In vivo evaluation of brain iron in Alzheimer disease using magnetic resonance imaging.

BACKGROUND: The basal ganglia contain the highest levels of iron in the brain, and postmortem studies indicate a disruption of iron metabolism in the basal ganglia of patients with Alzheimer disease (AD). Iron can catalyze free radical reactions and may contribute to oxidative damage observed in AD brains. Treatments aimed at reducing oxidative damage have offered novel ways to delay the rate of progression and could possibly defer the onset of AD. Brain iron levels were quantified in vivo using a new magnetic resonance imaging method. METHODS: Thirty-one patients with AD and 68 control subjects participated in this study. A magnetic resonance imaging method was employed that quantifies the iron content of ferritin molecules (ferritin iron) with specificity through the combined use of high and low field-strength magnetic resonance imaging instruments. Three basal ganglia structures (caudate, putamen, and globus pallidus) and one comparison region (frontal lobe white matter) were evaluated. RESULTS: Basal ganglia ferritin iron levels were significantly increased in the caudate (P = .007; effect size, 0.69) and putamen (P = .008; effect size, 0.67) of AD subjects, with a trend toward an increase in the globus pallidus (P = .13). The increased basal ganglia ferritin iron levels were not a generalized phenomenon; white matter ferritin iron levels were unchanged in patients with AD (P = .50). CONCLUSIONS: The data replicate and extend prior results and suggest that basal ganglia ferritin iron levels are increased in AD. Prospective studies are needed to evaluate whether premorbid iron levels are increased in individuals who develop AD.

The incidence of T2-weighted MR imaging signal abnormalities in the brain of cocaine-dependent patients is age-related and region-specific.

BACKGROUND AND PURPOSE: Cocaine and its metabolites can produce vasospasm, and cocaine-dependent patients are at increased risk for stroke. Based on previous case reports, we hypothesized that the incidence of hyperintense brain lesions observed on T2-weighted MR images would also be increased in asymptomatic cocaine-dependent individuals. METHODS: Sixty-two male "crack" (smoked) cocaine-dependent participants ranging in age from 25 to 66 years were compared with 116 normal male control participants ranging in age from 25 to 80 years. Those with histories of neurologic symptoms or illnesses were excluded. The severity of hyperintense lesions was rated on a 0- to 3-point scale, and ratings of 3 were used in the data analysis as an indicator of a probable pathologic process. Three regions were separately rated: the cerebral white matter, insular subcortex white matter, and subcortical gray matter (basal ganglia and thalamus region). RESULTS: Significantly increased risk of severe lesions was observed in the two white matter regions of the cocaine-dependent group (odds ratio of 16.7 and 20.3) but not in the subcortial gray matter region (odds ratio of 1.4). In the insula subcortex white matter, the risk of lesions increased with age in the cocaine-dependant sample, but remained essentially absent among normal controls through the age of 80 years. In the cerebral white matter, the relationship of age and risk of lesion among normal participants was similar in shape to that in cocaine-dependent participants, but equivalent risk was seen 20 years earlier among cocaine-dependent participants. CONCLUSIONS: Cocaine-dependent participants had a significantly increased age-related risk of white matter damage. The possible clinical implications of this damage are discussed.

Increased basal ganglia iron levels in Huntington disease.

OBJECTIVE: To quantify in vivo brain ferritin iron levels in patients with Huntington disease (HD) and normal control subjects. DESIGN AND SUBJECTS: A magnetic resonance imaging method that can quantify ferritin iron levels with specificity in vivo was employed to study 11 patients with HD and a matched group of 27 normal controls. Three basal ganglia structures (caudate, putamen, and globus pallidus) and 1 comparison region (frontal lobe white matter) were evaluated. RESULTS: Basal ganglia iron levels were significantly increased (P<.002) in patients with HD, and this increase occurred early in the disease process. This was not a generalized phenomenon, as white matter iron levels were lower in patients with HD. CONCLUSIONS: The data suggest that increased iron levels may be related to the pattern of neurotoxicity observed in HD. Reducing the oxidative stress associated with increased iron levels may offer novel ways to delay the rate of progression and possibly defer the onset of HD.

Magnetic resonance imaging evidence of "silent" cerebrovascular toxicity in cocaine dependence.

BACKGROUND: Cocaine and its metabolites can produce vasospasm. Cocaine-dependent (CD) patients are at increased risk for stroke, and a high frequency of brain perfusion defects has been observed in clinically asymptomatic CD subjects. This is the first controlled magnetic resonance imaging (MRI) study of clinically asymptomatic CD subjects. METHODS: Two age-matched groups of male subjects (61 CD and 57 control) participated in the study. Subjects with a history of neurologic symptoms or major medical or neurologic illness, such as hypertension, diabetes, or significant head trauma, were excluded. The severity of hyperintense lesions observed on T2-weighted MRI images were rated on a 0-3-point scale by an experienced radiologist who was blind to all clinical data. Ratings of 3 were felt to be significant indicators of a possible disease process and were used in the data analysis. Three regions were separately rated: the cerebral white matter, subinsular white matter, and subcortical gray matter (basal ganglia and thalamus region). RESULTS: Despite the exclusion criteria minimizing risk factors for cerebrovascular events, 17 of the 61 (27.9%) CD subjects and 4 of 57 (7%) of the control subjects had severe hyperintense lesions suggestive of subclinical or "silent" anoxic vascular events. Significant group differences were observed in the two white matter regions but not in the subcortical gray matter region. The risk of severe white matter lesions in the CD group increased with age, reaching 50% in the oldest age quartile (46-58 years), and this increase was not related to the number of years cocaine was used. CONCLUSIONS: The data suggest that asymptomatic CD patients are a heterogeneous population with a significantly increased age-related risk of white matter neurovascular toxicity. Premature neurovascular damage may impact treatment outcomes and, as the CD population ages, may manifest as an increased incidence of cognitive deficits.

Relationship between blood pressure and subcortical lesions in healthy elderly people.

BACKGROUND AND PURPOSE: The relationship between blood pressure (BP) and heart rate (HR) and MRI assessments of subcortical T2 hyperintensities was evaluated in healthy elderly men and women. METHODS: Casual and 24-hour ambulatory BPs and HR measurements were taken of 144 elderly individuals, aged 55 to 79 years. Subjects had no evidence of previous health disorders. MRI scans of white matter, subcortical gray matter, and insular subcortex were coded for severity of hyperintensities. RESULTS: Mean casual BP for the group was 120/72 mm Hg. With age and sex accounted for, individuals with the highest severity rating of white matter hyperintensities had higher casual, awake, and sleep systolic BPs; higher awake diastolic BPs; greater awake systolic BP variability; and a smaller nocturnal fall in systolic and diastolic BPs than individuals with less severe ratings. Higher severity ratings for subcortical gray matter hyperintensities were associated with elevations in casual, awake, and asleep systolic BPs and a smaller HR drop during sleep. Subjects with higher ratings for the insular subcortex had higher systolic and diastolic BPs (casual, awake, and asleep), greater HR variability during sleep, and a smaller nocturnal fall in HR. CONCLUSIONS: Casual and 24-hour ambulatory BPs and some ambulatory HR measures are associated with subcortical lesions of the brain. Longitudinal studies are needed to further explore the relationship between white matter lesions and cardiovascular measures, as well as the significance of these lesions for cerebrovascular disease in healthy elderly subjects.

MR evaluation of age-related increase of brain iron in young adult and older normal males.

The purposes of this study were to extend the investigation of age-related increases in brain iron to a younger age group, replicate previously published results, and further evaluate the validity of a novel noninvasive magnetic resonance (MR) method for measuring tissue iron (ferritin) levels with specificity. The method consists of measuring the dependence of tissue transverse relaxation rates (R2) on the field strength of MR instruments. Two MR instruments operating at 1.5 and 0.5 T were used to measure the field-dependent R2 increase (FDRI) in the frontal white matter, caudate, putamen, and globus pallidus. A group of 13 normal adult males (ages 21-77), with seven subjects below and six above age 35, was examined. As expected from postmortem and prior FDRI data, robust and significant age-related increases in FDRI were observed in the caudate, putamen, and globus pallidus, with the globus pallidus FDRI increasing sharply in the second decade and reaching a plateau after age 30. In addition, we replicated previous reports showing very high correlations between FDRI and published brain iron levels for the four regions examined. The data replicate and extend previous FDRI observations on brain aging and are consistent with postmortem data on age-related increases in brain iron. These results are relevant to the investigation of age-related neurodegenerative diseases in which iron may catalyze toxic free radical reactions.