Dementia in PD was related to older age of symptoms onset and old age. Depression was associated with dementia or early age of PD onset. Depression seemed to contribute to the appearance of psychosis even more than dementia, especially in patients with younger age of symptoms onset.
Background: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing–remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF’s distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. Objective: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. Methods: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. Results: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1–98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13–0.20). Conclusion: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disorder caused by degeneration of motor neurons in the cerebral cortex, brainstem and spinal cord. Several clinical reports indicated sympathetic and parasympathetic dysfunction in ALS patients. In addition, we have recently reported elevated heart rate and blood pressure in transgenic (TG) mice carrying the SOD1 mutant form of the human SOD1 transgene (SOD1-G93A) even prior to the appearance of motor symptoms. In order to further elucidate the mechanisms underlying autonomic impairment in ALS we performed an immunohistochemical study of the intermediolateral nucleus (IML) column neurons (T2 - L2), superior cervical ganglia (SCG) and adrenal glands (AG) in TG and littermate wild-type (WT) mice at the age of 75 - 80 days. IML column neurons sections were stained with antibodies against choline acetyltransferase (ChAT), SOD1, ubiquitin and SMI31. SCG and AG sections were stained with antibodies against ChAT and tyrosine hydroxylase (TH). ChAT is predominantly located at preganglionic nerve terminals that innervate the AG, while TH is located in sympathetic neurons. Results showed that ChAT, SOD1 and ubiquitin expressions in IML column were significantly lower in the SOD1-G93A group compared to WT (p < 0.0001, p = 0.0042 and p < 0.0001, respectively). SMI31 measurements did not reveal any statistical differences between the two groups (p = 0.6187). TH expression in AG revealed a 24% decrease in the SOD1-G93A group compared to WT (p < 0.0001), while ChAT expression in the SCG was reduced by 28% (p < 0.0001). No significant differences were found for TH in SCG or for ChAT in AG. In conclusion, these results are consistent with preganglionic sympathetic denervation as a potential contributor to the abnormal sympathetic regulation in ALS.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons, but non-motor manifestations including autonomic dysfunction have been reported. To better understand the autonomic involvement in ALS we measured blood pressure (BP) changes. We evaluated blood pressure (BP) in a transgenic (TG) SOD1-G93A mouse model of ALS. BP was recorded in awake mice from six to 19 weeks of age by the tail-cuff method. TG mice (n =15) had significantly elevated BP compared to their wild-type (WT) siblings (n =14) even prior to the clinical appearance of motor dysfunction (at age 10-11 weeks, p =0.026). BP gradually decreased in TG mice but not in WT mice from age 10-11 weeks until the advanced stages of the disease (p for trend <0.002). The results indicate impairment of cardiovascular control in this ALS model.
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