Personalized Computational Causal Modeling of the Alzheimer Disease Biomarker Cascade.

BACKGROUND: Mathematical models of complex diseases, such as Alzheimer's disease, have the potential to play a significant role in personalized medicine. Specifically, models can be personalized by fitting parameters with individual data for the purpose of discovering primary underlying disease drivers, predicting natural history, and assessing the effects of theoretical interventions. Previous work in causal/mechanistic modeling of Alzheimer's Disease progression has modeled the disease at the cellular level and on a short time scale, such as minutes to hours. No previous studies have addressed mechanistic modeling on a personalized level using clinically validated biomarkers in individual subjects. OBJECTIVES: This study aimed to investigate the feasibility of personalizing a causal model of Alzheimer's Disease progression using longitudinal biomarker data. DESIGN/SETTING/PARTICIPANTS/MEASUREMENTS: We chose the Alzheimer Disease Biomarker Cascade model, a widely-referenced hypothetical model of Alzheimer's Disease based on the amyloid cascade hypothesis, which we had previously implemented mathematically as a mechanistic model. We used available longitudinal demographic and serial biomarker data in over 800 subjects across the cognitive spectrum from the Alzheimer's Disease Neuroimaging Initiative. The data included participants that were cognitively normal, had mild cognitive impairment, or were diagnosed with dementia (probable Alzheimer's Disease). The model consisted of a sparse system of differential equations involving four measurable biomarkers based on cerebrospinal fluid proteins, imaging, and cognitive testing data. RESULTS: Personalization of the Alzheimer Disease Biomarker Cascade model with individual serial biomarker data yielded fourteen personalized parameters in each subject reflecting physiologically meaningful characteristics. These included growth rates, latency values, and carrying capacities of the various biomarkers, most of which demonstrated significant differences across clinical diagnostic groups. The model fits to training data across the entire cohort had a root mean squared error (RMSE) of 0.09 (SD 0.081) on a variable scale between zero and one, and were robust, with over 90% of subjects showing an RMSE of < 0.2. Similarly, in a subset of subjects with data on all four biomarkers in at least one test set, performance was high on the test sets, with a mean RMSE of 0.15 (SD 0.117), with 80% of subjects demonstrating an RMSE < 0.2 in the estimation of future biomarker points. Cluster analysis of parameters revealed two distinct endophenotypic groups, with distinct biomarker profiles and disease trajectories. CONCLUSION: Results support the feasibility of personalizing mechanistic models based on individual biomarker trajectories and suggest that this approach may be useful for reclassifying subjects on the Alzheimer's clinical spectrum. This computational modeling approach is not limited to the Alzheimer Disease Biomarker Cascade hypothesis, and can be applied to any mechanistic hypothesis of disease progression in the Alzheimer's field that can be monitored with biomarkers. Thus, it offers a computational platform to compare and validate various disease hypotheses, personalize individual biomarker trajectories and predict individual response to theoretical prevention and therapeutic intervention strategies.

Computerized Cognitive Training in Mild Cognitive Impairment: Findings in African Americans and Caucasians.

BACKGROUND: African Americans with MCI may be at increased risk for dementia compared to Caucasians. The effect of race on the efficacy of cognitive training in MCI is unclear. METHODS: We used data from a two-site, 78-week randomized trial of MCI comparing intensive, home-based, computerized training with Web-based cognitive games or Web-based crossword puzzles to examine the effect of race on outcomes. The study outcomes were changes from baseline in cognitive and functional scales as well as MRI-measured changes in hippocampal volume and cortical thickness. Analyses used linear models adjusted for baseline scores. This was an exploratory study. RESULTS: A total of 105 subjects were included comprising 81 whites (77.1%) and 24 African Americans (22.8%). The effect of race on the change from baseline in ADAS-Cog-11 was not significant. The effect of race on change from baseline to week 78 in the Functional Activities Questionnaire (FAQ) was significant with African American participants' FAQ scores showing greater improvements at weeks 52 and 78 (P = 0.009, P = 0.0002, respectively) than white subjects. Within the CCT cohort, FAQ scores for African American participants showed greater improvement between baseline and week 78, compared to white participants randomized to CCT (P = 0.006). There was no effect of race on the UPSA. There was no effect of race on hippocampal or cortical thickness outcomes. CONCLUSIONS: Our preliminary findings suggest that web-based cognitive training programs may benefit African Americans with MCI at least as much as Caucasians, and highlight the need to further study underrepresented minorities in AD prevention trials. (Supported by the National Institutes of Health, National Institute on Aging; ClinicalTrials.gov number, NCT03205709.).

Expectancy Does Not Predict 18-month Treatment Outcomes with Cognitive Training in Mild Cognitive Impairment.

BACKGROUND: Computerized cognitive training (CCT) has emerged as a potential treatment option for mild cognitive impairment (MCI). It remains unclear whether CCT's effect is driven in part by expectancy of improvement. OBJECTIVES: This study aimed to determine factors associated with therapeutic expectancy and the influence of therapeutic expectancy on treatment effects in a randomized clinical trial of CCT versus crossword puzzle training (CPT) for older adults with MCI. DESIGN: Randomized clinical trial of CCT vs CPT with 78-week follow-up. SETTING: Two-site study - New York State Psychiatric Institute and Duke University Medical Center. PARTICIPANTS: 107 patients with MCI. INTERVENTION: 12 weeks of intensive training with CCT or CPT with follow-up booster training over 78 weeks. MEASUREMENTS: Patients rated their expectancies for CCT and CPT prior to randomization. RESULTS: Patients reported greater expectancy for CCT than CPT. Lower patient expectancy was associated with lower global cognition at baseline and older age. Expectancy did not differ by sex or race. There was no association between expectancy and measures of everyday functioning, hippocampus volume, or apolipoprotein E genotype. Expectancy was not associated with change in measures of global cognition, everyday functioning, and hippocampus volume from baseline to week 78, nor did expectancy interact with treatment condition. CONCLUSIONS: While greater cognitive impairment and increased age was associated with low expectancy of improvement, expectancy was not associated with the likelihood of response to treatment with CPT or CCT.

Financial Management Skills in Aging, MCI and Dementia: Cross Sectional Relationship to 18F-Florbetapir PET Cortical ß-amyloid Deposition.

BACKGROUND: There is a need to more fully characterize financial capacity losses in the preclinical and prodromal stages of Alzheimer's disease (AD) and their pathological substrates. OBJECTIVES: To test the association between financial skills and cortical ß-amyloid deposition in aging and subjects at risk for AD. DESIGN: Cross-sectional analyses of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI-3) study conducted across 50 plus sites in the US and Canada. SETTING: Multicenter biomarker study. PARTICIPANTS: 243 subjects (144 cognitively normal, 79 mild cognitive impairment [MCI], 20 mild AD). MEASUREMENTS: 18F-Florbetapir brain PET scans to measure global cortical ß-amyloid deposition (SUVr) and the Financial Capacity Instrument Short Form (FCI-SF) to evaluate an individual's financial skills in monetary calculation, financial concepts, checkbook/register usage, and bank statement usage. There are five sub scores and a total score (range of 0-74) with higher scores indicating better financial skill. RESULTS: FCI-SF total score was significantly worse in MCI [Cohen's d= 0.9 (95%CI: 0.6-1.2)] and AD subjects [Cohen's d=3.1(CI: 2.5-3.7)] compared to normals. Domain scores and completion times also showed significant difference. Across all subjects, higher cortical ß-amyloid SUVr was significantly associated with worse FCI-SF total score after co-varying for age, education, and cognitive score [Cohen's f2=0.751(CI: 0.5-1.1)]. In cognitively normal subjects, after covarying for age, gender, and education, higher ß -amyloid PET SUVr was associated with longer task completion time [Cohen's f2=0.198(CI: 0.06-0.37)]. CONCLUSION: Using a multicenter study sample, we document that financial capacity is impaired in the prodromal and mild stages of AD and that such impairments are, in part, associated with the extent of cortical ß-amyloid deposition. In normal aging, ß-amyloid deposition is associated with slowing of financial tasks. These data confirm and extend prior research highlighting the utility of financial capacity assessments in at risk samples.

White Matter Changes Related to Subconcussive Impact Frequency during a Single Season of High School Football.

BACKGROUND AND PURPOSE: The effect of exposing the developing brain of a high school football player to subconcussive impacts during a single season is unknown. The purpose of this pilot study was to use diffusion tensor imaging to assess white matter changes during a single high school football season, and to correlate these changes with impacts measured by helmet accelerometer data and neurocognitive test scores collected during the same period. MATERIALS AND METHODS: Seventeen male athletes (mean age, 16 ± 0.73 years) underwent MR imaging before and after the season. Changes in fractional anisotropy across the white matter skeleton were assessed with Tract-Based Spatial Statistics and ROI analysis. RESULTS: The mean number of impacts over a 10-g threshold sustained was 414 ± 291. Voxelwise analysis failed to show significant changes in fractional anisotropy across the season or a correlation with impact frequency, after correcting for multiple comparisons. ROI analysis showed significant (P < .05, corrected) decreases in fractional anisotropy in the fornix-stria terminalis and cingulum hippocampus, which were related to impact frequency. The effects were strongest in the fornix-stria terminalis, where decreases in fractional anisotropy correlated with worsening visual memory. CONCLUSIONS: Our findings suggest that subclinical neurotrauma related to participation in American football may result in white matter injury and that alterations in white matter tracts within the limbic system may be detectable after only 1 season of play at the high school level.

American Society of Functional Neuroradiology-Recommended fMRI Paradigm Algorithms for Presurgical Language Assessment.

INTRODUCTION: Functional MR imaging is increasingly being used for presurgical language assessment in the treatment of patients with brain tumors, epilepsy, vascular malformations, and other conditions. The inherent complexity of fMRI, which includes numerous processing steps and selective analyses, is compounded by institution-unique approaches to patient training, paradigm choice, and an eclectic array of postprocessing options from various vendors. Consequently, institutions perform fMRI in such markedly different manners that data sharing, comparison, and generalization of results are difficult. The American Society of Functional Neuroradiology proposes widespread adoption of common fMRI language paradigms as the first step in countering this lost opportunity to advance our knowledge and improve patient care. LANGUAGE PARADIGM REVIEW PROCESS: A taskforce of American Society of Functional Neuroradiology members from multiple institutions used a broad literature review, member polls, and expert opinion to converge on 2 sets of standard language paradigms that strike a balance between ease of application and clinical usefulness. ASFNR RECOMMENDATIONS: The taskforce generated an adult language paradigm algorithm for presurgical language assessment including the following tasks: Sentence Completion, Silent Word Generation, Rhyming, Object Naming, and/or Passive Story Listening. The pediatric algorithm includes the following tasks: Sentence Completion, Rhyming, Antonym Generation, or Passive Story Listening. DISCUSSION: Convergence of fMRI language paradigms across institutions offers the first step in providing a "Rosetta Stone" that provides a common reference point with which to compare and contrast the usefulness and reliability of fMRI data. From this common language task battery, future refinements and improvements are anticipated, particularly as objective measures of reliability become available. Some commonality of practice is a necessary first step to develop a foundation on which to improve the clinical utility of this field.

Predictive Utility of Marketed Volumetric Software Tools in Subjects at Risk for Alzheimer Disease: Do Regions Outside the Hippocampus Matter?

BACKGROUND AND PURPOSE: Alzheimer disease is a prevalent neurodegenerative disease. Computer assessment of brain atrophy patterns can help predict conversion to Alzheimer disease. Our aim was to assess the prognostic efficacy of individual-versus-combined regional volumetrics in 2 commercially available brain volumetric software packages for predicting conversion of patients with mild cognitive impairment to Alzheimer disease. MATERIALS AND METHODS: Data were obtained through the Alzheimer's Disease Neuroimaging Initiative. One hundred ninety-two subjects (mean age, 74.8 years; 39% female) diagnosed with mild cognitive impairment at baseline were studied. All had T1-weighted MR imaging sequences at baseline and 3-year clinical follow-up. Analysis was performed with NeuroQuant and Neuroreader. Receiver operating characteristic curves assessing the prognostic efficacy of each software package were generated by using a univariable approach using individual regional brain volumes and 2 multivariable approaches (multiple regression and random forest), combining multiple volumes. RESULTS: On univariable analysis of 11 NeuroQuant and 11 Neuroreader regional volumes, hippocampal volume had the highest area under the curve for both software packages (0.69, NeuroQuant; 0.68, Neuroreader) and was not significantly different (P > .05) between packages. Multivariable analysis did not increase the area under the curve for either package (0.63, logistic regression; 0.60, random forest NeuroQuant; 0.65, logistic regression; 0.62, random forest Neuroreader). CONCLUSIONS: Of the multiple regional volume measures available in FDA-cleared brain volumetric software packages, hippocampal volume remains the best single predictor of conversion of mild cognitive impairment to Alzheimer disease at 3-year follow-up. Combining volumetrics did not add additional prognostic efficacy. Therefore, future prognostic studies in mild cognitive impairment, combining such tools with demographic and other biomarker measures, are justified in using hippocampal volume as the only volumetric biomarker.

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.

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.

Effects of donepezil on cortical activation in mild cognitive impairment: a pilot double-blind placebo-controlled trial using functional MR imaging.

BACKGROUND AND PURPOSE: Cholinesterase-inhibitor therapy is approved for treatment of Alzheimer disease; however, application in patients with mild cognitive impairment (MCI) is still under active investigation. The purpose of this study was to determine the effect of such therapy on the neural substrates underlying memory processing in subjects with MCI by using functional MR imaging (fMRI). MATERIALS AND METHODS: Thirteen subjects with MCI (mean age, 68 +/- 6.9 years) enrolled in a multicenter double-blind placebo-controlled trial testing the clinical efficacy of the cholinesterase-inhibitor, donepezil, were studied with fMRI at baseline and following 12 or 24 weeks of therapy (single-site pilot study). The cognitive paradigm was delayed-response visual memory for novel faces. Within-group 1-sample t tests were performed on the donepezil and placebo groups at baseline and at follow-up. A repeated-measures analysis of variance design was used to look for a Treatment Group x Time interaction showing a significant donepezil- but not placebo-related change in blood oxygen level-dependent response during the course of the study. RESULTS: At baseline, both groups showed multiple areas of activation, including the bilateral dorsolateral prefrontal cortex, fusiform gyrus, and anterior cingulate cortex. On follow-up, the placebo group demonstrated a decreased extent of dorsolateral prefrontal activation, whereas the donepezil group demonstrated an increased extent of activation in the ventrolateral prefrontal cortex. Interaction demonstrated significant donepezil- but not placebo-related change in the left inferior frontal gyrus. CONCLUSIONS: Despite the limitations inherent to a pilot study of a small sample, our results point to specific cortical substrates underlying the actions of donepezil, which can be tested in future studies.

Hippocampal atrophy confounds template-based functional MR imaging measures of hippocampal activation in patients with mild cognitive impairment.

BACKGROUND AND PURPOSE: Functional MR imaging has been used to study patterns of hippocampal activation that distinguish pathologic from normal memory loss in the elderly population. Our objective was to assess whether hippocampal atrophy confounds measurements of hippocampal activation in subjects with mild cognitive impairment (MCI). METHODS: Twenty subjects with MCI and 20 elderly control subjects with objectively normal memory were studied at 4T during a face-name paradigm designed to activate the hippocampus. Hippocampal activation was measured using 2 separate approaches: applying a preset region of interest (ROI) in standardized template space and applying a manually drawn ROI in native subject space. Pearson correlation coefficients were calculated to compare group-dependent relationships between hippocampal volume and activation. Analysis of covariance (ANCOVA) was performed to assess group differences in hippocampal activation during encoding and retrieval. Age and hippocampal volume were included as covariates, as was a term for the interaction between hippocampal volume and group. RESULTS: When hippocampal activation was measured by the template-based method, the correlation coefficient in the right hippocampus of subjects with MCI but not control subjects during retrieval differed significantly from zero. There was a significant (P < .05) group-by-volume interaction in the ANCOVA model. No significant correlations or interactions were demonstrated when activation was measured in native subject space with manually drawn ROIs. CONCLUSION: Our findings suggest a potential confounding relationship between hippocampal volume and activation for subjects with MCI in template-based analyses. Template-based measures of hippocampal activation that do not adequately account for hippocampal atrophy should be used with caution in patients with MCI.

In vivo amyloid imaging in Alzheimer's disease.

Targeted approaches to therapy for Alzheimer's disease have evolved based on detailed understanding of the genetic, molecular biologic, and neuropathologic basis of the disease. Given the potential for greater treatment efficacy in the earlier stages of the disease, the notion of early diagnosis has become more relevant. Current clinical and imaging diagnostic approaches lack reliability in the preclinical and prodromal phases of the disease. We review emerging studies on imaging of the molecular substrate of the disease, most notably the amyloid peptide, which hope to increase early diagnostic efficacy. We offer a brief overview of the demographics, diagnostic criteria, and current imaging tests, followed by a review of amyloid biology and developments in cerebral amyloid imaging yielded by recent in vitro, in vivo and human studies.

Quantitative assessment of diffusion abnormalities in posterior reversible encephalopathy syndrome.

BACKGROUND AND PURPOSE: Previous studies have shown that lesions in posterior reversible encephalopathy syndrome are often isointense on diffusion-weighted MR images. We hypothesized that 1) apparent diffusion coefficient (ADC) maps using various thresholds would show larger abnormalities in posterior white matter (WM) and 2) isointense appearance of lesions on isotropic diffusion-weighted images results from a balance of T2 prolongation effects and diffusibility effects. METHODS: T2-weighted MR images from 11 patients were reviewed. Hyperintense lesions were located in both anterior and posterior WM in eight patients and solely in posterior WM in three patients. The ADC maps were produced by use of ADC values > or = 3 SD and > or = 10 SD above the mean value of normal WM. Lesions on diffusion-weighted images were classified as isointense or hypointense. ADC values within lesions (ADC(L)) were compared with those of normal WM (ADC(N)), and compared for isointense lesions and hypointense lesions. RESULTS: The distribution of lesions with ADC values > or = 3 SD was essentially identical to that on T2-weighted images. Regions with ADC values > or = 10 SD were found in both anterior WM and posterior WM in two patients and solely in posterior WM in nine patients. On diffusion-weighted images, lesions appeared isointense in seven patients and hypointense in four patients. Mean ADC(L)/ADC(N) for all lesions was 1.81; for hypointense lesions, 2.30. CONCLUSION: Vasogenic edema was more severe in posterior WM. Isointense lesions result from a balance of T2 effects and increased water diffusibility. Hypointense lesions have higher ADC values, which are not balanced by T2 effects.

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.

Cerebral abscesses: investigation using apparent diffusion coefficient maps.

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.

Use of exponential diffusion imaging to determine the age of ischemic infarcts.

OBJECTIVE: Diffusion-weighted magnetic resonance imaging (DWI) detects acute ischemic infarcts with high lesion conspicuity. Determination of infarct age is difficult on DWI alone because infarct signal intensity (SIinfarct) on DWI is influenced by T2 properties ("T2 shine-through"). Maps of the apparent diffusion coefficient (ADC) reflect pure diffusion characteristics without T2 effects but have low lesion conspicuity. Thus, in clinical practice, combined use of DWI and ADC maps is required. Exponential DWI (eDWI) is an innovative means of MRI-diffusion data analysis that merges the advantages of DWI and ADC maps. The authors hypothesized that SIinfarct on eDWI would correlate with infarct age. The authors studied 114 consecutive patients who had 120 ischemic strokes with clearly determined onset times and who underwent echo-planar DWI. The eDWI were generated by dividing the signal intensity on DWI by that on the corresponding T2 image on a pixel-by-pixel basis. SIinfarct on eDWI was measured in the lesion core and expressed as a percentage of contralateral control tissue. On eDWI, relative SIinfarct changed significantly with infarct age (P < .0001). When patients were sorted in infarct-age groups, no significant differences were found within the first 120 hours. However, for patients studied within 5 days, the mean relative SIinfarct was significantly higher compared with patients studied > or = 8 days after stroke (P < .05). For all infarcts up to 5 days old, the eDWI signal intensity was higher than control tissue (hyperintense appearance). All infarcts > 10 days old had an eDWI signal intensity lower than control tissue (hypointense appearance). The authors concluded that the use of eDWI, as a single set of images, reliably differentiates acute infarcts (< or = 5 days old) from infarcts > 10 days old. This feature would be expected to be helpful when the distinction between acute and nonacute infarction cannot be determined on clinical grounds.

Evaluation of white matter anisotropy in Krabbe disease with diffusion tensor MR imaging: initial experience.

PURPOSE: To compare diffusion tensor magnetic resonance imaging with conventional T2-weighted imaging for evaluation of white matter changes in patients with Krabbe disease. MATERIALS AND METHODS: In eight patients with Krabbe disease and eight age-matched control subjects, anisotropy maps were generated with diffusion tensor data by using echo-planar imaging with diffusion gradient encoding in six directions. Anisotropy maps and T2-weighted images were visually inspected. Relative anisotropy (RA) and normalized T2-weighted signal intensity in white matter tracts and gray matter nuclei were quantitatively compared between patients and controls (paired Student t test). RESULTS: Loss of diffusion anisotropy appeared on anisotropy maps as areas of decreased hyperintensity in patients with Krabbe disease. Differences in RA between Krabbe disease patients and control subjects were significant in eight of nine white matter structures studied (P =.001-.01) and in basal ganglia (P =.04). T2-weighted signal intensity was also significantly different in the same white matter structures (P =.006-.049) but not in basal ganglia. In the three patients imaged after stem cell transplantation, mean RA was between the RAs of untreated patients and control subjects. CONCLUSION: Diffusion tensor-derived anisotropy maps (a) provide a quantitative measure of abnormal white matter in patients with Krabbe disease, (b) are more sensitive than T2-weighted images for detecting white matter abnormality, and (c) may be a marker of treatment response.

Rapid three-dimensional MR imaging method for tracking a bolus of contrast agent through the brain.

A gradient-echo three-dimensional magnetic resonance imaging technique (principles of echo shifting with a train of observations, or PRESTO) is presented for use in tracking a bolus of paramagnetic contrast agent through the brain. The approach combines a segmented echo-planar type of acquisition with echo shifting, which leads to echo times that are longer than the repetition time. Unlike echo-planar imaging, the method maintains image resolution despite drastic T2* changes and frequency shifts.