Jeffrey R. Petrella

Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Developmental aspects of language processing: fMRI of verbal fluency in children and adults†

We examined developmental differences, in location and extent of fMRI language activation maps, between adults and children while performing a semantic fluency task. We studied 29 adults and 16 children with echo planar imaging BOLD fMRI at 1.5 T using covert semantic verbal fluency (generation of words to categories compared to rest) using a block design. Post task testing was administered to assess performance. Individual data were analyzed with an a priori region of interest approach from t maps (t = 4) and asymmetry indices (AI). Group studies were analyzed using SPM 99 (Wellcome, UK; fixed effect, corrected P < 0.0001). We found no significant differences in location or laterality of activation between adults and children for a semantic verbal fluency task. Adults activated more pixels than children in left inferior frontal gyrus and left middle frontal gyrus, but AIs were the similar across ages (r2 < 0.09). Extent or laterality of activation was not affected by performance (r2 < 0.15). The brain areas that process semantic verbal fluency are similar in children and adults. The laterality of activation does not change appreciably with age and appears to be strongly lateralized by age 7 years. Hum. Brain Mapping 18:176–185, 2003.

Default mode network connectivity in stable vs progressive mild cognitive impairment

Objective: Dysfunction of the default mode network (DMN) has been identified in prior cross-sectional fMRI studies of Alzheimer disease (AD) and mild cognitive impairment (MCI); however, no studies have examined its utility in predicting future cognitive decline. Methods: fMRI scans during a face–name memory task were acquired from a cohort of 68 subjects (25 normal control, 31 MCI, and 12 AD). Subjects with MCI were followed for 2.4 years (±0.8) to determine progression to AD. Maps of DMN connectivity were compared with a template DMN map constructed from elderly normal controls to obtain goodness-of-fit (GOF) indices of DMN expression. Indices were compared between groups and correlated with cognitive decline. Results: GOF indices were highest in normal controls, intermediate in MCI, and lowest in AD (p < 0.0001). In a predictive model (that included baseline GOF indices, age, education, Mini-Mental State Examination score, and an index of DMN gray matter volume), the effect of GOF index on progression from MCI to dementia was significant. In MCI, baseline GOF indices were correlated with change from baseline in functional status (Clinical Dementia Rating–sum of boxes) (r = −0.40, p < 0.04). However, there was no additional predictive value for DMN connectivity when baseline delayed recall was included in the models. Conclusions: fMRI connectivity indices distinguish patients with MCI who undergo cognitive decline and conversion to AD from those who remain stable over a 2- to 3-year follow-up period. Our data support the notion of different functional brain connectivity endophenotypes for “early” vs “late” MCI, which are associated with different baseline memory scores and different rates of progression and conversion.

Predicting Cognitive Decline in Subjects at Risk for Alzheimer Disease by Using Combined Cerebrospinal Fluid, MR Imaging, and PET Biomarkers

PURPOSE To assess the extent to which multiple Alzheimer disease (AD) biomarkers improve the ability to predict future decline in subjects with mild cognitive impairment (MCI) compared with predictions based on clinical parameters alone. MATERIALS AND METHODS All protocols were approved by the institutional review board at each site, and written informed consent was obtained from all subjects. The study was HIPAA compliant. Alzheimers Disease Neuroimaging Initiative (ADNI) baseline magnetic resonance (MR) imaging and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) studies for 97 subjects with MCI were used. MR imaging-derived gray matter probability maps and FDG PET images were analyzed by using independent component analysis, an unbiased data-driven method to extract independent sources of information from whole-brain data. The loading parameters for all MR imaging and FDG components, along with cerebrospinal fluid (CSF) proteins, were entered into logistic regression models (dependent variable: conversion to AD within 4 years). Eight models were considered, including all combinations of MR imaging, PET, and CSF markers with the covariates (age, education, apolipoprotein E genotype, Alzheimers Disease Assessment Scale-Cognitive subscale score). RESULTS Combining MR imaging, FDG PET, and CSF data with routine clinical tests significantly increased the accuracy of predicting conversion to AD compared with clinical testing alone. The misclassification rate decreased from 41.3% to 28.4% (P < .00001). FDG PET contributed more information to routine tests (P < .00001) than CSF (P = .32) or MR imaging (P = .08). CONCLUSION Imaging and CSF biomarkers can improve prediction of conversion from MCI to AD compared with baseline clinical testing. FDG PET appears to add the greatest prognostic information.

Cortical localization of reading in normal children An fMRI language study

Background: fMRI provides a noninvasive means of identifying the location and organization of neural networks that underlie cognitive functions. Objective: To identify, using fMRI, brain regions involved in processing written text in children. Methods: The authors studied nine normal right-handed native English-speaking children, aged 10.2 years (range 7.9 to 13.3 years), with two paradigms: reading Aesop’s Fables and “Read Response Naming” (reading a description of an object that was then silently named). Data were acquired using blood oxygen level-dependent fMRI. Group data were analyzed with statistical parametric mapping; individual data sets were analyzed with a region-of-interest approach from individual study t maps. The number of activated pixels was determined in brain regions and an asymmetry index (AI = [L − R]/[L + R]) calculated for each region. Results: The authors found strong activation in the left middle temporal gyrus and left midfrontal gyrus and variable activation in left inferior frontal gyrus for both reading tasks in the group analysis (z > 5.5 to 9.1). All subjects had strong left-sided lateralization for both tasks in middle/superior temporal gyrus, inferior frontal gyrus, and middle frontal gyrus (AI = 0.76 to 1.0 for t = 4). Reading Fables activated twice as many pixels in temporal cortex as the Read Response Naming task; activation in dorsolateral prefrontal cortex was similar for both tasks. Small homologous right middle temporal region activation was seen with reading a fable. Conclusions: The neural networks that process reading appear to be lateralized and localized by middle to late childhood. Reading text paradigms may prove useful for identifying frontal and temporal language-processing areas and for determining language dominance in children experiencing epilepsy or undergoing tumor surgery.

Prognostic Value of Posteromedial Cortex Deactivation in Mild Cognitive Impairment

Background Normal subjects deactivate specific brain regions, notably the posteromedial cortex (PMC), during many tasks. Recent cross-sectional functional magnetic resonance imaging (fMRI) data suggests that deactivation during memory tasks is impaired in Alzheimers disease (AD). The goal of this study was to prospectively determine the prognostic significance of PMC deactivation in mild cognitive impairment (MCI). Methodology/Principal Findings 75 subjects (34 MCI, 13 AD subjects and 28 controls) underwent baseline fMRI scanning during encoding of novel and familiar face-name pairs. MCI subjects were followed longitudinally to determine conversion to AD. Regression and analysis of covariance models were used to assess the effect of PMC activation/deactivation on conversion to dementia as well as in the longitudinal change in dementia measures. At longitudinal follow up of up to 3.5 years (mean 2.5±0.79 years), 11 MCI subjects converted to AD. The proportion of deactivators was significantly different across all groups: controls (79%), MCI-Nonconverters (73%), MCI-converters (45%), and AD (23%) (p<0.05). Mean PMC activation magnitude parameter estimates, at baseline, were negative in the control (−0.57±0.12) and MCI-Nonconverter (−0.33±0.14) groups, and positive in the MCI-Converter (0.37±0.40) and AD (0.92±0.30) groups. The effect of diagnosis on PMC deactivation remained significant after adjusting for age, education and baseline Mini-Mental State Exam (p<0.05). Baseline PMC activation magnitude was correlated with change in dementia ratings from baseline. Conclusion Loss of physiological functional deactivation in the PMC may have prognostic value in preclinical AD, and could aid in profiling subgroups of MCI subjects at greatest risk for progressive cognitive decline.

Cerebral abscesses: investigation using apparent diffusion coefficient maps

Abstract The combination of high signal and reduced apparent diffusion coefficients (ADC) within abscesses on diffusion-weighted MRI (DWI) has been reported as characteristic of abscesses, and useful for distinguishing them from cystic or necrotic neoplasms. To assess whether these are consistent findings in abscesses, we used DWI-derived ADC to investigate changes in water diffusibility in cerebral abscesses. We reviewed the MRI studies and clinical records of five patients with brain abscesses, who underwent DWI. Regions of interest were drawn within the abscesses on ADC maps, to obtain the ADC. The center of all five abscesses gave signal higher than that of white matter on DWI. The three largest also appeared bright on ADC maps, i. e., showed ADC substantially lower than those of normal white matter, consistent with restricted diffusion. However, the two smaller abscesses were not visible on ADC maps because their ADC were essentially the same as that of white matter; they did not show restricted diffusion. The absence of restricted diffusion within small abscesses may be related to intrinsic differences in molecular microenvironment between small and large abscesses, or to greater influence of volume averaging with surrounding edema on the ADC in smaller abscesses.

Investigation of long-term reproducibility of intrinsic connectivity network mapping: a resting-state fMRI study.

BACKGROUND AND PURPOSE: Connectivity mapping based on resting-state fMRI is rapidly developing, and this methodology has great potential for clinical applications. However, before resting-state fMRI can be applied for diagnosis, prognosis, and monitoring treatment for an individual patient with neurologic or psychiatric diseases, it is essential to assess its long-term reproducibility and between-subject variations among healthy individuals. The purpose of the study was to quantify the long-term test-retest reproducibility of ICN measures derived from resting-state fMRI and to assess the between-subject variation of ICN measures across the whole brain. MATERIALS AND METHODS: Longitudinal resting-state fMRI data of 6 healthy volunteers were acquired from 9 scan sessions during >1 year. The within-subject reproducibility and between-subject variation of ICN measures, across the whole brain and major nodes of the DMN, were quantified with the ICC and COV. RESULTS: Our data show that the long-term test-retest reproducibility of ICN measures is outstanding, with >70% of the connectivity networks showing an ICC > 0.60. The COV across 6 healthy volunteers in this sample was >0.2, suggesting significant between-subject variation. CONCLUSIONS: Our data indicate that resting-state ICN measures (eg, the correlation coefficients between fMRI signal-intensity profiles from 2 different brain regions) are potentially suitable as biomarkers for monitoring disease progression and treatment effects in clinical trials and individual patients. Because between-subject variation is significant, it may be difficult to use quantitative ICN measures in their current state as a diagnostic tool.

Infarct volume on apparent diffusion coefficient maps correlates with length of stay and outcome after middle cerebral artery stroke.

Background: Diffusion-weighted MRI (DWI) can depict acute ischemia based on decreased apparent diffusion coefficient (ADC) values. ADC maps, unlike DWI (which have contributions from T2 properties), solely reflect diffusion properties. Recent studies indicate that severity of neurological deficit corresponds with degree of ADC alteration. Purpose: To determine whether infarct volume on ADC maps correlates with length of hospitalization and clinical outcome in patients with acute ischemic middle cerebral artery (MCA) stroke. Study Population: Forty-five consecutive patients with acute (≤72 h) MCA infarcts seen on DWI. Methods: Infarct volume was determined by counting pixels with ADC values >3 SDs below the average ADC value of a contralateral control region. Infarct volume was correlated with length of hospitalization and 6-month outcome assessed with Glasgow Outcome Scale (GOS), Modified Rankin Score (mRS), Barthel Index (BI) and a dichotomized outcome status with favorable outcome defined as GOS 1, mRS ≤1 and BI ≧95. Results: Infarct volume on ADC maps ranged from 0.2 to 187 cm3 and was significantly correlated with length of hospitalization (p < 0.001, r = 0.67). Furthermore, ADC infarct volume was significantly correlated with GOS (r = 0.73), mRS (r = 0.68), BI (r = 0.67) and outcome status (r = 0.65) (each p < 0.001). Multiple logistic regression revealed a statistically significant correlation between ADC infarct volume and outcome status (p < 0.05), but none for Canadian Neurological Scale score, age and gender (p >0.05 each). Conclusion: Infarct volume measured by using a quantitative definition for infarcted tissue on ADC maps correlated significantly with length of hospitalization (as a possible surrogate marker for short-term outcome) and functional outcome after 6 months. ADC infarct volume may provide prognostic information for patients with acute ischemic MCA stroke.

Assessment of vasogenic edema in eclampsia using diffusion imaging.

Abstract We qualitatively assessed the regional distribution of vasogenic edema in a case of postpartum eclampsia. Although diffusion-weighted imaging showed no abnormalities, bilateral high signal was seen on T2-weighted images and apparent diffusion coefficient (ADC) maps. ADC of 1.45 ± 0.10 mm2/s × 10–3 for the posterior cerebral artery (PCA) territory and 1.22 ± 0.12 mm2/s × 10–3 for the watershed areas were significantly higher than those in the territories of the anterior (0.85 ± 0.07 mm2/s × 10–3) and middle cerebral (0.79 ± 0.06 mm2/s × 10–3)arteries (P < 0.05). The predilection of ADC changes within the PCA territory and in a previously undescribed watershed distribution supports the hypothesis that vasogenic edema in eclampsia is due to hypertension-induced failure of vascular autoregulation.