Progranulin genetic polymorphisms influence progression of disability and relapse recovery in multiple sclerosis.

BACKGROUND: Progranulin (GRN) is a multifunctional protein involved in inflammation and repair, and also a neurotrophic factor critical for neuronal survival. Progranulin is strongly expressed in multiple sclerosis (MS) brains by macrophages and microglia. METHODS: In this study we evaluated GRN genetic variability in 400 MS patients, in correlation with clinical variables such as disease severity and relapse recovery. We also evaluated serum progranulin levels in the different groups of GRN variants carriers. RESULTS: We found that incomplete recovery after a relapse is correlated with an increased frequency of the rs9897526 A allele (odds ratio (OR) 4.367, p = 0.005). A more severe disease course (Multiple Sclerosis Severity Score > 5) is correlated with an increased frequency of the rs9897526 A allele (OR 1.886, p = 0.002) and of the rs5848 T allele (OR 1.580, p = 0.019). Carriers of the variants associated with a more severe disease course (rs9897526 A, rs5848 T) have significantly lower levels of circulating progranulin (80.5 ± 9.1 ng/mL vs. 165.7 ng/mL, p = 0.01). CONCLUSION: GRN genetic polymorphisms likely influence disease course and relapse recovery in MS.

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.

Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter.

Gray matter (GM) lesions are recognized as important components of the pathology of multiple sclerosis (MS), and involvement of the deep gray matter (DGM) is suggested by magnetic resonance imaging. The aims of this study were to determine the frequency and distribution of lesions and characterize the inflammatory and neurodegenerative changes in DGM of MS patients. Histochemistry, immunohistochemistry, and morphometry were performed on whole coronal sections of 14 MS and 12 control (6 normal, 6 from amyotrophic lateral sclerosis patients) brains. Demyelinating lesions were frequent in MS DGM; most often in the thalamus and caudate, but they were also seen in the putamen, pallidum, claustrum, amygdala, hypothalamus, and substantia nigra. Most DGM lesions involved both GM and white matter. Inflammation in active DGM lesions was similar to that in lesions only in white matter but was less intense, and there was a preponderance of activated microglia, scarce myelin-laden macrophages, and a lesser extent of axonal damage. Neuronal loss was observed both in DGM lesions and nondemyelinated DGM with neuron atrophy in nondemyelinated DGM. In conclusion, demyelination and neurodegenerative changes are common in MS DGM and may contribute to clinical impairment. Inflammation in DGM lesions is intermediate between the destructive inflammation of white matter lesions and the minimal inflammation of cortical lesions. We hypothesize that alterations of glutamate reuptake mechanisms may contribute to these differences.

Duloxetine is effective in treating depression in multiple sclerosis patients: an open-label multicenter study.

OBJECTIVES: Duloxetine hydrochloride, a dual reuptake inhibitor of serotonin and norepinephrine, was evaluated for its therapeutic efficacy, safety, and tolerability in the treatment of depression in patients with multiple sclerosis (MS). Lifetime depression prevalence approaches 50% in MS patients. The aim of the study was to assess the safety and efficacy of duloxetine for treatment of depression in MS patients. METHODS: An open-label study evaluated the efficacy of 12 weeks of duloxetine administration (maximal dose = 60 mg/d) in MS patients with clinical depression. The Beck scale score variation after 4 (T1) and 12 (T2) weeks of treatment was used for the primary outcome measurement, whereas secondary outcome was measured using the Modified Fatigue Impact Scale. Safety was evaluated by recording treatment-related adverse events, monitoring vital signs, and recording frequency and reasons for interruption or discontinuation of treatment. RESULTS: Seventy-five patients were enrolled in the study. Sixty-three patients completed the study by continuing duloxetine treatment for 12 weeks (T2). Twelve subjects dropped out of the study because of adverse effects or noncompliance. Nausea was the most common adverse event reported. A significant reduction in the Beck Depression Inventory and Modified Fatigue Impact Scale scores, after both 4 and 12 weeks of therapy, was observed. CONCLUSIONS: The results suggest that duloxetine is well tolerated, safe, and effective in reducing depression and fatigue in MS patients.