R. Nick Bryan

Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects.

Accuracy in in vivo quantitation of brain function with positron emission tomography (PET) has often been limited by partial volume effects. This limitation becomes prominent in studies of aging and degenerative brain diseases where partial volume effects vary with different degrees of atrophy. The present study describes how the actual gray matter (GM) tracer concentration can be estimated using an algorithm that relates the regional fraction of GM to partial volume effects. The regional fraction of GM was determined by magnetic resonance imaging (MRI). The procedure is designated as GM PET. In computer simulations and phantom studies, the GM PET algorithm permitted a 100% recovery of the actual tracer concentration in neocortical GM and hippocampus, irrespective of the GM volume. GM PET was applied in a test case of temporal lobe epilepsy revealing an increase in radiotracer activity in GM that was undetected in the PET image before correction for partial volume effects. In computer simulations, errors in the segmentation of GM and errors in registration of PET and MRI images resulted in less than 15% inaccuracy in the GM PET image. In conclusion, GM PET permits accurate determination of the actual radiotracer concentration in human brain GM in vivo. The method differentiates whether a change in the apparent radiotracer concentration reflects solely an alteration in GM volume or rather a change in radiotracer concentration per unit volume of GM.

An image-processing system for qualitative and quantitative volumetric analysis of brain images

In this work, we developed, implemented, and validated an image-processing system for qualitative and quantitative volumetric analysis of brain images. This system allows the visualization and quantitation of global and regional brain volumes. Global volumes were obtained via an automated adaptive Bayesian segmentation technique that labels the brain into white matter, gray matter, and cerebrospinal fluid. Absolute volumetric errors for these compartments ranged between 1 and 3% as indicated by phantom studies. Quantitation of regional brain volumes was performed through normalization and tessellation of segmented brain images into the Talairach space with a 3D elastic warping model. Retest reliability of regional volumes measured in Talairach space indicated errors of < 1.5% for the frontal, parietal, temporal, and occipital brain regions. Additional regional analysis was performed with an automated hybrid method combining a region-of-interest approach and voxel-based analysis, named Regional Analysis of Volumes Examined in Normalized Space (RAVENS). RAVENS analysis for several subcortical structures showed good agreement with operator-defined volumes. This system has sufficient accuracy for longitudinal imaging data and is currently being used in the analysis of neuroimaging data of the Baltimore Longitudinal Study of Aging.

Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy

Background Persons with type 2 diabetes (T2D) are at risk for cognitive impairment and brain atrophy. The ACCORD Memory in Diabetes (MIND) Study investigated whether persons randomized to an intensive glycaemic therapeutic strategy targeting HbA1c to <6% had better cognitive function and a larger brain volume at 40 months than persons randomized to a standard strategy targeting HbA1c to 7%–7.9%.BACKGROUND People with type 2 diabetes are at risk of cognitive impairment and brain atrophy. We aimed to compare the effects on cognitive function and brain volume of intensive versus standard glycaemic control. METHODS The Memory in Diabetes (MIND) study was done in 52 clinical sites in North America as part of Action to Control Cardiovascular Risk in Diabetes (ACCORD), a double two-by-two factorial parallel group randomised trial. Participants (aged 55-80 years) with type 2 diabetes, high glycated haemoglobin A(1c) (HbA(1c)) concentrations (>7·5%; >58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive glycaemic control targeting HbA(1c) to less than 6·0% (42 mmol/mol) or a standard strategy targeting HbA(1c) to 7·0-7·9% (53-63 mmol/mol). Randomisation was via a centralised web-based system and treatment allocation was not masked from clinic staff or participants. We assessed our cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, at baseline and at 20 and 40 months. We assessed total brain volume (TBV), our primary brain structure outcome, with MRI at baseline and 40 months in a subset of participants. We included all participants with follow-up data in our primary analyses. In February, 2008, raised mortality risk led to the end of the intensive treatment and transition of those participants to standard treatment. We tested our cognitive function hypotheses with a mixed-effects model that incorporated information from both the 20 and 40 month outcome measures. We tested our MRI hypotheses with an ANCOVA model that included intracranial volume and factors used to stratify randomisation. This study is registered with ClinicalTrials.gov, number NCT00182910. FINDINGS We consecutively enrolled 2977 patients (mean age 62·5 years; SD 5·8) who had been randomly assigned to treatment groups in the ACCORD study. Our primary cognitive analysis was of patients with a 20-month or 40-month DSST score: 1378 assigned to receive intensive treatment and 1416 assigned to receive standard treatment. Of the 614 patients with a baseline MRI, we included 230 assigned to receive intensive treatment and 273 assigned to receive standard treatment in our primary MRI analysis at 40 months. There was no significant treatment difference in mean 40-month DSST score (difference in mean 0·32, 95% CI -0·28 to 0·91; p=0·2997). The intensive-treatment group had a greater mean TBV than the standard-treatment group (4·62, 2·0 to 7·3; p=0·0007). INTERPRETATION Although significant differences in TBV favoured the intensive treatment, cognitive outcomes were not different. Combined with the non-significant effects on other ACCORD outcomes, and increased mortality in participants in the intensive treatment group, our findings do not support the use of intensive therapy to reduce the adverse effects of diabetes on the brain in patients with similar characteristics to those of our participants. FUNDING US National Institute on Aging and US National Heart, Lung, and Blood Institute.

White Matter Hyperintensity on Cranial Magnetic Resonance Imaging A Predictor of Stroke

Background and Purpose— We have previously reported that several “silent” infarcts found on magnetic resonance imaging (MRI) were a risk factor for stroke. Several recent reports have shown that high white matter grade (WMG) and increasing WMG over time were risk factors for stroke. We tested the hypothesis that high WMG ≥2 was a predictor of risk for stroke, independent of other risk factors. Methods— We examined the extent of white matter hyperintensity on cranial MRI of 3293 participants from the Cardiovascular Health Study (CHS). The degree of white matter hyperintensity was graded from least severe (grade= 0) to most severe (grade= 9). Participants were followed-up for an average of 7 years for the occurrence of a stroke. Clinical stroke diagnoses were based on hospital records reviewed by an adjudication committee expert in stroke diagnosis. During this period, 278 strokes occurred. Results— The relative risk of stroke increased significantly as the WMG increased. The risk of stroke was 2.8% per year for participants with high WMG (grades ≥5), compared with only 0.6% for participants with grades 0 to 1. Conclusions— The risk of stroke with high WMG is independent of traditional stroke risk factors and persists when controlling for MRI infarcts, another subclinical imaging marker of cerebrovascular disease. Assessment of white matter disease may be valuable in assessing future risk of stroke.

Using a deformable surface model to obtain a shape representation of the cortex

This paper examines the problem of obtaining a mathematical representation of the outer cortex of the human brain, which is a key problem in several applications, including morphological analysis of the brain, and spatial normalization and registration of brain images. A parameterization of the outer cortex is first obtained using a deformable surface algorithm which, motivated by the structure of the cortex, is constructed to find the central layer of thick surfaces. Based on this parameterization, a hierarchical representation of the outer cortical structure is proposed through its depth map and its curvature maps at various scales. Various experiments on magnetic resonance data are presented.

Absolute Quantitation of Diffusion Constants in Human Stroke

BACKGROUND AND PURPOSE Animal studies have shown that MR diffusion imaging can outline acute ischemic regions before irreversible damage (infarction) occurs. To study evolution of ischemic lesions in humans, it is therefore important to quantify absolute diffusion constants (D values), but quantitation has not been reproducible among different clinics. These problems are explained, and a method for reproducible quantitation is suggested. METHODS Diffusion-weighted and absolute diffusion images were acquired, and the absolute apparent diffusion constants in three orthogonal spatial directions (Dxx, Dyy, and Dzz) were measured. These were combined to calculate images of the orientation-independent apparent diffusion parameter Dav = 1/3 Trace[D] = 1/3(Dxx + Dyy + Dzz). Values of the individual diffusion constants and Dav were evaluated in 6 patients and 6 normal volunteers. RESULTS Patient data show that comparison of diffusion constants between contralateral and ipsilateral hemispheres after ischemia may give results varying by more than 100% depending on orientation. Findings in normal-appearing regions containing a mixture of gray and white matter in patients (n = 5) and in normal volunteers (n = 6) show that Dav = (0.92+/-0.11) x 10(-3) mm2/s, with a small intersubject variation, whereas Dxx, Dyy, and Dzz vary strongly. Hemispheric ratios (ipsilateral/contralateral [I/C]) in these subjects were (I/C)Dav = 1.00+/-0.05, (I/C)Dxx = 1.02+/-0.15, (I/C)Dyy = 1.07+/-0.24, and (I/C)Dzz = 0.96+/-0.28. The individual subjects in this group all had an (I/C)Dav within 10% of unity, while the other three ratios showed intersubject variations as large as 100%. CONCLUSIONS (I/C)Dav ratios are a reliable means to quantitate changes in absolute diffusion constants for the study of stroke evolution independent of tissue orientation, gradient orientation, and diffusion time. The use of these ratios will enable reproducible intersubject and interclinic quantitation.

Neurofibromatosis type 1: The cognitive phenotype

Visuospatial deficits have been reported in patients with neurofibromatosis type 1 (NF 1), although detailed observations regarding academic achievement are conflicting. Using neurocognitive testing and magnetic resonance imaging, we studied 12 families, each comprising one child with NF 1, an unaffected sibling of the same age range (6 to 16 years), and both biologic parents. The Full Scale IQ ranged from 70 to 130 among children with NF 1 and from 99 to 139 among unaffected siblings. A significant (p < 0.01) pairwise difference was found between each child with NF 1 and sibling on the Full Scale IQ and the Verbal IQ. On a single visuospatial test, Judgement of Line Orientation, children with NF 1 did significantly worse than siblings (p < 0.01). Children with NF 1 had significant learning disabilities in written language and reading (p < 0.05) and in neuromotor dysfunction (p < 0.005) compared with siblings. A significant correlation was found between the pairwise lowering of the Full Scale IQ and Judgment of Line Orientation scores in children with NF 1 and the number of locations in which, on magnetic resonance imaging, T2-weighted hyperintensities were seen (Full Scale IQ: p < 0.0003; Judgment of Line Orientation score: p < 0.02). We conclude that NF 1 is associated with a significantly lower Full Scale IQ, multifocal cognitive deficits (Verbal IQ, Judgment of Line Orientation score), reading disability, and neuromotor deficit. Pairwise cognitive differences correlated with the number of brain lesions on magnetic resonance imaging.

Computer-Assisted Segmentation of White Matter Lesions in 3D MR images, Using Support Vector Machine

RATIONALE AND OBJECTIVES Brain lesions, especially white matter lesions (WMLs), are associated with cardiac and vascular disease, but also with normal aging. Quantitative analysis of WML in large clinical trials is becoming more and more important. MATERIALS AND METHODS In this article, we present a computer-assisted WML segmentation method, based on local features extracted from multiparametric magnetic resonance imaging (MRI) sequences (ie, T1-weighted, T2-weighted, proton density-weighted, and fluid attenuation inversion recovery MRI scans). A support vector machine classifier is first trained on expert-defined WMLs, and is then used to classify new scans. RESULTS Postprocessing analysis further reduces false positives by using anatomic knowledge and measures of distance from the training set. CONCLUSIONS Cross-validation on a population of 35 patients from three different imaging sites with WMLs of varying sizes, shapes, and locations tests the robustness and accuracy of the proposed segmentation method, compared with the manual segmentation results from two experienced neuroradiologists.

Premorbid Prevalence of ADHD and Development of Secondary ADHD After Closed Head Injury

OBJECTIVE To determine premorbid prevalence of attention-deficit hyperactivity disorder (ADHD) in children with moderate and severe closed head injury (CHI), to determine incidence of ADHD 1 year after injury, and to characterize children who develop ADHD by demographic, neuropsychiatric, and outcome variables. METHOD Ninety-nine children who had severe and moderate CHI were followed up for 1 year. Premorbid and 1-year postinjury psychiatric status were ascertained by parent and child structured interviews and questionnaires measuring affective lability, aggression, apathy, and social judgment. RESULTS Premorbid prevalence of ADHD was 0.20, significantly higher than in a reference population (0.045). Fifteen of the remaining 80 children (0.19) developed full ADHD criteria (except for age of onset) by the end of the first year. Children who developed secondary ADHD (S-ADHD) had significantly greater premorbid psychosocial adversity, posttraumatic affective lability and aggression, posttraumatic psychiatric comorbidity, and overall disability than children who did not develop S-ADHD. CONCLUSIONS There is an excess prevalence of premorbid ADHD among children who present with moderate and severe CHI. Children with high psychosocial adversity are more likely to develop S-ADHD after CHI. S-ADHD has criteria in common with personality change due to CHI, a deficit in behavioral inhibition being the major overlapping feature.

Retinal Microvascular Abnormalities and MRI-Defined Subclinical Cerebral Infarction: The Atherosclerosis Risk in Communities Study

Background and Purpose— Retinal microvascular abnormalities reflect cumulative small vessel damage from elevated blood pressure and may reflect subclinical cerebral microvascular changes. We examined their associations with MRI-defined cerebral infarcts. Methods— Population-based, cross-sectional study of 1684 persons 55 to 74 years of age without a history of clinical stroke, sampled from 2 US southeastern communities. Retinal photographs were obtained and graded for presence of retinal microvascular abnormalities, including arteriovenous nicking, focal arteriolar narrowing, retinal hemorrhages, soft exudates and microaneurysms. Photographs were also digitized, and retinal vessel diameters were measured and summarized as the arteriole-to-venule ratio (AVR). Cerebral MRI scans were graded for presence of cerebral infarct, defined as a lesion ≥3 mm diameter in a vascular distribution with typical imaging characteristics. Results— There were a total of 183 MRI cerebral infarcts. After adjustment for age, gender, race, 6-year mean arterial blood pressure, diabetes, and other stroke risk factors, cerebral infarcts were associated with retinal microvascular abnormalities, with odds ratios 1.90 (95% CI, 1.25 to 2.88) for arteriovenous nicking, 1.89 (95% CI, 1.22 to 2.92) for focal arteriolar narrowing, 2.95 (95% CI, 1.30 to 6.71) for blot hemorrhages, 2.08 (95% CI, 0.69, 6.31) for soft exudates, 3.17 (95% CI, 1.05 to 9.64) for microaneurysms, and 1.74 (95% CI, 0.95 to 3.21) for smallest compared with largest AVR. In stratified analyses, these associations were only present in persons with hypertension. Conclusions— Retinal microvascular abnormalities are associated with MRI-defined subclinical cerebral infarcts independent of stroke risk factors. These data suggest that retinal photography may be useful for studying subclinical cerebrovascular disease in population-based studies.