Steven D. Brass

Magnetic Resonance Imaging of Iron Deposition in Neurological Disorders

Deposition of iron in the brain is proposed to play a role in the pathophysiology of the normal aging process and neurodegenerative diseases. Whereas iron is required for normal neuronal metabolism, excessive levels can contribute to the formation of free radicals, leading to lipid peroxidation and neurotoxicity. Magnetic resonance imaging (MRI) is a powerful tool to detect excessive iron in the brain and longitudinally monitor changes in iron levels. Iron deposition is associated with a reduction in the T2 relaxation time, leading to hypointensity on spin-echo and gradient-echo T2-weighted images. The MRI changes associated with iron deposition have been observed both in normal aging and in various chronic neurological diseases, including multiple sclerosis, Alzheimer disease, and Parkinson disease. Magnetic resonance imaging metrics providing information about iron concentrations include R2, R2&vprime;, and R2*. The purpose of this review is to discuss the role of iron and its detection by MRI in various neurological disorders. We will review the basic biochemical properties of iron and its influence on MRI signal. We will also summarize the sensitivity and specificity of MRI techniques in detecting iron. The MRI and pathological findings pertaining to brain iron will be reviewed with respect to normal aging and a variety of neurological disorders. Finally, the biochemistry and pathophysiology surrounding iron, oxidative stress, free radicals, and lipid peroxidation in the brain will be discussed, including therapeutic implications. The potential role of iron deposition and its assessment by MRI provides exciting potential applications to the diagnosis, longitudinal monitoring, and therapeutic development for disorders of the brain.

Cognitive impairment is associated with subcortical magnetic resonance imaging grey matter T2 hypointensity in multiple sclerosis

Grey matter hypointensity on T2-weighted magnetic resonance imaging (MRI) scans, suggesting iron deposition, has been described in multiple sclerosis (MS) and is related to physical disability, disease course and brain atrophy. We tested the hypothesis that subcortical grey matter T2 hypointensity is related to cognitive impairment after adjusting for the effect of MRI lesion and atrophy measures. We studied 33 patients with MS and 14 healthy controls. Normalized T2 signal intensity in the caudate, putamen, globus pallidus and thalamus, total brain T1-hypointense lesion volume (T1LV), fluid-attenuated inversion-recovery-hyperintense lesion volume (FLLV) and brain parenchymal fraction (BPF) were obtained quantitatively. A neuropsychological composite score (NCS) encompassed new learning, attention, working memory, spatial processing and executive function. In each of the regions of interest, the normalized T2 intensity was lower in the MS versus control group (all P <0.001). Regression modelling tested the relative association between all MRI variables and NCS. Globus pallidus T2 hypointensity was the only variable selected in the final model (R2 = 0.301, P = 0.007). Pearson correlations between MRI and NCS were T1LV: r = -0.319; FLLV: r = -0.347; BPF: r = 0.374; T2 hypointensity of the caudate: r = 0.305; globus pallidus: r = 0.395; putamen: r = 0.321; and thalamus: r = 0.265. Basal ganglia T2 hypointensity and BPF demonstrated the strongest associations with cognitive impairment on individual cognitive subtests. Subcortical grey matter T2 hypointensity is related to cognitive impairment in MS, supporting the clinical relevance of T2 hypointensity as a biological marker of MS tissue damage. These data implicate a role for basal ganglia iron deposition in neuropsychological dysfunction.

Deep gray matter involvement on brain MRI scans is associated with clinical progression in multiple sclerosis.

Conventional brain MRI lesion measures have unreliable associations with clinical progression in multiple sclerosis (MS). Gray matter imaging may improve clinical‐MRI correlations.

Role of iron in neurotoxicity: a cause for concern in the elderly?

Purpose of reviewTo explore the role of iron physiology in the brain of healthy adults and review how increased brain iron deposition has been associated with common neurodegenerative diseases that affect the elderly. Recent findingsBecause iron plays a role in oxygen transportation, myelin synthesis, neurotransmitter production, and electron transfers, it serves as a crucial cofactor in normal central nervous metabolism. However, an increased level of brain iron may promote neurotoxicity due to free radical formation, lipid peroxidation, and ultimately, cellular death. Advanced neuroimaging techniques and pathological studies have demonstrated increased brain iron with aging, and increased iron deposition has also been observed in patients with a constellation of neurological diseases, including Alzheimers disease, Parkinsons disease, and stroke. SummaryPathologic and neurologic imaging coupled with experimentation have increased our understanding of the link between iron and neurodegeneration. A potential implication is that disease-modifying therapies aimed at removing excess iron may one day be part of the armamentarium employed by clinicians to decrease the burden of neurodegenerative diseases in the elderly.

Case 12-2009: A 46-year-old man with migraine, aphasia, and hemiparesis and similarly affected family members

From the Departments of Neurology (S.D.B.), Radiology (W.A.C.), and Pathology (M.P.F.), Massachusetts General Hospital, Boston; the Department of Neurology, Foothills Hospital, and the Department of Clinical Neurosciences, University of Calgary — both in Calgary, AB, Canada (E.E.S.); and the Departments of Neurology (S.D.B.), Cell Biology (J.F.A.-V.), Radiology (W.A.C.), and Pathology (M.P.F.), Harvard Medical School, Boston.

Acute demyelinating optic neuritis: A review

Acute demyelinating optic neuritis (ON) is a leading consideration in the differential diagnosis for young adults presenting with sudden onset of painful unilateral visual loss. Multiple sclerosis (MS) is believed to be the most common etiology for ON. Nearly 50% of MS patients will develop ON, and in 15-20% of cases, ON will be the initial manifestation of the illness. Conventional and emerging magnetic resonance imaging (MRI) techniques have provided greater insight into the pathophysiology of ON, and conventional MRI has also allowed clinicians to better estimate the future risk of MS. At 10 years after ON, patients with zero, one, or two or more brain lesions on T2-weighted MRI sequences demonstrated a 22%, 52%, and 56% risk of developing MS, respectively. Treatment with high dose intravenous methylprednisolone may accelerate visual recovery in patients with acute ON, but has little impact on long term visual outcome. Disease modifying therapies in patients with acute demyelinating ON should be considered as a treatment option at the time of initial presentation in those patients whose initial brain MRI shows demyelinating lesions as these therapies have been shown in to be effective at reducing the future risk of MS.

Case records of the Massachusetts General Hospital. Case 12-2009. A 46-year-old man with migraine, aphasia, and hemiparesis and similarly affected family members.

From the Departments of Neurology (S.D.B.), Radiology (W.A.C.), and Pathology (M.P.F.), Massachusetts General Hospital, Boston; the Department of Neurology, Foothills Hospital, and the Department of Clinical Neurosciences, University of Calgary — both in Calgary, AB, Canada (E.E.S.); and the Departments of Neurology (S.D.B.), Cell Biology (J.F.A.-V.), Radiology (W.A.C.), and Pathology (M.P.F.), Harvard Medical School, Boston.

Case 12-2009

From the Departments of Neurology (S.D.B.), Radiology (W.A.C.), and Pathology (M.P.F.), Massachusetts General Hospital, Boston; the Department of Neurology, Foothills Hospital, and the Department of Clinical Neurosciences, University of Calgary — both in Calgary, AB, Canada (E.E.S.); and the Departments of Neurology (S.D.B.), Cell Biology (J.F.A.-V.), Radiology (W.A.C.), and Pathology (M.P.F.), Harvard Medical School, Boston.

Case records of the Massachusetts General Hospital. Case 36-2008. A 59-year-old man with chronic daily headache.

Three months before admission, computed tomography (CT) of the head without contrast material revealed increased density and possible thickening of the dural and subdural spaces along the frontal lobes. Results of liver-function tests were normal; other results of laboratory tests are shown in Table 1. On follow-up evaluation, the patient reported difficulty sleeping and night sweats, dry mouth at night, polydipsia and polyuria (urinating up to 25 times per day and up to 6 times per night), and pain in the jaws when chewing. His wife noted that he snored at night, but she had not observed choking or apneic episodes. Approximately 30 years earlier, for several years, he had had annual episodes of fever, sweats, and myalgia of 1 week’s duration, each of which had resolved after the use of antibiotics. Twenty-three years earlier, a mediastinal mass, 7.5 cm by 10 cm, was resected, and pathological examination reportedly revealed caseating granulomas within a lymph node. Testing for tuberculosis was negative. The annual febrile episodes had ceased after the surgery.

Case Records of the Massachusetts General Hospital. Case 38-2009 - a 16-year-old boy with paroxysmal headaches and visual changes.

From the Departments of Neurology (S.D.B., K.S.K.), Neuro-Ophthalmology (M.J.D.), Neurosurgery (Z.W.), Radiology (W.A.C.), and Pathology (S.H.F.), Massachusetts General Hospital; and the Departments of Neurology (S.D.B., K.S.K.), Neurology (M.J.D.), Surgery (Z.W.), Radiology (W.A.C.), and Pathology (S.H.F.), Harvard Medical School.