Faculty Bibliography

Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane innate immune receptor of the immunoglobulin family. In the brain, TREM2 is found exclusively on microglia and its stimulation has been associated with antiinflammatory and protective effects. Activation of TREM2 also results in the formation of a proteolytic soluble product (sTREM2). Higher baseline CSF sTREM2 concentrations have been associated with a slower rate of cognitive decline and decreased longitudinal brain amyloid deposition in Alzheimer's disease (AD). Thus, it has been proposed that CSF sTREM2 might reflect an antiinflammatory state. In a previous study by our group (ACNP presentation 2017), cognitively unimpaired individuals with latelife major depression (LLMD) which is associated with increased risk for AD, showed significant reductions in CSF sTREM2 levels and a lack of significant correlations with CSF AD biomarkers compared to controls, consistent with the aforementioned hypothesis and that TREM2- mediated anti-inflammatory microglia activation might be impaired in this disorder. In the current report, we examined the relationship between longitudinal changes in CSF sTREM2 during a 3-year period and their relationship to LLMD diagnosis and changes in AD and inflammatory markers.
Method(s): Our baseline sample consisted of 51 subjects aged 60 years and older who completed a longitudinal observational study over three years and an optional lumbar puncture (LP). 38 of these individuals completed the LP at year 3 (20 with LLMD and 18 controls). We evaluated the effects of time on CSF TREM2 with related-samples Wilcoxon Signed Rank Test and the effect diagnosis on change in CSF sTREM2 with Mann Whitney U test. Correlations between change in CSF sTREM2 and CSF markers of AD (Abeta42, Abeta40, total-tau, p-tau181), inflammation (Il-6, Il-8), and Complement component 3 (C3) markers were run with Spearman's Rank test.
Result(s): Baseline CSF sTREM2 was significantly lower in the LLMD group vs controls (p = 0.03). There were no group differences in CSF sTREM2 from baseline to Year 3 (LLMD p = 0.82, Controls p = 0.18), nor did Year 3 differ between the LLMD and control group (p = 0.35). No differences were observed between controls and LLMD for the longitudinal change in CSF sTREM2, AD biomarkers and inflammatory markers. In the whole group, change in sTREM2 was significantly moderately correlated with change in CSF Abeta40 (rho = 0.54, p < 0.001), Abeta42 (rho = 0.48, p = 0.003), and PTau181 (rho = 0.34, p = 0.04). In the control group, change in sTREM2 was significantly correlated with change in CSF Abeta40 (rho = 0.58, p = 0.01) and Abeta42 (rho = 0.56, p = 0.02). In the LLMD group, change in sTREM2 was significantly correlated with change in CSF Abeta40 (rho = 0.50, p = 0.03), Tau (rho = 0.44, p = 0.05) and P-Tau181 (rho = 0.52, p = 0.02) but not with change in CSF Abeta42, a more specific marker of cerebral amyloidosis. Change in inflammatory markers (i.e., IL-6, IL-8) were not significantly correlated with change in sTREM2 (p > 0.05) for LLMD or controls, or the whole group. Change in sTREM2 was significantly correlated with C3 (rho = 0.35, p = 0.04) in the whole group.
Conclusion(s): There were no group differences in change in CSF sTREM2 during a 3-year period, nor any difference between baseline and year 3. The longitudinal increase in CSF sTREM2 during a 3-year period and its association with CSF AD biomarkers may reflect increased anti-inflammatory microglia activation and phagocytosis in response to pathological forms of AD biomarkers Abeta, tau, and p-tau 181. Interestingly, the CSF sTREM2 increase was associated with the increase CSF Abeta42 in controls, but not in LLMD. This finding suggests that upregulation of anti-inflammatory microglia and phagocytosis of brain amyloid deposits may be less efficient in LLMD. Similarly, the positive correlation between the longitudinal increase in CSF sTREM2 and the increase in CSF T-tau and Ptau181, which we found in the LLMD group but not in controls is also consistent with an upregulation of anti-inflammatory microglia in response to increased tau and neurofibrillary tangles, markers of neurodegeneration and AD, respectively. However, the change in CSF sTREM2 was correlated with the change in CSF C3 in the whole cohort; our group and others have also found positive correlations between CSF sTREM2 and CSF neurofilament light (NFL) protein, a biomarker of neuroaxonal damage. Taken together these results suggest that higher CSF sTREM2 concentrations may reflect not only upregulation of antiinflammatory microglia and phagocytosis in response to increased brain amyloid and tau pathology, but also increased neurotoxic effects which are possibly related to its reported intrinsic proinflammatory effects

Background and Objective/UNASSIGNED:Posttraumatic stress disorder (PTSD) is a serious and frequently debilitating psychiatric condition that can occur in people who have experienced traumatic stessors, such as war, violence, sexual assault and other life-threatening events. Treatment of PTSD and traumatic brain injury (TBI) in veterans is challenged by diagnostic complexity, partially due to PTSD and TBI symptom overlap and to the fact that subjective self-report assessments may be influenced by a patient's willingness to share their traumatic experiences and resulting symptoms. Corticotropin-releasing factor (CRF) is one of the main mediators of hypothalamic pituitary adrenal (HPA)-axis responses in stress and anxiety. Methods and Results/UNASSIGNED:We analyzed serum CRF levels in 230 participants including heathy controls (64), and individuals with PTSD (53), TBI (70) or PTSD+TBI (43) by enzyme immunoassay (EIA). Significantly lower CRF levels were found in both the PTSD and PTSD+TBI groups compared to healthy control (PTSD vs Controls: P=0.0014, PTSD + TBI vs Controls: P=0.0011) and chronic TBI participants (PTSD vs TBI: P<0.0001PTSD + TBI vs TBI: P<0.0001) , suggesting a PTSD-related mechanism independent from TBI and associated with CRF reduction. CRF levels negatively correlated with PTSD severity on the CAPS-5 scale in the whole study group. Conclusions/UNASSIGNED:Hyperactivation of the HPA axis has been classically identified in acute stress. However, the recognized enhanced feedback inhibition of the HPA axis in chronic stress supports our findings of lower CRF in PTSD patients. This study suggests that reduced serum CRF in PTSD should be further investigated. Future validation studies will establish if CRF is a possible blood biomarker for PTSD and/or for differentiating PTSD and chronic TBI symptomatology.

Identifying cerebral vulnerability in late life may help prevent or slow the progression of aging-related chronic diseases. However, non-invasive biomarkers aimed at detecting subclinical cerebral changes in the elderly are lacking. Here, we have examined the potential of plasma total tau (t-tau) for identifying cerebral and cognitive deficits in normal elderly subjects. Patterns of cortical thickness and cortical glucose metabolism were used as outcomes of cerebral vulnerability. We found that increased plasma t-tau levels were associated with widespread reductions of cortical glucose uptake, thinning of the temporal lobe, and memory deficits. Importantly, tau-related reductions of glucose consumption in the orbitofrontal cortex emerged as a determining factor of the relationship between cortical thinning and memory loss. Together, these results support the view that plasma t-tau may serve to identify subclinical cerebral and cognitive deficits in normal aging, allowing detection of individuals at risk for developing aging-related neurodegenerative conditions.

Introduction/UNASSIGNED:Plasma tau may be an accessible biomarker for Alzheimer's disease (AD), but the correlation between plasma and cerebrospinal fluid (CSF) tau and the value of combining plasma tau with CSF tau and phospho-tau (P-tau) are still unclear. Methods/UNASSIGNED:Plasma-tau, CSF-tau, and P-tau were measured in 97 subjects, including elderly cognitively normal controls (n = 68) and patients with AD (n = 29) recruited at the NYU Center for Brain Health, with comprehensive neuropsychological and magnetic resonance imaging evaluations. Results/UNASSIGNED: < .001, area under the receiver operating characteristic curve = 0.79) similarly to CSF tau and CSF P-tau and was negatively correlated with cognition in AD. Plasma and CSF tau measures were poorly correlated. Adding plasma tau to CSF tau or CSF P-tau significantly increased the areas under the receiver operating characteristic curve from 0.80 and 0.82 to 0.87 and 0.88, respectively. Discussion/UNASSIGNED:Plasma tau is higher in AD independently from CSF-tau. Importantly, adding plasma tau to CSF tau or P-tau improves diagnostic accuracy, suggesting that plasma tau may represent a useful biomarker for AD, especially when added to CSF tau measures.

Late-life major depression (LLMD) is a risk factor for the development of mild cognitive impairment and dementia, including Alzheimer's disease (AD) and vascular dementia. Immune dysregulation and changes in innate immune responses in particular, have been implicated in the pathophysiology of both LLMD and AD. Complement system, a key component of the innate immune mechanism, is known to play an important role in synaptic plasticity and cognitive functions. However, its role in LLMD remains unknown. In the present study, we examined the levels of complement component 3 (C3, the convergence point of all complement activation pathways) in the cerebrospinal fluid (CSF) of elderly depressed subjects compared to healthy controls; as well as the relationship of CSF C3 levels with amyloid-beta (Aβ42 and Aβ40), total tau (T-tau) and phosphorylated tau (P-tau) proteins and cognition scores. CSF was obtained from 50 cognitively intact volunteers (major depression group, N = 30; comparison group, N = 20) and analyzed for levels of C3 by ELISA. C3 levels were marginally lower in the major depression group relative to the comparison group. We did not find any significant association of C3 with the AD biomarkers Aβ42 reflecting plaque pathology, P-tau related to tau pathology or the neurodegeneration biomarker T-tau. In contrast, C3 was positively correlated with CSF Aβ40, which may reflect Aβ deposition in cerebral vessel walls. We observed a negative correlation between C3 levels and Total Recall on the Buschke Selective Reminding Test (BSRT) for memory performance in the depressed subjects when controlling for education. This initial evidence on C3 status in LLMD subjects may have implications for our understanding of the pathophysiology of major depression especially in late life.

Background: Alzheimer's disease (AD) is thought to involve a cerebrovascular component and AD shares many risk factors with cardiovascular diseases. Amyloid beta (Abeta) is neurotoxic and damages brain microcirculation. Abeta production is up-regulated by hypoxia. Oxygen availability and extraction not only depends on the increase in cerebral blood flow (CBF) but also on the decrease of capillary transit-time heterogeneity (CTH). Structural or functional damage caused to the brain microcirculation will reduce the oxygen availability by a reduction in CBF and increased CTH (capillary dysfunction). Carbonic anhydrase inhibitors (CAIs) have shown to reduce the Abeta neurovascular mitochondrial toxicity, but the effect of this treatment in brain hemodynamics has not been evaluated. The present work aims to investigate the effect of long-term treatment with carbonic anhydrase inhibitors (CAIs) on the neurovascular response in Tg-SweDI mice.
Method(s): All experiments were approved by the Danish Animal Inspectorate. Tg-SwDI mice (4 months old) were fed for 140 - 150 days with a diet supplemented with acetazolamide (G1), methazolamide (G2) or no medication (G3). The groups were randomized and researchers were blind during the data acquisition. A control group of wild-type (WT; G4) mice was included. We performed imaging in awake head-restrained TgSwDI and WT mice through a cranial window placed onto the somatosensory area of the barrel cortex. We estimated relative changes in brain hemodynamics during whiskers stimulation (10 s). We estimated CBF and cerebral blood volume (rCBV) using laser Doppler flowmetry and optical intrinsic signal imaging, respectively. Two-photon imaging was employed to estimate intravascular oxygen partial pressure (ptO2), mean transit-time (MTT), CTH and capillary hemodynamics.
Result(s): Our preliminary analysis in awake WT mice (G4; N = 7) shows that functional activation produced an increase in regional CBF and CBV of 9.41 +/-3.7% and 1.49+/-0.35%, respectively. During activation, MTT and CTH respectively decreased 14.06 +/-5.92% and 23.28 +/- 9.60%. Arterial and venous ptO2 increased by 1.33 +/- 0.33% and 2.60 +/-0.56%. The estimated OEF showed a decrease of 12.4% +/-2.9%. A blinded analysis is currently assessed to evaluate the effect of CAIs on the brain hemodynamic response to functional activation.
Conclusion(s): Our work describes the signature of capillary dysfunction in an AD mouse model. Our results also enable us to elucidate the effect of the carbonic anhydrase inhibitors in capillary dysfunction in AD

BACKGROUND:There is wide interest in developing prognostic models in non-small-cell lung cancer (NSCLC) due to the heterogeneity of the disease. Models developed at other healthcare institutions may not be directly applicable for patients treated at the Department of Veterans Affairs (VA). External validation of a candidate prognostic model among VA patients would be crucial before it can be implemented to aid clinical decision-making. METHODS:A prognostic model for mortality developed in the Military Health System (MHS) was applied to data from the VA Precision Oncology Data Repository (VA-PODR), which is available to researchers inside and outside the VA at the Veterans Precision Oncology Data Commons (VPODC). Measures of discrimination and calibration were calculated for the MHS model. The MHS model was also refitted in VA-PODR data using the same risk factors to compare the effect of specific factors and predictive performance when the model is developed using VA data. RESULTS:Time-dependent AUC of the MHS prognostic model was 0.788, 0.806, 0.780, and 0.779 for predicting survival at 1, 2, 3, and 5 years following diagnosis, respectively. Significant discrepancies were found between predicted and observed rates of survival, particularly for later years. When the model is refit in VA-PODR data, it achieved cross-validated AUCs of 0.739, 0.773, 0.769, and 0.807 at the same time points, and discrepancies between predicted and observed survival were reduced. CONCLUSIONS:Validation of the MHS prognostic model in VA-PODR demonstrates that its discrimination remains strong when applied to VA patients. Nevertheless, further calibration to VA data may be needed to improve its risk estimation performance. This study highlights the utility of VA-PODR and the VPODC as a national resource for developing analytic tools that are well adapted to the Veteran population.

A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.

Traumatic brain injury (TBI) and Alzheimer's disease (AD) are devastating neurological disorders, whose complex relationship is not completely understood. Cerebrovascular pathology, a key element in both conditions, could represent a mechanistic link between Aβ/tau deposition after TBI and the development of post concussive syndrome, dementia and chronic traumatic encephalopathy (CTE). In addition to debilitating acute effects, TBI-induced neurovascular injuries accelerate amyloid β (Aβ) production and perivascular accumulation, arterial stiffness, tau hyperphosphorylation and tau/Aβ-induced blood brain barrier damage, giving rise to a deleterious feed-forward loop. We postulate that TBI can initiate cerebrovascular pathology, which is causally involved in the development of multiple forms of neurodegeneration including AD-like dementias. In this review, we will explore how novel biomarkers, animal and human studies with a focus on cerebrovascular dysfunction are contributing to the understanding of the consequences of TBI on the development of AD-like pathology.

Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication and as possible therapeutic agents in inflammation-mediated demyelinating diseases, including multiple sclerosis (MS). In the present study, we investigated whether intravenously administered EVs derived from mesenchymal stem cells (MSCs) from human adipose tissue might mediate recovery in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease, a progressive model of MS. SJL/J mice were subjected to EV treatment once the disease was established. We found that intravenous EV administration improved motor deficits, reduced brain atrophy, increased cell proliferation in the subventricular zone and decreased inflammatory infiltrates in the spinal cord in mice infected with TMEV. EV treatment was also capable of modulating neuroinflammation, given glial fibrillary acidic protein and Iba-1 staining were reduced in the brain, whereas myelin protein expression was increased. Changes in the morphology of microglial cells in the spinal cord suggest that EVs also modulate the activation state of microglia. The clear reduction in plasma cytokine levels, mainly in the Th1 and Th17 phenotypes, in TMEV mice treated with EVs confirms the immunomodulatory ability of intravenous EVs. According to our results, EV administration attenuates motor deficits through immunomodulatory actions, diminishing brain atrophy and promoting remyelination. Further studies are necessary to establish EV delivery as a possible therapy for the neurodegenerative phase of MS.