Faculty Bibliography

Subjective cognitive decline (SCD) is associated with preclinical Alzheimer's disease (AD). Suboptimal sleep is also a risk factor for cognitive decline, but with unclear relationship to SCD. We conducted a retrospective cross-sectional study in a biracial research cohort of 148 cognitively normal older adults who underwent quantification of SCD (Cognitive Change Index; CCI), sleepiness (Epworth Sleepiness Scale; ESS), depression (Geriatric Depression Scale; GDS), and amyloid/tau PET. ESS score was associated with total, amnestic, and non-amnestic CCI scores, after adjustment for GDS, amyloid/tau burden, and race. This supports future longitudinal work on how sleepiness impacts SCD outcomes.

This article provides an overview of the FireVoxel software for quantitative analysis of medical images and its applications in the field. We describe FireVoxel's user interface, multi-layer design, dynamic parametric models, and several turn-key workflows. Additionally, we discuss its application in recent imaging projects. We outline basic image analysis tools such as segmentation, non-uniformity correction, and coregistration through a pictorial overview, with a focus on deformable coregistration and motion correction. Several example workflows and image-based dynamic modeling are also highlighted. Furthermore, we analyze peer-reviewed studies that utilized FireVoxel for image processing, categorizing published papers based on body structures/organs, image processing methods, and imaging modalities. For comparison, we searched the Ovid MEDLINE database to assess the general use of medical image analysis software. FireVoxel is used by over 3000 users worldwide, with 528 articles, including 413 in English, published in the past 15 years. MRI is the most commonly used imaging modality (78.2%), followed by CT (14.5%) and PET (7.3%). The most frequently used methods are dynamic modeling, segmentation, texture analysis, and coregistration. FireVoxel is commonly used in abdominal and genitourinary imaging studies, where it appears to fill a niche due to the lack of alternative software. The search of the Ovid MEDLINE suggests that quantitative medical imaging studies, on the other hand, focus on the brain and cardiovascular system. FireVoxel offers an effective set of quantitative tools, particularly for abdominal and genitourinary imaging, likely due to its ability to manage patient motion and correct for MR artifacts. The software is especially valuable for processing dynamic studies. The steady increase in publications utilizing FireVoxel reflects growing interest in this software and its relevance for image-based research.

High-dimensional multinomial regression models are very useful in practice but have received less research attention than logistic regression models, especially from the perspective of statistical inference. In this work, we analyze the estimation and prediction error of the contrast-based

BACKGROUND:Postacute Covid-19 patients commonly present with respiratory symptoms; however, a noninvasive imaging method for quantitative characterization of respiratory patterns is lacking. PURPOSE/OBJECTIVE:To evaluate if quantitative characterization of respiratory pattern on free-breathing higher temporal resolution MRI stratifies patients by cardiopulmonary symptom burden. STUDY TYPE/METHODS:Prospective analysis of retrospectively acquired data. SUBJECTS/METHODS:A total of 37 postacute Covid-19 patients (25 male; median [interquartile range (IQR)] age: 58 [42-64] years; median [IQR] days from acute infection: 335 [186-449]). FIELD STRENGTH/SEQUENCE/UNASSIGNED:0.55 T/two-dimensional coronal true fast imaging with steady-state free precession (trueFISP) at higher temporal resolution. ASSESSMENT/RESULTS:Patients were stratified into three groups based on presence of no (N = 11), 1 (N = 14), or ≥2 (N = 14) cardiopulmonary symptoms, assessed using a standardized symptom inventory within 1 month of MRI. An automated lung postprocessing workflow segmented each lung in each trueFISP image (temporal resolution 0.2 seconds) and respiratory curves were generated. Quantitative parameters were derived including tidal lung area, rates of inspiration and expiration, lung area coefficient of variability (CV), and respiratory incoherence (departure from sinusoidal pattern) were. Pulmonary function tests were recorded if within 1 month of MRI. Qualitative assessment of respiratory pattern and lung opacity was performed by three independent readers with 6, 9, and 23 years of experience. STATISTICAL TESTS/METHODS:Analysis of variance to assess differences in demographic, clinical, and quantitative MRI parameters among groups; univariable analysis and multinomial logistic regression modeling to determine features predictive of patient symptom status; Akaike information criterion to compare the quality of regression models; Cohen and Fleiss kappa (κ) to quantify inter-reader reliability. Two-sided 5% significance level was used. RESULTS:; CV: 0.072, 0.067, and 0.058). Respiratory incoherence was significantly higher in patients with two or more symptoms than in those with one or no symptoms (0.05 vs. 0.043 vs. 0.033). There were no significant differences in patient age (P = 0.19), sex (P = 0.88), lung opacity severity (P = 0.48), or pulmonary function tests (P = 0.35-0.97) among groups. Qualitative reader assessment did not distinguish between groups and showed slight inter-reader agreement (κ = 0.05-0.11). DATA CONCLUSION/CONCLUSIONS:Quantitative respiratory pattern measures derived from dynamic higher-temporal resolution MRI have potential to stratify patients by symptom burden in a postacute Covid-19 cohort. LEVEL OF EVIDENCE/METHODS:3 TECHNICAL EFFICACY: Stage 3.

PURPOSE/OBJECTIVE:The pathological hallmarks of Alzheimer's disease (AD), amyloid, tau, and associated neurodegeneration, are present in the cortical gray matter (GM) years before symptom onset, and at significantly greater levels in carriers of the apolipoprotein E4 (APOE4) allele. Their respective biomarkers, A/T/N, have been found to correlate with aspects of brain biochemistry, measured with magnetic resonance spectroscopy (MRS), indicating a potential for MRS to augment the A/T/N framework for staging and prediction of AD. Unfortunately, the relationships between MRS and A/T/N biomarkers are unclear, largely due to a lack of studies examining them in the context of the spatial and temporal model of T/N progression. Advanced MRS acquisition and post-processing approaches have enabled us to address this knowledge gap and test the hypotheses, that glutamate-plus-glutamine (Glx) and N-acetyl-aspartate (NAA), metabolites reflecting synaptic and neuronal health, respectively, measured from regions on the Braak stage continuum, correlate with: (i) cerebrospinal fluid (CSF) p-tau181 level (T), and (ii) hippocampal volume or cortical thickness of parietal lobe GM (N). We hypothesized that these correlations will be moderated by Braak stage and APOE4 genotype. METHODS:We conducted a retrospective imaging study of 34 cognitively unimpaired elderly individuals who received APOE4 genotyping and lumbar puncture from pre-existing prospective studies at the NYU Grossman School of Medicine between October 2014 and January 2019. Subjects returned for their imaging exam between April 2018 and February 2020. Metabolites were measured from the left hippocampus (Braak II) using a single-voxel semi-adiabatic localization by adiabatic selective refocusing sequence; and from the bilateral posterior cingulate cortex (PCC; Braak IV), bilateral precuneus (Braak V), and bilateral precentral gyrus (Braak VI) using a multi-voxel echo-planar spectroscopic imaging sequence. Pearson and Spearman correlations were used to examine the relationships between absolute levels of choline, creatine, myo-inositol, Glx, and NAA and CSF p-tau181, and between these metabolites and hippocampal volume or parietal cortical thicknesses. Covariates included age, sex, years of education, Fazekas score, and months between CSF collection and MRI exam. RESULTS:There was a direct correlation between hippocampal Glx and CSF p-tau181 in APOE4 carriers (Pearson's r = 0.76, p = 0.02), but not after adjusting for covariates. In the entire cohort, there was a direct correlation between hippocampal NAA and hippocampal volume (Spearman's r = 0.55, p = 0.001), even after adjusting for age and Fazekas score (Spearman's r = 0.48, p = 0.006). This relationship was observed only in APOE4 carriers (Pearson's r = 0.66, p = 0.017), and was also retained after adjustment (Pearson's r = 0.76, p = 0.008; metabolite-by-carrier interaction p = 0.03). There were no findings in the PCC, nor in the negative control (late Braak stage) regions of the precuneus and precentral gyrus. CONCLUSIONS:Our findings are in line with the spatially- and temporally-resolved Braak staging model of pathological severity in which the hippocampus is affected earlier than the PCC. The correlations, between MRS markers of synaptic and neuronal health and, respectively, T and N pathology, were found exclusively within APOE4 carriers, suggesting a connection with AD pathological change, rather than with normal aging. We therefore conclude that MRS has the potential to augment early A/T/N staging, with the hippocampus serving as a more sensitive MRS target compared to the PCC.

Magnetization transfer MRI is sensitive to semi-solid macromolecules, including amyloid beta, and has previously been used to discriminate Alzheimer's disease (AD) patients from controls. Here, we fit an unconstrained 2-pool quantitative MT (qMT) model, i.e., without constraints on the longitudinal relaxation rate

INTRODUCTION/BACKGROUND:We examined whether hypertension (HTN) was associated with Alzheimer's disease-related biomarkers in cerebrospinal fluid (CSF) and how changes in blood pressure (BP) related to changes in CSF biomarkers over time. METHODS:A longitudinal observation of cognitively healthy normotensive subjects (n = 134, BP < 140/90, with no antihypertensive medication), controlled HTN (n = 36, BP < 140/90, taking antihypertensive medication), and 35 subjects with uncontrolled HTN (BP ≥ 140/90). The follow-up range was 0.5to15.6 years. RESULTS:Total tau (T-tau) and phospho-tau181 (P-tau 181) increased in all but controlled HTN subjects (group×time interaction: p < 0.05 for both), but no significant Aβ42 changes were seen. Significant BP reduction was observed in uncontrolled HTN, and it was related to increase in T-tau (p = 0.001) and P-tau 181 (p < 0.001). DISCUSSION/CONCLUSIONS:Longitudinal increases in T-tau and P-tau 181 were observed in most subjects; however, only uncontrolled HTN had both markers increase alongside BP reductions. We speculate cumulative vascular injury renders the brain susceptible to relative hypoperfusion with BP reduction. HIGHLIGHTS/CONCLUSIONS:Over the course of the study, participants with uncontrolled HTN at baseline showed greater accumulation of CSF total tau and phospho-tau181 (P-tau 181) than subjects with normal BP or with controlled HTN. In the group with uncontrolled HTN, increases in total tau and P-tau 181 coincided with reduction in BP. We believe this highlights the role of HTN in vascular injury and suggests decline in cerebral perfusion resulting in increased biomarker concentrations in CSF. Medication use was the main factor differentiating controlled from uncontrolled HTN, indicating that earlier treatment was beneficial for preventing accumulations of pathology.

BACKGROUND:(p-tau), as well as the trajectories of these CSF measures obtained longitudinally. RESULTS:A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. CONCLUSIONS:We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.

PURPOSE/OBJECTIVE: METHODS: RESULTS: CONCLUSIONS:

BACKGROUND:C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. METHODS:F]-FBB identified 8 amyloid PET positive (Aβ+) and 16 Aβ- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. RESULTS:LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aβ+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. CONCLUSION/CONCLUSIONS:The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.