Progranulin expression in brain tissue and cerebrospinal fluid levels in multiple sclerosis.

BACKGROUND: Progranulin (PGRN) is a fundamental neurotrophic factor, and is also involved in inflammation and wound repair. PGRN may have pro- or anti-inflammatory properties, depending upon proteolysis of the anti-inflammatory parent PGRN protein and the generation of pro-inflammatory granulin peptides. OBJECTIVES: Our objectives were as follows: (1) to evaluate the presence and distribution of PGRN in multiple sclerosis (MS) brain tissue, correlating it with demyelination and inflammation; (2) to evaluate cerebrospinal fluid (CSF) PGRN concentrations in patients with MS and controls, in relationship to the clinical features of the disease. METHODS: Our study involved the following: (1) neuropathological study of PGRN on post-mortem tissue of 19 MS and six control brains; (2) evaluation of PGRN CSF concentration in 40 MS patients, 15 non-inflammatory controls and five inflammatory controls (viral encephalitis). RESULTS: In active demyelinating lesions, PGRN was expressed on macrophages/microglia. In the normal-appearing white matter (NAWM), expression of PGRN was observed on activated microglia. PGRN was expressed by neurons and microglia in cortical lesions and in normal-appearing cortex. No expression of PGRN was observed in controls, except on neurons. PGRN CSF concentrations were significantly higher in patients with relapsing-remitting MS during relapses and in progressive MS patients, compared with relapsing-remitting MS patients during remissions and with non-inflammatory controls. CONCLUSIONS: PGRN is strongly expressed in MS brains, by macrophages/microglia in active lesions, and by activated microglia in the NAWM; PGRN CSF concentrations in MS are correspondingly increased in conditions of enhanced macrophage/microglia activation, such as during relapses and in progressive MS.

Outcome Predictors in First-Ever Ischemic Stroke Patients: A Population-Based Study.

Background. There is scant population-based information regarding predictors of stroke severity and long-term mortality for first-ever ischemic strokes. The aims of this study were to determine the characteristics of patients who initially presented with first-ever ischemic stroke and to identify predictors of severity and long-term mortality. Methods. Data were collected from the population-based Cerebrovascular Aosta Registry. Between 2004 and 2008, 1057 patients with first-ever ischemic stroke were included. Variables analysed included comorbidities, sociodemographic factors, prior-to-stroke risk factors, therapy at admission and pathophysiologic and metabolic factors. Multivariate logistic regression models, Kaplan-Meier estimates, and Cox proportional Hazards model were used to assess predictors. Results. Predictors of stroke severity at admission were very old age (odds ratio [OR] 2.98, 95% confidence interval [CI] 1.75-5.06), female gender (OR 1.73, 95% CI 1.21-2.40), atrial fibrillation (OR 2.76, 95% CI 1.72-4.44), low ejection fraction (OR 2.22, CI 95% 1.13-4.32), and cardioembolism (OR 2.0, 95% CI 1.36-2.93). Predictors of long-term mortality were very old age (hazard ratio [HR] 2.02, 95% CI 1.65-2.47), prestroke modified Rankin scale 3-5 (HR 1.82; 95% CI 1.46-2.26), Charlson Index ≥2 (HR 1.97; 95% CI 1.62-2.42), atrial fibrillation (HR 1.43, 95% CI 1.04-1.98), and stroke severity (HR 3.54, 95% CI 2.87-4.36). Conclusions. Very old age and cardiac embolism risk factors are the independent predictors of stroke severity. Moreover, these factors associated with other comorbid medical conditions influence independently long-term mortality after ischemic stroke.