Search

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., Competing Interests: JRP has served on medical advisory boards for cortechs.ai, Biogen and icometrix. PMD has received grants, advisory/board fees and/or stock from several health and technology companies. PMD is a co- inventor on several patents for the diagnosis or treatment of dementias. No competing interest is declared for other authors.

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., (© 2018 by American Journal of Neuroradiology.)

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., (© 2017 by American Journal of Neuroradiology.)

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., (© 2017 by American Journal of Neuroradiology.)

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.

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.

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.

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.

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.

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.

Objective: The purpose of our study was to test the hypothesis that the apparent diffusion coefficient (ADC) of normal-appearing white matter increases with advancing age., Subjects and Methods: We selected 38 patients with normal MR imaging findings from 332 patients undergoing clinical MR imaging. Diffusion-weighted MR imaging was performed with diffusion gradients applied in three orthogonal directions. For each patient, the average ADC on trace-weighted diffusion images of white matter at prespecified regions of interest and at the thalamus were compared with the patient's age., Results: For the white matter, ADC sorted by patient age in decades increased with advancing age. Patients at least 60 years old had significantly higher ADC (0.769 +/- 0.019 mm(2)/sec x 10(-3)) than patients less than 60 years old (0.740 +/- 0.013 mm(2)/sec x 10(-3)) (p < 0.001). Comparison of individual white matter ADC and age showed a significant increase with advancing age (p < 0.0001). For the thalamus, the average ADC among patients at least 60 years old (0.766 +/- 0.015 mm(2)/sec x 10(-3)) exceeded the average ADC for patients less than 60 years old (0.745 +/- 0.022 mm(2)/sec x 10(-3)) (p < 0.05). However, comparison of individual thalamic ADC and patient ages, although showing a trend to higher ADC with increasing age, did not reach statistical significance (p = 0.06)., Conclusion: Advancing age is associated with a small but statistically significant increase of water diffusibility in human white matter. A similar trend was present in the thalamus. These increases may reflect mild structural changes associated with normal aging.

Purpose: We examined age-related changes in baseline regional cerebral blood volume (rCBV) and response to acetazolamide stimulation by using dynamic contrast-enhanced MR imaging., Methods: Thirty healthy volunteers ranging widely in age (23 to 82 years) were examined before and after intravenous injection of acetazolamide with dynamic susceptibility contrast-enhanced MR imaging. rCBV values were normalized for intersubject and intrasubject comparison by estimating an arterial input function directly from the imaging data. Preacetazolamide baseline rCBV and the percentage volume change index (PVCI) of the postacetazolamide to preacetazolamide state were calculated and examined as a function of age., Results: Older adults (>50 years) had lower baseline rCBV per unit tissue than did younger adults (<50 years), but higher rCBV after acetazolamide stimulation. Baseline rCBV tended to decrease with age in the medial frontal and frontoparietal gray matter regions. Response to acetazolamide stimulation, measured by PVCI, showed a significant age-related increase in gray matter, approximately 0.5% per year., Conclusion: rCBV can be significantly increased after acetazolamide stimulation in the healthy aged. These results support the notion that age-related decreases in rCBV measured at rest reflect reduced regional metabolic requirements rather than reduced capacity for regional substrate delivery. These data serve as a normative baseline for comparison studies of rCBV vascular reserve in aging persons with various cerebrovascular disorders.

Purpose: To determine whether whole-brain acetazolamide-induced changes in regional cerebral blood volume (rCBV) can be assessed on a conventional gradient 1.5-T MR system using 3-D dynamic susceptibility contrast-enhanced MR imaging., Methods: A 3-D frequency-shifted (FS) burst technique was used to assess the intravascular first pass of contrast agent. Changes in rCBV were calculated in 40 volunteers before and after acetazolamide (n = 30) or saline (n = 10) injection using customized analysis software on an independent workstation. A single-section gradient-echo technique with better spatial resolution was used in one additional volunteer to examine the effect of partial volume averaging on calculation of absolute rCBV., Results: A statistically significant increase in rCBV (gray matter = 23%, white master = 32.5%) was noted after acetazolamide compared with saline. Baseline fractional CBVs were 22% +/- 3% for gray matter and 12% +/- 2% for white matter. Partial volume averaging was probably responsible for a systematic but linear overestimation of absolute rCBV., Conclusion: Acetazolamide-induced changes in rCBV can be assessed using 3-D dynamic susceptibility contrast-enhanced MR imaging with FS-burst on a conventional gradient 1.5-T MR system. Values obtained with this technique overestimate absolute rCBV but are systematically biased and can be used for intersubject and intrasubject ratio comparisons.

Purpose: To investigate the relationship between the enhancement pattern of a multiple sclerosis lesion and its magnetization transfer effect., Methods: Fifty-four lesions were chosen from 29 patients with multiple sclerosis on the basis of enhancement pattern on contrast-enhanced T1-weighted MR images. They included 14 homogeneously enhancing lesions, 26 nonenhancing lesions, and 14 ring-enhancing lesions. Magnetization transfer ratios of the homogeneously enhancing lesions, nonenhancing lesions, and central portion of the ring-enhancing lesions were measured. Means were calculated and compared., Results: The magnetization transfer ratios for homogeneously enhancing lesions were higher (mean, 32.2%; SD, 3.4%) than those for nonenhancing lesions (mean 29.4%; SD, 4.3%) and for the central portion of ring-enhancing lesions (mean, 24.5%; SD, 4.0%). Significant differences were found between the ring-enhancing lesions and the homogeneously enhancing lesions and between the ring-enhancing lesions and the nonenhancing lesions., Conclusion: We found a relationship between decreased magnetization transfer ratios and those enhancement patterns in which myelin is known to be decreased histopathologically. Thus, use of the magnetization transfer technique may increase the specificity of MR imaging in assessing the extent of residual myelination in multiple sclerosis lesions.