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Damage to the vascular system may play a major role in a number of key neurological diseases than has heretofore been thought. ... This proposal will highlight the need to rethink the role of both arterial and venous disease in aging and cancer for the former and MS, stroke and traumatic brain injury (TBI) for the latter. Therefore, my main focus is on the role of vascular damage in neurological diseases and the overarching hypothesis of this proposal is:

Hypothesis One: “A major cause of diverse neurological diseases is vascular damage, the effects of which can be seen with magnetic resonance imaging (MRI).”

Hypothesis Two: “Iron can serve as a surrogate marker for tissue damage, it can be seen in the form of ferritin and hemosiderin using SWI and will directly show the presence of vascular damage.”

Hypothesis Three: “Monitoring the early involvement of the microvascular system will make it possible to discover the etiology/pathogenesis of these diseases, to diagnose them more effectively at an earlier stage and hence to treat them more successfully.”

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It has been long thought that iron misregulation is associated with neurodegenerative disease. There is an extensive recent review of iron in neurodegenerative diseases by Kell (30). Although this will require much more detailed experimentation (30) there is certainly some evidence for it in specific disease such as neuroferritinopathy, aceruloplasminemia and hemochromatosis, for example. In the latter case, Thomas and Jankovic (31) stated: "The presence of central nervous system superficial siderosis and central nervous system vasculitis, in association with systemic hemosiderosis, may be the neurological manifestation of hemochromatosis." (In hemochromatosis, iron levels are sometimes reduced with either chelation or with phlebotomy.) They go on to note that iron elevation follows dopaminergic cell death. On a different but related note, there is some suggestion that the amount of stored iron might also play a role in risks of white matter damage post injury (31). Sullivan suggests that there is evidence that oxidative DNA damage as measured by 80HdG correlates with the amount of stored iron. A very interesting paper by Patt et al (33) and another by Grant et al (34) both suggest that reduced iron levels are associated with reduced damage to the brain. The former reports that: "Gerbils fed a low iron diet for 8 weeks had decreased brain and serum iron levels, less neuroloigical deficits and decreased brain edema after temporary unilateral carotid ligation (ischemia) and then reperfusion than gerbls fed a control standard of iron diet." The latter reports that experimental automimmune encephalomyelitis (EAE) did not develop in low iron mice. They also suggest that: "The mechanism of EAE inhibition in iron deficient mice likely involves the delivery and metabolism of iron for optimal CD4+ T-cell development." In their paper they also comment that iron supplementation has been shown to increase progression and mortality in HIV-infected people and that iron chelation in mice with EAE also reduced the clinical severity of the symptoms.