Suppressed POL-1 pathway activity in BMS.

<p>A schematic model demonstrating the suppressed POL-1 pathway activity in BMS leading to activation of P53 dependent apoptosis. Over-expressed genes are depicted in red, down-expressed genes in green.</p

POL-1 pathway key genes verification by qRT-PCR.

<p>White dots represent BMS patients (N = 20), black dots represent RRMS patients (N = 15). Data are presented as relative quantification values using ΔCT method. The house keeping gene GAPDH expression levels were used as internal control for sample normalization. Low level of the POL-1 pathway key genes POLR1D (p = 0.001), RRN3 (p = 0.03) and LRPPRC (p = 0.03) is demonstrated in BMB patients as compared with RRMS patients.</p

Modeling of Cognitive Impairment by Disease Duration in Multiple Sclerosis: A Cross-Sectional Study

<div><p>Background/Aims</p><p>Large-scale population studies measuring rates and dynamics of cognitive decline in multiple sclerosis (MS) are lacking. In the current cross-sectional study we evaluated the patterns of cognitive impairment in MS patients with disease duration of up to 30 years.</p><p>Methods</p><p>1,500 patients with MS were assessed by a computerized cognitive battery measuring verbal and non-verbal memory, executive function, visual spatial perception, verbal function, attention, information processing speed and motor skills. Cognitive impairment was defined as below one standard deviation (SD) and severe cognitive impairment as below 2SD for age and education matched healthy population norms.</p><p>Results</p><p>Cognitive performance in our cohort was poorer than healthy population norms. The most frequently impaired domains were information processing speed and executive function. MS patients with secondary-progressive disease course performed poorly compared with clinically isolated syndrome, relapsing-remitting and primary progressive MS patients. By the fifth year from disease onset, 20.9% of patients performed below the 1SD cutoff for impairment, p = 0.005, and 6.0% performed below the 2SD cutoff for severe cognitive impairment, p = 0.002. By 10 years from onset 29.3% and 9.0% of patients performed below the 1SD and 2SD cutoffs, respectively, p = 0.0001. Regression modeling suggested that cognitive impairment may precede MS onset by 1.2 years.</p><p>Conclusions</p><p>The rates of cognitive impairment in this large sample of MS patients were lower than previously reported and severe cognitive impairment was evident only in a relatively small group of patients. Cognitive impairment differed significantly from expected normal distribution only at five years from onset, suggesting the existence of a therapeutic window during which patients may benefit from interventions to maintain cognitive health.</p></div

Descriptive data for 1500 MS patients.

<p>P = p by ANOVA after Bonferroni correction for group comparison; p^a = p between CIS and SPMS; p^b = p between RRMS and SPMS; p^c = p between PPMS and SPMS. N = number; SE = standard error of the mean; CIS = clinically isolated syndrome; RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; PPMS = primary progressive multiple sclerosis; EDSS- Expanded disability status scale; IMD – Immunomodulatory drugs.</p

Cognitive performance by GCS within the first year from MS onset, N = 187.

<p>Cognitive performance by GCS within the first year from MS onset, N = 187.</p

Percent of MS patients with cognitive impairment by disease duration.

<p>The percent of patients with impairment in GCS at a cutoff of 85 (1SD below the normalized mean, white bars) and at a cutoff of 70 (2SD below the normalized mean, black bars) is presented by disease duration. The dashed bars represent the percent of patients with GCS ≥85. N = number of patients; *p≤0.005; **p<0.001; ***p<0.05.</p