Cerebral Hemodynamics and Stroke in HIV-associated TB Meningitis.

Abstract
Tuberculous meningitis (TBM) disproportionally affects people in low- and middle-income countries and is
associated with high morbidity and mortality. Stroke is a common complication in TBM and can lead to severe
irreversible neurological disability. Studies on TBM-associated stroke pathology, however, have focused
primarily on HIV-uninfected individuals. The overall objective of this proposal is to use transcranial doppler and
brain imaging to understand changes in cerebral blood vessels and cerebral blood flow in order to determine
changes in cerebrovascular responsiveness, characterize patterns of stroke, and describe long-term
neurocognitive outcomes in HIV-associated TBM. The central hypothesis is that in HIV-infected individuals,
TBM causes extensive cerebral vascular narrowing and impaired cerebrovascular responsiveness, decreased
cerebral blood flow, and ultimately stroke. The central hypothesis will be tested by pursuing three specific aims:
1) describe changes in cerebrovascular responsiveness in HIV-associated TBM; 2) characterize the patterns of
stroke in HIV-associated TBM and determine whether it is associated with vasculopathy and/or impairments in
cerebrovascular responsiveness; and 3) determine if impaired cerebrovascular responsiveness predicts long-
term neurological outcome in HIV-associated TBM. Under Aim 1, transcranial doppler will be used to take
repeated measurements of the middle cerebral artery flow velocity and pulsatility index. A subset of study
subjects will also have dynamic measurements made in response to stimuli (inhaled CO2, changes in blood
pressure, and motor tasks). We will determine whether cerebrovascular responsiveness is impaired in HIV-
associated TBM by comparing measurements to those of control patients with no neurological infection. Under
Aim 2, all study subjects will have a brain MRI performed within the first 2-weeks of TBM treatment to identify
the presence of a cerebral artery stroke and the associated cerebral artery territory. We will compare TCD
readings between participants with or without stroke. Under Aim 3, we will examine how TCD measurements at
study enrolment relate to the results of neurocognitive testing at month 2 and functional assessment at month
6. Ultimately, the long-term goal of the proposal is to describe how impaired cerebrovascular responsiveness in
HIV-associated TBM contributes to the development of strokes and resulting neurocognitive impairment and
disability. The research proposed in this application is innovative because it incorporates the use of
transcranial doppler at the bedside, to be used in real time, in the care of subjects with TBM. The proposed
research is significant because it is expected to provide strong scientific justification for the development of
future clinical trials testing targeted interventions to improve cerebrovascular responsiveness and prevent the
development of strokes in HIV-associated TBM. Ultimately, such knowledge has the potential of preventing the
development of irreversible neurological injury and improving both short and long-term outcomes.

Grant Number: 5R21NS134516-02
NIH Institute/Center: NIH
Principal Investigator: Mahsa Abassi