Cingulum bundle white matter lesions influence antidepressant response in late-life depression: a pilot study.

BACKGROUND: Late-life depression is associated with white matter hyperintense lesions (WMLs) occurring in specific fiber tracts. In this study, we sought to determine if greater WML severity in the cingulum bundle or uncinate fasciculus was associated with poor short-term antidepressant response. METHODS: Eleven depressed elders completed a baseline cranial 3T MRI and received antidepressant treatment following a medication algorithm. MRIs were analyzed to measure the fraction of each fiber tract׳s volume occupied by WMLs. Statistical analyses examined the effect of dichotomized fiber tract WML severity on three- and six-month depression severity after controlling for age and baseline depression severity. RESULTS: Greater WML severity in the left hemispheric cingulum bundle adjacent to the hippocampus was associated with greater post-treatment depression severity at three- (F1,7=6.42, p=0.0390) and six-month assessments (F1,5=9.62, p=0.0268). Other fiber tract WML measures were not significantly associated with outcomes. LIMITATIONS: The study had a small sample size and analyses were limited to only a priori fiber tracts. CONCLUSIONS: This pilot study supports the hypothesis that focal damage to the cingulum bundle may contribute to poor short-term antidepressant response. These findings warrant further investigation with a larger, more definitive study.

Fiber tract-specific white matter lesion severity Findings in late-life depression and by AGTR1 A1166C genotype.

Past work demonstrated that late-life depression is associated with greater severity of ischemic cerebral hyperintense white matter lesions, particularly frontal lesions. However, these lesions are also associated with other neuropsychiatric deficits, so these clinical relationships may depend on which fiber tracts are damaged. We examined the ratio of lesion to nonlesioned white matter tissue within multiple fiber tracts between depressed and nondepressed elders. We also sought to determine if the AGTR1 A1166C and BDNF Val66Met polymorphisms contributed to vulnerability to lesion development in discrete tracts. The 3T structural MR images and blood samples for genetic analyses were acquired on 54 depressed and 37 nondepressed elders. Lesion maps were created through an automated tissue segmentation process and applied to a probabilistic white matter fiber tract atlas allowing for identification of the fraction of the tract occupied by lesion. The depressed cohort exhibited a significantly greater lesion ratio only in the left upper cingulum near the cingulate gyrus (F((1,86)) = 4.62, P = 0.0344), supporting past work implicating cingulate dysfunction in the pathogenesis of depression. In the 62 Caucasian subjects with genetic data, AGTR1 C1166 carriers exhibited greater lesion ratios across multiple tracts including the anterior thalamic radiation and inferior fronto-occipital fasciculus. In contrast, BDNF Met allele carriers exhibited greater lesion ratios only in the frontal corpus callosum. Although these findings did not survive correction for multiple comparisons, this study supports our hypothesis and provides preliminary evidence that genetic differences related to vascular disease may increase lesion vulnerability differentially across fiber tracts.

Computer-assisted measurement of retinal vascular width and tortuosity in retinopathy of prematurity.

OBJECTIVES: To validate the accuracy of ROPtool software in measuring retinal vascular width and tortuosity in a large image set compared with expert diagnoses. METHODS: Tortuosity and dilation indexes generated by ROPtool were compared with 3 expert consensus grades of normal, pre-plus, or plus disease for 368 quadrants in 92 RetCam (Clarity Medical Systems, Pleasanton, California) fundus images. Sensitivity and specificity of ROPtool software in diagnosing tortuosity and dilation sufficient for plus and pre-plus disease were calculated. These measures were compared with individual accuracies of 3 experienced pediatric ophthalmologists. RESULTS: The mean tortuosity indexes for expert-diagnosed categories of normal, pre-plus, and plus disease were 7.04, 18.73, and 34.62, respectively (P < .001), and the mean dilation indexes were 9.63, 12.05, and 13.61, respectively (P < .001). When optimal tortuosity and dilation index thresholds (from receiver operating characteristic curves) were applied, resultant sensitivity and specificity were 0.913 and 0.863, respectively, for plus tortuosity and 0.782 and 0.840, respectively, for plus dilation. These values were comparable to the performance of examiners judged against the same expert panel. CONCLUSION: ROPtool version 2.1.5 accurately measures tortuosity and dilation of posterior pole blood vessels in RetCam images, corresponding well with expert diagnostic categories of normal, pre-plus, and plus disease and performing comparably to experienced examiners.

A pilot study using ROPtool to measure retinal vascular dilation.

BACKGROUND: Plus disease is abnormal retinal vascular dilation and tortuosity, and it is now the primary indication for laser treatment in retinopathy of prematurity (ROP). ROPtool is a computer program that measures retinal arteriolar tortuosity. Our aim was to assess the accuracy of ROPtool's newly developed measurement of retinal vascular width (dilation). METHODS: ROPtool was used to measure the width of 154 blood vessels in 20 high-quality RetCam images from 20 premature infants. ROPtool's accuracy was determined by comparing results with the mean grades of 2 authors who scored retinal vascular dilation using a 10-point scale. RESULTS: There was very good correlation (r = 0.80) between ROPtool's measurement of retinal vascular dilation and author judgment. Areas under receiver operating characteristics curves for identification of dilation sufficient for plus disease and for pre-plus disease were 0.93 and 0.90, respectively. At an optimal point on the receiver operating characteristics curve, ROPtool's sensitivity for diagnosing dilation sufficient for plus disease was 89% (24/27), and its specificity was 83% (106/127). CONCLUSION: In addition to measuring retinal vascular tortuosity, ROPtool now accurately measures retinal vascular width in high-quality RetCam images. Application of this technology has the potential to remove subjectivity from the assessment of plus disease.

Tortuosity of arterioles and venules in quantifying plus disease.

BACKGROUND: Plus disease is the major criterion for laser treatment of retinopathy of prematurity. ROPtool is a computer program that traces retinal blood vessels and measures their tortuosity. Our objectives were to determine (1) whether examiners could accurately discriminate between arterioles and venules and (2) whether tortuosity sufficient for plus disease and pre-plus disease was assessed most accurately by considering arterioles, venules, or both. METHODS: One hundred retinal vessels were identified in 25 images randomly selected from 184 total images. Three pediatric ophthalmologists independently designated vessels as arteriole or venule. Seventy-seven images that had at least 1 traceable arteriole and venule in each quadrant were analyzed by ROPtool, and the results were compared with the consensus of 3 expert examiners. Receiver operating characteristics (ROC) curves were generated and areas under the curves calculated to quantify the diagnostic utility of ROPtool's assessment of tortuosity of arterioles, venules, and both. RESULTS: Three pediatric ophthalmologists agreed on the designation of arteriole or venule for 83 of 100 blood vessels. With the use of expert consensus as the reference standard, areas under the ROC curves for identification of tortuosity sufficient for plus disease were 0.91, 0.70, and 0.93 for arterioles, venules, and both, respectively. Areas under the ROC curves for identification of tortuosity sufficient for pre-plus disease were 0.91, 0.63, and 0.90 for arterioles, venules, and both, respectively. CONCLUSIONS: When considering whether tortuosity is sufficient for plus or pre-plus disease, the assessment of either arterioles alone or of arterioles and venules together resulted in high diagnostic accuracy.

Evolution of plus disease in retinopathy of prematurity: quantification by ROPtool.

PURPOSE: The primary indication for laser treatment in retinopathy of prematurity (ROP) is plus disease, or abnormal dilation and tortuosity of arterioles and venules. ROPtool is a computer program that traces retinal blood vessels and measures their width and tortuosity. Our purpose was to gain insight into the evolution of plus disease by applying ROPtool to RetCam images from eyes of infants who had serial photographs taken during their ROP screening period. METHODS: Serial images were collected from eyes of 62 infants screened for ROP as part of another study. Fifty-nine images of one eye of 7 infants who developed plus disease were selected and analyzed by ROPtool. The average tortuosity of the most tortuous blood vessel and the average width of the most dilated vessel in each quadrant were calculated for each image. RESULTS: Tortuosity increased from an average of 7.72 units at the first examination to 24.44 units at the examination with maximum tortuosity, or an increase of 217% over a mean time period of 6.2 weeks. Two eyes had an increase in tortuosity of more than 500% from the first examination. Vessel width increased from an average of 8.60 units at the first examination to 11.03 units at the examination with maximum blood vessel width, or an increase of 28% over a mean time period of 5.1 weeks. CONCLUSIONS: ROPtool can measure changes in retinal vascular dilation and tortuosity in individual eyes over time. As plus disease develops, changes in tortuosity are sometimes very large, whereas changes in vessel width tend to be more subtle. Quantification of plus disease over time may help to improve our understanding of its mechanism and to monitor disease progression or response to treatment.

APOE related hippocampal shape alteration in geriatric depression.

Late-onset depression often precedes the onset of dementia associated with the hippocampal degeneration. Using large deformation diffeomorphic metric mapping (LDDMM), we evaluated apolipoprotein E epsilon-4 allele (apoE E4) effects on hippocampal volume and shape in 38 depressed patients without the apoE E4, 14 depressed patients with one apoE E4, and 31 healthy comparison subjects without the apoE E4. The hippocampal volumes were manually assessed. We applied a diffeomorphic template generation procedure for creating the hippocampal templates based on a subset of the population. The LDDMM mappings were used to generate the hippocampal shape of each subject and characterize the surface deformation of each hippocampus relative to the template. Such deformation was modeled as random field characterized by the Laplace-Beltrami basis functions in the template coordinates. Linear regression was used to examine group differences in the hippocampal volume and shape. We found that there were significant hippocampal shape alternations in both depressed groups while the groups of depressed patients and the group of healthy subjects did not differ in the hippocampal volume. The depressed patients with one apoE E4 show more pronounced shape inward-compression in the anterior CA1 than the depressed patients without the apoE E4 when compared with the healthy controls without the apoE E4. Thus, hippocampal shape abnormalities in late-onset depressed patients with one apoE E4 may indicate future conversion of this group to AD at higher risk than depressed patients without the apoE E4.

Computer-assisted assessment of plus disease in retinopathy of prematurity using video indirect ophthalmoscopy images.

PURPOSE: "ROPtool" is a computer program that measures retinal blood vessel tortuosity. Our aim was to determine the feasibility and accuracy of analyzing images with ROPtool, which were obtained using video indirect ophthalmoscopy. METHODS: Forty-five posterior pole still images captured from indirect ophthalmoscopy video clips were selected; 20 were selected for high quality and 25 were randomly selected. One of the authors (S.A.) used ROPtool to measure tortuosity for each quadrant of each image. Two of the authors (D.K.W. and S.F.F.) independently judged tortuosity on a 10-point scale, and their averaged grades were used as the reference standard. RESULTS: Among randomly selected images, ROPtool was able to trace at least two major vessels in 43 of 100 quadrants (43%). Lighter fundus pigment color was associated with ROPtool's ability to analyze images (P = 0.004). When considering analyzable images only, ROPtool's sensitivity in detecting tortuosity sufficient for plus disease was 83% (5/6) and specificity was 90% (18/20). ROPtool's sensitivity for pre-plus tortuosity was 100% (9/9) and specificity was 71% (12/17). CONCLUSION: ROPtool is useful for analyzing video indirect ophthalmoscopy images only when applied to those with high quality. When analyzing these images, ROPtool has very good accuracy compared to consensus of experienced examiners.

Hippocampus shape analysis and late-life depression.

Major depression in the elderly is associated with brain structural changes and vascular lesions. Changes in the subcortical regions of the limbic system have also been noted. Studies examining hippocampus volumetric differences in depression have shown variable results, possibly due to any volume differences being secondary to local shape changes rather than differences in the overall volume. Shape analysis offers the potential to detect such changes. The present study applied spherical harmonic (SPHARM) shape analysis to the left and right hippocampi of 61 elderly subjects with major depression and 43 non-depressed elderly subjects. Statistical models controlling for age, sex, and total cerebral volume showed a significant reduction in depressed compared with control subjects in the left hippocampus (F(1,103) = 5.26; p = 0.0240) but not right hippocampus volume (F(1,103) = 0.41; p = 0.5213). Shape analysis showed significant differences in the mid-body of the left (but not the right) hippocampus between depressed and controls. When the depressed group was dichotomized into those whose depression was remitted at time of imaging and those who were unremitted, the shape comparison showed remitted subjects to be indistinguishable from controls (both sides) while the unremitted subjects differed in the midbody and the lateral side near the head. Hippocampal volume showed no difference between controls and remitted subjects but nonremitted subjects had significantly smaller left hippocampal volumes with no significant group differences in the right hippocampus. These findings may provide support to other reports of neurogenic effects of antidepressants and their relation to successful treatment for depressive symptoms.

Accuracy of ROPtool vs individual examiners in assessing retinal vascular tortuosity.

OBJECTIVE: To prospectively determine if tortuosity assessment by a computer program (ROPtool) that traces retinal blood vessels and measures their tortuosity was more accurate than that of individual pediatric ophthalmologists. METHODS: One hundred eighty-five high-quality RetCam images from premature infants were circulated to 3 retinopathy of prematurity (ROP) experts and 3 other pediatric ophthalmologists ("examiners") who graded the tortuosity in each quadrant as normal, pre-plus, or plus. These same images were analyzed using ROPtool. RESULTS: Using expert consensus as the standard, ROPtool's overall accuracy of 95% (175 of 185) for identifying tortuosity sufficient for plus disease was similar to that of examiner 1 (93%; 172 of 185; P = .50), examiner 2 (93%; 172 of 185; P = .50), and examiner 3 (91%; 168 of 185; P = .10). ROPtool's sensitivity of 97% (36 of 37) compared favorably with that of examiner 1 (65%; 24 of 37; P < .001), examiner 2 (70%; 26 of 37; P < .001), and examiner 3 (81%; 30 of 37; P = .06). CONCLUSION: Computer-assisted analysis of retinal images can potentially reduce subjectivity in the diagnosis of plus disease and optimize timing of follow-up and treatment for ROP.

A pilot study using "ROPtool" to quantify plus disease in retinopathy of prematurity.

PURPOSE: The accurate diagnosis of plus disease is critical to optimize the timing of laser treatment. Unfortunately, it is highly subjective and error-prone. "ROPtool" is a computer program that automatically traces retinal blood vessels and measures their tortuosity and dilation. Our aims were to pilot ROPtool, determine its reliability and validity, and establish appropriate numerical thresholds for plus and pre-plus disease. METHODS: Twenty high-quality images of the posterior poles of premature infants were collected. Two of the authors (DKW and SFF) independently judged tortuosity and dilation separately as plus, pre-plus, or normal for each quadrant of each image. Disagreements were adjudicated, and the results were considered to be the standard for comparison to ROPtool. These two authors then separately used ROPtool to analyze the same 20 images. RESULTS: For determination of tortuosity sufficient for plus disease, ROPtool interuser agreement was 95% (19/20), compared with 90% (18/20) agreement by investigator judgment. Eye-level (2 MDs x 20 eyes) sensitivity of ROPtool in detecting tortuosity sufficient for plus disease averaged 95% (21/22) and specificity averaged 78% (14/18). Quadrant-level (2 MDs x 20 eyes x 4 quadrants) sensitivity averaged 85% (66/78) and specificity averaged 77% (63/82). A numeric threshold for pre-plus disease equal to 70% of the average tortuosity of the standard photograph of plus disease resulted in mean sensitivity of 89% (103/116) and mean specificity of 82% (36/44) in distinguishing quadrant-level tortuosity sufficient for pre-plus disease or worse from normal. CONCLUSIONS: ROPtool can reduce subjectivity and thereby enhance the evaluation of plus and pre-plus disease.

A novel 3D partitioned active shape model for segmentation of brain MR images.

A 3D Partitioned Active Shape Model (PASM) is proposed in this paper to address the problems of the 3D Active Shape Models (ASM). When training sets are small. It is usually the case in 3D segmentation, 3D ASMs tend to be restrictive. This is because the allowable region spanned by relatively few eigenvectors cannot capture the full range of shape variability. The 3D PASM overcomes this limitation by using a partitioned representation of the ASM. Given a Point Distribution Model (PDM), the mean mesh is partitioned into a group of small tiles. In order to constrain deformation of tiles, the statistical priors of tiles are estimated by applying Principal Component Analysis to each tile. To avoid the inconsistency of shapes between tiles, training samples are projected as curves in one hyperspace instead of point clouds in several hyperspaces. The deformed points are then fitted into the allowable region of the model by using a curve alignment scheme. The experiments on 3D human brain MRIs show that when the numbers of the training samples are limited, the 3D PASMs significantly improve the segmentation results as compared to 3D ASMs and 3D Hierarchical ASMs.