TNF Brain Syndrome

TNF is an immune signaling molecule. Increasing scientific evidence suggests that excess (pathologic) levels of TNF, if present in the brain, may impair brain function. Physiological levels of TNF are involved in the regulation of normal brain processes, such as the regulation of synaptic function(1-3). In the 1980’s Clark and his colleagues suggested that excess TNF was involved in the pathophysiology of brain dysfunction associated with malaria(4, 5). In 1988, the clinical results of the initial human trials of recombinant TNF for use in oncology gave a further clue to the essential role of TNF in brain physiology, as three of the initial clinical trial participants demonstrated transient focal neurological dysfunction after TNF infusion(6, 7). More than a decade later researchers discovered that TNF levels 25 times normal were present in the cerebrospinal fluid of patients with Alzheimer’s disease(8). INR physicians have published clinical evidence suggesting that excess TNF is a mediator of brain dysfunction in a variety of brain disorders(9-19). The accumulating evidence suggests the existence of a “TNF brain syndrome”, defined as “a shared phenotype of brain dysfunction induced by excess TNF in brain disorders of diverse aetiology.(17)”(20, 21) In 2013-2014, increasing evidence of the favorable effects of TNF inhibitors in ameliorating brain dysfunction or mortality in the clinical setting and in basic science models suggests the validity of such a concept(19, 22-33).

1. Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440(7087):1054-9.
2. Santello M, Volterra A. TNF-alpha in synaptic function: switching gears. Trends Neurosci. 2012;35(10):638-47.
3. Faingold CL. Chapter 7: Network Control Mechanisms: Cellular Inputs, Neuroactive Substances, and Synaptic Changes. In: Faingold CL, Blumenfeld H, editors. Neuronal Networks in Brain Function, CNS Disorders, and Therapeutics: Elsevier; 2014.