Outcome of Stroke Patients with Unknown Onset and Unknown Time Last Known Well Undergoing Endovascular Therapy.

PURPOSE: Endovascular treatment (ET) in patients with large vessel occlusion stroke (LVOS) with unknown onset or an extended time window can be safe and effective if patients are selected by defined clinical and imaging criteria; however, it is unclear if these criteria should also be applied to patients with unknown onset and unknown time last known well. In this study, we aimed to assess whether absent information on the time patients were last known to be well impacts outcome in patients with unknown onset LVOS. METHODS: We analyzed patients who were enrolled in the German Stroke Registry-Endovascular Treatment between 2015 and 2019. Patients with unknown onset and unknown time last known well (LKWu) were compared to patients with known onset (KO) and to patients with unknown onset but known time last known well (LKWk) regarding clinical and imaging baseline characteristics and outcome. RESULTS: Out of 5909 patients, 561 presented with LKWu (9.5%), 1849 with LKWk (31.3%) and 3499 with KO (59.2%). At 90 days, functional independency was less frequent in LKWu (27.0%) compared to KO (42.6%) and LKWk patients (31.8%). These differences were not significant after adjusting for confounders. A main confounder was the initial Alberta stroke program early CT score. CONCLUSION: The LKWu patients had a similar outcome after ET as KO and LKWk patients after adjusting for confounders. Thus, ET should not be withheld if the time last known well is unknown. Instead, LKWu patients may be selected for ET using the same criteria as in LKWk patients.

Endovascular thrombectomy in young patients with stroke.

BACKGROUND: Endovascular treatment (ET) is standard of care in patients with acute ischemic stroke due to large vessel occlusion, but data on ET in young patients remain limited. AIM: We aim to compare outcomes for young stroke patients undergoing ET in a matched cohort. METHODS: We analyzed patients from an observational multicenter cohort with acute ischemic stroke and ET, the German Stroke Registry-Endovascular Treatment trial. Baseline characteristics, procedural parameters, and functional outcome at 90 days were compared between young (<50 years) and older (⩾50 years) patients with and without nearest-neighbor 1:1 propensity score matching. RESULTS: Out of 6628 acute ischemic stroke patients treated with ET, 363 (5.5%) were young. Young patients differed with regard to prognostic outcome characteristics. Specifically, National Institutes of Health Stroke Scale (NIHSS) at admission was lower (median 13, interquartile range (IQR) 8-17 vs. 15, IQR 9-19, p < 0.001), and prestroke dependence was less frequent (2.9% vs. 12.2%, p < 0.001) than in older patients. Compared to a matched cohort of older patients, ET was faster (time from groin puncture to flow restoration, 35 vs. 45 min, p < 0.001) and intracranial hemorrhage was less frequent in young patients (10.0% vs. 25.9%, p < 0.001). Good functional outcome (modified Rankin Scale (mRS) 0-2) at 3 months was achieved more frequently in young patients (71.6% vs. 44.1%, p < 0.001), and overall mortality was lower (6.7% vs. 25.4%, p < 0.001). Among previously employed young patients (n = 177), 37.9% returned to work at 3-month follow-up, while 74.1% of the remaining patients were still undergoing rehabilitation. CONCLUSION: Young stroke patients undergoing ET have better outcomes compared to older patients, even when matched for prestroke condition, comorbidities, and stroke severity. Hence, more liberal guidelines to perform ET for younger patients may have to be established by future studies.

Antithrombotic treatment and outcome after endovascular treatment and acute carotid artery stenting in stroke patients with atrial fibrillation.

BACKGROUND: Oral anticoagulation (OAC) is the mainstay of secondary prevention in ischemic stroke patients with atrial fibrillation (AF). However, in AF patients with large vessel occlusion stroke treated by endovascular therapy (ET) and acute carotid artery stenting (CAS), the optimal antithrombotic medication remains unclear. METHODS: This is a subgroup analysis of the German Stroke Registry-Endovascular Treatment (GSR-ET), a prospective multicenter cohort of patients with large vessel occlusion stroke undergoing ET. Patients with AF and CAS during ET were included. We analyzed baseline and periprocedural characteristics, antithrombotic strategies and functional outcome at 90 days. RESULTS: Among 6635 patients in the registry, a total of 82 patients (1.2%, age 77.9 ± 8.0 years, 39% female) with AF and extracranial CAS during ET were included. Antithrombotic medication at admission, during ET, postprocedural and at discharge was highly variable and overall mortality in hospital (21%) and at 90 days (39%) was high. Among discharged patients (n = 65), most frequent antithrombotic regimes were dual antiplatelet therapy (DAPT, 37%), single APT + OAC (25%) and DAPT + OAC (20%). Comparing DAPT to single or dual APT + OAC, clinical characteristics at discharge were similar (median NIHSS 7.5 [interquartile range, 3-10.5] vs 7 [4-11], p = 0.73, mRS 4 [IQR 3-4] vs. 4 [IQR 3-5], p = 0.79), but 90-day mortality was higher without OAC (32 vs 4%, p = 0.02). CONCLUSIONS: In AF patients who underwent ET and CAS, 90-day mortality was higher in patients not receiving OAC. REGISTRATION: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03356392.

Mechanical Thrombectomy in Patients with Acute Ischemic Stroke and Concomitant Intracranial Hemorrhage.

PURPOSE: Intravenous thrombolysis and mechanical thrombectomy (MT) are standard of care in patients with acute ischemic stroke due to large vessel occlusion. Data on MT in patients with intracranial hemorrhage prior to intervention is limited to anecdotal reports, as these patients were excluded from thrombectomy trials. METHODS: We analyzed patients from an observational multicenter cohort with acute ischemic stroke and endovascular treatment, the German Stroke Registry-Endovascular Treatment trial, with intracranial hemorrhage before MT. Baseline characteristics, procedural parameters and functional outcome at 90 days were analyzed and compared to a propensity score matched cohort. RESULTS: Out of 6635 patients, we identified 32 patients (0.5%) with acute ischemic stroke due to large vessel occlusion and preinterventional intracranial hemorrhage who underwent MT. Risk factors of intracranial hemorrhage were head trauma, oral anticoagulation and intravenous thrombolysis. Overall mortality was high (50%) but among patients with a premorbid modified Rankin scale (mRS) of 0-2 (n = 15), good clinical outcome (mRS 0-2) at 90 days was achieved in 40% of patients. Periprocedural and outcome results did not differ between patients with and without preinterventional intracranial hemorrhage. CONCLUSION: Preinterventional intracranial hemorrhage in acute ischemic stroke patients with large vessel occlusion is rare. The use of MT is technically feasible and a substantial number of patients achieve good clinical outcome, indicating that MT should not be withheld in patients with preinterventional intracranial hemorrhage.

Synergistic Effect on Neurodegeneration by N-Truncated Aß4-42 and Pyroglutamate Aß3-42 in a Mouse Model of Alzheimer's Disease.

The N-terminally truncated pyroglutamate Aß3-42 (AßpE3-42) and Aß4-42 peptides are known to be highly abundant in the brain of Alzheimer's disease (AD) patients. Both peptides show enhanced aggregation and neurotoxicity in comparison to full-length Aß, suggesting that these amyloid peptides may play an important role in the pathogenesis of AD. The aim of the present work was to study the direct effect of the combination of AßpE3-42 and Aß4-42 on ongoing AD-related neuron loss, pathology, and neurological deficits in transgenic mice. Bigenic mice were generated by crossing the established TBA42 and Tg4-42 mouse models expressing the N-truncated Aß peptides AßpE3-42 and Aß4-42, respectively. After generation of the bigenic mice, detailed phenotypical characterization was performed using either immunostainings to evaluate amyloid pathology or quantification of neuron numbers using design-based stereology. The elevated plus maze was used to study anxiety levels. In order to evaluate sensori-motor deficits, the inverted grid, the balance beam and the string suspension tasks were applied. We could demonstrate that co-expression of AßpE3-42 and Aß4-42 accelerates neuron loss in the CA1 pyramidal layer of young bigenic mice as seen by reduced neuron numbers in comparison to single transgenic homozygous mice expressing either AßpE3-42 or Aß4-42. This observation coincides with the robust intraneuronal Aß accumulation observed in the bigenic mice. In addition, loss of anxiety and motor deficits were enhanced in an age-dependent manner. The sensori-motor deficits correlate with the abundant spinal cord pathology, as demonstrated by robust intracellular Aß accumulation within motor neurons and extracellular Aß deposition. Our observations demonstrate that a combination of AßpE3-42 and Aß4-42 has a stronger effect on ongoing AD pathology than the peptides alone. Therefore, AßpE3-42 and Aß4-42 might represent excellent potential therapeutic targets and diagnostic markers for AD.

Endothelial LRP1 transports amyloid-ß(1-42) across the blood-brain barrier.

According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor-related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-ß (Aß) brain accumulation and drives Alzheimer's disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in Aß transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. Moreover, the relevance of systemic Aß clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slco1c1-CreER(T2) Lrp1(fl/fl) mice) and used these mice to accurately evaluate LRP1-mediated Aß BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [125I] Aß(1-42). Additionally, in the 5xFAD mouse model of AD, brain endothelial-specific Lrp1 deletion reduced plasma Aß levels and elevated soluble brain Aß, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic Aß elimination via the BBB. Together, our results suggest that receptor-mediated Aß BBB clearance may be a potential target for treatment and prevention of Aß brain accumulation in AD.

Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X.

Full-length Aß1-42 and Aß1-40, N-truncated pyroglutamate Aß3-42 and Aß4-42 are major variants in the Alzheimer brain. Aß4-42 has not been considered as a therapeutic target yet. We demonstrate that the antibody NT4X and its Fab fragment reacting with both the free N-terminus of Aß4-x and pyroglutamate Aß3-X mitigated neuron loss in Tg4-42 mice expressing Aß4-42 and completely rescued spatial reference memory deficits after passive immunization. NT4X and its Fab fragment also rescued working memory deficits in wild type mice induced by intraventricular injection of Aß4-42. NT4X reduced pyroglutamate Aß3-x, Aßx-40 and Thioflavin-S positive plaque load after passive immunization of 5XFAD mice. Aß1-x and Aßx-42 plaque deposits were unchanged. Importantly, for the first time, we demonstrate that passive immunization using the antibody NT4X is therapeutically beneficial in Alzheimer mouse models showing that N-truncated Aß starting with position four in addition to pyroglutamate Aß3-x is a relevant target to fight Alzheimer's disease.

Neuron Loss and Behavioral Deficits in the TBA42 Mouse Model Expressing N-Truncated Pyroglutamate Amyloid-ß3-42.

Pyroglutamate-modified amyloid-ß (Aß) at amino acid position three (Aß(pE3-42)) is gaining considerable attention as a potential key player in the pathogenesis of Alzheimer's disease (AD). Aß(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability, and cellular toxicity. The aim of the present work was to study the effect of Aß(pE3-42) expression on neuron loss and associated behavioral deficits using the TBA42 transgenic mouse model. Expression of pyroglutamate Aß(3-42) triggers hippocampal CA1 neuron loss and behavioral deficits in the TBA42 mouse model. Mice elicited significant neuron death (-35% at the age of 12 months), deficits in the spatial reference memory, working memory, loss of anxiety, and severe motor deficits in an age-dependent manner. These results support a major pathological function of pyroglutamate Aß in AD.