A new data analysis approach for measuring longitudinal changes of metabolism in cognitively normal elderly adults.

INTRODUCTION: Previously, we discussed several critical barriers in including [18F] fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) imaging of preclinical Alzheimer's disease (AD) subjects. These factors included the reference region selection and intensity normalization of PET images and the within- and across-subject variability of affected brain regions. In this study, we utilized a novel FDG-PET analysis, the regional FDG time correlation coefficient, rFTC, that can address and resolve these barriers and provide a more sensitive way of monitoring longitudinal changes in metabolism of cognitively normal elderly adults. The rFTC analysis captures the within-subject similarities between baseline and follow-up regional radiotracer distributions. METHODS: The rFTC trajectories of 27 cognitively normal subjects were calculated to identify 1) trajectories of rFTC decline in individual cognitively normal subjects; 2) how these trajectories correlate with the subjects' cognitive test scores, baseline cerebrospinal fluid (CSF) levels of amyloid beta (Aß), and apolipoprotein E4 (APOE-E4) status; and 3) whether similar trajectories are observed in regional/composite standardized uptake value ratio (SUVR) values. RESULTS: While some of the subjects maintained a stable rFTC trajectory, other subjects had declining and fluctuating rFTC values. We found that the rFTC decline was significantly higher in APOE-E4 carriers compared to noncarriers (p=0.04). We also found a marginally significant association between rFTC decline and cognitive decline measured by Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS_cog) decline (0.05). In comparison to the rFTC trajectories, the composite region of interest (ROI) SUVR trajectories did not change in any of the subjects. No individual/composite ROI SUVR changes contributed significantly to explaining changes in ADAS_cog, conversion to mild cognitive impairment (MCI), or any general changes in clinical symptoms. CONCLUSION: The rFTC decline may serve as a new biomarker of early metabolic changes before the MCI stage.

Reference tissue normalization in longitudinal (18)F-florbetapir positron emission tomography of late mild cognitive impairment.

BACKGROUND: Semiquantitative methods such as the standardized uptake value ratio (SUVR) require normalization of the radiotracer activity to a reference tissue to monitor changes in the accumulation of amyloid-ß (Aß) plaques measured with positron emission tomography (PET). The objective of this study was to evaluate the effect of reference tissue normalization in a test-retest (18)F-florbetapir SUVR study using cerebellar gray matter, white matter (two different segmentation masks), brainstem, and corpus callosum as reference regions. METHODS: We calculated the correlation between (18)F-florbetapir PET and concurrent cerebrospinal fluid (CSF) Aß1-42 levels in a late mild cognitive impairment cohort with longitudinal PET and CSF data over the course of 2 years. In addition to conventional SUVR analysis using mean and median values of normalized brain radiotracer activity, we investigated a new image analysis technique-the weighted two-point correlation function (wS2)-to capture potentially more subtle changes in Aß-PET data. RESULTS: Compared with the SUVRs normalized to cerebellar gray matter, all cerebral-to-white matter normalization schemes resulted in a higher inverse correlation between PET and CSF Aß1-42, while the brainstem normalization gave the best results (high and most stable correlation). Compared with the SUVR mean and median values, the wS2 values were associated with the lowest coefficient of variation and highest inverse correlation to CSF Aß1-42 levels across all time points and reference regions, including the cerebellar gray matter. CONCLUSIONS: The selection of reference tissue for normalization and the choice of image analysis method can affect changes in cortical (18)F-florbetapir uptake in longitudinal studies.

Modeling clustered activity increase in amyloid-beta positron emission tomographic images with statistical descriptors.

BACKGROUND: Amyloid-beta (Aß) imaging with positron emission tomography (PET) holds promise for detecting the presence of Aß plaques in the cortical gray matter. Many image analyses focus on regional average measurements of tracer activity distribution; however, considerable additional information is available in the images. Metrics that describe the statistical properties of images, such as the two-point correlation function (S2), have found wide applications in astronomy and materials science. S2 provides a detailed characterization of spatial patterns in images typically referred to as clustering or flocculence. The objective of this study was to translate the two-point correlation method into Aß-PET of the human brain using 11C-Pittsburgh compound B (11C-PiB) to characterize longitudinal changes in the tracer distribution that may reflect changes in Aß plaque accumulation. METHODS: We modified the conventional S2 metric, which is primarily used for binary images and formulated a weighted two-point correlation function (wS2) to describe nonbinary, real-valued PET images with a single statistical function. Using serial 11C-PiB scans, we calculated wS2 functions from two-dimensional PET images of different cortical regions as well as three-dimensional data from the whole brain. The area under the wS2 functions was calculated and compared with the mean/median of the standardized uptake value ratio (SUVR). For three-dimensional data, we compared the area under the wS2 curves with the subjects' cerebrospinal fluid measures. RESULTS: Overall, the longitudinal changes in wS2 correlated with the increase in mean SUVR but showed lower variance. The whole brain results showed a higher inverse correlation between the cerebrospinal Aß and wS2 than between the cerebrospinal Aß and SUVR mean/median. We did not observe any confounding of wS2 by region size or injected dose. CONCLUSION: The wS2 detects subtle changes and provides additional information about the binding characteristics of radiotracers and Aß accumulation that are difficult to verify with mean SUVR alone.

Longitudinal progression of cognitive decline correlates with changes in the spatial pattern of brain 18F-FDG PET.

UNLABELLED: Evaluating the symptomatic progression of mild cognitive impairment (MCI) caused by Alzheimer disease (AD) is practically accomplished by tracking performance on cognitive tasks, such as the Alzheimer Disease Assessment Scale's cognitive subscale (ADAS_cog), the Mini-Mental Status Examination (MMSE), and the Functional Activities Questionnaire (FAQ). The longitudinal relationships between cognitive decline and metabolic function as assessed using (18)F-FDG PET are needed to address both the cognitive and the biologic progression of disease state in individual subjects. We conducted an exploratory investigation to evaluate longitudinal changes in brain glucose metabolism of individual subjects and their relationship to the subject's changes of cognitive status. METHODS: We describe a method to determine correlations in (18)F-FDG spatial distribution over time. This parameter is termed the regional (18)F-FDG time correlation coefficient (rFTC). By using linear mixed-effects models, we determined the difference in the rFTC decline rate between controls and subjects at high risk of developing AD, such as individuals with MCI or the presence of apolipoprotein E (APOE)-ε4 allele. The association between each subject's rFTC and performance on cognitive tests (ADAS_cog, MMSE, and FAQ) was determined with 2 different correlation methods. All subject data were downloaded from the Alzheimer Disease Neuroimaging Initiative. RESULTS: The rFTC values of controls remained fairly constant over time (-0.003 annual change; 95% confidence interval, -0.010-0.004). In MCI patients, the rFTC declined faster than in controls by an additional annual change of -0.02 (95% confidence interval, -0.030 to -0.010). In MCI patients, the decline in rFTC was associated with cognitive decline (ADAS_cog, P = 0.011; FAQ, P = 0.0016; MMSE, P = 0.004). After a linear effect of time was accounted for, visit-to-visit changes in rFTC correlated with visit-to-visit changes in all 3 cognitive tests. CONCLUSION: Longitudinal changes in rFTC detect subtle metabolic changes in individuals associated with variations in their cognition. This analytic tool may be useful for a patient-based monitoring of cognitive decline.

Modeling brain tissue volumes over the lifespan: quantitative analysis of postmortem weights and in vivo MR images.

Normative measurements of brain gray matter and white matter tissue volumes across the lifespan have not yet been established. The purpose of this article was to use mathematical modeling and analytical functions to demonstrate the growth trajectory of gray matter and white matter from age 0 to age 90. For each gender, brain weight functions were generated by utilizing existing autopsy data from 4400 subjects. Brain gray matter, white matter and lateral ventricular volumes were measured from 39 MR volumes of normal individuals. These were converted to weight by multiplying the tissue volumes by the specific gravity of that tissue. White matter volumes were described by a saturating exponential function, and the gray matter volume function was calculated by subtracting the white matter weight function from the brain weight function. For each gender, equations were generated for white matter and gray matter volumes as a function of age over the lifespan.

The "Got D'ViBE?" study: an inter-institutional project assessing vitamin D and mammographic breast density.

A multi-institutional collaboration was forged to implement a study of the relationship between Vitamin D and breast density among medically underserved women. This effort resulted in techniques to measure vitamin D levels, breast density, and sunlight exposure. Outcomes from this collaboration may provide insight to researchers conducting similar investigations.

Quantifying cerebral changes in adolescence with MRI and deformation based morphometry.

PURPOSE: To identify and quantify structural changes in the maturing brain between childhood and adolescence. MATERIALS AND METHODS: Two three-dimensional T1-weighted MR volumes of the brain were acquired from eight subjects, 6 to 7 years apart. The subjects were 9 to 12 years old on the first scan and 15 to 19 years old on the second scan. The MR scans were converted to one millimeter isotropic volumes, globally aligned with a rigid transform, inhomogeneity corrected, and nonrigid deformation fields between the aligned volumes were calculated. Masks for brain regions were automatically warped with the deformation fields and volumes of brain regions calculated. Color overlays based on the nonrigid deformation fields were generated to identify local volume changes. RESULTS: Gray matter decreased as much as 60% and white matter increased as much as 250%. The biggest gray matter changes were in the head of the caudates, areas of the putamens, and areas of the thalamus. Some of the biggest white matter changes were in the forceps minor, forceps major, and internal capsule. CONCLUSION: Deformation based morphometry with serial scans provides a method to study regional structural changes with brain growth and maturation.

Implementing pediatric growth charts into an electronic health record system.

Electronic health record (EHR) systems are increasingly being adopted in pediatric practices; however, requirements for integrated growth charts are poorly described and are not standardized in current systems. The authors integrated growth chart functionality into an EHR system being developed and installed in a multispecialty pediatric clinic in an academic medical center. During a three-year observation period, rates of electronically documented values for weight, stature, and head circumference increased from fewer than ten total per weekday, up to 488 weight values, 293 stature values, and 74 head circumference values (p<0.001 for each measure). By the end of the observation period, users accessed the growth charts an average 175 times per weekday, compared to 127 patient visits per weekday to the sites that most closely monitored pediatric growth. Because EHR systems and integrated growth charts can manipulate data, perform calculations, and adapt to user preferences and patient characteristics, users may expect greater functionality from electronic growth charts than from paper-based growth charts.

Extracting data from a DICOM file.

DICOM v3.0 is a vendor-independent standard for digital medical images that describes a file format and network protocol for the exchange of images between computer systems. When simply viewing a DICOM file, it is not necessary for the user to understand the details of the entire DICOM standard. However, understanding parts of the standard is essential when DICOM files are read and processed by a user-generated program. This paper offers an overview of information a user needs to write a program for extracting the image and acquisition parameters from a DICOM file.

Characterizing changes in MR images with color-coded Jacobians.

Image registration is the process of establishing spatial correspondence between two images or between two image volumes. Registration can be achieved by rigid, elastic, or a combination of rigid and elastic transforms that attempt to bring the two images into coincidence. A rigid transform accounts for differences in positioning and an elastic transform describes deformations due to differences in tissue properties, temporal changes due to growth or atrophy, or differences between individuals. Deformation-based morphometry uses the resulting deformation fields from these transforms to evaluate differences between the images being registered. Three methods of registration were evaluated: rigid (affine) transformation, elastic optical flow transformation, and elastic spline transformation. All three methods produce vector deformation fields that map each point in one image to a point in the other image. A 12-color map of the transformation Jacobian was used to represent local volume changes. Using the three registration methods, color-mapped Jacobians were determined using a simulated three-dimensional block with known translation, rotation, expansion, contraction, and intensity modulations. Color-coded Jacobians were also generated for experimentally measured magnetic resonance image volumes of water-filled balloons and 7-year-old twin boys. Color-coded Jacobians overlaid on anatomical images provide a convenient method to identify regional tissue expansion and contraction.

Longitudinal brain metabolic characterization of chronic alcoholics with proton magnetic resonance spectroscopy.

BACKGROUND: Proton magnetic resonance spectroscopy may elucidate the molecular underpinnings of alcoholism-associated brain shrinkage and the progression of alcohol dependence. METHODS: Using proton magnetic resonance spectroscopy, we determined absolute concentrations of -acetylaspartate (NAA), creatine/phosphocreatine (Cr), and choline (Cho)-containing compounds and -inositol (mI) in the anterior superior cerebellar vermis and frontal lobe white matter in 31 alcoholics and 12 normal controls. All patients were examined within 3 to 5 days of their last drink. Patients who did not relapse were again studied after 3 weeks and 3 months of abstinence by using an on-line repositioning technique that allows reliable localization of volumes of interest (VOIs). RESULTS: At 3 to 5 days after the last drink, frontal white matter metabolite concentrations were not significantly different from those of normal controls, whereas brain tissue in the VOI was reduced. Cerebellar [NAA] and [Cho] and brain and cerebellar volumes were decreased, but [Cr], [mI], and VOI brain tissue volume were not significantly different. Eight patients relapsed before 3 weeks (ER), 12 relapsed between 3 weeks and 3 months (LR), and 11 did not relapse (NR) during 3 months. Cerebellar [NAA] was reduced only in ER patients, despite the fact that ER patients drank for significantly fewer years and earlier in life than LR or NR patients. After 3 months, in the 11 continuously abstinent patients, cerebellar [NAA] and brain and cerebellar volumes increased; cerebellar [Cho], [Cr], and [mI] and VOI brain tissue did not change significantly. CONCLUSIONS: Decreased [NAA] and [Cho] in cerebellar vermis indicate a unique sensitivity to alcohol-induced brain injury. Cerebellar [NAA] increased with abstinence, but reduced [Cho] persisted beyond 3 months. Further studies are needed to determine whether low cerebellar [NAA] is a risk factor for, or consequence of, malignant, early-onset alcoholism.

Proton magnetic resonance spectroscopy in the brain: report of AAPM MR Task Group #9.

AAPM Magnetic Resonance Task Group #9 on proton magnetic resonance spectroscopy (MRS) in the brain was formed to provide a reference document for acquiring and processing proton (1H) MRS acquired from brain tissue. MRS is becoming a common adjunct to magnetic resonance imaging (MRI), especially for the differential diagnosis of tumors in the brain. Even though MR imaging is an offshoot of MR spectroscopy, clinical medical physicists familiar with MRI may not be familiar with many of the common practical issues regarding MRS. Numerous research laboratories perform in vivo MRS on other magnetic nuclei, such as 31P, 13C, and 19F. However, most commercial MR scanners are generally only capable of spectroscopy using the signals from protons. Therefore this paper is of limited scope, giving an overview of technical issues that are important to clinical proton MRS, discussing some common clinical MRS problems, and suggesting how they might be resolved. Some fundamental issues covered in this paper are common to many forms of magnetic resonance spectroscopy and are written as an introduction for the reader to these methods. These topics include shimming, eddy currents, spatial localization, solvent saturation, and post-processing methods. The document also provides an extensive review of the literature to guide the practicing medical physicist to resources that may be useful for dealing with issues not covered in the current article.