into how complement and complement inhibition interacts with t-PA and rehabilitation therapy
(translationally important), while layered on two major stroke comorbidities; ageing and smoking. Cigarette
smoke (a patient modifiable risk factor) and age are associated with a higher risk of mortality, more severe
disability, longer hospital stays and worse overall functional recovery in stroke patients, and age is also
associated with a poorer response to thrombolytic therapy. Military personnel have a significantly higher rate of
smoking than the general U.S. population, and it remains significantly higher among older age Veterans and
Veterans with diseases such as PTSD, addiction, and HIV. However, despite continuous recommendations
from the Stroke Treatment Academic Industry Roundtable (STAIR) committee and funding bodies, few studies
have addressed the mechanisms underlying how these comorbidities contribute to worse outcomes.
 In four specific aims, we propose to: 1. Determine the effects of age and smoking on acute and chronic
complement-dependent neuroinflammation after stroke, and investigate the effect of complement modulation in
the setting of age and smoking co-morbidities; 2. Determine how complement and a modified
neuroinflammatory response induced by age and cigarette smoke exposure interact with the current standards
of care t-PA and rehabilitation therapy; 3. Investigate complement inhibition as a chronic treatment strategy for
stroke, and the role of complement in both injury and repair chronically; 4. For translational relevance,
investigate the correlation between systemic complement activity and serum levels of IgM antibodies and
stroke outcomes in acute stroke patients with co-morbidities.

## Key facts

- **NIH application ID:** 10066265
- **Project number:** 5I01RX001141-07
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Stephen Tomlinson
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066265

## Citation

> US National Institutes of Health, RePORTER application 10066265, Impact of Comorbidities on Stroke Outcomes and Treatments (5I01RX001141-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10066265. Licensed CC0.

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