Lesion Volume in Relapsing Multiple Sclerosis is Associated with Perivascular Space Enlargement at the Level of the Basal Ganglia.

BACKGROUND AND PURPOSE: Perivascular spaces surround the blood vessels of the brain and are involved in neuroimmune functions and clearance of metabolites via the glymphatic system of the brain. Enlarged perivascular spaces could be a marker of dysfunction in these processes and, therefore, are highly relevant to monitoring disease activity in MS. This study aimed to compare the number of enlarged perivascular spaces in people with relapsing MS with MR imaging markers of inflammation and brain atrophy. MATERIALS AND METHODS: Fifty-nine patients (18 with clinically isolated syndrome, 22 with early and 19 with late relapsing-remitting MS) were scanned longitudinally (mean follow-up duration = 19.6 [SD, 0.5] months) using T2-weighted, T1-weighted, and FLAIR MR imaging. Two expert raters identified and counted enlarged perivascular spaces on T2-weighted MR images from 3 ROIs (the centrum semiovale, basal ganglia, and midbrain). Baseline and change with time in the number of enlarged perivascular spaces were correlated with demographics and lesion and brain volumes. RESULTS: Late relapsing-remitting MS had a greater average number of enlarged perivascular spaces at baseline at the level of the basal ganglia (72.3) compared with early relapsing-remitting MS (60.5) and clinically isolated syndrome (54.7) (F = 3.4, P = .042), and this finding correlated with lesion volume (R = 0.44, P = .0004) but not brain atrophy (R = -0.16). Enlarged perivascular spaces increased in number with time in all regions, and the rate of increase did not differ among clinical groups. CONCLUSIONS: Enlarged perivascular spaces at the level of the basal ganglia are associated with greater neuroinflammatory burden, and the rate of enlargement appears constant in patients with relapsing-remitting disease phenotypes.

Speech metrics, general disability, brain imaging and quality of life in multiple sclerosis.

BACKGROUND AND PURPOSE: Objective measurement of speech has shown promising results to monitor disease state in multiple sclerosis. In this study, we characterize the relationship between disease severity and speech metrics through perceptual (listener based) and objective acoustic analysis. We further look at deviations of acoustic metrics in people with no perceivable dysarthria. METHODS: Correlations and regression were calculated between speech measurements and disability scores, brain volume, lesion load and quality of life. Speech measurements were further compared between three subgroups of increasing overall neurological disability: mild (as rated by the Expanded Disability Status Scale ≤2.5), moderate (≥3 and ≤5.5) and severe (≥6). RESULTS: Clinical speech impairment occurred majorly in people with severe disability. An experimental acoustic composite score differentiated mild from moderate (P < 0.001) and moderate from severe subgroups (P = 0.003), and correlated with overall neurological disability (r = 0.6, P < 0.001), quality of life (r = 0.5, P < 0.001), white matter volume (r = 0.3, P = 0.007) and lesion load (r = 0.3, P = 0.008). Acoustic metrics also correlated with disability scores in people with no perceivable dysarthria. CONCLUSIONS: Acoustic analysis offers a valuable insight into the development of speech impairment in multiple sclerosis. These results highlight the potential of automated analysis of speech to assist in monitoring disease progression and treatment response.

Cognitive processing speed deficits in multiple sclerosis: Dissociating sensorial and motor processing changes from cognitive processing speed.

BACKGROUND: The assessment of cognitive information processing speed (IPS) is complicated in MS, with altered performance on tests such as the Symbol Digit Modalities Test (SDMT) potentially representing changes not only within cognitive networks but in the initial sensorial transmission of information to cognitive networks, and/or efferent transmission of the motor response. OBJECTIVE: We aimed to isolate and characterise cognitive IPS deficits in MS using ocular motor tasks; a prosaccade task (used to assess and control for sensorial and motor IPS) which was then used to adjust performance on the Simon task (cognitive IPS). METHODS: All participants (22 MS patients with early disease, 22 healthy controls) completed the ocular motor tasks and the SDMT. The Simon task assessed cognitive IPS by manipulating the relationship between a stimulus location and its associated response direction. Two trial types were interleaved: (1) congruent, where stimulus location = response direction; or (2) incongruent, where stimulus location ≠ response direction. RESULTS MS patients did not perform differently to controls on the SDMT. For OM tasks, when sensorial and motor IPS was controlled, MS patients had significantly slower cognitive IPS (incongruent trials only) and poorer conflict resolution. SDMT performance did not correlate with slower cognitive IPS in MS patients, highlighting the limitation of using SDMT performance to interpret cognitive IPS changes in patients with MS. CONCLUSION: Cognitive IPS deficits in MS patients are dissociable from changes in other processing stages, manifesting as impaired conflict resolution between automatic and non-automatic processes. Importantly, these results raise concerns about the SDMT as an accurate measure of cognitive IPS in MS.

Social Isolation Alters Social and Mating Behavior in the R451C Neuroligin Mouse Model of Autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder typified by impaired social communication and restrictive and repetitive behaviors. Mice serve as an ideal candidate organism for studying the neural mechanisms that subserve these symptoms. The Neuroligin-3 (NL3) mouse, expressing a R451C mutation discovered in two Swedish brothers with ASD, exhibits impaired social interactions and heightened aggressive behavior towards male mice. Social interactions with female mice have not been characterized and in the present study were assessed in male NL3R451C and WT mice. Mice were housed in social and isolation conditions to test for isolation-induced increases in social interaction. Tests were repeated to investigate potential differences in interaction in naïve and experienced mice. We identified heightened interest in mating and atypical aggressive behavior in NL3R451C mice. NL3R451C mice exhibited normal social interaction with WT females, indicating that abnormal aggressive behavior towards females is not due to altered motivation to engage. Social isolation rearing heightened interest in social behavior in all mice. Isolation housing selectively modulated the response to female pheromones in NL3R451C mice. This study is the first to show altered mating behavior in the NL3R451C mouse and has provided new insights into the aggressive phenotype in this model.

Brain structure and intragenic DNA methylation are correlated, and predict executive dysfunction in fragile X premutation females.

DNA methylation of the Fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary has been associated with executive dysfunction in female carriers of a FMR1 premutation (PM: 55-199 CGG repeats), whereas neuroanatomical changes have been associated with executive dysfunction in PM males. To our knowledge, this study for the first time examined the inter-relationships between executive function, neuroanatomical structure and molecular measures (DNA methylation and FMR1 mRNA levels in blood) in PM and control (<44 CGG repeats) females. In the PM group, FMR1 intron 1 methylation was positively associated with executive function and cortical thickness in middle and superior frontal gyri, and left inferior parietal gyrus. By contrast, in the control group, FMR1 intron 1 methylation was negatively associated with cortical thickness of the left middle frontal gyrus and superior frontal gyri. No significant associations were revealed for either group between FMR1 mRNA and neuroanatomical structure or executive function. In the PM group, the lack of any significant association between FMR1 mRNA levels and phenotypic measures found in this study suggests that either FMR1 expression is not well conserved between tissues, or that FMR1 intron 1 methylation is linked to neuroanatomical and cognitive phenotype in PM females via a different mechanism.

The occurrence of dystonia in upper-limb multiple sclerosis tremor.

BACKGROUND: The pathophysiology of multiple sclerosis (MS) tremor is uncertain with limited phenotypical studies available. OBJECTIVE: To investigate whether dystonia contributes to MS tremor and its severity. METHODS: MS patients (n = 54) with and without disabling uni- or bilateral upper limb tremor were recruited (39 limbs per group). We rated tremor severity, writing and Archimedes spiral drawing; cerebellar dysfunction (SARA score); the Global Dystonia Scale (GDS) for proximal and distal upper limbs, dystonic posturing, mirror movements, geste antagoniste, and writer's cramp. RESULTS: Geste antagoniste, mirror dystonia, and dystonic posturing were more frequent and severe (p < 0.001) and dystonia scores were correlated with tremor severity in tremor compared to non-tremor patients. A 1-unit increase in distal dystonia predicted a 0.52-Bain unit (95% confidence interval (CI) 0.08-0.97), p = 0.022) increase in tremor severity and a 1-unit (95% CI 0.48-1.6, p = 0.001) increase in drawing scores. A 1-unit increase in proximal dystonia predicted 0.93-Bain unit increase (95% CI 0.45-1.41, p < 0.001) in tremor severity and 1.5-units (95% CI 0.62-2.41, p = 0.002) increase in the drawing score. Cerebellar function in the tremor limb and tremor severity was correlated (p < 0.001). CONCLUSIONS: Upper limb dystonia is common in MS tremor suggesting that MS tremor pathophysiology involves cerebello-pallido-thalamo-cortical network dysfunction.

Diffusion tensor imaging of acute inflammatory lesion evolution in multiple sclerosis.

The initiating events in multiple sclerosis (MS) plaque formation are poorly understood. Retrospective analysis of serial imaging data can improve the understanding of tissue changes characterising acute MS lesion evolution. This study aimed to assess lesion evolution using diffusion tensor imaging data from serially acquired scans from 22 patients with MS. Mean diffusivity (MD) and fractional anisotropy (FA) were measured from 13 suitable plaques from five patients and carefully matched regions of contralateral normal-appearing white matter. Measurement times were on average: 5 months and 1 month prior to, during, and 1 month and 2 months post gadolinium-enhancement. A significant increase in MD (7.25%) but no change in FA was observed in white matter areas that exhibited enhancement 5 months later. The pre-lesional MD increase was significantly correlated with the MD increase 2 months subsequent to enhancement (R=0.73, p=0.04) but not to the MD increase during enhancement (R=0.11). These results suggest that MD is sensitive to tissue changes that precede blood-brain barrier (BBB) breakdown by at least 5 months and that MD assessments may predict injury following BBB restoration.

A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis.

OBJECTIVE: Higher latitude, lower ultraviolet exposure, and lower serum 25-hydroxyvitamin D (25OHD) correlate with higher multiple sclerosis (MS) prevalence, relapse rate, and mortality. We therefore evaluated the effects of high-dose vitamin D2 (D2) in MS. METHODS: Adults with clinically active relapsing-remitting MS (RRMS) were randomized to 6 months' double-blind placebo-controlled high-dose vitamin D2, 6,000 IU capsules, dose adjusted empirically aiming for a serum 25OHD 130-175 nM. All received daily low-dose (1,000 IU) D2 to prevent deficiency. Brain MRIs were performed at baseline, 4, 5, and 6 months. Primary endpoints were the cumulative number of new gadolinium-enhancing lesions and change in the total volume of T2 lesions. Secondary endpoints were Expanded Disability Status Scale (EDSS) score and relapses. RESULTS: Twenty-three people were randomized, of whom 19 were on established interferon or glatiramer acetate (Copaxone) treatment. Median 25OHD rose from 54 to 69 nM (low-dose D2) vs 59 to 120 nM (high-dose D2) (p = 0.002). No significant treatment differences were detected in the primary MRI endpoints. Exit EDSS, after adjustment for entry EDSS, was higher following high-dose D2 than following low-dose D2 (p = 0.05). There were 4 relapses with high-dose D2 vs none with low-dose D2 (p = 0.04). CONCLUSION: We did not find a therapeutic advantage in RRMS for high-dose D2 over low-dose D2 supplementation. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that high-dose vitamin D2 (targeting 25OHD 130-175 nM), compared to low-dose supplementation (1,000 IU/d), was not effective in reducing MRI lesions in patients with RRMS.

Validation of linear cerebral atrophy markers in multiple sclerosis.

Linear measures of cerebral ventricular enlargement may act as surrogate measures of cerebral atrophy in multiple sclerosis (MS). Linear atrophy markers were measured from routine MRI scans during a population survey of 171 Tasmanian MS patients and 91 healthy controls. Thirty-five Victorian MS clinic patients were recruited as a validation cohort with 14 of these re-assessed 4 years later. In the population survey, we measured three linear brain atrophy markers: inter-caudate distance (ICD), third ventricle width (TVW) and frontal horn width (FHW). TVW (OR 2.0, p=0.001) and ICD (OR 16.1, p<0.001) differentiated between MS cases and controls. In the validation study, we correlated the intercaudate ratio (ICR=ICD/brain width) and third ventricular ratio (TVR=TVW/brain width) with brain parenchymal volume. Cross-sectionally, ICR (R=-0.453, p<0.01) and TVR (R=-0.653, p<0.01) were correlated with brain parenchymal volume. Longitudinally, brain parenchymal volume loss was inversely correlated with increased ICD (R=-0.77, p<0.01) and TVW (R=-0.71, p<0.01). This study shows that ICD measurements obtained from clinical MRI scans are valid brain atrophy measures for use in monitoring MS progression.

Sézary T-cell activating factor is a Chlamydia pneumoniae-associated protein.

We previously identified a protein that was stimulatory for malignant Sézary T cells, termed Sézary T-cell activating factor (SAF). However, the identity of this protein has not been fully elucidated, nor has it's role been determined in the pathogenesis of cutaneous T-cell lymphoma (CTCL). The basis for epidermotropism and proliferation of malignant cells in the skin of patients with CTCL is unknown. Using a monoclonal antibody inhibitory for SAF activity, we demonstrated that SAF is present in the skin of 16 of 27 samples from patients with mycosis fungoides, the predominant form of CTCL. In this report, the SAF determinant is demonstrated to be associated with Chlamydia pneumoniae bacteria by immunohistochemistry, immunoelectron microscopy, and culture analysis. Reactivity of antibodies against an outer membrane protein of C. pneumoniae or against the lipopolysaccharide of Chlamydiae spp. demonstrated that these determinants are coexpressed in 90% of the SAF-positive samples. We confirmed the presence of C. pneumoniae DNA and RNA in the skin by PCR and reverse transcription-PCR and by sequence analysis of the PCR products. The expression of the C. pneumoniae antigens and SAF appears to be associated with active disease in that C. pneumoniae antigens were absent or greatly diminished in the skin of three patients examined after Psoralen and long-wave UVA radiation treatment. Our results suggest that SAF is a Chlamydia-associated protein and that further investigation is warranted to determine whether SAF and C. pneumoniae play a role in the pathogenesis of CTCL.

[Maternal phenylketonuria. Problems in detecting and risk educating identified females]. / Maternale Phenylketonurie. Problematik der Auffindung und Risikoaufklärung betroffener Frauen.

Maternal PKU is an embryo-fetopathy caused by elevated plasmaphenylalanine levels in pregnant women with hyperphenylalaninemia and phenylketonuira. Leading symptoms are microcephaly, mental retardatioin and congenital malformations, especially congenital heart disease. Maternal PKU becomes more important since early treated and normally developed girls with PKU are reaching their reproductive age in increasing numbers. There is a lack of adequate knowledge about the dangers of maternal PKU in at-risk women. Only 43% of these women in the Federal Republic of Germany are located by now and can be informed and instructed. Ways and conditions of tracking are described.

[Epidemiological studies of increasing appearances of Proteus inconstans (Providencia stuartii) infections (author's transl)]. / Epidemiologische Untersuchungen bei gehäuftem Auftreten von Proteus-inconstans-(Providencia stuartii-)Infektionen.

Since proteus inconstans turns out to be the causative agent of an increasing amount of hospital infections, studies on this species are necessary. By means of bacteriocines, biochemical reactions and antibiograms 53 strains were subclassified. 47 strains displayed same biochemical properties, 44 strains showed the same antibiogram. By the method on the basis of bacteriocine typing 15 groups were established. The strains with the same biochemical properties and the same antibiograms could be further subclassified. The distribution of the different bacteriocine groups showed that the infections were not due to a single strain. In contrast there were some indices for cross-infections on some stations.