One-year regional brain volume changes as potential predictors of cognitive function in multiple sclerosis: a pilot study.

BACKGROUND: The most reliable magnetic resonance imaging (MRI) marker of cognitive dysfunction in multiple sclerosis (MS) is brain atrophy. However, 1-year volumetric changes prior to cognitive assessment were never studied as potential predictors of cognition, which we aim to assess with this pilot work. METHODS: Twenty-two MS patients were submitted to a baseline measure of 83 regional brain volumes with MRI and re-evaluated 1 year later; they were also tested with the Brief International Cognitive Assessment for MS (BICAMS): sustained attention and processing speed were examined with the Symbol Digit Modalities Test (SDMT), verbal and visuo-spatial learning and memory with the learning trials from the California Verbal Learning Test-II (CVLT) and the Brief Visuo-spatial Memory Test-revised (BVMT), respectively. Controlling for age, sex, and years of education, a multivariate linear regression model was created for each cognitive score at 1-year follow-up in a backward elimination manner, considering cross-sectional regional volumes and 1-year volume changes as potential predictors. RESULTS: Decreases in the volumes of the left amygdala and the right lateral orbitofrontal cortex in the year prior to assessment were identified as possible predictors of worse performance in verbal memory (P = 0.009) and visuo-spatial memory (P = 0.001), respectively, independently of cross-sectional brain regional volumes at time of testing. CONCLUSION: Our work reveals novel 1-year regional brain volume changes as potential predictors of cognitive deficits in MS. This suggests a possible role of these regions in such deficits and might contribute to uncover cognitively deteriorating patients, whose detection is still unsatisfying in clinical practice.

Fly and treat: Endovascular treatment of ruptured aneurysms at an insular tertiary center.

(Objectives) Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition associated with poor outcomes. Early intervention is critical, particularly in low-volume hospitals, which are advised to transfer aSAH patients to high-volume centers. This study examines a novel protocol implemented in 2016 at Região Autónoma da Madeira, a Portuguese island. It involves the mobilization of experienced neurointerventionalists from high-volume hospitals to provide aSAH treatment. (Methods) We conducted a retrospective analysis on 30 aSAH patients who underwent endovascular treatment at the island center between November 2016 and April 2022. Additionally, we included a comparison group of 74 aSAH patients, treated with the endovascular approach at Hospital de Braga (high volume center at Portugal mainland). (Results) There was no statistical difference in patients' clinical severity between both hospitals (median WFNS score of 1). Although 90 % of patients in the novel protocol group received treatment within 3 days, we observed a significant delay compared to Hospital de Braga. Rates of aneurysm occlusion and intra-procedure complications between the two groups were similar. At the 3-months follow-up, there were no statistically significant differences between groups regarding patients that achieved a modified Rankin score of 2 or less. However, the island center exhibited a significantly higher mortality rate. (Conclusions) Overall, our results suggest that making the neurointerventionalist fly to an insular center is feasible and allows most patients to be treated within the first 72 h, as recommended. We highlight some potential recommendations for implementing this model and discuss possible causes that might justify the high mortality rate.

Safety and Outcome of Revascularization Treatment in Patients With Acute Ischemic Stroke and COVID-19: The Global COVID-19 Stroke Registry.

BACKGROUND AND OBJECTIVES: COVID-19-related inflammation, endothelial dysfunction, and coagulopathy may increase the bleeding risk and lower the efficacy of revascularization treatments in patients with acute ischemic stroke (AIS). We aimed to evaluate the safety and outcomes of revascularization treatments in patients with AIS and COVID-19. METHODS: This was a retrospective multicenter cohort study of consecutive patients with AIS receiving intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) between March 2020 and June 2021 tested for severe acute respiratory syndrome coronavirus 2 infection. With a doubly robust model combining propensity score weighting and multivariate regression, we studied the association of COVID-19 with intracranial bleeding complications and clinical outcomes. Subgroup analyses were performed according to treatment groups (IVT-only and EVT). RESULTS: Of a total of 15,128 included patients from 105 centers, 853 (5.6%) were diagnosed with COVID-19; of those, 5,848 (38.7%) patients received IVT-only and 9,280 (61.3%) EVT (with or without IVT). Patients with COVID-19 had a higher rate of symptomatic intracerebral hemorrhage (SICH) (adjusted OR 1.53; 95% CI 1.16-2.01), symptomatic subarachnoid hemorrhage (SSAH) (OR 1.80; 95% CI 1.20-2.69), SICH and/or SSAH combined (OR 1.56; 95% CI 1.23-1.99), 24-hour mortality (OR 2.47; 95% CI 1.58-3.86), and 3-month mortality (OR 1.88; 95% CI 1.52-2.33). Patients with COVID-19 also had an unfavorable shift in the distribution of the modified Rankin score at 3 months (OR 1.42; 95% CI 1.26-1.60). DISCUSSION: Patients with AIS and COVID-19 showed higher rates of intracranial bleeding complications and worse clinical outcomes after revascularization treatments than contemporaneous non-COVID-19 patients receiving treatment. Current available data do not allow direct conclusions to be drawn on the effectiveness of revascularization treatments in patients with COVID-19 or to establish different treatment recommendations in this subgroup of patients with ischemic stroke. Our findings can be taken into consideration for treatment decisions, patient monitoring, and establishing prognosis. TRIAL REGISTRATION INFORMATION: The study was registered under ClinicalTrials.gov identifier NCT04895462.

Coding of social novelty in the hippocampal CA2 region and its disruption and rescue in a 22q11.2 microdeletion mouse model.

The hippocampal CA2 region is essential for social memory. To determine whether CA2 activity encodes social interactions, we recorded extracellularly from CA2 pyramidal neurons (PNs) in male mice during social behavior. Although CA2 neuronal firing showed only weak spatial selectivity, it accurately encoded contextual changes and distinguished between a novel and a familiar mouse. In the Df(16)A+/- mouse model of the human 22q11.2 microdeletion, which confers a 30-fold increased risk of schizophrenia, CA2 social coding was impaired, consistent with the social memory deficit observed in these mice; in contrast, spatial coding accuracy was greatly enhanced. CA2 PNs were previously found to be hyperpolarized in Df(16)A+/- mice, likely due to upregulation of TREK-1 K+ current. We found that TREK-1 blockade rescued social memory and CA2 social coding in Df(16)A+/- mice, supporting a crucial role for CA2 in the normal encoding of social stimuli and in social behavioral dysfunction in disease.

Phospholipase D1 Ablation Disrupts Mouse Longitudinal Hippocampal Axis Organization and Functioning.

Phosphatidic acid (PA) is a signaling lipid involved in the modulation of synaptic structure and functioning. Based on previous work showing a decreasing PA gradient along the longitudinal axis of the rodent hippocampus, we asked whether the dorsal hippocampus (DH) and the ventral hippocampus (VH) are differentially affected by PA modulation. Here, we show that phospholipase D1 (PLD1) is a major hippocampal PA source, compared to PLD2, and that PLD1 ablation affects predominantly the lipidome of the DH. Moreover, Pld1 knockout (KO) mice show specific deficits in novel object recognition and social interaction and disruption in the DH-VH dendritic arborization differentiation in CA1/CA3 pyramidal neurons. Also, Pld1 KO animals present reduced long-term depression (LTD) induction and reduced GluN2A and SNAP-25 protein levels in the DH. Overall, we observe that PLD1-derived PA reduction leads to differential lipid signatures along the longitudinal hippocampal axis, predominantly affecting DH organization and functioning.

A circuit from hippocampal CA2 to lateral septum disinhibits social aggression.

Although the hippocampus is known to be important for declarative memory, it is less clear how hippocampal output regulates motivated behaviours, such as social aggression. Here we report that pyramidal neurons in the CA2 region of the hippocampus, which are important for social memory, promote social aggression in mice. This action depends on output from CA2 to the lateral septum, which is selectively enhanced immediately before an attack. Activation of the lateral septum by CA2 recruits a circuit that disinhibits a subnucleus of the ventromedial hypothalamus that is known to trigger attack. The social hormone arginine vasopressin enhances social aggression by acting on arginine vasopressin 1b receptors on CA2 presynaptic terminals in the lateral septum to facilitate excitatory synaptic transmission. In this manner, release of arginine vasopressin in the lateral septum, driven by an animal's internal state, may serve as a modulatory control that determines whether CA2 activity leads to declarative memory of a social encounter and/or promotes motivated social aggression.

A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory dynamics.

Recent results suggest that social memory requires the dorsal hippocampal CA2 region as well as a subset of ventral CA1 neurons. However, it is unclear whether dorsal CA2 and ventral CA1 represent parallel or sequential circuits. Moreover, because evidence implicating CA2 in social memory comes largely from long-term inactivation experiments, the dynamic role of CA2 in social memory remains unclear. Here, we use pharmacogenetics and optogenetics in mice to acutely and reversibly silence dorsal CA2 and its projections to ventral hippocampus. We show that dorsal CA2 activity is critical for encoding, consolidation, and recall phases of social memory. Moreover, dorsal CA2 contributes to social memory by providing strong excitatory input to the same subregion of ventral CA1 that contains the subset of neurons implicated in social memory. Thus, our studies provide new insights into a dorsal CA2 to ventral CA1 circuit whose dynamic activity is necessary for social memory.

Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction.

Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.

Identification of Fluorescent Small Molecule Compounds for Synaptic Labeling by Image-Based, High-Content Screening.

Few tools are available for noninvasive imaging of synapses in the living mammalian brain. Current paradigms require the use of genetically modified mice or viral delivery of genetic material to the brain. To develop an alternative chemical approach, utilizing the recognition of synaptic components by organic small molecules, we designed an imaging-based, high-content screen in cultured cortical neurons to identify molecules based on their colocalization with fluorescently tagged synaptic proteins. We used this approach to screen a library of ∼7000 novel fluorescent dyes, and identified a series of compounds in the xanthone family that exhibited consistent synaptic labeling. Follow-up studies with one of these compounds, CX-G3, demonstrated its ability to label acidic organelles and in particular synaptic vesicles at glutamatergic synapses in cultured neurons and murine brain tissue, indicating the potential of this screening approach to identify promising lead compounds for use as synaptic markers, sensors, and targeting devices.

Input-Timing-Dependent Plasticity in the Hippocampal CA2 Region and Its Potential Role in Social Memory.

Input-timing-dependent plasticity (ITDP) is a circuit-based synaptic learning rule by which paired activation of entorhinal cortical (EC) and Schaffer collateral (SC) inputs to hippocampal CA1 pyramidal neurons (PNs) produces a long-term enhancement of SC excitation. We now find that paired stimulation of EC and SC inputs also induces ITDP of SC excitation of CA2 PNs. However, whereas CA1 ITDP results from long-term depression of feedforward inhibition (iLTD) as a result of activation of CB1 endocannabinoid receptors on cholecystokinin-expressing interneurons, CA2 ITDP results from iLTD through activation of δ-opioid receptors on parvalbumin-expressing interneurons. Furthermore, whereas CA1 ITDP has been previously linked to enhanced specificity of contextual memory, we find that CA2 ITDP is associated with enhanced social memory. Thus, ITDP may provide a general synaptic learning rule for distinct forms of hippocampal-dependent memory mediated by distinct hippocampal regions.