Faculty Bibliography

BACKGROUND:Deep medullary veins (DMVs) play important roles within the cerebrovascular network related to brain drainage and clearance. Although they have been previously correlated with brain volume, it is unknown whether their count is specifically correlated with subcortical or cortical volume changes. PURPOSE/OBJECTIVE:This study aims to better understand the relationship between DMVs, subcortical (lateral ventricle to intracranial volume ratio (ICV)) and cortical atrophy (cortical thickness) to identify whether DMVs can be a predictor of volume changes in these regions. METHODS:We performed a retrospective analysis of 332 cognitively healthy subjects previously followed between 2010 and 2019. Imaging and patient charts were analyzed for baseline demographic and clinical characteristics. Patients underwent a standardized cognitive interview and received a magnetic resonance imaging scan to assess DMVs, cortical thickness, lateral ventricle and global gray matter (GM) volumes, white matter lesions (WMLs) and microbleeds. RESULTS:Among 332 patients (62% female, median age 70), lateral ventricle/ICV was significantly related to DMV count (p<0.001). Similarly, sex stratified analyses confirmed that a larger lateral ventricle/ICV ratio, but not cortical thickness or global GM volumes, was associated with fewer DMVs. In the entire group, subcortical atrophy remained a significant predictor of DMVs even after accounting for baseline characteristics, WMLs, microbleeds and total gray matter volume. CONCLUSIONS:In a large cohort of cognitively unaffected people, subcortical, but not cortical, atrophy was significantly correlated with venous health as measured by DMVs. Reduced DMVs are a strong predictor of ventricular enlargement.

Diffusion Magnetic Resonance Imaging (dMRI) simulations in geometries mimicking the microscopic complexity of human tissues enable the development of innovative biomarkers with unprecedented fidelity to histology. Simulation-informed dMRI has traditionally focussed on brain imaging, and it has neglected other applications, as for example body cancer imaging, where new non-invasive biomarkers are still sought. This article fills this gap by introducing a Monte Carlo diffusion simulation framework informed by histology, for enhanced body dMR microstructural imaging: the Histo-μSim approach. We generate dictionaries of synthetic dMRI signals with coupled tissue properties from virtual cancer environments, reconstructed from hematoxylin-eosin stains of human liver biopsies. These enable the data-driven estimation of properties such as the intrinsic extra-cellular diffusivity, cell size or cell membrane permeability. We compare Histo-μSim to metrics from well-established analytical multi-compartment models in silico, on fixed mouse tissues scanned ex vivo (kidneys, spleens, and breast tumours) and in cancer patients in vivo. Results suggest that Histo-μSim is feasible in clinical settings, and that it delivers metrics that more accurately reflect histology as compared to analytical models. In conclusion, Histo-μSim offers histologically-meaningful tissue descriptors that may increase the specificity of dMRI towards cancer, and thus play a crucial role in precision oncology.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Vascular dysfunction contributes to Alzheimer disease (AD) and related dementias (ADRDs), but the underlying mechanisms remain unclear. Previous studies link midlife hemostasis and platelet aggregation measures to late-life dementia risk. We aimed to determine whether platelet aggregation in midlife is associated with imaging markers of AD pathology. METHODS:F-flortaucipir) PET uptake in dementia-free, middle-aged adults from the Framingham Heart Study. Co-primary outcomes included amyloid and tau uptake in AD-vulnerable regions. We also examined an MRI-based cortical thickness signature of AD risk as a secondary outcome. We used multivariable regression models adjusted for demographic and clinical factors, considering potential nonlinear associations. RESULTS:< 0.035), consistent with a neurodegenerative pattern. DISCUSSION/CONCLUSIONS:Our findings indicate that platelet aggregation is linked to PET and MRI markers of AD pathology as early as midlife. These findings support further investigation of platelet-mediated mechanisms in AD pathogenesis.

BACKGROUND:Effective interpersonal communication is associated with improved health-related outcomes, yet it is unclear to what extent this occurs in triadic clinic visits for persons living with dementia (PLWD) and few tools exist to characterize triadic interpersonal communication and assess its effectiveness. The objective of this project is to characterize the interpersonal communication that occurs during triadic visits for PLWD, examine how interpersonal communication is related to health outcomes and use this understanding to adapt an innovative clinic visit audio recording intervention, HealthPAL (Personal Audio Library) for use in this setting. METHODS:Following the NIH Stage Model, we will redesign a visit recording platform, HealthPAL, which leverages natural language processing to structure visit information. In Aim 1, we will use an explanatory sequential mixed methods design. Informed by the Behavior Change Wheel, targets for behavior change will be identified using quantitative assessment of interpersonal communication during triadic visits (200 dyads, 3 visits annually; ∼600 visits), supplemented by semi-structured interviews with a purposive sample of triads (n = 42); In Aim 2, we will use participatory design methods (n = 60) to redesign HealthPAL using findings from Aim 1; and in Aim 3, we will use an open label, single-arm, multi-site pilot trial (n = 30) to determine usability, feasibility and acceptability of HealthPAL and gather preliminary data on its impact on interpersonal communication in triadic AD/ADRD visits. We hypothesize: (1) Constructs from models of interpersonal communication will be associated with health-related outcomes; (2) HealthPAL will surpass usability, feasibility, and acceptability metrics for dyads and clinicians. DISCUSSION/CONCLUSIONS:This work is a necessary first step to improving PLWD triadic care by identifying behaviors that impact triadic interpersonal communication and their associations with health-related outcomes. The novel intervention that we will develop--the use of visit recordings--and the diverse and extensive data we will collect will serve as a unique resource that can be leveraged to address other gaps in clinical knowledge related to the care of PLWD.

BACKGROUND:The Enhanced Quality in Primary Care for Elders with Diabetes-ADRD (EQUIPED-ADRD) is a quality improvement and pragmatic cluster-randomized controlled trial that uses clinical decision guidelines to streamline the care of older adults with diabetes mellitus and Alzheimer's disease/Alzheimer's disease-related Dementia (DM-AD/ADRD). This study tests whether the EQUIPED-ADRD intervention will increase the proportion of older adults with DM and AD/ADRD with desirable glycemic ranges, and reduce treatment burden, dementia severity, and healthcare utilization among participants and their care partners in the intervention arm compared to those in the control arm. METHODS:We will recruit older adults (≥65 years) with both DM and AD/ADRD diagnoses, who have care partners, and receive care at the enrolled New York University clinics. The intervention involves the use of panel managers to streamline the integration of clinical decision guidelines among primary care providers and improve the experiences of care partners and patients. Those in the control arm will have no panel management. We will conduct surveys and interviews, and extract data from EMR and Medicare claims to assess the association between the intervention and primary and secondary outcomes. The primary outcome is achieving within-range HbA1c, while the secondary outcomes include measures of healthcare utilization. Patient and care partner treatment burden, dementia symptoms, and care partner diabetes care distress. CONCLUSIONS:The EQUIPED-ADRD intervention (implemented between 2018 and 2021) will assess the effect of an institutional guideline on the quality of life and health outcomes of older adults with DM-AD/ADRD and their care partners. Clinical Trial NumberNCT03723707.

Cerebral amyloid angiopathy (CAA), present in more than 90% of Alzheimer's disease (AD) cases, associates with focal ischemia and neurovascular dysfunction. Genetic variants at positions 21-23 of amyloid beta (Aβ), among them the Dutch mutation (AβE22Q), are primarily linked to CAA and the development of cerebral hemorrhages. An important contributor to CAA pathogenesis is the dysregulation of mitochondria-mediated pathways with concomitant induction of oxidative stress. Using biochemical assays and immunofluorescence microscopy, this work demonstrates the exacerbated formation of reactive oxygen species (ROS) in human brain microvascular endothelial cells after short exposure to soluble oligomers of synthetic homologues of Aβ1-42 and the Dutch variant, inducing lipid peroxidation and protein carbonylation, both markers of oxidative stress. The heterogeneity of the soluble oligomeric assemblies inducing this oxidative response was highlighted by their reactivity with two conformational antibodies recognizing specific and mutually exclusive epitopes associated with either soluble prefibrillar oligomers or soluble fibrillar oligomers. Treatment with the multitarget antioxidants Trolox and methazolamide significantly attenuated the Aβ-mediated ROS production and reduced oxidative stress markers to basal levels. Our data highlight the damaging role of heterogeneous Aβ oligomers and the preventing effect of antioxidants, suggesting ROS modulation as a complementary therapeutic strategy to preserve neurovascular unit integrity.

BACKGROUND:Infliximab (IFX) is commonly used in the management of acute severe ulcerative colitis (ASUC), yet up to 30% of individuals still require colectomy within 1 year. Clinical data characterizing these patients, however, are limited. AIMS/OBJECTIVE:We aimed to determine risk factors for colectomy among patients with ASUC who received in-hospital IFX treatment. METHODS:We performed a retrospective analysis of patients with ASUC who were treated with at least one dose of IFX while admitted between 2014 and 2022. Cox proportional hazards (PH) models were used to assess demographic, clinical, and laboratory risk factors for colectomy within 30 days and 1 year of IFX initiation. RESULTS:Overall, 36/170 (21.2%) patients underwent colectomy within 1 year of IFX initiation, with 22 (12.9%) individuals requiring colectomy within 30 days. On univariable analysis, concomitant Clostridioides difficile infection during admission, a ≤50% decrease in C-reactive protein (CRP) and experiencing 3 or more bowel movements per day within 48 hours after an initial IFX dose were significantly associated with 1-year colectomy. On multivariable Cox PH analysis, C. difficile infection during admission (aHR=2.92, 95% CI: 1.12-7.58) and a higher CRP/albumin ratio on admission (aHR=1.13, 95% CI: 1.01-1.27) were associated with increased colectomy risk within 1 year of IFX initiation. CONCLUSIONS:C. difficile infection and a higher CRP/albumin ratio on admission are associated with decreased time to colectomy within 1 year of IFX among patients presenting with ASUC. These factors may aid in early risk stratification to minimize delays in JAK-inhibitor initiation or surgical referral.

BACKGROUND AND PURPOSE/OBJECTIVE:Mild traumatic brain injury (MTBI) is a common public health concern with potential long-term consequences, yet its underlying pathophysiology remains poorly understood. Clinical heterogeneity of individuals having diverse extent and array of symptoms has impeded the identification of reliable imaging biomarkers. Traditional group-level analyses may obscure biologically meaningful subtypes. This study uses latent class analysis (LCA) to classify MTBI subjects into symptom-defined subgroups and examines corresponding WM microstructural alterations using advanced diffusion MRI. MATERIALS AND METHODS/METHODS:Sixty-one MTBI patients within one month of injury completed the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). LCA was used to identify symptom-based subgroups. Of these, 54 MTBI patients underwent multi-shell diffusion MRI and were compared with 31 controls. WM changes were assessed across subgroups using ROI-based diffusion analyses. RESULTS:LCA identified three distinct MTBI subgroups: those with minimal to no symptoms (31.5%), the cognitively symptomatic (38.9%), and the more globally symptomatic (29.6%). The three groups were associated with different patterns of diffusion MRI differences compared with controls. The cognitively symptomatic subgroup showed predominantly central WM differences, the globally symptomatic subgroup exhibited more peripheral differences with right-hemisphere predominance and sparing the corpus callosum, marked by reduced fractional anisotropy and kurtosis and elevated diffusivities, the less symptomatic subgroup demonstrated focal differences in the callosal genu, with increased fractional anisotropy and kurtosis and decreased diffusivity measures. CONCLUSIONS:MTBI comprises biologically distinct phenotypes with subgroup-specific WM signatures on diffusion MRI. Even individuals with minimal to no symptoms show WM differences compared with controls, underscoring the limitations of symptom reporting alone. Integrating symptom-based classification with advanced diffusion MRI may improve diagnostic precision to help risk stratification and provide insight into mechanisms of injury. ABBREVIATIONS/BACKGROUND:LCA = latent class analysis; MTBI = mild traumatic brain injury; RPQ = Rivermead post-concussion symptoms questionnaire.

PURPOSE/OBJECTIVE:Many studies estimate that more than 50% of non-hospitalized patients with long-COVID develop moderate to severe autonomic dysfunction. However, the specific impact of autonomic dysfunction as it relates to quality of life in long-COVID is not fully understood. The aim of the current study is to assess autonomic symptoms and quality-of-life in patients with Post-Acute Sequelae of COVID-19 (PASC) recruited from a neurology department outpatient setting. METHODOLOGY/METHODS:In a two-year follow-up study of a baseline cohort of 93 non-hospitalized SARS-CoV-2 laboratory-positive patients evaluated for PASC between November 2020-August 2021, 44 participants completed follow-up telephone questionnaires examining quality-of-life as well as neurologic and autonomic symptoms. RESULTS:Among 93 participants, 44 (47 %) completed the two-year follow-up evaluation and 27 (61 %) were female with a median age of 55 years (IQR = 24-88). Most participants (95 %, 42/44) were vaccinated against COVID-19 and 43 % (19/44) had a pre-existing neurological disorder. Median time from index COVID-19 infection to follow-up was 26 months (IQR = 23-17), with a median of 15 months (IQR = 15-16) between visits. Fatigue, word finding difficulty, and changes in memory were the most commonly reported PASC symptoms. Sixty-six percent (29/44) of individuals met criteria for autonomic dysfunction as defined by the Composite Autonomic Symptom Score-31 (COMPASS-31) scale. Secretomotor and gastrointestinal subdomains demonstrated significant associations with Neuro-QoL metrics for Anxiety, Depression, and Fatigue. For every 1 additional PASC symptom reported at a follow-up study visit, there was an average increase of 1.5 points on the COMPASS-31 composite score. In addition, visual disturbances and sleep impairment were both associated with increased autonomic dysfunction. CONCLUSION/CONCLUSIONS:The strong association between autonomic dysfunction and reduced QoL in PASC and the relation to insomnia, visual dysfunction, and functional impairment are valuable findings, reinforcing the clinical impact of these symptoms longitudinally after index COVID-19 infection.

Early diagnosis and noninvasive monitoring of neurological disorders require sensitivity to elusive cellular-level alterations that occur much earlier than volumetric changes observable with the millimeter-resolution of medical imaging modalities. Morphological changes in axons, such as axonal varicosities or beadings, are observed in neurological disorders, as well as in development and aging. Here, we reveal the sensitivity of time-dependent diffusion MRI (dMRI) to the structurally disordered axonal morphology at the micrometer scale. Scattering theory uncovers the two parameters that determine the diffusive dynamics of water along axons: the average reciprocal cross-section and the variance of long-range cross-sectional fluctuations. This theoretical development allows us to predict dMRI metrics sensitive to axonal alterations over tens of thousands of axons in seconds rather than months of simulations in a male rat model of traumatic brain injury, and is corroborated with ex vivo dMRI. Our approach bridges the gap between micrometers and millimeters in resolution, offering quantitative and objective biomarkers applicable to a broad spectrum of neurological disorders.