Faculty Bibliography
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316
The nonlinear relationship between cerebrospinal fluid Aβ42 and tau in preclinical Alzheimer's disease
Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1-42 (Aβ42) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer's disease (AD). However, the preclinical prediction accuracy for low CSF Aβ42 levels, a surrogate for brain Aβ42 deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Aβ initiated cascade. CSF Aβ42 and tau data from 3 normal aging cohorts (45-90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of Aβ42 and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (Aβ2) best describes the relationship for CSF Aβ42 with CSF tau levels. Furthermore we found that the relationship between Aβ42 and tau changes with age-between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between Aβ42 and tau. The quadratic effect appears to be unique to Aβ42, as Aβ38 and Aβ40 showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of Aβ42. Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in Aβ42. Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Aβxx analyte levels prior to Aβ42 deposition in brain.
PMCID:5802432
PMID: 29415068
ISSN: 1932-6203
CID: 2947732
3D Registration of mpMRI for Assessment of Prostate Cancer Focal Therapy
RATIONALE AND OBJECTIVES: This study aimed to assess a novel method of three-dimensional (3D) co-registration of prostate magnetic resonance imaging (MRI) examinations performed before and after prostate cancer focal therapy. MATERIALS AND METHODS: We developed a software platform for automatic 3D deformable co-registration of prostate MRI at different time points and applied this method to 10 patients who underwent focal ablative therapy. MRI examinations were performed preoperatively, as well as 1 week and 6 months post treatment. Rigid registration served as reference for assessing co-registration accuracy and precision. RESULTS: Segmentation of preoperative and postoperative prostate revealed a significant postoperative volume decrease of the gland that averaged 6.49 cc (P = .017). Applying deformable transformation based on mutual information from 120 pairs of MRI slices, we refined by 2.9 mm (max. 6.25 mm) the alignment of the ablation zone, segmented from contrast-enhanced images on the 1-week postoperative examination, to the 6-month postoperative T2-weighted images. This represented a 500% improvement over the rigid approach (P = .001), corrected by volume. The dissimilarity by Dice index of the mapped ablation zone using deformable transformation vs rigid control was significantly (P = .04) higher at the ablation site than in the whole gland. CONCLUSIONS: Our findings illustrate our method's ability to correct for deformation at the ablation site. The preliminary analysis suggests that deformable transformation computed from mutual information of preoperative and follow-up MRI is accurate in co-registration of MRI examinations performed before and after focal therapy. The ability to localize the previously ablated tissue in 3D space may improve targeting for image-guided follow-up biopsy within focal therapy protocols.
PMCID:6025844
PMID: 29122471
ISSN: 1878-4046
CID: 2772952
Lepidic Predominant Pulmonary Lesions (LPL): CT-based Distinction From More Invasive Adenocarcinomas Using 3D Volumetric Density and First-order CT Texture Analysis
RATIONALE AND OBJECTIVES: This study aimed to differentiate pathologically defined lepidic predominant lesions (LPL) from more invasive adenocarcinomas (INV) using three-dimensional (3D) volumetric density and first-order texture histogram analysis of surgically excised stage 1 lung adenocarcinomas. MATERIALS AND METHODS: This retrospective study was institutional review board approved and Health Insurance Portability and Accountability Act compliant. Sixty-four cases of pathologically proven stage 1 lung adenocarcinoma surgically resected between September 2006 and October 2015, including LPL (n = 43) and INV (n = 21), were evaluated using high-resolution computed tomography. Quantitative measurements included nodule volume, percent solid volume (% solid), and first-order texture histogram analysis including skewness, kurtosis, entropy, and mean nodule attenuation within each histogram quartile. Binomial logistic regression models were used to identify the best set of parameters distinguishing LPL from INV. RESULTS: Univariate analysis of 3D volumetric density and histogram features was statistically significant between LPL and INV groups (P < .05). Accuracy of a binomial logistic model to discriminate LPL from INV based on size and % solid was 85.9%. With optimized probability cutoff, the model achieves 81% sensitivity, 76.7% specificity, and area under the receiver operating characteristic curve of 0.897 (95% confidence interval, 0.821-0.973). An additional model based on size and mean nodule attenuation of the third quartile (Hu_Q3) of the histogram achieved similar accuracy of 81.3% and area under the receiver operating characteristic curve of 0.877 (95% confidence interval, 0.790-0.964). CONCLUSIONS: Both 3D volumetric density and first-order texture analysis of stage 1 lung adenocarcinoma allow differentiation of LPL from more invasive adenocarcinoma with overall accuracy of 85.9%-81.3%, based on multivariate analyses of either size and % solid or size and Hu_Q3, respectively.
PMID: 28844845
ISSN: 1878-4046
CID: 2679872
Diagnosis of Normal-Pressure Hydrocephalus: Use of Traditional Measures in the Era of Volumetric MR Imaging
Purpose To assess the diagnostic performance of the callosal angle (CA) and Evans index (EI) measures and to determine their role versus automated volumetric methods in clinical radiology. Materials and Methods Magnetic resonance (MR) examinations performed before surgery (within 1-5 months of the MR examination) in 36 shunt-responsive patients with normal-pressure hydrocephalus (NPH; mean age, 75 years; age range, 58-87 years; 26 men, 10 women) and MR examinations of age- and sex-matched patients with Alzheimer disease (n = 34) and healthy control volunteers (n = 36) were studied. Three blinded observers independently measured EI and CA for each patient. Volumetric segmentation of global gray matter, white matter, ventricles, and hippocampi was performed by using software. These measures were tested by using multivariable logistic regression models to determine which combination of metrics is most accurate in diagnosis. Results The model that used CA and EI demonstrated 89.6%-93.4% accuracy and average area under the curve of 0.96 in differentiating patients with NPH from patients without NPH (ie, Alzheimer disease and healthy control). The regression model that used volumetric predictors of gray matter and white matter was 94.3% accurate. Conclusion CA and EI may serve as a screening tool to help the radiologist differentiate patients with NPH from patients without NPH, which would allow for designation of patients for further volumetric assessment. (c) RSNA, 2017.
PMCID:5621717
PMID: 28498794
ISSN: 1527-1315
CID: 2548722
CSF clearance in Alzheimer Disease measured with dynamic PET
Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer's disease (AD) comes from primarily from rodent models. However, unlike rodents where predominant extra-cranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Using dynamic Positron Emission Tomography (PET) with 18F-THK5117 a tracer for tau pathology, the ventricular CSF time activity was used as a biomarker for CSF clearance. We tested three hypotheses: 1. Extra-cranial CSF is detected at the superior turbinates; 2. CSF clearance is reduced in AD; and 3. CSF clearance is inversely associated with amyloid deposition. Methods: 15 subjects, 8 with AD and 7 normal control volunteers were examined with 18F-THK5117. 10 subjects additionally received 11C-PiB PET scans and 8 were PiB positive. Ventricular time activity curves (TAC) of 18F-THK5117 were used to identify highly correlated TAC from extra-cranial voxels. Results: For all subjects, the greatest density of CSF positive extra-cranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinates CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.
PMCID:5577629
PMID: 28302766
ISSN: 1535-5667
CID: 2490122
Proton MR spectroscopy of lesion evolution in multiple sclerosis: Steady-state metabolism and its relationship to conventional imaging
Although MRI assessment of white matter lesions is essential for the clinical management of multiple sclerosis, the processes leading to the formation of lesions and underlying their subsequent MRI appearance are incompletely understood. We used proton MR spectroscopy to study the evolution of N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho), and myo-inositol (mI) in pre-lesional tissue, persistent and transient new lesions, as well as in chronic lesions, and related the results to quantitative MRI measures of T1-hypointensity and T2-volume. Within 10 patients with relapsing-remitting course, there were 180 regions-of-interest consisting of up to seven semi-annual follow-ups of normal-appearing white matter (NAWM, n = 10), pre-lesional tissue giving rise to acute lesions which resolved (n = 3) or persisted (n = 3), and of moderately (n = 9) and severely hypointense (n = 6) chronic lesions. Compared with NAWM, pre-lesional tissue had higher Cr and Cho, while compared with lesions, pre-lesional tissue had higher NAA. Resolving acute lesions showed similar NAA levels pre- and post-formation, suggesting no long-term axonal damage. In chronic lesions, there was an increase in mI, suggesting accumulating astrogliosis. Lesion volume was a better predictor of axonal health than T1-hypointensity, with lesions larger than 1.5 cm3 uniformly exhibiting very low (<4.5 millimolar) NAA concentrations. A positive correlation between longitudinal changes in Cho and in lesion volume in moderately hypointense lesions implied that lesion size is mediated by chronic inflammation. These and other results are integrated in a discussion on the steady-state metabolism of lesion evolution in multiple sclerosis, viewed in the context of conventional MRI measures. Hum Brain Mapp, 2017. (c) 2017 Wiley Periodicals, Inc.
PMCID:5510951
PMID: 28523763
ISSN: 1097-0193
CID: 2563072
Insulin resistance among obese middle-aged is associated with decreased cerebrovascular reactivity
OBJECTIVE: To evaluate differences in cerebrovascular reactivity (CVR) to mild hypercapnia in obese/overweight individuals with and without insulin resistance (IR) compared to comparable lean controls. METHODS: A total of 60 cognitively normal participants (20 lean controls and 24 obese/overweight individuals with and 16 without IR) were evaluated using a high spatial resolution arterial spin labeling MRI technique at rest and during mild hypercapnia. We analyzed group differences in CVR in cerebral cortex and ascertained the relationships between CVR, IR, and body mass index (BMI). RESULTS: Obese/overweight participants with and without IR had significantly lower CVR to hypercapnia than lean controls after controlling for age, sex, and the presence of hypertension (F2,53 = 5.578, p = 0.006 eta2p = 0.174). In the obese/overweight participants with IR, there was a significant correlation between higher CVR and a measure of insulin sensitivity, even after accounting for BMI (rp = 0.575, p = 0.004). In contrast, there was no relationship between CVR and BMI when controlling for IR. No such relationships existed for the other 2 groups. CONCLUSIONS: IR is associated with impaired CVR; the relationship appears to be driven by the degree of IR and not by obesity. These rarely reported results suggest that early forms of cerebrovascular dysfunction exist among obese middle-aged individuals with significant IR but without type 2 diabetes mellitus. These functional vascular abnormalities may help explain the associations among IR, diabetes, and dementia, and suggest that interventions aiming to improve IR or CVR may help prevent cognitive decline later in life.
PMCID:5513815
PMID: 28615420
ISSN: 1526-632x
CID: 2595142
Lumbar Puncture Test in Normal Pressure Hydrocephalus: Does the Volume of CSF Removed Affect the Response to Tap?
BACKGROUND AND PURPOSE: There is limited evidence to support the use of high-volume lumbar taps over lower-volume taps in the diagnosis of normal pressure hydrocephalus. The purpose of this study is to detect whether the volume of CSF removed from patients undergoing high-volume diagnostic lumbar tap test for normal pressure hydrocephalus is significantly associated with post-lumbar tap gait performance. MATERIALS AND METHODS: This retrospective study included 249 consecutive patients who underwent evaluation for normal pressure hydrocephalus. The patients were analyzed both in their entirety and as subgroups that showed robust response to the lumbar tap test. The volume of CSF removed was treated as both a continuous variable and a discrete variable. Statistical tests were repeated with log-normalized volumes. RESULTS: This study found no evidence of a relationship between the volume of CSF removed during the lumbar tap test and subsequent gait test performance in the patient population (Pearson coefficient r = 0.049-0.129). Log normalization of the volume of CSF removed and controlling for age and sex failed to yield a significant relationship. Subgroup analyses focusing on patients who showed greater than 20% improvement in any of the gait end points or who were deemed sufficiently responsive clinically to warrant surgery also yielded no significant relationships between the volume of CSF removed and gait outcomes, but there were preliminary findings that patients who underwent tap with larger-gauge needles had better postprocedure ambulation among patients who showed greater than 20% improvement in immediate time score (P = .04, n = 62). CONCLUSIONS: We found no evidence to support that a higher volume of CSF removal impacts gait testing, suggesting that a high volume of CSF removal may not be necessary in a diagnostic lumbar tap test.
PMID: 28473344
ISSN: 1936-959x
CID: 2545882
Clinical applicability and relevance of fibroglandular tissue segmentation on routine T1 weighted breast MRI
PURPOSE: To evaluate clinical applicability of fibroglandular tissue (FGT) segmentation on routine T1 weighted breast MRI and compare FGT quantification with radiologist assessment. METHODS: FGT was segmented on 232 breasts and quantified, and was assessed qualitatively by four breast imagers. RESULTS: FGT segmentation was successful in all 232 breasts. Agreement between radiologists and quantified FGT was moderate to substantial (kappa=0.52-0.67); lower quantified FGT was associated with disagreement between radiologists and quantified FGT (P
PMID: 27951458
ISSN: 1873-4499
CID: 2363342
Development and evaluation of an automated atlas-based data analysis method for dynamic microPET mouse brain studies [Meeting Abstract]
Objectives: MicroPET imaging has been increasingly performed on mouse models for a variety of human CNS disorders. Despite high demand, digital mouse brain atlases based on PET are still lacking. Further, most microPET systems do not provide means of mapping mouse brain with atlas. For quantitative data analysis and accurate anatomical localization, the development and evaluation of an automated atlas-based data analysis on microPET mouse brain studies is presented. Methods: MicroPET imaging studies were performed after injection of F-18 labeled Amyvid (a tracer for imaging amyloid (Aa) plaques) in isoflurane-anesthetized adult mice using Inveon PET/CT (Siemens). The list mode dynamic PET data were collected for 30-60 min and rebinned using a Fourier rebinning algorithm. A CT scan was also performed for attenuation correction and anatomical co-registration. A 3D digital magnetic resonance microscopy (MRM)-based volume of interest (VOI) atlas generated from live C57BL/6J adult mouse brain was used for brain mapping (Ma et al., 2008). Landmarks, including left and right centroids of midears and eyes (4 landmarks), were generated on atlas template and individual mouse CT images. Co-registration of atlas, CT and PET was performed using Firevoxel (FVX) (https://urldefense.proofpoint.com/v2/url?u=https- 3A__wp.nyu.edu_Firevoxel&d=DgIBAg&c=j5oPpO0eBH1iio48DtsedbOBGmuw5jHLjgvtN2r4ehE&r=KRXe NoRy5_8lkSwAJG5vjS1yT0aFSItfe494dmkdSVs&m=B4bFtJccWjUzJ- dbK1qURkxJmihDqjf87yIgZlYKTMk&s=soyp2V3_QGPs--q8qXcfkDHjv7kMngxeekpEknOQoi8&e= ) and time-activity curves (TAC) for 20 specific 3D brain regions were generated. For comparison, an expert in mouse neuroanatomy manually drew corresponding VOIs on PET-CT co-registered images derived from IRW (Inveon data analysis software without atlas). The TACs thus generated via both methods were compared. For further evaluation, the tracer uptake and kinetics in both tau and Aa transgenic mouse models were also compared. Results: Using FVX, single step co-registration of atlas, CT and PET was accomplished in seconds (by one-button pressing) and the TACs for specific ROIs of mouse brain were automatically generated after co-registration. In contrast, it took an average of 15 min to manually draw a single VOI (total 5 hours/mouse for 20 VOIs) directly on CT images using Inveon IRW without an atlas, a process that required an expert in mouse neuroanatomy. Overall, the TACs for the corresponding VOIs derived from IRW and FVX were similar in counts and shapes. Most importantly, this VOI atlas-based method can provide unbiased measures of radioactivity concentration from PET studies. The results from studies of tau vs. Aa transgenic mouse models after injection of Amyvid showed an apparent difference in the tracer uptake and kinetics (Fig. 1). Conclusions: We have demonstrated the feasibility to map mouse brain with an automated atlas-based co-registration for data analysis of microPET brain studies using FVX. This novel time-saving data analysis methodology, unachievable with current microPET imaging systems, will facilitate accurate assessment and spatial localization of brain signals in mouse model studies for a variety of human CNS disorders
EMBASE:613981705
ISSN: 1860-2002
CID: 2415632
