Background and Purpose Susceptibility MRI contrast variations reflect alterations in brain iron and myelin content- making this imaging tool relevant to studies of multiple sclerosis lesion heterogeneity. In this study we aimed to characterize the relationship of high-field, susceptibility contrasts in multiple sclerosis lesions to clinical outcomes. Materials and Methods Twenty-four subjects with multiple sclerosis underwent 7-tesla MRI of the brain, disability exams, and a fatigue inventory. R2*, frequency, and relative susceptibility (from quantitative susceptibility mapping) were analyzed in 306 white matter lesions. Results Most lesions were hypointense on R2* (88% without a rim, 5% with). Lesions that were hyperintense on quantitative susceptibility mapping were more frequent in relapsing-remitting than progressive multiple sclerosis (54% vs. 35%, p = 0.018). Hyperintense lesion rims on quantitative susceptibility maps were more common in progressive multiple sclerosis and higher levels of disability and fatigue. Mean lesion R2* was inversely related to disability and fatigue and significantly reduced in progressive multiple sclerosis. Relative susceptibility was lower lesions in progressive multiple sclerosis (median -0.018 ppm, range -0.070 – 0.022) than relapsing-remitting (median -0.010 ppm, range -0.062 – 0.052, p = 0.003). Conclusion A progressive clinical phenotype, greater disability, and fatigue were associated with lower R2* and relative susceptibility values (suggestive of low iron due to oligodendrocyte loss) and rimmed lesions (suggestive of chronic inflammation) in this multiple sclerosis cohort. Lesion heterogeneity on susceptibility MRI may help explain disability in multiple sclerosis and provide a window into the processes of demyelination, oligodendrocyte loss, and chronic lesion inflammation.
ObjectiveThe aim of the study was to describe longitudinal changes in serum lipids among HIV-infected men receiving highly active antiretroviral therapy (HAART) with long-term follow-up. MethodsA total of 304 HIV-infected men who initiated HAART and who had serum lipid measurements prior to and for up to 7 years after HAART initiation were identified from the Multicenter AIDS Cohort Study (MACS). Mean levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were examined at biannual time-points. ResultsSignificant lipid changes were seen within 0.5 years of HAART initiation but increases in TC ( 1 1.09 mmol/L), LDL-C ( 1 0.57 mmol/L), HDL-C ( 1 0.16 mmol/L) and non-HDL-C ( 1 0.91 mmol/L) reached peak levels 2-3 years after HAART initiation. Declines in serum TC, LDL-C and non-HDL-C in subsequent years occurred concurrently with a substantial increase in use of lipid-lowering medications (from 1% usage pre-HAART to 43% 6-7 years after HAART initiation) but the proportion of men who either were treated with cholesterol-lowering medication or had elevated cholesterol levels (45.18 mmol/L) did not change during the 2-7-year interval after HAART. Mean HDL-C also decreased after 2-3 years and was low (o1.04 mmol/L) in 55% of HIV-infected men 6-7 years after HAART initiation. ConclusionsAtherogenic serum lipids increased early after the initiation of HAART, peaked at 2-3 years and remained high or required treatment thereafter. Low HDL-C levels persisted in the majority of men. The long-term effects of lipid abnormalities on cardiovascular risk and the effectiveness and toxicity of prolonged use of lipid-lowering medications in combination with HAART are not known.Keywords: cohort studies, dyslipidemia, HAART, HIV-1, HIV infection Introduction HIV-1 infection has been associated with reductions in serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and with elevations in triglycerides (TG) observed later in the disease course [1][2][3]. Use of single or dual nucleoside reverse transcriptase inhibitors (NRTIs) was not associated with significant changes in serum lipid levels. However, within 2 years of the widespread availability of potent protease inhibitor (PI)-based highly active antiretroviral therapy (HAART), there were numerous reports of moderate to severe changes in serum lipids as well as other metabolic alterations [4][5][6][7][8][9][10][11][12]. These observations were initially anecdotal or based on limited case series, but in recent years large randomized clinical trials of HAART have routinely included prospective measurement of serum lipids [13,14].Several important questions regarding the impact of serum lipid abnormalities in HAART-treated individuals remain unanswered. The incidence of cardiovascular events among HAART recipients has been assessed in several large cohort and database studies [15][16][17][18][19]. In aggregate, these studies suggest a small but sig...
The accumulation of β-amyloid plaques is a hallmark of Alzheimer's disease (AD), and recently published data suggest that increased brain iron burden may reflect pathologies that synergistically contribute to the development of cognitive dysfunction. While preclinical disease stages are considered most promising for therapeutic intervention, the link between emerging AD-pathology and earliest clinical symptoms remains largely unclear. In the current study we therefore investigated local correlations between iron and β-amyloid plaques, and their possible association with cognitive performance in healthy older adults. 116 older adults (mean age 75 ± 7.4 years) received neuropsychological testing to calculate a composite cognitive score of performance in episodic memory, executive functioning, attention, language and communication. All participants were scanned on a combined PET-MRI instrument and were administered T1-sequences for anatomical mapping, quantitative susceptibility mapping (QSM) for assessing iron, and 18F-Flutemetamol-PET for estimating β-amyloid plaque load. Biological parametric mapping (BPM) was used to generate masks indicating voxels with significant (p < 0.05) correlation between susceptibility and 18F-Flutemetamol-SUVR. We found a bilateral pattern of clusters characterized by a statistical relationship between magnetic susceptibility and 18F-Flutemetamol-SUVR, indicating local correlations between iron and β-amyloid plaque deposition. For two bilateral clusters, located in the frontal and temporal cortex, significant relationships (p<0.05) between local β-amyloid and the composite cognitive performance score could be observed. No relationship between whole-cortex β-amyloid plaque load and cognitive performance was observable. Our data suggest that the local correlation of β-amyloid plaque load and iron deposition may provide relevant information regarding cognitive performance of healthy older adults. Further studies are needed to clarify pathological correlates of the local interaction of β-amyloid, iron and other causes of altered magnetic susceptibility.
The clinical implications of a failure to achieve high CD4 cell counts while receiving virally suppressive highly active antiretroviral therapy (HAART) are uncertain. MethodsWe analysed data from HIV-infected men participating in the Multicenter AIDS Cohort Study (MACS) to elucidate associations between CD4 cell counts achieved during virally suppressive HAART and risks of AIDS or death. Inclusion criteria were: CD4 cell count o200 cells/mL before HAART initiation; 2 viral load (VL) determinations after HAART initiation; and sustained viral suppression, defined as all VL o50 HIV-1 RNA copies/mL, but allowing a single VL of 50-1000 copies/mL. ResultsOne hundred and twenty-one men were included; median age was 42 years. After first VL o50 copies/mL, six participants had a new AIDS diagnosis and seven died. The median CD4 cell count change/year (cells/mL) after first VL o50 copies/mL was zero among patients who either developed AIDS or died vs. 39 among those who did not meet either endpoint (P 5 0.119). After controlling for time from HAART initiation to first VL o50 copies/mL, age at first VL o50 copies/ mL, history of AIDS and antiretroviral therapy (ART) experience before HAART, the hazard ratio for AIDS or death at CD4 cell count of 200 vs. 4350 cells/mL was 10.7 (P 5 0.013), and at CD4 cell count of 201-350 vs. 4350 cells/mL was 8.54 (P 5 0.014). ConclusionIn this cohort, lower CD4 cell count at the time of viral suppression was associated with increased risk of AIDS or death.
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