Neuroinflammation-Induced Parvalbumin Interneuron and Oscillation Deficits Might Contribute to Neurobehavioral Abnormities in a Two-Hit Model of Depression

Background: Depression is a common neuropsychiatric disorder that causes profound disability worldwide, yet the underlying mechanism remains unclear. Thus, the present study aimed to evaluate the effects of a two-hit model of depression on glial activation, parvalbumin (PV) interneuron, oscillation activity, and behavior alternations, and whether chronic fluoxetine treatment can reverse these abnormalities. Methods: Male mice were submitted to lipopolysaccharide (LPS) injection, followed by a modified chronic unpredictable stress (CUS) protocol. Results: In our study, we showed that mice exposed to LPS and CUS exhibited reduced body weight, anhedonic-like behavior as well as cognitive and anxiety symptoms. These behavioral alternations were related to enhanced neuroinflammation, as reflected by significantly increased IL-1β and IL-6 levels and microglia activation in the prefrontal cortex (PFC). In addition, mice exposed to LPS and CUS displayed significantly decreased PV expression and disturbance of theta and gamma oscillations in the PFC. However, chronic fluoxetine treatment reversed most of these abnormalities. Conclusion: Our study of this two-hit model of depression is clinically relevant and suggests the combination of different etiological and pathophysiological components of depression may provide with a more translational value.

Abstract P525: Endovascular Thrombectomy Outcomes in Transferred Octogenarians: A Multicenter Pooled Analysis

Background: Acute ischemic strokes outcomes may be less favorable in elderly patients. Whether transferring octogenarians with large vessel occlusion (LVO) for endovascular thrombectomy (EVT) results in similar outcomes to younger patients is uncertain. Methods: A pooled cohort from 6 centers (Europe, US) from 1/2014 to 5/2020 of pts with (ICA, M1, M2) LVO transferred for EVT ≤ 24 hrs from LKW. Patients were stratified into < 80 vs ≥ 80 years old. We compared 90 day functional independence and safety outcomes and assessed for predictors of good outcome (mRS 0-2) and profound disability (mRS 5-6). Results: Of 1176 pts received EVT as transfers, 216 (18%) were octogenarians. Baseline NIHSS was higher in octogenarians [19 (14, 22) vs 17 (12, 21), p<0.001], while IV tPA (52% vs 54%, p=0.52) and time LKW to EVT center [285 (193, 537) vs 272 (190, 470) min, p=0.15] were similar. Functional independence rates were lower in patients ≥ 80 as compared to < 80 (26% vs 46%, aOR 0.50, 95%CI 0.34-0.75, p=0.001). sICH was similar (8.6 vs 9.9%, p=0.56), but octogenarians had significantly higher 90-day mortality (42% vs 17%, p<0.001). Milder strokes (aOR 0.88, 95%CI 0.86-0.91, p<0.001), earlier presentation (aOR 0.95, 95%CI 0.91-0.98, p=0.004) and IV tPA (aOR 1.34, 95%CI 0.98-1.84, p=0.069) were associated with higher functional independence odds after EVT in octogenarians. Higher stroke severity (12% for each point, aOR=1.12, 95%CI 1.11-1.17-, p<0.001) and delayed reperfusion (3% for each additional hr, aOR 1.03, 95%CI 1.00-1.06, p=0.071) were associated with profound disability following EVT in octogenarians. Conclusion: EVT may be associated with lower independence rates in transferred octogenarians with LVO. Milder stroke severity, earlier presentation and IV thrombolysis increased the odds of good outcomes in octogenarians. Severe strokes and later treatment were associated with profound disability. Optimized selection and workflow is warranted in transferring elderly patients for EVT.

Arm Activity Measure (ArmA): Psychometric Evaluation of the Swedish Version

Spasticity after an injury to the central nervous system (CNS) can cause profound disability (1). The prevalence of spasticity differs among various diagnoses, depending on how it is defined. Spasticity is reported to be present in 80% of patients with spinal cord injury (SCI) (2, 3), 60% of patients with traumatic brain injury (TBI) (4), and 30% of patients with stroke (5, 6). The consequences of spasticity in the upper limb (UL) range from reduced grip control to a clenched fist and can prevent prehension and grasp, which are critical for independence in activities of daily living (ADLs) (7). Left untreated, spasticity can lead to severe contractures, deformity, pain, and involuntary movement and severely compromise occupational performance [3, 9-11]. Since being active is fundamentally important for all living beings, and participation in activities is necessary for human physical and mental wellbeing (8), disabling UL spasticity can have devastating consequences.

Abstract WMP12: Benefits of Thrombectomy Among Patients Who Did Not Achieve Functional Independence in DEFUSE 3

Background: While endovascular thrombectomy (EVT) patients may not achieve functional independence, they may avoid devastating outcomes as in profound disability/death. Methods: DEFUSE 3 patients who did not achieve mRS 0-2 were assessed for a shift towards reductions in severe (mRS 4-6) and profound (mRS 5-6) disability, mortality, length of stay (LOS) and increased rates of home/rehabilitation discharges. Results: 126 of the 182 randomized in DEFUSE 3 did not achieve mRS 0-2 (EVT 51, MM 75). Baseline characteristics were similar. EVT was associated with a higher mRS 3 rate (28% vs 18%) and lower rates of severe (72% vs 82%) and profound disability (39% vs. 50%), EVT vs MM respectively, with a trend for a shift towards less disability aOR=1.6 (95%CI=0.9-3.2, P=0.138), figure 1. Mortality rates were numerically lower with EVT (25% vs 31, p=0.528). EVT patients had a trend for shorter LOS (8.6 (6.5-13.7) vs 9.3 (7.1-16.3) days, p=0.156) and increased rates of home/rehabilitation discharges 51% vs. 40%, p=0.224. Older age correlated independently with severe disability aOR=1.04 per year/age, (95%CI=1.01-1.07, p=0.023) as did more severe strokes, aOR per NIHSS point=1.07, 95%CI=0.99-1.15, P=0.096). Larger final infarct volumes had a trend towards severe disability in EVT aOR=1.005, 95%CI=0.996-1.013, p=0.257, but not in MM aOR=1.0 (95% CI 0.993-1.007, p=0.966). Lack of reperfusion (>90% Tmax>6 reduction) had a strong trend for severe disability in MM (83% in non-reperfusers vs. 50% for reperfusers), p=0.056, but not in EVT: 77% vs. 63%, p=0.484. Conclusion: In patients who did not achieve functional independence, EVT resulted in reduced rates of severe and profound disability, decreased length of stay and increased home and rehabilitation discharges. Older patients, more severe strokes and those who did not achieve reperfusion were more likely to have severe disability especially if not treated with EVT. EVT may result in avoiding severe disability in elderly patients.

Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations

ObjectiveTo describe clinical, biochemical, and molecular genetic findings in a large inbred family in which 4 children with a severe early-onset epileptic-dyskinetic encephalopathy, with suppression burst EEG, harbored homozygous mutations of phosphatidylinositol glycan anchor biosynthesis, class P (PIGP), a member of the large glycosylphosphatidylinositol (GPI) anchor biosynthesis gene family.MethodsWe studied clinical features, EEG, brain MRI scans, whole-exome sequencing (WES), and measured the expression of a subset of GPI-anchored proteins (GPI-APs) in circulating granulocytes using flow cytometry.ResultsThe 4 affected children exhibited a severe neurodevelopmental disorder featuring severe hypotonia with early dyskinesia progressing to quadriplegia, associated with infantile spasms, focal, tonic, and tonic-clonic seizures and a burst suppression EEG pattern. Two of the children died prematurely between age 2 and 12 years; the remaining 2 children are aged 2 years 7 months and 7 years 4 months. The homozygous c.384del variant of PIGP, present in the 4 patients, introduces a frame shift 6 codons before the expected stop signal and is predicted to result in the synthesis of a protein longer than the wild type, with impaired functionality. We demonstrated a reduced expression of the GPI-AP CD16 in the granulocytic membrane in affected individuals.ConclusionsPIGP mutations are consistently associated with an epileptic-dyskinetic encephalopathy with the features of early infantile epileptic encephalopathy with profound disability and premature death. CD16 is a valuable marker to support a genetic diagnosis of inherited GPI deficiencies.