Faculty Bibliography

Background: An elevated neutrophil"“lymphocyte ratio (NLR) in blood has been associated with Alzheimer"™s disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer"™s Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (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.

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.

PURPOSE/OBJECTIVE: METHODS: RESULTS: CONCLUSIONS:

Introduction: Alzheimer"™s Disease (AD) typically starts in the medial temporal lobe, then develops into a neurodegenerative cascade which spreads to other brain regions. People with subjective cognitive decline (SCD) are more likely to develop dementia, especially in the presence of amyloid pathology. Thus, we were interested in the white matter microstructure of the medial temporal lobe in SCD, specifically the lower cingulum bundle that leads into the hippocampus. Diffusion tensor imaging (DTI) has been shown to differentiate SCD participants who will progress to mild cognitive impairment from those who will not. However, the biology underlying these DTI metrics is unclear, and results in the medial temporal lobe have been inconsistent. Methods: To better characterize the microstructure of this region, we applied DTI to cognitively normal participants in the Cam-CAN database over the age of 55 with cognitive testing and diffusion MRI available (N = 325, 127 SCD). Diffusion MRI was processed to generate regional and voxel-wise diffusion tensor values in bilateral lower cingulum white matter, while T1-weighted MRI was processed to generate regional volume and cortical thickness in the medial temporal lobe white matter, entorhinal cortex, temporal pole, and hippocampus. Results: SCD participants had thinner cortex in bilateral entorhinal cortex and right temporal pole. No between-group differences were noted for any of the microstructural metrics of the lower cingulum. However, correlations with delayed story recall were significant for all diffusion microstructure metrics in the right lower cingulum in SCD, but not in controls, with a significant interaction effect. Additionally, the SCD group showed an accelerated aging effect in bilateral lower cingulum with MD, AxD, and RD. Discussion: The diffusion profiles observed in both interaction effects are suggestive of a mixed neuroinflammatory and neurodegenerative pathology. Left entorhinal cortical thinning correlated with decreased FA and increased RD, suggestive of demyelination. However, right entorhinal cortical thinning also correlated with increased AxD, suggestive of a mixed pathology. This may reflect combined pathologies implicated in early AD. DTI was more sensitive than cortical thickness to the associations between SCD, memory, and age. The combined effects of mixed pathology may increase the sensitivity of DTI metrics to variations with age and cognition.

INTRODUCTION/UNASSIGNED:Alzheimer's Disease (AD) typically starts in the medial temporal lobe, then develops into a neurodegenerative cascade which spreads to other brain regions. People with subjective cognitive decline (SCD) are more likely to develop dementia, especially in the presence of amyloid pathology. Thus, we were interested in the white matter microstructure of the medial temporal lobe in SCD, specifically the lower cingulum bundle that leads into the hippocampus. Diffusion tensor imaging (DTI) has been shown to differentiate SCD participants who will progress to mild cognitive impairment from those who will not. However, the biology underlying these DTI metrics is unclear, and results in the medial temporal lobe have been inconsistent. METHODS/UNASSIGNED: = 325, 127 SCD). Diffusion MRI was processed to generate regional and voxel-wise diffusion tensor values in bilateral lower cingulum white matter, while T1-weighted MRI was processed to generate regional volume and cortical thickness in the medial temporal lobe white matter, entorhinal cortex, temporal pole, and hippocampus. RESULTS/UNASSIGNED:SCD participants had thinner cortex in bilateral entorhinal cortex and right temporal pole. No between-group differences were noted for any of the microstructural metrics of the lower cingulum. However, correlations with delayed story recall were significant for all diffusion microstructure metrics in the right lower cingulum in SCD, but not in controls, with a significant interaction effect. Additionally, the SCD group showed an accelerated aging effect in bilateral lower cingulum with MD, AxD, and RD. DISCUSSION/UNASSIGNED:The diffusion profiles observed in both interaction effects are suggestive of a mixed neuroinflammatory and neurodegenerative pathology. Left entorhinal cortical thinning correlated with decreased FA and increased RD, suggestive of demyelination. However, right entorhinal cortical thinning also correlated with increased AxD, suggestive of a mixed pathology. This may reflect combined pathologies implicated in early AD. DTI was more sensitive than cortical thickness to the associations between SCD, memory, and age. The combined effects of mixed pathology may increase the sensitivity of DTI metrics to variations with age and cognition.

Progressive white matter degeneration in periventricular and deep white matter regions appears as white matter hyperintensities (WMH) on MRI scans. To date, periventricular WMHs are often associated with vascular dysfunction. Here, we demonstrate that ventricular inflation resulting from cerebral atrophy and hemodynamic pulsation with every heartbeat leads to a mechanical loading state of periventricular tissues that significantly affects the ventricular wall. Specifically, we present a physics-based modeling approach that provides a rationale for ependymal cell involvement in periventricular WMH formation. Building on eight previously created 2D finite element brain models, we introduce novel mechanomarkers for ependymal cell loading and geometric measures that characterize lateral ventricular shape. We show that our novel mechanomarkers, such as maximum ependymal cell deformations and maximum curvature of the ventricular wall, spatially overlap with periventricular WMH locations and are sensitive predictors for WMH formation. We also explore the role of the septum pellucidum in mitigating mechanical loading of the ventricular wall by constraining the radial expansion of the lateral ventricles during loading. Our models consistently show that ependymal cells are stretched thin only in the horns of the ventricles irrespective of ventricular shape. We therefore pose that periventricular WMH etiology is strongly linked to the deterioration of the over-stretched ventricular wall resulting in CSF leakage into periventricular white matter. Subsequent secondary damage mechanisms, including vascular degeneration, exacerbate lesion formation and lead to progressive growth into deep white matter regions.

BACKGROUND:There is a well documented relationship between cardiovascular risk factors and the development of brain injury, which can lead to cognitive dysfunction. Hypertension (HTN) is a condition increasing the risk of silent and symptomatic ischemic brain lesions. Although benefits of hypertension treatment are indisputable, the target blood pressure value where the possibility of tissue damage is most reduced remains under debate. METHOD/METHODS:Our group performed a cross-sectional (n = 376) and longitudinal (n = 188) study of individuals without dementia or stroke (60% women n = 228, age 68.5 ± 7.4 years; men n = 148, age 70.7 ± 6.9 years). Participants were split into hypertensive (n = 169) and normotensive (n = 207) groups. MR images were obtained on a 3T system. Linear modeling was performed in hypertensive and normotensive cohorts to investigate the relationship between systolic (SBP) and diastolic (DBP) blood pressure, white matter lesion (WML), and brain volumes. RESULTS:Participants in the hypertensive cohort showed a quadratic relationship between SBP and WML, with the lowest amounts of WML being measured in participants with readings at approximately 124 mmHg. Additionally, the hypertensive cohort also exhibited a quadratic relationship between DBP and mean hippocampal volume; participants with readings at approximately 77 mmHg showing the largest volumes. Longitudinally, all groups experienced WML growth, despite different BP trajectories, further suggesting that WML expansion may occur despite or because of BP reduction in individuals with compromised vascular system. CONCLUSION/CONCLUSIONS:Overall, our study suggests that in the hypertensive group there is a valley of mid-range blood pressures displaying less pathology in the brain.

In large clinical centers a small subset of patients present with hydrocephalus that requires surgical treatment. We aimed to develop a screening tool to detect such cases from the head MRI with performance comparable to neuroradiologists. We leveraged 496 clinical MRI exams collected retrospectively at a single clinical site from patients referred for any reason. This diagnostic dataset was enriched to have 259 hydrocephalus cases. A 3D convolutional neural network was trained on 16 manually segmented exams (ten hydrocephalus) and subsequently used to automatically segment the remaining 480 exams and extract volumetric anatomical features. A linear classifier of these features was trained on 240 exams to detect cases of hydrocephalus that required treatment with surgical intervention. Performance was compared to four neuroradiologists on the remaining 240 exams. Performance was also evaluated on a separate screening dataset of 451 exams collected from a routine clinical population to predict the consensus reading from four neuroradiologists using images alone. The pipeline was also tested on an external dataset of 31 exams from a 2nd clinical site. The most discriminant features were the Magnetic Resonance Hydrocephalic Index (MRHI), ventricle volume, and the ratio between ventricle and brain volume. At matching sensitivity, the specificity of the machine and the neuroradiologists did not show significant differences for detection of hydrocephalus on either dataset (proportions test, p > 0.05). ROC performance compared favorably with the state-of-the-art (AUC 0.90-0.96), and replicated in the external validation. Hydrocephalus cases requiring treatment can be detected automatically from MRI in a heterogeneous patient population based on quantitative characterization of brain anatomy with performance comparable to that of neuroradiologists.

Demyelination is observed in both healthy aging and age-related neurodegenerative disorders. While the significance of myelin within the cortex is well acknowledged, studies focused on intracortical demyelination and depth-specific structural alterations in normal aging are lacking. Using the recently available Human Connectome Project Aging dataset, we investigated intracortical myelin in a normal aging population using the T1w/T2w ratio. To capture the fine changes across cortical depths, we employed a surface-based approach by constructing cortical profiles traveling perpendicularly through the cortical ribbon and sampling T1w/T2w values. The curvatures of T1w/T2w cortical profiles may be influenced by differences in local myeloarchitecture and other tissue properties, which are known to vary across cortical regions. To quantify the shape of these profiles, we parametrized the level of curvature using a nonlinearity index (NLI) that measures the deviation of the profile from a straight line. We showed that NLI exhibited a steep decline in aging that was independent of local cortical thinning. Further examination of the profiles revealed that lower T1w/T2w near the gray-white matter boundary and superficial cortical depths were major contributors to the apparent NLI variations with age. These findings suggest that demyelination and changes in other T1w/T2w related tissue properties in normal aging may be depth-specific and highlight the potential of NLI as a unique marker of microstructural alterations within the cerebral cortex.