Hippocampal dysfunction in Gulf War veterans: investigation with ASL perfusion MR imaging and physostigmine challenge

Abstract

Purpose: To determine, with arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging and physostigmine challenge, if abnormal hippocampal blood flow in ill Gulf War veterans persists 11 years after initial testing with single photon emission computed tomography and nearly 20 years after the 1991 Gulf War.

Materials and methods: The local institutional review board approved this HIPAA-compliant study. Veterans were screened for contraindications and gave written informed consent before the study. In a semiblinded retrospective protocol, veterans in three Gulf War illness groups-syndrome 1 (impaired cognition), syndrome 2 (confusion-ataxia), and syndrome 3 (central neuropathic pain)-and a control group received intravenous infusions of saline in an initial session and physostigmine in a second session, 48 hours later. Each infusion was followed by measurement of hippocampal regional cerebral blood flow (rCBF) with pulsed ASL. A mixed-effects linear model adjusted for age was used to test for differences in rCBF after the cholinergic challenge across the four groups.

Results: Physostigmine significantly decreased hippocampal rCBF in control subjects (P < .0005) and veterans with syndrome 1 (P < .05) but significantly increased hippocampal rCBF in veterans with syndrome 2 (P < .005) and veterans with syndrome 3 (P < .002). The abnormal increase in rCBF was found to have progressed to the left hippocampus of the veterans with syndrome 2 and to both hippocampi of the veterans with syndrome 3.

Conclusion: Chronic hippocampal perfusion dysfunction persists or worsens in veterans with certain Gulf War syndromes. ASL MR imaging examination of hippocampal rCBF in a cholinergic challenge experiment may be useful as a diagnostic test for this condition.

Figure 1:

Image shows ASL perfusion imaging slab position. The oblique coronal ASL imaging sections were positioned to cover the head of the hippocampus, with the inferior edge of the imaging slab parallel to the longitudinal anteroposterior axis of the hippocampus and tangent to the gyrus of the temporal lobe, by using T1-weighted high-spatial-resolution anatomic images for accurate reference.

Figure 2:

Oblique coronal images in healthy veteran. Top row: coregistered T1-weighted high-spatial-resolution anatomic MP-RAGE images with overlaid hippocampus ROIs. Second row: proton density–weighted images from the saline session. Third row: perfusion-weighted images from the saline session. Bottom row: perfusion-weighted images from the physostigmine session.

Figure 3a:

(a–d) Graphs show results of the cholinergic challenge experiment in Gulf War veterans with syndromes 1–3 (Syn 1, Syn2, and Syn 3, respectively) compared with those in a control group of well veterans (Con). (a, b) Graphs show group mean ASL-measured rCBF in the (a) left and (b) right hippocampus in session 1 (saline infusion) and session 2 (physostigmine [physo] infusion). (c, d) Graphs show group mean changes in ASL-measured rCBF in the (c) left and (d) right hippocampus with P values from contrasts in the mixed-effects linear model testing differences between syndrome groups and the control group. Error bars = standard errors of the mean.

Figure 3b:

(a–d) Graphs show results of the cholinergic challenge experiment in Gulf War veterans with syndromes 1–3 (Syn 1, Syn2, and Syn 3, respectively) compared with those in a control group of well veterans (Con). (a, b) Graphs show group mean ASL-measured rCBF in the (a) left and (b) right hippocampus in session 1 (saline infusion) and session 2 (physostigmine [physo] infusion). (c, d) Graphs show group mean changes in ASL-measured rCBF in the (c) left and (d) right hippocampus with P values from contrasts in the mixed-effects linear model testing differences between syndrome groups and the control group. Error bars = standard errors of the mean.

Figure 3c:

(a–d) Graphs show results of the cholinergic challenge experiment in Gulf War veterans with syndromes 1–3 (Syn 1, Syn2, and Syn 3, respectively) compared with those in a control group of well veterans (Con). (a, b) Graphs show group mean ASL-measured rCBF in the (a) left and (b) right hippocampus in session 1 (saline infusion) and session 2 (physostigmine [physo] infusion). (c, d) Graphs show group mean changes in ASL-measured rCBF in the (c) left and (d) right hippocampus with P values from contrasts in the mixed-effects linear model testing differences between syndrome groups and the control group. Error bars = standard errors of the mean.

Figure 3d:

(a–d) Graphs show results of the cholinergic challenge experiment in Gulf War veterans with syndromes 1–3 (Syn 1, Syn2, and Syn 3, respectively) compared with those in a control group of well veterans (Con). (a, b) Graphs show group mean ASL-measured rCBF in the (a) left and (b) right hippocampus in session 1 (saline infusion) and session 2 (physostigmine [physo] infusion). (c, d) Graphs show group mean changes in ASL-measured rCBF in the (c) left and (d) right hippocampus with P values from contrasts in the mixed-effects linear model testing differences between syndrome groups and the control group. Error bars = standard errors of the mean.

Figure 4a:

(a, b) Graphs show hippocampus rCBF changes elicited by physostigmine challenge in Gulf War veterans with syndromes 1–3 (Syn 1, Syn2, and Syn 3, respectively) with or without PTSD compared with a control group of well veterans (Con). (a) ○ = Subjects given a diagnosis of PTSD; ● = subjects without PTSD, with P values from contrasts in the mixed-effects linear model testing differences between syndrome groups without PTSD and the control group (top) and pooled differences between syndrome groups irrespective of PTSD status (bottom). (b) PTSD status does not affect the differences among the syndrome groups shown in a. Error bars = standard errors of the mean.

Figure 4b:

(a, b) Graphs show hippocampus rCBF changes elicited by physostigmine challenge in Gulf War veterans with syndromes 1–3 (Syn 1, Syn2, and Syn 3, respectively) with or without PTSD compared with a control group of well veterans (Con). (a) ○ = Subjects given a diagnosis of PTSD; ● = subjects without PTSD, with P values from contrasts in the mixed-effects linear model testing differences between syndrome groups without PTSD and the control group (top) and pooled differences between syndrome groups irrespective of PTSD status (bottom). (b) PTSD status does not affect the differences among the syndrome groups shown in a. Error bars = standard errors of the mean.