Case report: Cerebral amyloid angiopathy-related inflammation in a patient with granulomatosis with polyangiitis.

Background: Cerebral amyloid angiopathy-related inflammation (CAA-ri) defines a subacute autoimmune encephalopathy, which is presumably caused by increased CSF concentrations of anti-Aß autoantibodies. This autoinflammatory reaction is temporally and regionally associated with microglial activation, inflammation and radiological presence of vasogenic edema. Clinical characteristics include progressive demential development as well as headache and epileptic seizures. In the absence of histopathologic confirmation, the criteria defined by Auriel et al. allow diagnosis of probable resp. possible CAA-ri. CAA-ri shows responsiveness to immunosuppressive therapies and a possible coexistence with other autoinflammatory diseases. Methods: We present a case report and literature review on the diagnosis of CAA-ri in a patient with known granulomatosis with polyangiitis (GPA). Results: Initially, the presented patient showed neuropsychiatric abnormalities and latent arm paresis. Due to slight increase in CSF cell count, an initial antiviral therapy was started. MR tomography showed a pronounced frontotemporal edema as well as cerebral microhemorrhages, leading to the diagnosis of CAA-ri. Subsequent high-dose steroid treatment followed by six intravenous cyclophosphamide pulses resulted in decreased CSF cell count and regression of cerebral MRI findings. Conclusion: The symptoms observed in the patient are consistent with previous case reports on CAA-ri. Due to previously known GPA, we considered a cerebral manifestation of this disease as a differential diagnosis. However, absence of pachymeningitis as well as granulomatous infiltrations on imaging made cerebral GPA less likely. An increased risk for Aß-associated pathologies in systemic rheumatic diseases is discussed variously.

Long-term functional outcome and quality of life 2.5 years after thrombolysis in acute ischemic stroke.

BACKGROUND: Evaluation of outcome after stroke is largely based on assessment of gross function 3 months after stroke onset using scales such as mRS. Cognitive or social functions, level of symptom burden or emotional health are not usually assessed, nor are data available on long-term functional outcomes years after stroke. METHODS: Analysis of 1141 patients with AIS treated with IVT from two major German university hospitals between 2017 and 2020. Patient characteristics and short-term outcome were analysed from patient records. Long-term outcome of 228 patients with prior written informed consent was assessed via telephone survey using mRS and PROMs (EQ-5D-5L, EQ-VAS) 2.5 years after stroke. RESULTS: Predictors of excellent to good long-term outcome were younger age, event to door time ≤ 2 h, NIHSS ≤ 6 on admission and NIHSS ≤ 6 after IVT. Stroke recurrence was a negative predictor. Predictors of excellent quality of life at 2.5 years included age < 73 years, lower NIHSS after IVT, absence of hypertension. Quality of life was rated in all dimensions with a medium score of 1 and a medium EQ-VAS of 70, representing the good general health status of this stroke population. CONCLUSION: Main predictors of an excellent to good long-term outcome and excellent QoL 2.5 years after stroke are younger age, lower NIHSS, and event to door time ≤ 2 h. Research on long-term outcome after disease and treatment is of utmost importance, as it has the ability to reveal the patient true functional outcome and quality of life and to provide information on the status of independence and self-esteem.

Clinical and Computerized Volumetric Analysis of Posterior Fossa Decompression for Space-Occupying Cerebellar Infarction.

Background and Purpose: Surgical decompression of the posterior fossa is often performed in cases with a space-occupying cerebellar infarction to prevent coma and death. In this study, we analyzed our institutional experience with this condition. We specifically attempted to address timing issues and investigated the role of cerebellar necrosectomy using imaging data and conducting volumetric analyses. Methods: We retrospectively studied pertinent clinical and imaging data, including computerized volumetric analyses (preoperative/postoperative infarction volume, necrosectomy volume, and posterior fossa volume), from all 49 patients who underwent posterior fossa decompression surgery for cerebellar infarction in our department from January 2012 to January 2021. Results: Thirty-five (71%) patients had a Glasgow Coma Scale (GCS) of 14-15 at admission vs. only 14 (29%) before vs. 41 (84%) following surgery. Seven (14%) patients had preventive surgery (initial GCS 14-15, preoperative GCS change ≤ 1). Only 18 (37%) patients had an mRS score of 0-3 at discharge. Estimated overall survival was 70.5% at 1 year. Interestingly, 18/20 (90%) surviving cases had a modified Rankin Scale (mRS) outcome of 0-3 (mRS 0-2: 12/20 [60%]) 1 year after surgery. Surgical timing, including preventive surgery and mass effect of the infarct, in the posterior fossa assessed semi-quantitatively (Kirollos grade) and with volumetric parameters that were not predictive of the patients' (functional) outcomes. Conclusion: Posterior fossa decompression for cerebellar infarction is a life-saving procedure, but rapid recovery of the GCS after surgery does not necessarily translate into good functional outcome. Many patients died during follow-up, but long-term mRS outcomes of 4-5 are rare. Surgery should probably aim primarily at pressure relief, and our clinical as well as volumetric data suggest that the impact of removing an infarcted tissue may be limited. It is presumably relatively safe to initially withhold surgery in cases with a GCS of 14-15.

Transient Global Amnesia (TGA): Younger Age and Absence of Cerebral Microangiopathy Are Potentially Predisposing Factors for TGA Recurrence.

Background: Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear etiology for a period of less than 24 h. TGA occurs as a single event in most cases. Prevalence rates of recurrent TGA vary widely from 5.4 to 27.1%. This retrospective study aimed to determine predictors for TGA recurrence. Methods: Cardiovascular risk profile and magnetic resonance imaging (MRI) of 340 hospitalized TGA patients between 2011 and 2020 were retrospectively analyzed. The median follow-up period amounted to 4.5 ± 2.7 years. Comparisons were made between TGA patients with and without subsequent recurrence. Results: TGA patients with subsequent recurrence were significantly younger (recurrent vs. single episode, 63.6 ± 8.6 years vs. 67.3 ± 10.5 years, p = 0.032) and showed a lower degree of cerebral microangiopathy compared to TGA patients without recurrence. The mean latency to recurrence was 3.0 years ± 2.1 years after the first episode. In a subgroup analysis, patients with at least five years of follow-up (N = 160, median follow-up period 7.0 ± 1.4 years) had a recurrence rate of 11.3%. A 24.5% risk of subsequent TGA recurrence in the following five years was determined for TGA patients up to 70 years of age without microangiopathic changes on MRI (Fazekas' score 0). Conclusion: Younger TGA patients without significant microangiopathy do have an increased recurrence risk. In turn, pre-existing cerebrovascular pathology, in the form of chronic hypertension and cerebral microangiopathy, seems to counteract TGA recurrence.

Transient Global Amnesia (TGA): Influence of Acute Hypertension in Patients Not Adapted to Chronic Hypertension.

Objective: Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear etiology for a period of <24 h. Several studies showed differences in vascular risk factors between TGA compared to transient ischemic attack (TIA) or healthy controls with varying results. This retrospective and cross-sectional study compares the cardiovascular risk profile of TGA patients with that of acute stroke patients. Methods: Cardiovascular risk profile and MR imaging of 277 TGA patients was retrospectively analyzed and compared to 216 acute ischemic stroke patients (26% TIA). Results: TGA patients were significantly younger and predominantly female compared to stroke patients. A total of 90.6% of TGA patients underwent MRI, and 53% of those showed hippocampal diffusion-weighted imaging (DWI) lesions. Scores for cerebral microangiopathy were lower in TGA patients compared to stroke patients. After statistical correction for age, TGA patients had higher systolic and diastolic blood pressure, higher cholesterol levels, lower HbA1c, as well as blood glucose levels, and lower CHA2DS2-VASc scores. Stroke patients initially displayed higher CRP levels than TIA and TGA patients. TGA patients without DWI lesions were older and showed higher CHA2DS2-VASc scores compared to TGA patients with DWI lesions. Conclusion: This study revealed significant differences between TGA and stroke patients in regard to the cardiovascular risk profile. Our main findings show a strong association between acute hypertensive peaks and TGA in patients not adapted to chronic hypertension, indicating a vascular cause of the disease.

Atrial Fibrillation in Patients with Embolic Stroke of Undetermined Source during 3 Years of Prolonged Monitoring with an Implantable Loop Recorder.

BACKGROUND: Undocumented atrial fibrillation (AF) is suspected as a main stroke cause in patients with embolic stroke of undetermined source (ESUS), but its prevalence is largely unknown. This prospective study therefore aimed at delineating the prevalence of AF in patients with ESUS using continuous cardiac monitoring by implantable loop recorder (ILR) with daily remote interrogation over a period of 3 years and its clinical consequences, including recurrent stroke. METHODS: In consecutive patients with an ESUS diagnosis after complete work-up, an ILR was implanted and followed by daily remote monitoring until AF was detected or a follow-up of at least 3 years was completed. Additionally, the ILR was interrogated in-hospital in 6-month intervals. RESULTS: A total of 123 patients (74 male, mean age 65 ± 9 years) were enrolled and completed the 3 years study period. AF was detected in 51 patients (41.4%). In 43 of the 51 AF positive patients (84%) oral anticoagulation was established. Recurrent strokes occurred in 18 patients (14.6%) of this ESUS population, 9 of these patients being AF positive (17.6% of the AF-positive patients) and 9 being AF negative (12.5% of AF-negative patients). Patients with AF were slightly older than patients without AF (63.1 ± 8.8 vs. 67.5 ± 9.6 years, p = 0.12). Other parameters such as CHA2DS2-VASc score, infarct localization, micro- and macroangiopathy, carotid or aortic plaques, or stroke recurrence were not significantly different between groups. CONCLUSION: In ESUS patients, early implantation of an ILR with cardiac monitoring and remote transmission over a 3-year period detected AF in 41.4% and resulted in oral anticoagulation in 84% of these patients.

Detection of Atrial Fibrillation on Stroke Units: Comparison of Manual versus Automatic Analysis of Continuous Telemetry.

BACKGROUND: Detection of atrial fibrillation (AF) is one of the primary diagnostic goals for patients on a stroke unit. Physician-based manual analysis of continuous ECG monitoring is regarded as the gold standard for AF detection but requires considerable resources. Recently, automated computer-based analysis of RR intervals was established to simplify AF detection. The present prospective study analyzes both methods head to head regarding AF detection specificity, sensitivity, and overall effectiveness. METHODS: Consecutive stroke patients without history of AF or proof of AF in the admission ECG were enrolled over the period of 7 months. All patients received continuous ECG telemetry during the complete stay on the stroke unit. All ECGs underwent automated analysis by a commercially available program. Blinded to these results, all ECG tracings were also assessed manually. Sensitivity, specificity, time consumption, costs per day, and cost-effectiveness were compared. RESULTS: 216 consecutive patients were enrolled (70.7 ± 14.1 years, 56% male) and 555 analysis days compared. AF was detected by manual ECG analysis on 37 days (6.7%) and automatically on 57 days (10.3%). Specificity of the automated algorithm was 94.6% and sensitivity 78.4% (28 [5.0%] false positive and 8 [1.4%] false negative). Patients with AF were older and had more often arterial hypertension, higher NIHSS at admission, more often left atrial dilatation, and a higher CHA2DS2-VASc score. Automation significantly reduced human resources but was more expensive compared to manual analysis alone. CONCLUSION: Automatic AF detection is highly specific, but sensitivity is relatively low. Results of this study suggest that automated computer-based AF detection should be rather complementary to manual ECG analysis than replacing it.

Antimyelin antibodies as predictors of disability after clinically isolated syndrome.

There is controversy whether determination of antibodies against myelin, myelin oligodendrocyte glycoprotein, and myelin basic protein in serum from patients with a first episode suggestive of multiple sclerosis is of prognostic value. We evaluated whether detection of antimyelin antibodies in serum indicates a worse course with earlier time to a second relapse and increased progression of disability. We conducted a prospective study at the Department of Neurology, Inselspital Bern, Switzerland from 2004 to 2008 in patients presenting with a clinically isolated syndrome (CIS) and a follow-up of at least 4 months. Antimyelin antibodies were assessed by Western blot. Results were correlated with clinical course and sex. Among 93 consecutive patients with a CIS, 74 (80%) were positive for either one or both antimyelin antibodies. A relapse occurred in 49 (53%) and the median EDSS was 2 (range 1-3.5) after a mean observation period of 20 months. Presence of antimyelin antibodies at CIS neither increased the risk for a second relapse nor for progression of disability. Stratification for gender did not reveal differences for any of the clinical surrogates. The sole determination of antimyelin antibodies in serum is of limited prognostic value for the identification of patients with different short-term course.

Adaptation of neuronal cells to chronic oxidative stress is associated with altered cholesterol and sphingolipid homeostasis and lysosomal function.

Chronic oxidative stress has been causally linked to several neurodegenerative disorders. As sensitivity for oxidative stress greatly differs between brain regions and neuronal cell types, specific cellular mechanisms of adaptation to chronic oxidative stress should exist. Our objective was to identify molecular mechanisms of adaptation of neuronal cells after applying chronic sublethal oxidative stress. We demonstrate that cells resistant to oxidative stress exhibit altered cholesterol and sphingomyelin metabolisms. Stress-resistant cells showed reduced levels of molecules involved in cholesterol trafficking and intracellular accumulation of cholesterol, cholesterol precursors, and metabolites. Moreover, stress-resistant cells exhibited reduced SMase activity. The altered lipid metabolism was associated with enhanced autophagy. Treatment of stress-resistant cells with neutral SMase reversed the stress-resistant phenotype, whereas it could be mimicked by treatment of neuronal cells with a specific inhibitor of neutral SMase. Analysis of hippocampal and cerebellar tissue of mouse brains revealed that the obtained cell culture data reflect the in vivo situation. Stress-resistant cells in vitro showed similar features as the less vulnerable cerebellum in mice, whereas stress-sensitive cells resembled the highly sensitive hippocampal area. These findings suggest an important role of the cell type-specific lipid profile for differential vulnerabilities of different brain areas toward chronic oxidative stress.

Effect of interferon-beta and atorvastatin on Th1/Th2 cytokines in multiple sclerosis.

Beneficial effects by both interferon-beta and statin treatment in patients with multiple sclerosis (MS) may be linked to interference with the Th1/Th2 cytokine balance. We determined patterns of Th1/Th2 cytokines (interleukin (IL)-1beta, IL-2, IL-6, IL-12p70, tumor-necrosis factor (TNF)-alpha and interferon-gamma, and IL-4, IL-5 and IL-10, respectively) in the serum of patients with relapsing-remitting MS treated with 250microg interferon-beta 1b or with interferon-beta plus 40mg atorvastatin. In treatment naïve patients with MS, a trend for lower TNF-alpha serum levels compared to controls was detected (P=0.08). Interferon-beta treatment increased TNF-alpha levels, while a trend for lowering of IL-5 serum levels was found (P=0.07). Addition of atorvastatin raised IL-12p70 serum levels (P<0.05). Mean levels of two Th2 cytokines (IL-4, IL-10) showed a non-significant increase after addition of atorvastatin. We conclude that interferon-beta and atorvastatin exert divergent action on Th1/Th2 serum cytokines levels in MS. Supplemental atorvastatin might promote a Th1-type response by raising IL-12p70. Further studies are required to support a Th2 cytokine shift by atorvastatin in patients with MS.

Neuronal differentiation of human mesenchymal stem cells: changes in the expression of the Alzheimer's disease-related gene seladin-1.

Seladin-1 (SELective Alzheimer's Disease INdicator-1) is an anti-apoptotic gene, which is down-regulated in brain regions affected by Alzheimer's disease (AD). In addition, seladin-1 catalyzes the conversion of desmosterol into cholesterol. Disruption of cholesterol homeostasis in neurons may increase cell susceptibility to toxic agents. Because the hippocampus and the subventricular zone, which are affected in AD, are the unique regions containing stem cells with neurogenic potential in the adult brain, it might be hypothesized that this multipotent cell compartment is the predominant source of seladin-1 in normal brain. In the present study, we isolated and characterized human mesenchymal stem cells (hMSC) as a model of cells with the ability to differentiate into neurons. hMSC were then differentiated toward a neuronal phenotype (hMSC-n). These cells were thoroughly characterized and proved to be neurons, as assessed by molecular and electrophysiological evaluation. Seladin-1 expression was determined and found to be significantly reduced in hMSC-n compared to undifferentiated cells. Accordingly, the total content of cholesterol was decreased after differentiation. These original results demonstrate for the first time that seladin-1 is abundantly expressed by stem cells and appear to suggest that reduced expression in AD might be due to an altered pool of multipotent cells.

Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication.

Hypermutations in hepatitis B virus (HBV) DNA by APOBEC3 cytidine deaminases have been detected in vitro and in vivo, and APOBEC3G (A3G) and APOBEC3F (A3F) have been shown to inhibit the replication of HBV in vitro, but the presumably low or even absent hepatic expression of these enzymes has raised the question as to their physiological impact on HBV replication. We show that normal human liver expresses the mRNAs of APOBEC3B (A3B), APOBEC3C (A3C), A3F, and A3G. In primary human hepatocytes, interferon alpha (IFN-alpha) stimulated the expression of these cytidine deaminases up to 14-fold, and the mRNAs of A3G, A3F, and A3B reached expression levels of 10%, 3%, and 3%, respectively, relative to GAPDH mRNA abundance. On transfection, the full-length protein A3B(L) inhibited HBV replication in vitro as efficiently as A3G or A3F, whereas the truncated splice variant A3B(S) and A3C had no effect. A3B(L) and A3B(S) were detected predominantly in the nucleus of uninfected cells; however, in HBV-expressing cells both proteins were found also in the cytoplasm and were associated with HBV viral particles, similarly to A3G and A3F. Moreover, A3G, A3F, and A3B(L), but not A3B(S), induced extensive G-to-A hypermutations in a fraction of the replicated HBV genomes. In conclusion, the editing enzymes A3B(L), A3F, and most markedly A3G, which are expressed in liver and up-regulated by IFN-alpha in hepatocytes, are candidates to contribute to the noncytolytic clearance of HBV.

DHCR24 gene expression is upregulated in melanoma metastases and associated to resistance to oxidative stress-induced apoptosis.

The DHCR24 gene encoding for the 3beta-hydroxysterol delta24-reductase, an oxidoreductase involved in cholesterol biosynthesis, was isolated by subtractive hybridization as highly expressed in a short-term melanoma cell line derived from a cutaneous metastases (S/M2) compared to that obtained from the autologous primary tumor (S/P). DHCR24 (alias seladin-1, diminuto/dwarf1 homolog) has been reported to act as an antiapoptotic factor in neurons. Gene expression analysis by Northern blot confirmed that DHCR24 was 5-fold upregulated in S/M2 compared to S/P cells. High levels of DHCR24 gene expression were detected in 13/25 melanoma metastases and in 1/7 primary melanomas by real-time PCR, indicating that upregulation of this gene may occur in melanoma progression. In S/M2 cells, high DHCR24 gene expression associated with resistance to apoptosis triggered by oxidative stress induced by exposure to hydrogen peroxide. DHCR24 gene transfer was shown to protect melanoma cells from H2O2-induced cytotoxicity. Although higher cholesterol levels were shown in S/M2 cells compared to S/P cells, DHCR24 gene transfer did not increase cholesterol content. To evaluate whether DHCR24 acts as an antiapoptotic factor in melanoma metastases, the cytotoxic effect of chemotherapeutic agents was tested in DHCR24 transfectants and in the presence of a DHCR24 inhibitor, U18666A. High DHCR24 gene expression in transfectants did not result in a higher resistance to cytotoxic agents; treatment with U18666A was cytotoxic in S/P cells with a lower DHCR24 content and showed additive cytotoxic effect only when associated with H2O2 and not with cysplatin or etoposide, indicating that the DHCR24 protective effect is exerted through an oxidative stress-specific mechanism.

Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila.

Beta-amyloid peptides that are cleaved from the amyloid precursor protein (APP) play a critical role in Alzheimer's disease (AD) pathophysiology. Here, we show that in Drosophila, the targeted expression of the key genes of AD, APP, the beta-site APP-cleaving enzyme BACE, and the presenilins led to the generation of beta-amyloid plaques and age-dependent neurodegeneration as well as to semilethality, a shortened life span, and defects in wing vein development. Genetic manipulations or pharmacological treatments with secretase inhibitors influenced the activity of the APP-processing proteases and modulated the severity of the phenotypes. This invertebrate model of amyloid plaque pathology demonstrates Abeta-induced neurodegeneration as a basic biological principle and may allow additional genetic analyses of the underlying molecular pathways.

Expression of the novel adrenocorticotropin-responsive gene selective Alzheimer's disease indicator-1 in the normal adrenal cortex and in adrenocortical adenomas and carcinomas.

Selective Alzheimer's disease indicator-1 (seladin-1) is a novel gene with antiapoptotic activity that is down-regulated in vulnerable brain regions in Alzheimer's disease. This gene encodes 3-beta-hydroxysterol Delta-24-reductase (DHCR24), which converts desmosterol into cholesterol. In the adrenal cortex, increased expression of seladin-1/DHCR24, which appears to be modulated by ACTH, has been recently reported in cortisol-secreting adenomas, compared with the adjacent atrophic tissue. In our study, we measured the expression level of seladin-1/DHCR24 in cortisol- (n = 18) and aldosterone-secreting (n = 16) adrenocortical adenomas, in carcinomas (n = 17), and in normal adrenal glands (n = 8) by quantitative real-time RT-PCR. The amount of seladin-1/DHCR24 mRNA was significantly reduced in carcinomas (total RNA, 2.5 +/- 0.8 pg/ micro g) compared with the other groups (P < 0.01). Western blot analysis confirmed the mRNA results. Similarly, in adrenal malignancies, significantly reduced levels of expression of the ACTH receptor gene were found. In the adrenal cancer cell line H295R and in primary cultures from adrenocortical cells, ACTH (1 nM) and forskolin (10 micro M) effectively increased seladin-1/DHCR24 expression, confirming that seladin-1/DHCR24 is modulated by the ACTH/cAMP-driven pathway. In summary, this is the first demonstration that seladin-1/DHCR24 expression is reduced in adrenal cancer, suggesting that it might be viewed as a new potential marker of adrenal malignancies.