Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Oral complaints in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Acute myeloid leukemia belongs to proliferative diseases of the hematopoietic system. It is currently the leading indication for allogeneic hematopoietic stem cell transplantation. This study was designed to determine the most common subjective oral mucosa complaints in patients with acute myeloid leukemia after allogeneic hematopoietic cell transplantation, in relation to the type of conditioning used. MATERIAL AND METHODS: Eighty patients diagnosed with acute myeloid leukemia were assigned to two groups depending on the intensity of the conditioning regimen before transplantation: myeloablative and reduced-intensity chemotherapy. The oral symptoms were evaluated based on an authorial questionnaire designed for this analysis. The following oral mucosa subjective complaints were included: pain, paraesthesia, burning mouth sensation, taste disorders, excessive salivation, halitosis, and dryness of the oral mucosa. RESULTS: The most commonly reported subjective oral complaint in the examined patients was xerostomia, which was found in 92% of patients during the second visit, followed by spontaneous pain in the mouth (55%), burning (36%), and dysgeusia (20%). It occurred significantly more frequently in patients who underwent myeloablative conditioning. Moreover, it was observed that the frequency of complaints increased considerably after the transplantation, reaching a peak intensity during the second week following the procedure. CONCLUSIONS: Oral complaints significantly decrease the patients' quality of life during the transplantation and may lead to premature termination of the treatment. As the number of transplantations in patients with acute myeloid leukemia increases, further investigations of oral complaints and symptoms induced by the disease itself and by the therapeutic approaches are required.

Subsyndromal delirium is associated with poor functional outcome after ischaemic stroke.

BACKGROUND AND PURPOSE: Subsyndromal delirium (SSD) refers to patients with delirious symptoms who do not meet the criteria for delirium. The aim was to determine the prognostic significance of SSD in stroke patients. METHODS: In all, 564 patients with ischaemic stroke (median age 71 years, 50.5% female) were included. The Confusion Assessment Method was used to assess symptoms of delirium and the Diagnostic and Statistical Manual of Mental Disorders, 5th edn, criteria were used to diagnose delirium. SSD was defined as one or more core features of delirium without fulfilling diagnostic criteria. Functional outcome was assessed using the modified Rankin Scale at 3 and 12 months after stroke. RESULTS: Delirium was diagnosed in 23.4% of patients and SSD in 10.3% of patients. SSD was associated with increased risk of poor functional outcome. The adjusted odds ratios (ORs) for unfavourable outcome at 3 and 12 months were 2.88 [95% confidence interval (CI) 1.43-5.79, P < 0.01] and 2.93 (95% CI 1.39-6.22, P < 0.01), respectively. In multivariate analysis, delirium was an independent predictor of poor functional outcome at 3 months (OR 6.41, 95% CI 3.36-12.21, P < 0.01) and 12 months (OR 6.11, 95% CI 3.05-12.27, P < 0.01) after stroke. Delirium was also independently associated with increased risk of death within 3 months (hazard ratio 3.68, 95% CI 1.69-8.02, P < 0.01) and 12 months (hazard ratio 3.76, 95% CI 2.05-6.90, P < 0.01). SSD was not associated with increased risk of death. CONCLUSIONS: In SSD patients the risk of poor functional outcome after stroke is increased and intermediate between patients with and patients without delirium.

The Effect of Repetitive Transcranial Magnetic Stimulation on Motor Symptoms in Hereditary Spastic Paraplegia.

Background: Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited disorders affecting predominantly the motor cortex and pyramidal tract, which results in slowly progressing gait disorders, as well as spasticity and weakness of lower extremities. Repetitive transcranial magnetic stimulation (rTMS) has been previously investigated as a therapeutic tool for similar motor deficits in a number of neurologic conditions. The aim of this randomized, controlled trial was to investigate the therapeutic potential of rTMS in various forms of HSP, including pure and complicated forms, as well as adrenomyeloneuropathy. Methods: We recruited 15 patients (five women and 10 men; mean age 43.7 ± 10.6 years) with the mentioned forms of HSP. The intervention included five sessions of bilateral 10 Hz rTMS over primary motor areas of the muscles of lower extremities and five sessions of similar sham stimulation. Results: One patient dropped out due to seizure, and 14 patients completed the study protocol. After real stimulation, the strength of the proximal and distal muscles of lower extremities increased, and the spasticity of the proximal muscles decreased. Change in spasticity was still present during follow-up assessment. No effect was observed regarding gait velocity. No changes were seen after sham stimulation. A post hoc analysis revealed an inverse relation between motor threshold and the change of the strength after active rTMS. Conclusions: rTMS may have potential in improving weakness and spasticity of lower extremities in HSP, especially of proximal muscles whose motor areas are located more superficially. This trial is registered with Clinicaltrials.gov NCT03627416.

Polymorphism in the chemokine receptor 7 gene (CCR7) is associated with previous myocardial infarction in patients undergoing elective coronary angiography.

Coronary artery disease (CAD) remains a major cause of death in developed countries. Both environmental and, less known, genetic factors contribute to progression of CAD to myocardial infarction (MI). Immune system is activated in patients with CAD through dendritic cells (DCs), which present plaque antigens to T lymphocytes. Production of proinflammatory cytokines by activated T cells contributes to plaque rupture in MI. Chemokine receptor 7 (CCR7) on DCs is required for their chemotaxis from plaque to lymph nodes. This makes possible an interaction of DCs with T lymphocytes and initiation of specific immune response. We hypothesized that single nucleotide polymorphisms (SNPs) in CCR7 gene locus are associated with previous MI in patients with CAD. To test this hypothesis, we genotyped six SNPs from the CCR7 gene locus in 300 consecutive patients, admitted for elective coronary angiography. We performed univariate-, multivariate- (including potential confounders) and haplotype-based tests of association of SNPs with previous MI and results of angiography. Allele A of rs17708087 SNP was associated with previous MI. This association remained significant after adjustment for age, sex, smoking, hypercholesterolaemia and drugs used by patients (odds ratio 2.13, 95% confidence interval: 1.13-3.86). Therefore, we conclude that CCR7 gene locus harbours a polymorphism that modifies risk of MI in patients with CAD. Replication of this association could be sought in a prospective cohort of initially healthy individuals.

Use of dairies by postreproductive flocks of European starlings.

Knowledge of the behavior and movement patterns of European starlings (Sturnus vulgaris L.) is important to wildlife managers that seek to resolve conflicts at livestock facilities. We captured and radio tagged 10 starlings at each of 5 dairies in northeastern Ohio. From September 19 to October 31, 2007, we obtained sufficient data from 40 birds to study their behavior and movements. The birds visited the dairies where they were initially captured (home sites) on 85% of the days, spending 58% of each day at the dairies. Onsite arrival and departure times were 2.5h after sunrise and 3.1h before sunset. Daily visits by radio-tagged cohorts from the other dairies were greatest for the 2 most proximate dairies (1.3 km apart), with number of visits between this pairing >7× that of the 9 other pairings combined (4.1-6.5 km apart). Two birds used their home sites intermittently as roosts, arriving 3.8h before sunset and departing 0.2h after sunrise. In addition to using home-site roosts, these birds also used a distant roost (22km) that was used by 36 of the 40 birds. The efficacy of starling management programs, especially lethal management, depends on degree of site fidelity, use of other facilities, and roosting behavior. For example, starlings that use dairies as roosting sites may require a different management strategy than required at dairies used as daytime sites because of differences in arrival and departure behavior. Our research will help resource managers evaluate current management strategies already in place and change them, if needed, to fit the behavior profile of starlings using dairies and other types of livestock facilities.

Interleukin 6-174G>C polymorphism and risk of aneurysmal subarachnoid hemorrhage: case-control study and meta-analysis.

OBJECTIVES: Vascular inflammation contributes to the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH). Interleukin 6 (IL6) is a proinflammatory cytokine involved in many vascular pathologies. Two studies analyzing an association of the functional IL6 gene -174G>C promoter polymorphism with aSAH provided inconsistent results. The aim of this study was to investigate whether this IL6 polymorphism is associated with aSAH in a Polish population. MATERIAL AND METHODS: We genotyped 276 aSAH patients and 581 unrelated control subjects. All were of Caucasian origin. In addition, a meta-analysis combining results of the current and previously published studies was conducted. RESULTS: The distribution of IL6 genotypes and alleles did not differ significantly between aSAH (GG - 29.7%, GC - 50.0%, CC - 20.2%, G - 54.7%) and control subjects (GG - 32.0%, GC - 47.3%, CC - 20.7%, G - 44.3%). In the meta-analysis, the IL6-174G>C polymorphism was not associated with aSAH risk either. CONCLUSIONS: We failed to find an association between the IL6 -174G>C polymorphism and aSAH in analyzed European populations.

Recent advances in fungal serine protease inhibitors.

Four types of antifungal drugs are available that include inhibitors of ergosterol synthesis, of fungal RNA biosynthesis, and of cell wall biosynthesis as well as physiochemical regulators of fungal membrane sterols. Increasing resistance to antifungal drugs can severely limit treatment options of fungal nail infections, vaginal candidiasis, ringworm, blastomycosis, histoplasmosis, and Candida infections of the mouth, throat, and esophagus, among other infections. Development of strategies focused on new fungicides can effectively help tackle troublesome fungal diseases. The virulence and optimal growth of fungi depend on various extracellular secreted factors, among which proteases, such as serine proteases, are of particular interest. A specific extracellular proteolytic system enables fungi to survive and penetrate the tissues. Given the role of fungal proteases in infection, any molecule capable of selectively and specifically inhibiting their activity can lead to the development of potential drugs. Owing to their specific mode of action, fungal protease inhibitors can avoid fungal resistance observed with currently available treatments. Although fungal secreted proteases have been extensively studied as potential virulence factors, our understanding of the substrate specificity of such proteases remains poor. In this review, we summarize the recent advances in the design and development of specific serine protease inhibitors and provide a brief history of the compounds that inhibit fungal serine protease activity.

Paraoxonase 1 gene polymorphisms do not influence the response to treatment in Alzheimer's disease.

BACKGROUND: Acetylcholinesterase inhibitors (AChEIs) are the treatment of choice for patients with Alzheimer's disease (AD). However, their efficacy is moderate and differs from patient to patient. Recent studies suggest that the Q192R variant of the paraoxonase 1 gene (PON1) might affect individual susceptibility to these drugs. METHODS: We investigated the influence of 3 single nucleotide polymorphisms (SNPs) in PON1 (rs 662, rs 854560, rs 705381) and the APOE common polymorphism in 101 Polish patients with late-onset AD in response to treatment with AChEIs. RESULTS: No significant differences were observed between carriers and non-carriers of the PON1 SNPs or the APOE common polymorphism in terms of treatment response. These results did not change after stratification of APOE status. CONCLUSION: Our results suggest that both the investigated PON1 and APOE common SNPs do not influence treatment response to AChEIs in patients with AD.

Paraoxonase gene polymorphism and the risk for Alzheimer's disease in the polish population.

BACKGROUND: The relationship between different paraoxonase (PON) gene polymorphisms and the risk of Alzheimer's disease (AD) was studied several times and the results were controversial. METHODS: We investigated the association of 4 single-nucleotide polymorphisms (SNPs) of the PON1 (M55L; Q192R; -161C/T) and the PON2 (C311S) genes that were shown to affect the risk of sporadic AD. We studied 360 Caucasian cases with late-onset AD and 354 nondemented controls. RESULTS: No significant differences were observed between the studied PON SNPs and AD risk. The results did not change after stratification of the apolipoprotein E status. Meta-analyses of studies in Caucasians assessing the associations between the PON1 M55L, -161C/T and Q192R SNPs and the risk of AD were performed, and no associations were found. CONCLUSION: Our results suggest that the studied PON1 and PON2 polymorphisms are not associated with late-onset AD.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study.

OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

Association between hyperglycemia, heart failure and mortality in stroke patients.

BACKGROUND: Acute hyperglycemia predicts increased mortality after stroke. The aim of our study was to determine if acute stroke patients with hyperglycemia suffer from increased rate of in-hospital adverse events which could influence survival such as pneumonia, heart failure and myocardial infarction. METHODS: In a retrospective study with prospective follow-up, 689 patients with first-ever ischaemic stroke and high frequency of cardiovascular diseases were eligible. Follow-up period was 1-7 years (14 308 person-months). RESULTS: The frequency of in-hospital heart failure and nosocomial pneumonia was the highest in patients without pre-hospital diagnosis of diabetes mellitus and with fasting glucose >or=7 mmol/l (50% and 20.2%, respectively) and the lowest in patients without pre-hospital diagnosis of diabetes and fasting glucose

Interleukin-1 gene -511 CT polymorphism and the risk of Alzheimer's disease in a Polish population.

Interleukin-1 is a potent proinflammatory cytokine involved in the pathophysiology of Alzheimer's disease (AD). We genotyped IL-1beta (-511 C/T) and the apolipoprotein E (APOE) common polymorphisms in a large case-controlled study in a Polish population. We included 332 patients with late-onset AD and 220 controls without any neurological deficit, cognitive complaints and history of neurological diseases, aged > or = 65 years. The distribution of the IL-1beta (-511 C/T) genotypes was similar to that in the controls (AD: C/C = 45.8%, C/T = 44.6%, T/T = 9.6% vs. controls: C/C = 53.9%, C/T = 38.3%, T/T = 7.3%, p > 0.05). Our study confirms previous reports that APOE epsilon4 is strongly related to the risk of AD (odds ratio = 6.60, 95% confidence interval 4.19-10.41). APOE status did not affect the distribution of the studied IL-1beta polymorphism. The IL-1beta (-511 C/T) polymorphism is not a risk factor for late-onset AD in a Polish population.

A-G-4G haplotype of PAI-1 gene polymorphisms -844 G/A, HindIII G/C, and -675 4G/5G is associated with increased risk of ischemic stroke caused by small vessel disease.

BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) is the major inhibitor of fibrinolysis. It was reported that PAI-1 gene polymorphisms affected PAI-1 level and might therefore influence the risk of vascular diseases, including stroke. We studied the association of three common polymorphisms in PAI-1 gene (-844 G/A, -675 4G/5G, and HindIII G/C) with the odds of different causes of ischemic stroke. METHODS: We studied 390 patients with ischemic stroke due to large vessel disease (n = 117), small vessel disease (n = 121), and cardioembolism (n = 152) as well as 291 controls. The etiology of ischemic stroke was established using TOAST criteria. PAI-1 polymorphisms were genotyped with restriction fragment length polymorphism and single strand conformation polymorphism method. RESULTS: A-G-4G haplotype of PAI-1 gene was found more frequently in stroke patients with small vessel disease than in control subjects (44.9% vs 35.7%; P = 0.02). No association was found between investigated genotype or allele frequencies and distinct causes of ischemic stroke. CONCLUSIONS: Our results demonstrate that A-G-4G PAI-1 gene haplotype is associated with increased risk of small vessel disease stroke, but this study does not support an association of -844 G/A, -675 4G/5G, and HindIII G/C PAI-1 gene polymorphisms with particular etiology of ischemic stroke.

Brain inflammasomes in stroke and depressive disorders: Regulation by oestrogen.

Neuroinflammation is a devastating pathophysiological process that results in brain damage and neuronal death. Pathogens, cell fragments and cellular dysfunction trigger inflammatory responses. Irrespective of the cause, inflammasomes are key intracellular multiprotein signalling platforms that sense neuropathological conditions. The activation of inflammasomes leads to the auto-proteolytic cleavage of caspase-1, resulting in the proteolysis of the pro-inflammatory cytokines interleukin (IL)1ß and IL18 into their bioactive forms. It also initiates pyroptosis, a type of cell death. The two cytokines contribute to the pathogenesis in acute and chronic brain diseases and also play a central role in human aging and psychiatric disorders. Sex steroids, in particular oestrogens, are well-described neuroprotective agents in the central nervous system. Oestrogens improve the functional outcome after ischaemia and traumatic brain injury, reduce neuronal death in Parkinson's and Alzheimer's disease, as well as in amyotrophic lateral sclerosis, attenuate glutamate excitotoxicity and the formation of radical oxygen species, and lessen the spread of oedema after damage. Moreover, oestrogens alleviate menopause-related depressive symptoms and have a positive influence on depressive disorders probably by influencing growth factor production and serotonergic brain circuits. Recent evidence also suggests that inflammasome signalling affects anxiety- and depressive-like behaviour and that oestrogen ameliorates depression-like behaviour through the suppression of inflammasomes. In the present review, we highlight the most recent findings demonstrating that oestrogens selectively suppress the activation of the neuroinflammatory cascade in the brain in acute and chronic brain disease models. Furthermore, we aim to describe putative regulatory signalling pathways involved in the control of inflammasomes. Finally, we consider that psychiatric disorders such as depression also contain an inflammatory component that could be modulated by oestrogen.

Prefrontal N-acetylaspartate and poststroke recovery: a longitudinal proton spectroscopy study.

BACKGROUND AND PURPOSE: Functional imaging studies suggest that poststroke recovery is related to the reorganization in both contralesional and ipsilesional prefrontal cortex. Little is known, however, about how longitudinal metabolic changes in prefrontal regions relate to the improvement after stroke. We sought to determine whether poststroke recovery is associated with changes in N-acetylaspartate/creatine (NAA/Cr) ratio within contralesional prefrontal regions. MATERIALS AND METHODS: Twenty-seven patients with a first ischemic stroke located outside the frontal lobes were included. Proton MR spectroscopy ((1)H-MRS) was performed on a 1.5T scanner. Point-resolved spectroscopy sequence (PRESS) was used. NAA/Cr was measured both in ipsilesional and contralesional prefrontal regions in early (14 +/- 6 days after stroke) and chronic phases of the disease (110 +/- 30 days after). Patients' neurologic status was assessed using Scandinavian Stroke Scale (SSS) at discharge from the stroke unit and during second (1)H-MRS examination. RESULTS: Subjects showing increased contralesional NAA/Cr from first to follow-up examination improved significantly more on the SSS than patients not showing this increase. Analysis was performed while correcting for change in NAA/Cr levels in the ipsilesional hemisphere. For the whole group, the change in contralesional NAA/Cr was significantly correlated to the change in SSS scores (r = 0.40, P = .03). Change in the ipsilesional NAA/Cr measures did not correlate with the change in SSS scores. CONCLUSION: Poststroke recovery was related to the increase in contralesional prefrontal NAA/Cr. This association may reflect recovery mechanisms involving the nonaffected hemisphere. Further assessment of these regions may provide information about mechanisms contributing to neurologic improvement.

Hypoalbuminemia in acute ischemic stroke patients: frequency and correlates.

OBJECTIVE: Hypoalbuminemia in acute stroke patients is associated with increased mortality and morbidity. The aim of our study was to determine the frequency and correlates of hypoalbuminemia in unselected cohort of patients with acute cerebral infarction. DESIGN: Prospective study. SETTING: University hospital. SUBJECTS: Seven hundred and five consecutive ischemic stroke patients. METHODS: Albumin and other serum protein fractions were measured within 36 h after stroke using electrophoresis. RESULTS: Hypoalbuminemia defined as serum albumin level <35 g/l was found in 45.5% of patients. Serum albumin level correlates significantly with age (r=-0.13, P<0.01), Scandinavian Stroke Scale score (r=0.14, P<0.01), body temperature on admission (r=0.14, P<0.01), leukocyte count (r=-0.17, P<0.01), fasting glucose (r=-0.16, P<0.01), total cholesterol (r=0.14, P<0.01), alpha1-globulin (r=-0.48, P<0.01), alpha2-globulin (r=-0.49, P<0.01), beta-globulin (r=-0.26, P<0.01) and gamma-globulin (r=-0.35, P<0.01). CONCLUSIONS: Hypoalbuminemia is a frequent finding in acute stroke patients and it is associated with more severe stroke and pro-inflammatory pattern of serum protein electrophoresis.

Thrombolysis and thrombectomy in patients treated with dabigatran with acute ischemic stroke: Expert opinion.

Systemic thrombolysis with rt-PA is contraindicated in patients with acute ischemic stroke anticoagulated with dabigatran. This expert opinion provides guidance on the use of the specific reversal agent idarucizumab followed by rt-PA and/or thrombectomy in patients with ischemic stroke pre-treated with dabigatran. The use of idarucizumab followed by rt-PA is covered by the label of both drugs.

The sphingosine 1-phosphate receptor agonist FTY720 is neuroprotective after cuprizone-induced CNS demyelination.

BACKGROUND AND PURPOSE: Modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes within the lymph nodes. Here, we evaluated the potential of an agonist at this receptor, FTY720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection. EXPERIMENTAL APPROACH: In this study, we used the cuprizone model in male C57BL/6 mice and tested the promyelinating and neuroprotective effects of FTY720 after acute and chronic toxin-induced experimental demyelination. We used histological, immunohistochemical and gene expression methods. KEY RESULTS: The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone-induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein-positive spheroids in axons was less distinct in FTY720-treated animals, indicating that this compound alleviated ongoing axonal damage. CONCLUSIONS AND IMPLICATIONS: We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by FTY720 treatment. FTY720 preserved CNS integrity by direct interaction with brain resident cells, the actions of which are still to be defined.