N-Acetylcysteine Alleviates Cortical Glutathione Deficit and Improves Symptoms in CFS: An In Vivo Validation Study using Proton Magnetic Resonance Spectroscopy
N. Weiduschata , X. Maoa , D. Vub , M. Blateb , G. Kanga , H.S. Mangatc , A. Artisd , S. Banerjeed , G. Langeb , C. Henchcliffec , B.H. Natelsonb , D.C. Shungua
a Departments of Radiology, c Neurology and Neuroscience, and d Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA; b Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, NY, USA;
OBJECTIVES We previously reported a robust 36% deficit of occipital cortex glutathione (GSH) – the primary tissue antioxidant – in patients with CFS compared to healthy comparison (HC) subjects, a finding that implicated oxidative stress in the disorder. The primary objective of the present study was to assess whether supplementing CFS patients with the GSH synthetic precursor N-acetylcysteine (NAC) daily for 4 weeks would spur in situ synthesis and significant elevation of cortical GSH compared to baseline, as assessed in vivo with proton magnetic resonance spectroscopy ( 1 H MRS).
METHODS For this pilot clinical study, we recruited 16 medication-free patients meeting the CDC criteria for CFS and 15 HC subjects. Following baseline measurement of occipital cortex GSH with 1 H MRS and administration of a battery of clinical assessments, both CFS and HC participants received a 4-week supplement of 1800mg NAC/day. After 4 weeks, identical 1 H MRS scan and clinical assessments were conducted to determine the effect of NAC on cortical GSH levels and on CFS symptoms as assessed with the CDC CFS symptom inventory.
RESULTS At baseline, controlling for age and race, cortical GSH levels were 15% lower in CFS than in HC (95%CI: -0.0005,0; p=0.04, one-tailed as the differences and direction of changes were postulated a priori). Following 4 weeks of daily NAC supplementation, cortical GSH levels rose significantly relative to baseline (95%CI: 0.0001,0.0006; p=0.004, one-tailed) in CFS patients to match those in HC, which did not differ compared to baseline (95%CI: - 0.0002,0.0003; p=0.33, one-tailed). Lastly, NAC supplementation markedly improved symptoms in CFS patients, with significant decreases in CDC CFS symptom inventory total scores (95%CI: -51.5-9.6; p=0.006), case definition scores (95%CI: -28.2-2 .0; p=0.03) and “other symptoms” scores (95%CI: -24.0-7.3; p<0.001). However, GSH levels did not correlate with any clinical measure.
CONCLUSION The results of this study have provided the very first direct evidence that NAC crosses the blood-brain barrier to spur in situ synthesis and elevation of cortical GSH. Significantly, increasing cortical GSH levels with NAC ameliorated symptoms in CFS patients. Future studies evaluating the clinical efficacy, and optimal dose and treatment duration of NAC are warranted.
Dikoma C. Shungu, Ph.D., Professor of Physics in Radiology, Fellow of the International Society for Magnetic Resonance in Medicine (FISMRM); Chief, Laboratory for Advanced MRS Research Citigroup Biomedical Imaging Center, Weill Cornell Medicine; 516 E 72nd Street, New York, NY 10065.
Email:
dcs7001@med.cornell.edu.
Funding source: NIH Grant # 1 R21 NR013650.
There are no conflicts of interest to declare or disclose.
