Verbal fluency refers to the ability to generate words quickly and efficiently according to predefined phonological or semantic criteria. Deficits in verbal fluency limit patients' ability to ...communicate effectively and to function well in social setups. Multiple sclerosis (MS) patients suffer from various cognitive impairments, and some of them experience language deficits as well. The goal of this study is to examine the contribution of the dorsal and ventral language pathways to verbal fluency in MS patients. All patients (
= 33) underwent diffusion MRI (dMRI) and fluency measurements. Diffusion parameters were calculated along dorsal and ventral language-related pathways and their right-hemispheric homologs, identified individually in each patient. Significant correlations were found between fluency measures and mean fractional anisotropy (FA) in several pathways, including the left fronto-temporal arcuate fasciculus (AF
), bilateral inferior fronto-occipital fasciculus (IFOF), and bilateral frontal aslant tract. Along-tract correlations revealed a more selective pattern of associations: letter-based fluency was associated with FA in a segment of the left AF
(dorsal pathway), while category-based fluency was associated with FA in a segment of the right IFOF (ventral pathway). The observed pattern of associations, mapping letter-based fluency to the dorsal stream and category-based fluency to the ventral stream, fits well within the dual stream framework of language processing. Further studies will be necessary to assess whether these associations generalize to the typical adult population or whether they are tied to the clinical state.
Cerebral Cavernous Malformations Ganmore, Ithamar; Achiron, Anat
The New England journal of medicine,
2017-Jul-06, Letnik:
377, Številka:
1
Journal Article
Multiple Sclerosis (MS) has been linked to a variety of environmental risk factors, including smoking, Epstein-Barr Virus infection, and childhood obesity. There is some evidence to support a ...relationship between alcohol consumption and MS risk, but this finding has been inconsistent across cohorts. A protective link between alcohol consumption and MS risk is seen in Swedish and Danish cohorts, however evidence from other cohorts and mendelian randomisation studies have failed to support this relationship. We assessed the relationship between alcohol consumption (never vs. ever drinking) and MS in 409,228 individuals (2100 with MS) from UK Biobank (UKB). We used multivariable logistic regression models adjusted for age and sex. To determine whether there was evidence of statistical interaction between alcohol consumption and HLA-DRB1*15:01 genotype, we calculated interaction on the additive and multiplicative scales. We analysed data from 2100 individuals with MS (72.3% female, median age at recruitment 56) and 407,128 controls (53.9% female, median age at recruitment 58). We found no evidence for an association between alcohol consumption and MS risk (OR = 1.12, 95% CI 0.61-2.08, p = 0.314). As expected, the HLA-DRB1*15:01 allele was strongly associated with MS risk (OR = 2.72, 95% CI 2.72-2.72, p < 2 × 10
). We found no evidence of statistical interaction between non-drinking and MS risk on either the multiplicative scale (p = 0.8) or on the additive scale (Attributable Proportion = 0.03, 95% CI - 0.43-0.29, P = 0.45). Empirical power calculations indicated reasonable statistical power (85%) to detect a protective effect of alcohol consumption of Relative Risk ≤ 0.7. We were thus unable to replicate findings from other cohorts within UK Biobank. The inconsistent association seen between studies may reflect limited statistical power to detect a weak effect, differences in population characteristics, or the lack of a true causal association.
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.
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.
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.
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.
Background:
The rate of post-relapse residual disability in patients with relapsing–remitting multiple sclerosis (RRMS) treated with disease-modifying drugs (DMD) has not been studied.
Objective:
To ...assess relapse residual disability in DMD-treated RRMS patients.
Methods:
We followed DMD-treated RRMS patients presenting with acute relapse who received high-dose steroids. Increases in Expanded Disability Status Scale (EDSS) of at least 2.0, 1.0–1.5 or 0.5 were defined as severe, moderate or mild relapses, respectively. The proportions of patients with post-relapse residual disability defined as the failure to regain pre-relapse neurological status at 1, 4 and 12 months were evaluated.
Results:
Out of 1672 relapses in DMD-treated RRMS patients, 17% were severe. In patients who presented with a severe relapse, we observed post-relapse residual disability of at least 1.0 EDSS point in 60.1%, 55.9% and 48.2% of patients at 1, 2 and 12 months of follow-up, respectively. Post-relapse residual disability of at least 2.0 EDSS points was observed in 37.4%, 30.7% and 20.7% of patients after 1, 2 and 12 months, respectively.
Conclusion:
A high rate of incomplete recovery was seen 12 months following severe relapse among RRMS patients and may contribute to the accumulation of long-term disability.
Multiple sclerosis (MS) may lead to cognitive decline over-time.
Characterize cognitive performance in MS patients with long disease duration treated with disease modifying drugs (DMD) in relation to ...disability and determine the prevalence of cognitive resilience.
Cognitive and functional outcomes were assessed in 1010 DMD-treated MS patients at least 10 years from onset. Cognitive performance was categorized as high, moderate or low, and neurological disability was classified according to the Expanded Disability Status Scale (EDSS) as mild, moderate or severe. Relationship between cognitive performance and disability was examined.
After a mean disease duration of 19.6 (SD = 7.7) years, low cognitive performance was observed in 23.7% (N = 239), moderate performance in 42.7% (N = 431), and 33.7% (N = 340) had high cognitive performance, meeting the definition of cognitively resilient patients. Within the group of patients with low cognitive performance, severe disability was observed in 50.6% (121/239), while in the group of patients with high cognitive performance, mild disability was observed in 64.4% (219/340). Differences between the group of patients with high cognitive performance and severe disability (4.5%) and the group of patients with low cognitive performance and mild disability (5.0%) were not accounted for by DMD treatment duration.
The majority of DMD treated MS patients did not have cognitive decline that could impair their quality of life after disease of extended duration.
Abstract Multiple sclerosis (MS) is characterized in most patients by a relapsing-remitting disease course. However, the trigger of relapse and the transformation that switches relapse into remission ...are not clearly understood. To evaluate the key molecular pathways operating in MS relapse and remission we performed peripheral blood gene-expression profiling in 123 MS patients either in relapse (n = 34) or remission (n = 89) and in comparison with 41 matched healthy subjects using Affymetrix microarray technology. Our findings suggest that the relapsing-remitting pattern of MS is an ongoing process where inflammation is persistently active in the background of a changing magnitude of processes associated with TBX21-mediated immune suppression and activation of BDNF-related neuroprotection.
Longitudinal data are vital in order to understand intra individual gait changes with the progression of multiple sclerosis (MS). Therefore, the primary aim of this study was to explore the ...relationship between changes in disability with changes in major spatio-temporal parameters of gait in people with MS (PwMS). PwMS (n = 83) completed two gait assessments performed at separate time points (M1, M2). For each individual, the absolute difference between the Expanded Disability Status Scale (EDSS) score, key spatio-temporal parameters of gait, Falls Efficacy Scale International (FES-I), and the 12-item Multiple Sclerosis Walking Scale (MSWS-12), were calculated. The mean time difference between M1 and M2 was 2.5 (SD = 1.7) years. At M2, PwMS presented with shorter strides, a wider base of support, increased perceived mobility difficulties and fear of falling compared with M1. According to the odds ratio (OR) analysis, the odds of experiencing an increase in the EDSS score was significantly higher once the MSWS-12 score increased at M2 compared with M1 (OR = 7.930, p = 0.004). This observation was highlighted specifically in people with mild-moderate MS (OR = 12.427, p < 0.001). The increase in the EDSS score was not associated with changes in key spatio-temporal parameters of gait. The present study provides a better understanding of gait and disease progression in PwMS, highlighting the significant role of the MSWS-12.
Background:
The motoric cognitive risk (MCR) syndrome, defined as the coexistence of slow gait and subjective cognitive complaints, has as yet not been researched in people with multiple sclerosis ...(pwMS).
Objective:
To examine the prevalence of the MCR syndrome in pwMS and its association with disability, disease duration, perceived fatigue, and fear of falling.
Methods:
The study comprised 618 pwMS 43.7 (SD = 12.6) years, 61.7% females. Gait speed was measured by the GAITRite™ electronic walkway (CIR Systems, Inc. Haverton, PA, USA). Cognitive status was defined according to the global cognitive score computed by the NeuroTrax™ cognitive battery (NeuroTrax Corporation, Medina, NY, USA). The sample was divided into four main groups: ‘normal’, ‘cognitively impaired’, ‘gait impaired’ or ‘MCR’. Perceived fatigue was assessed by the Modified Fatigue Impact Scale; fear of falling by the Falls Efficacy Scale International.
Results:
Sixty-three (10.2%) patients were diagnosed with MCR. The percentage of subjects categorized as MCR was 26.0% in severely disabled pwMS compared with 10.9%, 6.0%, and 4.6% in moderately, mildly and very mildly disabled pwMS, respectively. Subjects in the MCR group presented with elevated fatigue compared with patients classified as normal 49.7 (SD = 23.3) vs 26.5 (SD = 19.2), p < 0.001. Fear of falling was significantly higher in the MCR and gait impairment groups compared with the cognitively impaired and normal groups.
Conclusions:
The current study corroborates the presence of MCR in pwMS. Nevertheless, future longitudinal research is warranted to better understand its application.
Abstract
Background
Targeting RNA polymerase-1 (POL1) machinery is a new strategy for suppression of multiple sclerosis (MS) relapse activity. Oral administration of POL1 inhibitor RAM-589.555, which ...is characterized by high permeability and bioavailability in naïve mice, ameliorates proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) by suppressing activated autoreactive lymphocytes. We assessed the accessibility of RAM-589.555 to the central nervous system (CNS) of EAE-mice and further investigated its immunomodulatory effects on CNS-resident astro- and micro-glial cells in-vitro and in-vivo.
Methods
Effects of RAM-589.555 on activated microglia and astrocyte viability, proliferation, and secretion of neurotrophic factors were assessed in-vitro. The pharmacokinetic of RAM-589.555 was evaluated in the blood and central nervous system (CNS) of EAE-affected mice. High-dimensional single-cell mass cytometry was applied to characterize the effect of RAM-589.555 on EAE-affected mice’s CNS-resident micro- and astroglial cells and CNS-infiltrating immune cells, which were obtained seven days after RAM-589.555 administration at EAE onset. Simultaneously, the expression level of pre-rRNA, the POL1 end product, was assessed in blood cells, microglia, and astrocytes to monitor RAM-589.555 effects.
Results
RAM-589.555 demonstrated blood and CNS permeability in EAE mice. In-vitro, incubation with 400 nM of RAM-589.555 significantly reduced viability and proliferation of lipopolysaccharide (LPS)-activated microglia by 70% and 45% (
p
< 0.05), respectively, while tumor necrosis factor α (TNFα)-activated astrocytes were not affected. The secretion of neurotrophic factors was preserved. Furthermore, 7 days after administration of RAM-589.555 at EAE onset, the level of pre-rRNA transcript in peripheral blood mononuclear cells (PBMC) was decreased by 38.6% (
p
= 0.02), while levels of pre-rRNA transcript in microglia and astrocytes remained unchanged. The high-dimensional single-cell mass cytometry analysis showed decreased percentages of CNS-resident microglia and astrocytes, diminished pro-inflammatory cytokines (IL-1β, IL-6, IL-12, IL-17, TNFα, and IFNγ), and an increase of their anti-inflammatory cytokines (IL-4, IL-10, and TGFβ) in RAM-589.555-treated compared to vehicle-treated mice (
p
< 0.05).
Conclusions
These data correlate RAM-589.555-induced clinical amelioration and its CNS-permeability to decreased CNS-inflammation, and decreased micro- and astrogliosis, while restoring micro- and astroglial anti-inflammatory and neuroprotective capacity.
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