Faculty Bibliography

Although cognitive impairment is common in multiple sclerosis (MS), its pathophysiology is still poorly understood. Abnormalities of cerebral blood flow (CBF) have long been acknowledged in MS and advances in perfusion magnetic resonance imaging (MRI) allow for their assessment in vivo. We investigated the relationship between regional perfusion changes and neuropsychological (NP) dysfunctions in patients with relapsing-remitting and primary-progressive MS. Absolute CBF, cerebral blood volume (CBV) and mean transit time were measured in 32 MS patients and 11 healthy controls using dynamic susceptibility contrast-enhanced T2(*)-weighted MRI. A comprehensive NP test battery was administered to all patients. A mixed model analysis of covariance was performed for group comparisons in terms of perfusion measures in normal-appearing white matter (NAWM) and deep gray matter (GM). Pearson's correlations were used to describe the association of perfusion metrics with NP Z-scores. CBF and CBV values were significantly decreased in both NAWM and deep GM in MS patients compared with controls (P=0.01). In all patients, deep GM CBF was significantly associated with Rey Complex Figure Test (RCFT)-Copy (r=0.5; P=0.001) and deep GM CBV and NAWM CBV were significantly associated with Color-Word Interference Inhibition Switching test (D-KEFSIS) (r=0.4; P=0.008 and r=0.4; P=0.02). However, the only associations that remained significant after Bonferroni correction were between deep GM CBF and RCFT-Copy (P=0.006), and deep GM CBV and D-KEFSIS (P=0.04). Our results suggest a role for tissue perfusion impairment in NP dysfunction in MS. Large-scale studies are needed to characterize better this association.Journal of Cerebral Blood Flow & Metabolism advance online publication, 2 May 2007; doi:10.1038/sj.jcbfm.9600504

OBJECTIVE: Diffusion tensor imaging (DTI) allows in vivo delineation of brainstem white matter tracts. The purpose of this study was to determine whether or not abnormalities of DTI metrics and fiber tractography correlate with neurological deficits and clinical status in patients with primary posterior fossa tumors. METHODS: A review of patients with primary posterior fossa tumors who underwent magnetic resonance imaging with DTI was performed. Patients were stratified by tumor type (well-circumscribed or infiltrating lesions). Fractional anisotropy (FA) color maps were used to localize the corticospinal tracts within the brainstem. FA, mean diffusivity, and eigenvalues were measured. Tractography was performed. Correlations between DTI metrics and clinical status and between DTI metrics and neurological examination findings were assessed within each patient group using Bonferroni correction for multiple comparisons. Comparisons of DTI metrics were also made between patient groups (infiltrating lesions versus well-circumscribed lesions). RESULTS: Thirty patients were studied (mean age, 14.1 yr; 16 male, 14 female). Eighteen patients had infiltrating lesions and 12 had well-circumscribed lesions. Twelve patients (four well-circumscribed and eight infiltrating) demonstrated motor weakness on physical examination (four right, three left, five bilateral). Patients with well-circumscribed lesions and weakness had higher mean diffusivity and lower FA in the contralateral corticospinal tract (P < 0.05). No such association was seen in patients with infiltrating tumors. In 102 total patient-years of follow-up (average follow-up period, 4.2 yr), 17 patients (six well-circumscribed and 11 infiltrating lesions) demonstrated complete response or stable disease and six patients (three well-circumscribed and three infiltrating lesions) demonstrated progressive disease or death. No differences were seen in terms of DTI metrics between patients with infiltrating lesions and those with well-circumscribed lesions. Patients with well-circumscribed tumors and a bad outcome had significantly lower transverse eigenvalue measures in the corticospinal tracts compared with those with a more favorable clinical status (P < 0.05). CONCLUSION: In patients with well-circumscribed primary posterior fossa masses, higher mean diffusivity and lower FA in the brainstem corticospinal tract are associated with contralateral motor deficits; lower transverse eigenvalue may be observed with an unfavorable clinical outcome

PURPOSE: To compare routine ROI analysis and three different histogram analyses in the grading of glial neoplasms. The hypothesis is that histogram methods can provide a robust and objective technique for quantifying perfusion data in brain gliomas. Current region-of-interest (ROI)-based methods for the analysis of dynamic susceptibility contrast perfusion magnetic resonance imaging (DSC MRI) data are operator-dependent. MATERIALS AND METHODS: A total of 92 patients underwent conventional and DSC MRI. Multiple histogram metrics were obtained for cerebral blood flow (CBF), cerebral blood volume (CBV), and relative CBV (rCBV) maps using tumoral (T), peritumoral (P), and total tumoral (TT) analysis. Results were compared to histopathologic grades. Statistical analysis included Mann-Whitney (MW) tests, Spearman rank correlation coefficients, logistic regression, and McNemar tests. RESULTS: The maximum value of rCBV (rCBV(max)) showed highly significant correlation with glioma grade (r = 0.734, P < 0.001). The strongest histogram correlations (P < 0.0001) occurred with rCBV(T) SD (r = 0.718), rCBV(P) SD(25) (r = 0.724) and rCBV(TT) SD(50) (r = 0.685). Multiple rCBV(T), rCBV(P), and rCBV(TT) histogram metrics showed significant correlations. CBF and CBV histogram metrics were less strongly correlated with glioma grade than rCBV histogram metrics. CONCLUSION: Histogram analysis of perfusion MR provides prediction of glioma grade, with peritumoral metrics outperforming tumoral and total tumoral metrics. Further refinement may lead to automated methods for perfusion data analysis. J. Magn. Reson. Imaging 2007;26:1053-1063. (c) 2007 Wiley-Liss, Inc

PURPOSE: To determine if increased perfusion using dynamic susceptibility contrast perfusion MRI (DSC MRI) in gliomas may be predictive of 1p19q deletions. Loss of heterozygosity of chromosomes 1p and 19q confers responsiveness to chemotherapy improving survival in gliomas. MATERIALS AND METHODS: We retrospectively reviewed 16 patients who had DSC MRI and molecular studies of their excised gliomas for 1p19q deletions. Allelic status was assessed by loss of heterozygosity using polymerase chain reaction (PCR). DNA was extracted from paraffin curls of brain tumor sections and nail clippings. Relative cerebral blood volume (rCBV) measurements were then statistically compared with the presence of 1p and 19q deletions. RESULTS: Patients with 1p19q deletions (N = 7) demonstrated rCBV values of 10.54 +/- 2.93. Patients without 1p deletions (N = 9) had rCBV values of 4.84 +/- 2.4 (P = 0.012). Logistic regression demonstrated that rCBV was able to predict the presence of a 1p deletion to significance levels of 0.038 and 0.044, adjusted and not adjusted for age and sex, respectively. The kappa coefficient for the agreement between predicted deletion status using rCBV and the truedeletion status was 0.746 (P = 0.0028). Deletions of 19q alone, or together with 1p deletions, were not associated with high rCBV. CONCLUSION: Histopathologic, molecular, and imaging evidence supports increased neovascularity in gliomas with 1p deletions in this preliminary study. We propose a diagnostic algorithm to obtain molecular studies in gliomas demonstrating high rCBV.

BACKGROUND AND PURPOSE: Histogram analysis can be applied to dynamic susceptibility contrast (DSC) perfusion MR imaging datasets and can be as effective as traditional region-of-interest (ROI) measurements of relative cerebral blood volume (rCBV), an operator-dependent method. We compare the routine ROI method with histogram analysis in the grading of glial neoplasms. MATERIALS AND METHODS: Ninety-two patients underwent conventional and DSC MR imaging. Routine rCBV (rCBVmax) measurements were obtained from ROIs of the maximal abnormality within the glioma. Histogram analysis rCBVT was performed with an ROI drawn around the maximal tumor diameter. Spearman rank correlations measured associations among glioma grade, rCBVmax, and histogram measures. Mann-Whitney tests compared grade with respect to rCBV and histogram measures. Logistic regression and McNemar test compared the utility of rCBVmax and histogram measures for detecting high grade gliomas. RESULTS: Routine rCBVmax analysis showed significant correlation with grade (r = 0.734, P < .001). Histogram rCBVT metrics showed significant correlation with grade (P < .008); the 3 highest were rCBVT SD, SD50, and mean25 (r = 0.718, 0.684, and 0.683, respectively). Grade could be predicted by rCBVmax (P < .001) as well as rCBV(T) (P < .008). Three rCBVT histogram measures (SD, SD25, and SD50) detected high-grade glioma with significantly higher specificity than rCBVmax when the diagnostic tests were constrained to have at least 95% sensitivity. CONCLUSION: rCBVT histogram analysis is as effective as rCBVmax analysis in the correlation with glioma grade. Inexperienced operators may obtain perfusion metrics using histogram analyses that are comparable with those obtained by experienced operators using ROI analysis.

BACKGROUND AND PURPOSE: Hypoperfusion of the normal-appearing white matter in multiple sclerosis (MS) may be related to ischemia or secondary to hypometabolism from wallerian degeneration (WD). This study evaluated whether correlating perfusion and diffusion tensor imaging (DTI) metrics in normal-appearing corpus callosum could provide support for an ischemic mechanism for hypoperfusion. MATERIALS AND METHODS: Fourteen patients with relapsing-remitting MS (RRMS) and 17 control subjects underwent perfusion MR imaging and DTI. Absolute measures of cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) were calculated. Mean diffusivity (MD) and fractional anisotropy (FA) maps were computed from DTI data. After visual coregistration of perfusion and DTI images, regions of interest were placed in the genu, central body, and splenium of normal-appearing corpus callosum. Pearson product-moment correlation coefficients were calculated using mean DTI and perfusion measures in each region. RESULTS: In the RRMS group, CBF and CBV were significantly correlated with MD in the splenium (r = 0.83 and r = 0.63, respectively; both P < .001) and in the central body (r = 0.86 and r = 0.65, respectively; both P < .001), but not in the genu (r = 0.23 and 0.25, respectively; both P is nonsignificant). No significant correlations were found between MTT and DTI measures or between FA and any perfusion measure in the RRMS group. No significant correlations between diffusion and perfusion metrics were found in control subjects. CONCLUSION: In the normal-appearing corpus callosum of patients with RRMS, decreasing perfusion is correlated with decreasing MD. These findings are more consistent with what would be expected in primary ischemia than in secondary hypoperfusion from WD.

OBJECTIVES: To assess the presence of perfusion abnormalities in the deep gray matter of patients with relapsing-remitting and primary progressive multiple sclerosis (MS) in comparison with healthy controls and to investigate the impact of perfusion impairment on clinical disability and fatigue. DESIGN: Survey. SETTING: Research-oriented hospital. Patients Twenty-two patients with MS and 11 age- and sex-matched healthy volunteers. Intervention Absolute cerebral blood flow, cerebral blood volume, and mean transit time were measured in the thalamus, putamen, and caudate nuclei. MAIN OUTCOME MEASURES: Decrease of cerebral blood flow in the deep gray matter of patients with MS and correlation between perfusion impairment and the severity of fatigue. RESULTS: The cerebral blood flow value averaged over the thalamus, putamen, and caudate nuclei was significantly lower in patients with primary progressive MS (P<.001) and in patients with relapsing-remitting MS (P = .01) compared with controls, and there was a trend for patients with primary progressive MS to have lower average cerebral blood flow than patients with relapsing-remitting MS (P = .06). With respect to cerebral blood volume, there was a significant difference between patients with primary progressive MS and controls (P<.001) and between the 2 groups of patients (P = .03) but not between patients with relapsing-remitting MS and controls (P>.30). The fatigue score was significantly correlated with cerebral blood flow (r = 0.4; P<.001) and cerebral blood volume (r = 0.5; P = .004). CONCLUSION: The decrease of tissue perfusion in the deep gray matter of patients with MS is associated with the severity of fatigue

This study aimed to determine regional pattern of tissue perfusion in the normal-appearing white matter (NAWM) of patients with primary-progressive (PP), relapsing-remitting (RR) multiple sclerosis (MS) and healthy controls, and to investigate the association between perfusion abnormalities and clinical disability. Using dynamic susceptibility contrast (DSC) perfusion MRI at 3 T, we studied 22 patients with clinically definite MS, 11 with PP-MS and 11 with RR-MS and 11 age- and gender-matched healthy volunteers. The MRI protocol included axial dual-echo, dynamic susceptibility contrast enhanced (DSC) T2*-weighted and post-contrast T1-weighted images. Absolute cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were measured in the periventricular, frontal, occipital NAWM and in the splenium of the corpus callosum. Compared to controls, CBF and CBV were significantly lower in all NAWM regions in both PP-MS patients (p values from <0.0001 to 0.001) and RR-MS (p values from <0.0001 to 0.020). Compared to RR-MS, PP-MS patients showed significantly lower CBF in the periventricular NAWM (p=0.002) and lower CBV in the periventricular and frontal NAWM (p values: 0.0029 and 0.022). EDSS was significantly correlated with the periventricular CBF (r=-0.48, p=0.0016) and with the periventricular and frontal CBV (r=-0.42, p=0.015; r=-0.35, p=0.038, respectively). This study suggests that the hemodynamic abnormalities of NAWM have clinical relevance in patients with MS. DSC perfusion MRI might provide a relevant objective measure of disease activity and treatment efficacy

BACKGROUND AND PURPOSE: Glial cancer cells can be found well beyond the MR imaging T2 signal-intensity hyperintensity. To quantify the extent of the diffuse microstructural tissue damage possibly due to the presence of these satellite tumor cells, we investigated the relationships between global metabolic and microstructural abnormalities in the normal-appearing brain regions of patients with newly diagnosed glioma. MATERIAL AND METHODS: Ten patients (6 men, 4 women) with radiologically suspected untreated supratentorial glial tumors and 9 healthy controls (5 men, 4 women) were studied with T1- and T2-weighted MR imaging, diffusion-weighted echo-planar MR imaging, and whole-brain N-acetylaspartate (WBNAA) proton MR spectroscopy. The relationship between the WBNAA concentration, the mean diffusivity (MD), and fractional anisotropy (FA) values in a large contralateral normal-appearing white matter (NAWM) brain region was investigated with the Spearman rank correlation test. RESULTS: WBNAA values were significantly lower (P < .001) in patients (9.7 +/- 1.7 mmol/L) than controls (13.1 +/- 1.1 mmol/L). MD values were higher (P = .0001) in patients (0.95 +/- 0.07 mm(2)s(-1)) than in controls (0.61 +/- 0.04 mm(2)s(-1)). FA values did not differ between patients (0.42 +/- 0.08) and controls (0.43 +/- 0.041). A strong inverse correlation between WBNAA and MD (r = -0.88, P = .0008) was found in the patients but not in controls (r = 0.012, P = .975). CONCLUSION: The correlation between the WBNAA and MD in the contralateral NAWM suggests that the microstructural damage possibly related to the presence of infiltrative tumor cells contributes to WBNAA decline in these patients