Showing papers by "Ann M. Stowe published in 2015"

Stroke induces a rapid adaptive autoimmune response to novel neuronal antigens.

Abstract: Stroke affects millions of people worldwide every year. Despite this prevalence, mechanisms of long-term injury and repair within the ischemic brain are still understudied. Sterile inflammation occurs in the injured brain after stroke, with damaged tissue exposing central nervous system (CNS)-derived antigen that could initiate potential autoimmune responses. We used a standard immunology-based recall response assay for murine immune cells, isolated from the cervical lymph nodes and spleen after transient stroke, to determine if stroke induces autoreactivity to CNS target antigens. Our assays included novel neuronal peptides, in addition to myelin-, nuclear-, glial-, and endothelial-derived peptides. Autoimmune responses to an antigen were considered positive based on proliferation and activation over non-stimulated conditions. Stroke induced a significant increase in autoreactive CD4+ and CD8+ T cells, as well as autoreactive CD19+ B cells, as early as 4 days after stroke onset. Mice with large infarct volumes exhibited early T and B cell autoreactivity to NR2A, an NMDA receptor subunit, in cells isolated from lymph nodes but not spleen. Mice with small infarct volumes exhibited high autoreactivity to MAP2, a dendritic cytoskeletal protein, as well as myelin-derived peptides. This autoimmunity was maintained through 10 days post-stroke in both lymph nodes and spleen for all lymphocyte subsets. Sham surgery also induced early autoreactive B cell responses to MAP2 and myelin. Based on these observations, we hypothesize that stroke induces a secondary, complex, and dynamic autoimmune response to neuronal antigens with the potential to potentiate, or perhaps even ameliorate, long-term neuroinflammation.

Amyloid burden and sleep blood pressure in amnestic mild cognitive impairment

Abstract: Objective: To determine whether cortical β-amyloid (Aβ) deposition is associated with circadian blood pressure (BP) profiles and dynamic cerebral blood flow (CBF) regulation in patients with amnestic mild cognitive impairment (aMCI). Methods: Forty participants with aMCI were included in this study. Cortical Aβ depositions were measured by 18 F-florbetapir PET and expressed as the standardized uptake value ratio (SUVR) relative to the cerebellum. Circadian BP profiles were measured by 24-hour ambulatory monitoring during awake and sleep periods. The dipping status of sleep BP (i.e., the percent changes from the awake BP) was calculated and dichotomized into the dipper (≥10%) and nondipper ( Results: Age was positively correlated with a greater Aβ deposition in the posterior cingulate, precuneus, and mean cortex. Accounting for the age effect, attenuated reductions in sleep systolic BP were associated with higher levels of posterior cingulate SUVR. Consistently, the nondippers exhibited a higher SUVR in the posterior cingulate than the dippers. Transfer function gain between changes in BP and CBF velocity was diminished in the nondippers, and moreover those individuals with a lower gain exhibited a higher SUVR in the posterior cingulate. Conclusions: Attenuated reductions in sleep BP are associated with a greater Aβ burden in the posterior cingulate and altered dynamic CBF regulation in patients with aMCI.

A Distinct Class of Antibodies May Be an Indicator of Gray Matter Autoimmunity in Early and Established Relapsing Remitting Multiple Sclerosis Patients

Abstract: *These authors contributed equally to the work in this manuscript.We have previously identified a distinct class of antibodies expressed by B cells in the cerebrospinal fluid (CSF) of early and established relapsing remitting multiple sclerosis (RRMS) patients that is not observed in healthy donors. These antibodies contain a unique pattern of mutations in six codons along VH4 antibody genes that we termed the antibody gene signature (AGS). In fact, patients who have such B cells in their CSF are identified as either having RRMS or developing RRMS in the future. As mutations in antibody genes increase antibody affinity for particular antigens, the goal for this study was to investigate whether AGS(+) antibodies bind to brain tissue antigens. Single B cells were isolated from the CSF of 10 patients with early or established RRMS. We chose 32 of these B cells that expressed antibodies enriched for the AGS for further study. We generated monoclonal full-length recombinant human antibodies (rhAbs) and used both immunological assays and immunohistochemistry to investigate the capacity of these AGS(+) rhAbs to bind brain tissue antigens. AGS(+) rhAbs did not recognize myelin tracts in the corpus callosum. Instead, AGS(+) rhAbs recognized neuronal nuclei and/or astrocytes, which are prevalent in the cortical gray matter. This pattern was unique to the AGS(+) antibodies from early and established RRMS patients, as AGS(+) antibodies from an early neuromyelitis optica patient did not display the same reactivity. Prevalence of CSF-derived B cells expressing AGS(+) antibodies that bind to these cell types may be an indicator of gray matter-directed autoimmunity in early and established RRMS patients.

Quantification of neurovascular protection following repetitive hypoxic preconditioning and transient middle cerebral artery occlusion in mice.

Abstract: Experimental animal models of stroke are invaluable tools for understanding stroke pathology and developing more effective treatment strategies. A 2 week protocol for repetitive hypoxic preconditioning (RHP) induces long-term protection against central nervous system (CNS) injury in a mouse model of focal ischemic stroke. RHP consists of 9 stochastic exposures to hypoxia that vary in both duration (2 or 4 hr) and intensity (8% and 11% O2). RHP reduces infarct volumes, blood-brain barrier (BBB) disruption, and the post-stroke inflammatory response for weeks following the last exposure to hypoxia, suggesting a long-term induction of an endogenous CNS-protective phenotype. The methodology for the dual quantification of infarct volume and BBB disruption is effective in assessing neurovascular protection in mice with RHP or other putative neuroprotectants. Adult male Swiss Webster mice were preconditioned by RHP or duration-equivalent exposures to 21% O2 (i.e. room air). A 60 min transient middle cerebral artery occlusion (tMCAo) was induced 2 weeks following the last hypoxic exposure. Both the occlusion and reperfusion were confirmed by transcranial laser Doppler flowmetry. Twenty-two hr after reperfusion, Evans Blue (EB) was intravenously administered through a tail vein injection. 2 hr later, animals were sacrificed by isoflurane overdose and brain sections were stained with 2,3,5- triphenyltetrazolium chloride (TTC). Infarcts volumes were then quantified. Next, EB was extracted from the tissue over 48 hr to determine BBB disruption after tMCAo. In summary, RHP is a simple protocol that can be replicated, with minimal cost, to induce long-term endogenous neurovascular protection from stroke injury in mice, with the translational potential for other CNS-based and systemic pro-inflammatory disease states.

Enhancing motor performance improvement by personalizing non-invasive cortical stimulation with concurrent functional near-infrared spectroscopy and multi-modal motor measurements

Abstract: Transcranial direct current stimulation (tDCS) is a non-invasive cortical stimulation technique that can facilitate task specific plasticity that can improve motor performance. Current tDCS interventions uniformly apply a chosen electrode montage to a subject population without personalizing electrode placement for optimal motor gains. We propose a novel perturbation tDCS (ptDCS) paradigm for determining a personalized electrode montage in which tDCS intervention yields maximal motor performance improvements during stimulation. PtDCS was applied to ten healthy adults and five stroke patients with upper hemiparesis as they performed an isometric wrist flexion task with their non-dominant arm. Simultaneous recordings of torque applied to a stationary handle, muscle activity by electromyography (EMG), and cortical activity by functional near-infrared spectroscopy (fNIRS) during ptDCS helped interpret how cortical activity perturbations by any given electrode montage related to changes in muscle activity and task performance quantified by a Reaction Time (RT) X Error product. PtDCS enabled quantifying the effect on task performance of 20 different electrode pair montages placed over the sensorimotor cortex. Interestingly, the electrode montage maximizing performance in all healthy adults did not match any of the ones being explored in current literature as a means of improving the motor performance of stroke patients. Furthermore, the optimal montage was found to be different in each stroke patient and the resulting motor gains were very significant during stimulation. This study supports the notion that task-specific ptDCS optimization can lend itself to personalizing the rehabilitation of patients with brain injury.