Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:Previous hippocampal proton MR spectroscopic imaging distinguished patients with schizophrenia from controls by elevated Cr levels and significantly more variable NAA and Cho concentrations. This goal of this study was to ascertain whether this metabolic variability is associated with clinical features of the syndrome, possibly reflecting heterogeneous hippocampal pathologies and perhaps variability in its "positive" (psychotic) and "negative" (social and emotional deficits) symptoms. MATERIALS AND METHODS/METHODS:, we examined the association of NAA and Cho levels with research diagnostic interviews and clinical symptom ratings of the patients. Metabolite concentrations were previously obtained with 3D proton MR spectroscopic imaging at 3T, a technique that facilitates complete coverage of this small, irregularly shaped, bilateral, temporal lobe structure. RESULTS: ≥  .055). CONCLUSIONS:These preliminary findings suggest that NAA and Cho variations reflect different pathophysiologic processes, consistent with microgliosis/astrogliosis and/or lower vitality (reduced NAA) and demyelination (elevated Cho). In particular, the active state-related symptoms, including psychosis and mania, were associated with demyelination. Consequently, their deviations from the means of healthy controls may be a marker that may benefit precision medicine in selection and monitoring of schizophrenia treatment.

Background: Despite studies suggesting that blacks may be at greater risk of developing AD, there have been few studies investigating health disparities, and blacks have been underrepresented in many prominent AD biomarker studies and clinical trials. The current ATN biomarker classification system may not fully account for health disparities and can't explain the increased prevalence among blacks for both AD and AD vascular risks of diabetes and hypertension when compared to whites. Research on cognitive aging has traditionally focused on how decline in various cortical and hippocampal (Hip) regions influences cognition. However, tau pathology emerges decades before amyloid pathology, appearing first in the brainstem (BS); particularly in the locus coeruleus (LC), the source of brain's norepinephrine (NE). Our decade-long studies in humans using a norepinephrine transporter (NET)-selective radiotracer ([11C]MRB) have demonstrated a special vulnerability of LC to aging and stress.
Method(s): Co-registration of PET (dynamic [11C]MRB), MRI and the FreeSurfer (FS) atlas images of each individual was used to generate regional time-activity curves using Firevoxel. Binding potential (BPND) values were determined using MRTM2 with occipital as the reference region. Annual percent change (APC) of BPND was calculated based on linear regression (APC = 100 x (em-1), m: slope) and effects of age, gender and ethnicity on tracer binding were evaluated.
Result(s): For all HC (N=31), with both genders and all races included, age-sensitive decline of NET availability was observed; e.g., 0.3-0.5%/yr for Hip, BS and olfactory. However, our data reveals that the decline rate of NET is much faster among blacks starting in the mid-30s, particularly in black males; e.g., 2-3%/yr vs. 0.14-0.23%/yr in thalamus and brainstem for black males vs. white males (p < 0.00001).
Conclusion(s): In addition to our previously determined age effect on MRB-NET binding, this report further reveals the role of ethnicity effects on NET availability. Our study showed that a faster decline of LC-NE function occurs in blacks, possibly caused by cumulative stress to socioeconomic disadvantage and racial discrimination and may be responsible for the different disease expression among blacks. Thus, NET availability imaging represents a novel biomarker approach to racial-dependent strategies for diagnosis and assessment of therapeutic interventions

The human brain functions at the center of a network of systems aimed at providing a structural and immunological layer of protection. The cerebrospinal fluid (CSF) maintains a physiological homeostasis that is of paramount importance to proper neurological activity. CSF is largely produced in the choroid plexus where it is continuous with the brain extracellular fluid and circulates through the ventricles. CSF movement through the central nervous system has been extensively explored. Across numerous animal species, the involvement of various drainage pathways in CSF, including arachnoid granulations, cranial nerves, perivascular pathways, and meningeal lymphatics, has been studied. Among these, there is a proposed CSF clearance route spanning the olfactory nerve and exiting the brain at the cribriform plate and entering lymphatics. While this pathway has been demonstrated in multiple animal species, evidence of a similar CSF egress mechanism involving the nasal cavity in humans remains poorly consolidated. This review will synthesize contemporary evidence surrounding CSF clearance at the nose-brain interface, examining across species this anatomical pathway, and its possible significance to human neurodegenerative disease. Our discussion of a bidirectional nasal pathway includes examination of the immune surveillance in the olfactory region protecting the brain. Overall, we expect that an expanded discussion of the brain-nose pathway and interactions with the environment will contribute to an improved understanding of neurodegenerative and infectious diseases, and potentially to novel prevention and treatment considerations.

In this study, we investigate the feasibility of using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), diffusion weighted imaging (DWI), and dynamic positron emission tomography (PET) for detection of metastatic lymph nodes in head and neck squamous cell carcinoma (HNSCC) cases. Twenty HNSCC patients scheduled for lymph node dissection underwent DCE-MRI, dynamic PET, and DWI using a PET-MR scanner within one week prior to their planned surgery. During surgery, resected nodes were labeled to identify their nodal levels and sent for routine clinical pathology evaluation. Quantitative parameters of metastatic and normal nodes were calculated from DCE-MRI (v_e, v_p, PS, F_p, K^trans), DWI (ADC) and PET (K_i, K₁, k₂, k₃) to assess if an individual or a combination of parameters can classify normal and metastatic lymph nodes accurately. There were 38 normal and 11 metastatic nodes covered by all three imaging methods and confirmed by pathology. 34% of all normal nodes had volumes greater than or equal to the smallest metastatic node while 4 normal nodes had SUV > 4.5. Among the MRI parameters, the median v_p, F_p, PS, and K^trans values of the metastatic lymph nodes were significantly lower (p = <0.05) than those of normal nodes. v_e and ADC did not show any statistical significance. For the dynamic PET parameters, the metastatic nodes had significantly higher k₃ (p value = 8.8 × 10^-8) and K_i (p value = 5.3 × 10^-8) than normal nodes. K₁ and k₂ did not show any statistically significant difference. K_i had the best separation with accuracy = 0.96 (sensitivity = 1, specificity = 0.95) using a cutoff of K_i = 5.3 × 10^-3 mL/cm³/min, while k₃ and volume had accuracy of 0.94 (sensitivity = 0.82, specificity = 0.97) and 0.90 (sensitivity = 0.64, specificity = 0.97) respectively. 100% accuracy can be achieved using a multivariate logistic regression model of MRI parameters after thresholding the data with K_i < 5.3 × 10^-3 mL/cm³/min. The results of this preliminary study suggest that quantitative MRI may provide additional value in distinguishing metastatic nodes, particularly among small nodes, when used together with FDG-PET.

Objectives: Alzheimer's disease (AD) is a major health challenge in our aging society. An improved understanding of its underlying pathological mechanisms is urgently needed to enable the development of effective treatments. Postmortem findings indicate that tau pathology emerges decades before amyloid pathology, appearing first in the brainstem; in particular in the locus coeruleus (LC), a small nucleus that is the source of most of the brain's norepinephrine (NE). Although very little is known about how the NE system changes during normal aging and its potential role in progression of preclinical stages of AD, our preliminary data using (S,S)-[¹¹C]MRB ([¹¹C]MRB) have documented an age-related decline in NE transporters (NET) availability starting in middle age, suggesting in vivo NET availability is a sensitive biomarker for aging and for changes during the preclinical stages of AD. In addition to the age effect, this report investigated the potential gender and ethnicity effects on NET availability.
Method(s): Dynamic [¹¹C]MRB images of healthy subjects were acquired for 120 min and individual structure MRI images were acquired for co-registration purposes. The segmentation of cortical and subcortical ROIs was automatically established via FreeSurfer (https://urldefense.proofpoint.com/v2/url?u=https-3A__surfer.nmr.mgh.harvard.edu_&d=DwIBAg&c=j5oPpO0eBH1iio48DtsedeElZfc04rx3ExJHeIIZuCs&r=CY_mkeBghQnUPnp2mckgsNSbUXISJaiBQUhM-Uz9W58&m=_uGsTvUTTD_GxqvwK245ZUiiSbzVraIboytFijFDOwU&s=HeAlDPi40HjMBca8e_BYWUls-gTNztvS9BIGKcmzNNI&e= ) based on the template MRI atlas (FS2005). Left and right olfactory (Ofac) regions were also generated using the Destrieux Atlas. With Firevoxel developed at NYU (https://urldefense.proofpoint.com/v2/url?u=https-3A__wp.nyu.edu_Firevoxel&d=DwIBAg&c=j5oPpO0eBH1iio48DtsedeElZfc04rx3ExJHeIIZuCs&r=CY_mkeBghQnUPnp2mckgsNSbUXISJaiBQUhM-Uz9W58&m=_uGsTvUTTD_GxqvwK245ZUiiSbzVraIboytFijFDOwU&s=RlC-AQtmqr84rzBwvDmgK_FCVdvbCfsFvuN-dVODTpM&e= ), PET, MRI, and the FS atlas images of each individual were coregistered using a mutual information algorithm with autofocus transformation that was tested and validated. Dynamic regional time-activity curves (TAC) were generated and MRTM2 was selected as the modeling method. Binding potential (BPND, a measure of specific binding with respect to non-displaceable uptake) values were automatically calculated, and tested by various starting time, parameter k2' and using two potential reference regions (caudate & occipital, low NET regions), for comparison and validation purposes. Annual percent change (APC) of regional BPND values was calculated based on linear regression (APC = 100 x (e - 1), m is the slope) and effects of age, gender and ethnicity on the NET-MRB binding were evaluated.
Result(s): Data presented here were based on t2* 20 min and k2' 0.021 min with occi as the reference region. For all HC (N=31), with both genders and all race included, the NET availability decline can be observed; e.g., -0.4%/yr for BS & ROfac. However, in gender-separated group analysis [M (N=19, age range: 23-55, avg=36.2+/-9.9) and F (N=12, age range 25-54, avg= 36.6+/-9.0)], while BPND values were not significantly different, there was a significant gender effect for APC (P <0.01) with decline rates faster for M (e.g., -0.8, -0.6, -0.5, & -0.4%/yr for TH, RAmyg, ROfac, & Hip, respectively), and significant decline starting from mid 30 (p<0.001). Gender effects were also observed in the group-level analyses in all white (N=16, 11M) and in all AA subgroups (N=14, 7M) with the decline rate faster for M than F, but APC difference did not reach significance (may be due to sample size and age range not completely matched). Interestingly, out of all investigated brain ROIs (16), avg BPND values of each ROI from AA (N=14, avg age 34+/-7) were consistently higher than those from white subjects (N=12, avg age 35+/-8)(P<0.000). However, the decline rate was consistently higher for AA than for white subjects (P<0.00001), e.g., the decline rate for AA-M: -3%/yr in LTH & RAmyg and over -1%/yr in BS & ROfac, and for AA-F: -2%/yr in BS & Ofac.
Conclusion(s): Compared to our previous age-related study of dopamine transporter (DAT), NET exhibited a faster decline rate than DAT. In addition to our previously determined age effect on MRB-NET binding, this report further reveals the role of gender and ethnicity effects on NET availability. A bigger sample size is warranted to investigate their effects on the NET availability

BACKGROUND AND PURPOSE/OBJECTIVE:In this study, we used power analysis to calculate required sample sizes to detect group-level changes in quantitative neuroanatomical estimates derived from MRI scans obtained from multiple imaging centers. Sample size estimates were derived from (i) standardized 3T image acquisition protocols and (ii) nonstandardized clinically acquired images obtained at both 1.5 and 3T as part of the multicenter Human Epilepsy Project. Sample size estimates were compared to assess the benefit of standardizing acquisition protocols. METHODS:Cortical thickness, hippocampal volume, and whole brain volume were estimated from whole brain T1-weighted MRI scans processed using Freesurfer v6.0. Sample sizes required to detect a range of effect sizes were calculated using (i) standard t-test based power analysis methods and (ii) a nonparametric bootstrap approach. RESULTS:A total of 32 participants were included in our analyses, aged 29.9 ± 12.62 years. Standard deviation estimates were lower for all quantitative neuroanatomical metrics when assessed using standardized protocols. Required sample sizes per group to detect a given effect size were markedly reduced when using standardized protocols, particularly for cortical thickness changes <.2 mm and hippocampal volume changes <10%. CONCLUSIONS:The use of standardized protocols yielded up to a five-fold reduction in required sample sizes to detect disease-related neuroanatomical changes, and is particularly beneficial for detecting subtle effects. Standardizing image acquisition protocols across scanners prior to commencing a study is a valuable approach to increase the statistical power of multicenter MRI studies.

PURPOSE/OBJECTIVE:To undertake an early proof of concept study on a novel, semi-automated texture-based scoring system in order to enhance the association between MRI lesions and clinically significant cancer. PATIENTS AND METHODS/METHODS:With ethics approval, 536 imaging volumes were generated from 20 consecutive patients who underwent mpMRI at time of biopsy. Volumes of interest (VOIs) included zonal anatomy segmentation and suspicious MRI lesion for cancer (Likert scale score greater than 2). Entropy (E), measuring heterogeneity, was computed from VOIs and plotted as a multiparametric score defined as Entropy Score (ES) = E ADC+ E Ktrans + E Ve+ E T2WI. The reference test that was used to define the ground truth comprised systematic saturation biopsies coupled with MRI targeted sampling. This generated 422 cores in all that were individually labelled and oriented in 3D. Diagnostic accuracy for detection of clinically significant prostate cancer (SPCa), defined as Gleason score of 3+4 (or higher) or more than 3mm of any grade of cancer on a single core, was assessed using Receiver Operating Characteristics, correlation and descriptive statistics. Proportion of cancerous lesions detected by ES and Visual Scoring (VS) were statistically compared using paired McNemar test. RESULTS:Any cancer (Gleason Score 6 to 8) was found in 12 of the 20 (60%) patients with a median PSA of 8.22ng/ml. SPCa (ES=17.96 ±0.72 NAT; CI 95%) showed a significant higher ES than non-SPCa (ES=15.33 ±0.76 NAT). ES correlated with Gleason Score (rs =0.5683, p=0.033) and maximum cancer core length (ρ = 0.781; p=0.0009). The Area Under the Curve for ES (0.89) and visual scoring (VS) (0.91) were not significantly different (p=0.75) for detection of SPCa among MRI lesions. Best ES estimated numerical threshold of 16.61 NATural information unit (NAT) led to a sensitivity of 100% and negative predictive value of 100%. The proportion of MRI lesion which found to positive for SPCa using this ES threshold (54%) was significantly higher (p<0.001) than those using VS (24% of score 3,4,5) in a paired analysis using McNemar test. 53% of MRI lesion would have avoided biopsy sampling without missing significant disease. CONCLUSION/CONCLUSIONS:Capturing heterogeneity of PCa across multiple MRI sequences with ES yielded high performances for the detection and stratification of SPca. ES outperformed visual scoring in predicting positivity of lesions, holding promise in the selection of targets for biopsy and calling for further understanding of this association.