Stroke-associated pneumonia according to mCDC criteria: impact on prognosis and antibiotic therapy.

Objective: The modified Centers for Disease Control and Prevention (mCDC) criteria have been proposed for diagnosing and managing stroke-associated pneumonia (SAP). The objective was to investigate the impact of SAP on stroke outcome depending on whether or not it conforms to mCDC criteria. Our secondary objective was to identify the responsible factors for antibiotic initiation in stroke patients. Methods: We conducted a prospective, multicenter, observational study of ischemic stroke patients with moderate to severe stroke (NIHSS≥4) admitted within 24 h. For 7 days, mCDC criteria were assessed daily, and infections and antibiotics were recorded. Pneumonias were divided into those fulfilling mCDC criteria (mCDC-SAP) or not (other pneumonias, OPn). The effect of each type of pneumonia on 3-month outcome was evaluated in separated logistic regression models. Factors associated with antibiotic initiation were explored using a random forest analysis. Results: Of the 342 patients studied, infections were diagnosed in 72 (21.6%), including 39 (11.7%) cases of pneumonia. Of them, 25 (7.5%) fulfilled mCDC criteria. Antibiotics were used in 92% of mCDC-SAP and 64.3% of OPn. In logistic regression analysis, mCDC-SAP, but not OPn, was an independent predictor of poor outcome [OR, 4.939 (1.022-23.868)]. The random forest analysis revealed that fever had the highest importance for antibiotic initiation. Interpretation: The mCDC criteria might be useful for detecting clinically relevant SAP, which is associated with poor outcomes. Isolated signs of infection were more important for antibiotic initiation than compliance with pre-defined criteria. Therefore, adherence to mCDC criteria might result in antibiotic saving without compromising clinical outcome.

Do stroke services still show sex differences? A multicenter study.

BACKGROUND: The issue of sex differences in stroke has gained concern in the past few years. However, multicenter studies are still required in this field. This study explores sex variation in a large number of patients and compares stroke characteristics among women in different age groups and across different countries. METHODS: This multicenter retrospective cross-sectional study aimed to compare sexes regarding risk factors, stroke severity, quality of services, and stroke outcome. Moreover, conventional risk factors in women according to age groups and among different countries were studied. RESULTS: Eighteen thousand six hundred fifty-nine patients from 9 countries spanning 4 continents were studied. The number of women was significantly lower than men, with older age, more prevalence of AF, hypertension, and dyslipidemia. Ischemic stroke was more severe in women, with worse outcomes among women (p: < 0.0001), although the time to treatment was shorter. Bridging that was more frequent in women (p:0.002). Analyzing only women: ischemic stroke was more frequent among the older, while hemorrhage and TIA prevailed in the younger and stroke of undetermined etiology. Comparison between countries showed differences in age, risk factors, type of stroke, and management. CONCLUSION: We observed sex differences in risk factors, stroke severity, and outcome in our population. However, access to revascularization was in favor of women.

Association of candidate genetic variants and circulating levels of ApoE/ApoJ with common neuroimaging features of cerebral amyloid angiopathy.

Introduction: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-ß (Aß) in brain vessels and is a main cause of lobar intracerebral hemorrhage (ICH) in the elderly. CAA is associated with magnetic resonance imaging (MRI) markers of small vessel disease (SVD). Since Aß is also accumulated in Alzheimer's disease (AD) in the brain parenchyma, we aimed to study if several single nucleotide polymorphisms (SNPs) previously associated with AD were also associated with CAA pathology. Furthermore, we also studied the influence of APOE and CLU genetic variants in apolipoprotein E (ApoE) and clusterin/apolipoprotein J (ApoJ) circulating levels and their distribution among lipoproteins. Methods: The study was carried out in a multicentric cohort of 126 patients with lobar ICH and clinical suspicion of CAA. Results: We observed several SNPs associated with CAA neuroimaging MRI markers [cortical superficial siderosis (cSS), enlarged perivascular spaces in the centrum semiovale (CSO-EPVS), lobar cerebral microbleeds (CMB), white matter hyperintensities (WMH), corticosubcortical atrophy and CAA-SVD burden score]. Concretely, ABCA7 (rs3764650), CLU (rs9331896 and rs933188), EPHA1 (rs11767557), and TREML2 (rs3747742) were significantly associated with a CAA-SVD burden score. Regarding circulating levels of apolipoproteins, protective AD SNPs of CLU [rs11136000 (T) and rs9331896 (C)] were significantly associated with higher HDL ApoJ content in the lobar ICH cohort. APOEε2 carriers presented higher plasma and LDL-associated ApoE levels whereas APOEε4 carriers presented lower plasma ApoE levels. Additionally, we observed that lower circulating ApoJ and ApoE levels were significantly associated with CAA-related MRI markers. More specifically, lower LDL-associated ApoJ and plasma and HDL-associated ApoE levels were significantly associated with CSO-EPVS, lower ApoJ content in HDL with brain atrophy and lower ApoE content in LDL with the extent of cSS. Discussion: This study reinforces the relevance of lipid metabolism in CAA and cerebrovascular functionality. We propose that ApoJ and ApoE distribution among lipoproteins may be associated with pathological features related to CAA with higher ApoE and ApoJ levels in HDL possibly enhancing atheroprotective, antioxidative, and anti-inflammatory responses in cerebral ß-amyloidosis.

Deep Learning Applied to Intracranial Hemorrhage Detection.

Intracranial hemorrhage is a serious medical problem that requires rapid and often intensive medical care. Identifying the location and type of any hemorrhage present is a critical step in the treatment of the patient. Detection of, and diagnosis of, a hemorrhage that requires an urgent procedure is a difficult and time-consuming process for human experts. In this paper, we propose methods based on EfficientDet's deep-learning technology that can be applied to the diagnosis of hemorrhages at a patient level and which could, thus, become a decision-support system. Our proposal is two-fold. On the one hand, the proposed technique classifies slices of computed tomography scans for the presence of hemorrhage or its lack of, and evaluates whether the patient is positive in terms of hemorrhage, and achieving, in this regard, 92.7% accuracy and 0.978 ROC AUC. On the other hand, our methodology provides visual explanations of the chosen classification using the Grad-CAM methodology.

Predictive Factors for Stroke and TIA Following Carotid Artery Stenting.

PURPOSE: Carotid artery stenting (CAS) is an effective and minimally invasive method for the treatment of extracranial carotid artery stenosis. The aim of the present study was to explore independent risk factors to predict cerebrovascular events following CAS to identify high-risk patients and improve the safety of CAS in this population. MATERIALS AND METHODS: HISPANIAS is a national prospective multicenter study that included 14 hospitals that collected data from patients who underwent CAS. We analyzed morbidity and mortality within 30 days after CAS, looking for factors that might be associated with cerebrovascular events (stroke and transient ischemic attack [TIA]). RESULTS: The HISPANIAS cohort included 757 patients: 80.32% were men, the mean age was 70.73 years, and 82.96% underwent symptomatic CAS. Cerebrovascular complications occurred in 42 patients (5.6%), including TIA in 24 patients (70.8% ipsilateral; mean 2.79 days after CAS) and stroke in 18 patients (72.2% ipsilateral; mean 6.72 days after CAS). The main independent clinical predictors of stroke/TIA identified by logistic regression were female sex (odds ratio [OR] 2.29, 95% CI 1.15-4.54) and diabetes (OR 3.29, 95% CI 1.71-6.40). Survival analysis showed that diabetic women, compared with the rest of the patients, had a higher number of events concentrated mainly in the first days after the intervention (p=0.003). CONCLUSION: Cerebrovascular ischemic complications after CAS continue to be a challenge for the management of these patients. Although there are other factors, female sex and the presence of diabetes are emerging as strong risk factors for the development of complications after symptomatic CAS. CLINICAL IMPACT: Carotid artery stenting (CAS) is an effective and minimally invasive method for the treatment of extracranial carotid artery stenosis. Although CAS has been regarded as a reliable and safety approach, some studies reported that CAS was associated with a higher risk of procedure-related stroke. Cerebrovascular complications after CAS continue to be a main problem and a challenge for the management of these patients. Therefore, it is essential to identify the factors involved in the development of these complications. Our study shows that the combination of female sex and diabetes is associated with a clearly worse outcome, with a greater number of events concentrated mainly in the first days. This is different from other studies that have explored each factor separately. It would be interesting to perform separate interventions for this group given the increased risk of complications.

Modeling the potential efficiency of a blood biomarker-based tool to guide pre-hospital thrombolytic therapy in stroke patients.

OBJECTIVES: Stroke treatment with intravenous tissue-type plasminogen activator (tPA) is effective and efficient, but as its benefits are highly time dependent, it is essential to treat the patient promptly after symptom onset. This study evaluates the cost-effectiveness of a blood biomarker test to differentiate ischemic and hemorrhagic stroke to guide pre-hospital treatment with tPA in patients with suspected stroke, compared with standard hospital management. The standard care for patients suffering stroke consists mainly in diagnosis, treatment, hospitalization and monitoring. METHODS: A Markov model was built with four health states according to the modified Rankin scale, in adult patients with suspected moderate to severe stroke (NIHSS 4-22) within 4.5 hours after symptom onset. A Spanish Health System perspective was used. The time horizon was 15 years. Quality-adjusted life-years (QALYs) and life-years gained (LYGs) were used as a measure of effectiveness. Short- and long-term direct health costs were included. Costs were expressed in Euros (2022). A discount rate of 3% was used. Probabilistic sensitivity analysis and several one-way sensitivity analyses were conducted. RESULTS: The use of a blood-test biomarker compared with standard care was associated with more QALYs (4.87 vs. 4.77), more LYGs (7.18 vs. 7.07), and greater costs (12,807€ vs. 12,713€). The ICER was 881€/QALY. Probabilistic sensitivity analysis showed that the biomarker test was cost-effective in 82% of iterations using a threshold of 24,000€/QALY. CONCLUSIONS: The use of a blood biomarker test to guide pre-hospital thrombolysis is cost-effective compared with standard hospital care in patients with ischemic stroke.

Relevance of Carotid Reocclusion in Tandem Lesions.

AIMS: Carotid reocclusion (CRO) after mechanical thrombectomy (MT) in acute ischemic stroke (AIS) due to tandem lesion (TL) or isolated internal carotid occlusion (ICO) is associated with worse clinical outcomes. Our aim was to analyze the predictors and clinical impact of CRO. METHODS: A retrospective single-center analysis of all patients with anterior circulation strokes who underwent MT prospectively included in a registry between 2017 and 2020 was performed. ICO and TL as stroke causes were included. Stent deployment was left to the discretion of the interventionist. All patients received at least intravenous aspirin during MT. CRO was assessed using ultrasound within the first 24 h after MT. Efficacy and safety of stenting were assessed. RESULTS: Among 1304 AIS cases, 218 (16.7%) were related to TL or ICO. Of them, 5% (n=11) were associated with internal CRO 24 h after the endovascular procedure. After adjusting per confounders, multivariate analysis showed that the independent variables associated with CRO were the TICI recanalization grade [TICI 2b-3; OR 0.1, 95% confidence interval (CI) 0.01-0.89, p=0.040], pial collateral circulation presence (OR 0.09, 95% CI 0.02-0.45, p=0.03), stent deployment during MT (OR 0.17, 95% CI 0.03-0.84, p=0.030), and general anesthesia use (OR 2.92, 95% CI 1.13-7.90, p=0.034). CRO showed a trend toward worst outcomes (modified Rankin scale 3-6) at 3 months (OR 3.4, 95% CI 0.96-12, p=0.057). After multivariate analysis, variables independently associated with worse outcomes at 90 days were intrastent platelet aggregation phenomena during endovascular therapy, admission National Institute of Health Stroke Scale, and age. Conversely, intravenous thrombolysis and TICI 2b-3 recanalization grade were identified as independent predictors of good outcomes at 90 days. CONCLUSIONS: CRO has a relevant clinical impact in our study, associating lower rates of good functional outcomes at 3 months. Independent factors of CRO were the recanalization degree, presence of pial collateral circulation, use of a stent as a protective factor, and use of general anesthesia during thrombectomy.

Diet Supplementation with Polyphenol-Rich Salicornia ramosissima Extracts Protects against Tissue Damage in Experimental Models of Cerebral Ischemia.

Strokes are the second most common cause of death worldwide and a leading cause of disability. Regular consumption of polyphenols has been shown to reduce the risk of suffering a cardiovascular event. For this reason, we have investigated the protective effect of Salicornia ramosissima, a seasonal halophyte that synthetizes high amounts of bioactive compounds, including polyphenols, in response to environmental stress. Aqueous, hydroalcoholic, and ethanolic extracts were prepared to investigate if dietary supplementation prior to ischemic challenge can prevent subsequent damage using two animal models. First, we screened the protective effect against hypoxia-reoxygenation in Drosophila melanogaster and observed that both ethanolic and hydroalcoholic extracts protected flies from the deleterious effects of hypoxia. Second, we confirmed the protective effect of S. ramosissima ethanolic extract against brain ischemia using the transient middle cerebral artery occlusion mice model. Four weeks of oral supplementation with the ethanolic extract before artery occlusion reduced infarct volume and lowered the plasma levels of the DNA peroxidant product 8-hydroxydeoxyguanosine. Phytochemical profiling of S. ramosissima ethanolic extract revealed 50 compounds. Thus, it represents a valuable source of bioactive compounds that show promising disease-modifying activities and could be further developed as an effective food supplement for the prevention or treatment of neurovascular disorders.

Association of blood-based biomarkers with radiologic markers and cognitive decline in atrial fibrillation patients.

BACKGROUND: Atrial fibrillation (AF) has been associated with an increased risk of silent brain infarcts (SBI) and cognitive impairment, even in patients with low embolic risk. We aimed to test the association between 11 blood-biomarkers representing different AF-related pathways, and SBI, white matter hyperintensities (WMH), and cognitive decline in patients with AF and low embolic risk. METHODS: The present study followed a cross-sectional design. 70 patients with a history of AF and CHADS2 score ≤1, and 10 controls with neither AF nor SBI were included. All patients underwent a 3T brain MRI. Cortical and large subcortical ischemic lesions were considered presumed embolic origin lesions. White matter hyperintensities (WMH) were measured according to the Fazekas scale. A subset of patients underwent cognitive evaluation with the MoCA test. Circulating proteins were measured under blind conditions in a laboratory at Roche Diagnostics, Germany. RESULTS: 45 patients presented SBI in the MRI, and 25 did not. Ang-2, FGF-23, and BMP-10 were increased in patients with SBI. Ang-2 was elevated only in patients with embolic infarcts, whereas FGF-23 and BMP-10 tended to be elevated in patients with both types of infarcts. Ang-2 (OR = 1.56 [0.94-2.59], p = 0.087), and BMP-10 (OR = 4.83 [0.99-23.60], p = 0.052) were the biomarkers that showed the highest association with SBI when entered in a multivariable logistic regression model corrected by age. No biomarker was found associated with WMH or mild cognitive impairment. CONCLUSIONS: BMP-10, and Ang-2 were increased in patients with SBI. Its usefulness to detect SBI in AF patients should be further explored.

Express improvement of acute stroke care accessibility in large regions using a centralized telestroke network.

Introduction: Acute ischemic stroke therapy has improved in recent decades, decreasing the rates of disability and death among stroke patients. Unfortunately, all health care systems have geographical disparities in infrastructure for stroke patients. A centralized telestroke network might be a low-cost strategy to reduce differences in terms of geographical barriers, equitable access, and quality monitoring across different hospitals. Aims: We aimed to quantify changes in stroke patients' geographic access to specialized evaluation by neurologists and to intravenous acute stroke reperfusion treatments following the rapid implementation of a centralized telestroke network in the large region of Andalusia (8.5 million inhabitants). Methods: We conducted an observational study using spatial and analytical methods to examine how a centralized telestroke network influences the quality and accessibility of stroke care for a large region. Results: In the pre-implementation period, 5,005,477 (59.72% of the Andalusian population) had access to specialized stroke care in less than 30 min. After the 5-month process of implementing the telestroke network, 7,832,988 (93.5%) inhabitants had an access time of less than 30 min, bridging the gap in acute stroke care in rural hospitals. Conclusions: A centralized telestroke network may be an efficient tool to reduce the differences in stroke care access and quality monitoring across different hospitals, especially in large regions with low population density.

Blood-Based Biomarkers to Search for Atrial Fibrillation in High-Risk Asymptomatic Individuals and Cryptogenic Stroke Patients.

Background: Atrial fibrillation (AF) increases the risk of ischemic stroke in asymptomatic individuals and may be the underlying cause of many cryptogenic strokes. We aimed to test the usefulness of candidate blood-biomarkers related to AF pathophysiology in two prospective cohorts representative of those populations. Methods: Two hundred seventy-four subjects aged 65-75 years with hypertension and diabetes from the AFRICAT cohort, and 218 cryptogenic stroke patients aged >55 years from the CRYPTO-AF cohort were analyzed. AF was assessed by 4 weeks of monitoring with a wearable Holter device (NuuboTM™). Blood was collected immediately before monitoring started. 10 candidate biomarkers were measured by automated immunoassays (Roche, Penzberg) in the plasma of all patients. Univariate and logistic regression analyses were performed in each cohort separately. Results: Atrial fibrillation detection rate was 12.4% (AFRICAT cohort) and 22.9% (CRYPTO-AF cohort). 4 biomarkers were significantly increased in asymptomatic individuals with AF [Troponin-T, Angiopoietin-2 (Ang-2), Endocan, and total N-terminal pro-B type natriuretic peptide (NT-proBNP)] and 7 biomarkers showed significantly higher concentrations in cryptogenic stroke patients with AF detection [growth differentiation factor 15, interleukin 6, Troponin-T, Ang-2, Bone morphogenic protein 10, Dickkopf-related protein 3 (DKK-3), and total NT-proBNP]. The models including Ang-2 and total NT-proBNP [AUC 0.764 (0.665-0.863)], and Ang-2 and DKK-3 [AUC = 0.733 (0.654-0.813)], together with age and sex, showed the best performance to detect AF in high-risk asymptomatic individuals, and in cryptogenic stroke patients, respectively. Conclusion: Blood-biomarkers, in particular, total NT-proBNP, DKK-3, and Ang-2, were associated with AF reflecting two mechanistically different pathways involved in AF pathophysiology (AF stretch and vascular changes). The combination of these biomarkers could be useful in AF screening strategies in the primary care setting and also for searching AF after cryptogenic stroke.

Proteins and pathways in atrial fibrillation and atrial cardiomyopathy underlying cryptogenic stroke.

Background: Atrial fibrillation (AF) is one of the most prevalent causes of cryptogenic stroke. Also, apart from AF itself, structural and remodelling changes in the atria might be an underlying cause of cryptogenic stroke. We aimed to discover circulating proteins and reveal pathways altered in AF and atrial cardiomyopathy, measured by left atrial volume index (LAVI) and peak atrial longitudinal strain (PALS), in patients with cryptogenic stroke. Methods: An aptamer array (including 1310 proteins) was measured in the blood of 20 cryptogenic stroke patients monitored during 28 days with a Holter device as a case-control study of the Crypto-AF cohort. Protein levels were compared between patients with (n = 10) and without AF (n = 10) after stroke, and the best candidates were tested in 111 patients from the same cohort (44 patients with AF and 67 without AF). In addition, in the first 20 patients, proteins were explored according to PALS and LAVI values. Results: Forty-six proteins were differentially expressed in AF cases. Of those, four proteins were tested in a larger sample size. Only DPP7, presenting lower levels in AF patients, was further validated. Fifty-seven proteins correlated with LAVI, and 270 correlated with PALS. NT-proBNP was common in all the discovery analyses performed. Interestingly, many proteins and pathways were altered in patients with low PALS. Conclusions: Multiple proteins and pathways related to AF and atrial cardiomyopathy have been revealed. The role of DPP7 as a biomarker for stroke aetiology should be further explored. Moreover, the present study may be considered hypothesis-generating.

High prevalence of obstructive sleep apnea syndrome in Spain's Stroke Belt.

OBJECTIVE: Spain's so-called Stroke Belt is an area with high prevalence of vascular disease. We aimed to determine the prevalence of undetected obstructive sleep apnea-hypopnea syndrome (OSAHS) among patients with acute ischemic stroke (AIS) in southern Spain. METHODS: We conducted a cross-sectional study at the Virgen Macarena University Hospital Stroke Unit during 2018 to 2019. We included patients <72 hours after AIS with a neuroimaging lesion and performed sleep tests. RESULTS: Seventy-two patients were included. The median participant age was 72 years. Mean body mass index was 27.07 kg/m2, and 40.28% were daily alcohol drinkers. Hypertension, atrial fibrillation, ischemic cardiomyopathy, and previous stroke were detected in 63.9%, 11.1%, 15.3%, and 17.6% of patients, respectively. Polygraphy was feasible in 91.38% of patients. The prevalence of OSAHS was 84.72% (apnea-hypopnea index ≥5). Patients with moderate and severe OSAHS were more likely to be obese and to have a larger neck circumference and facial palsy. The diagnostic criteria of central sleep apnea syndrome were met in only 1.38% of patients. CONCLUSIONS: The high prevalence of OSAHS found in the Spanish Stroke Belt justifies further investigation and development of a screening program as a strategy to identify patients with undetected OSAHS.

Gender Gap in the Leadership of Health Institutions: The Influence of Hospital-Level Factors.

Objective: To analyze whether the increased representation of women in the health field is accompanied by a greater presence in leadership positions in the public health system and whether there are differences according to the hospital level. Methods: A descriptive study of the distribution of leadership positions by sex and type of hospital within the health centers of a regional public health system. Results: In total, 74.01% of the professionals were women. The representation of women in management positions was 33.1%, and among service chiefs, it was 24.01%. In the service headings, we observed that surgical specialties had a lower representation of women (30.9% in medical specialties vs. 18.1% in surgical specialties, p<0.0001). By type of hospital, no differences were found in the management positions, but there were differences in the medical chiefs, with less female representation in the regional hospitals (28.6% vs. 39.7%, p=0.003). Conclusion: Women represent the majority in the public health system. Nonetheless, their representation in positions of greater responsibility and decision-making is very limited, being particularly low in county hospitals. Increasing female representation in these positions is a current challenge for society, and equality policies need to be developed and applied to minimize this gender gap.

Circulating AQP4 Levels in Patients with Cerebral Amyloid Angiopathy-Associated Intracerebral Hemorrhage.

Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage (ICH) in elderly patients. Growing evidence suggests a potential role of aquaporin 4 (AQP4) in amyloid-beta-associated diseases, including CAA pathology. Our aim was to investigate the circulating levels of AQP4 in a cohort of patients who had suffered a lobar ICH with a clinical diagnosis of CAA. AQP4 levels were analyzed in the serum of 60 CAA-related ICH patients and 19 non-stroke subjects by enzyme-linked immunosorbent assay (ELISA). The CAA-ICH cohort was divided according to the time point of the functional outcome evaluation: mid-term (12 ± 18.6 months) and long-term (38.5 ± 32.9 months) after the last ICH. Although no differences were found in AQP4 serum levels between cases and controls, lower levels were found in CAA patients presenting specific hemorrhagic features such as ≥2 lobar ICHs and ≥5 lobar microbleeds detected by magnetic resonance imaging (MRI). In addition, CAA-related ICH patients who presented a long-term good functional outcome had higher circulating AQP4 levels than subjects with a poor outcome or controls. Our data suggest that AQP4 could potentially predict a long-term functional outcome and may play a protective role after a lobar ICH.

Comparison of Plasma Lipoprotein Composition and Function in Cerebral Amyloid Angiopathy and Alzheimer's Disease.

Cerebral amyloid angiopathy (CAA) refers to beta-amyloid (Aß) deposition in brain vessels and is clinically the main cause of lobar intracerebral hemorrhage (ICH). Aß can also accumulate in brain parenchyma forming neuritic plaques in Alzheimer's disease (AD). Our study aimed to determine whether the peripheral lipid profile and lipoprotein composition are associated with cerebral beta-amyloidosis pathology and may reflect biological differences in AD and CAA. For this purpose, lipid and apolipoproteins levels were analyzed in plasma from 51 ICH-CAA patients (collected during the chronic phase of the disease), 60 AD patients, and 60 control subjects. Lipoproteins (VLDL, LDL, and HDL) were isolated and their composition and pro/antioxidant ability were determined. We observed that alterations in the lipid profile and lipoprotein composition were remarkable in the ICH-CAA group compared to control subjects, whereas the AD group presented no specific alterations compared with controls. ICH-CAA patients presented an atheroprotective profile, which consisted of lower total and LDL cholesterol levels. Plasma from chronic ICH-CAA patients also showed a redistribution of ApoC-III from HDL to VLDL and a higher ApoE/ApoC-III ratio in HDL. Whether these alterations reflect a protective response or have a causative effect on the pathology requires further investigation.