Prevalence and Associated Clinical Characteristics of Walking-Related Motor, Cognitive, and Fatigability in Progressive Multiple Sclerosis: Baseline Results From the CogEx Study

Background: People with progressive multiple sclerosis (PMS) present motor (eg, walking) and cognitive impairments, and report fatigue. Fatigue encompasses fatigability which is objectively measured by the capacity to sustain a motor or cognitive task. // Objective: To investigate the prevalence of walking and cognitive fatigability (CF) and the associated clinical characteristics in a large sample of PMS patients. // Methods: PMS patients (25-65 years old) were included from 11 sites (Europe and North America), having cognitive impairment (1.28 standard deviation below normative data for the symbol digit modality test [SDMT]). Walking fatigability (WF) was assessed using the distance walk index (DWI) and CF using the SDMT (scores from the last 30 seconds compared to the first 30 seconds). Additional measures were: cognitive assessment—Brief International Cognitive Assessment for multiple sclerosis (MS), cardiorespiratory fitness, 6-minute walk, physical activity, depressive symptoms, perceived fatigue—Modified Fatigue Impact Scale (MFIS), MS impact—MSIS-29, and walking ability. // Results: Of 298 participants, 153 (51%) presented WF (DWI = −28.9 ± 22.1%) and 196 (66%) presented CF (−29.7 ± 15%). Clinical characteristics (EDSS, disease duration, and use of assistive device) were worse in patients with versus without WF. They also presented worse scores on MSIS-29 physical, MFIS total and physical and reduced physical capacity. CF patients scored better in the MSIS-29 physical and MFIS psychosocial, compared to non-CF group. Magnitude of CF and WF were not related. // Conclusions: Half of the cognitively-impaired PMS population presented WF which was associated with higher disability, physical functions, and fatigue. There was a high prevalence of CF but without strong associations with clinical, cognitive, and physical functions. Trial Registration Number: The “CogEx-study,” www.clinicaltrial.gov identifier number: NCT03679468

Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice

Although soluble oligomeric and protofibrillar assemblies of Aβ-amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Aβ-fibrils in the amyloid plaques remains controversial. A widely held view in the field suggests that the fibrillization reaction proceeds ‘forward' in a near-irreversible manner from the monomeric Aβ peptide through toxic protofibrillar intermediates, which subsequently mature into biologically inert amyloid fibrils that are found in plaques. Here, we show that natural lipids destabilize and rapidly resolubilize mature Aβ amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Aβ but rather toward soluble amyloid protofibrils. We characterized these ‘backward' Aβ protofibrils generated from mature Aβ fibers and compared them with previously identified ‘forward' Aβ protofibrils obtained from the aggregation of fresh Aβ monomers. We find that backward protofibrils are biochemically and biophysically very similar to forward protofibrils: they consist of a wide range of molecular masses, are toxic to primary neurons and cause memory impairment and tau phosphorylation in mouse. In addition, they diffuse rapidly through the brain into areas relevant to AD. Our findings imply that amyloid plaques are potentially major sources of soluble toxic Aβ-aggregates that could readily be activated by exposure to biological lipids

Sagittal standing posture and its association with spinal pain: a school-based epidemiological study of 1196 Flemish adolescents before age at peak height velocity

Study design. Cross-sectional baseline dataset on the sagittal standing posture of 1196 adolescents. Objective. To describe and quantify common variations in the sagittal standing alignment in boys and girls who are in the same phase of growth, and to explore the association between habitual standing posture and measures for spinal pain. Summary of Background Data. Data on postural characteristics and spinal pain measures in adolescence is sparse, especially when somatic and biological maturity status is to be considered. Furthermore, our understanding of the relation between standing posture in the sagittal plane and spinal pain is deficient. Methods. Six hundred thirty-nine boys (mean ± SD age, 12.6±0.54 years) and 557 girls (10.6±0.47 years) with predicted years from peak height velocity (PHV) being 1.2±0.71 years and 1.2±0.59 years pre-PHV, respectively, were studied. Postural examination included the assessment of global alignment and local spinopelvic characteristics, using post-hoc analyses of digital images and direct body measurements (palpation, digital inclinometry, and wheeled accelerometry). Spinal pain experience was assessed by questionnaire. Results. A wide interindividual variation in sagittal posture characteristics was observed. Logistic regression analyses yielded global alignment parameters to be associated with low back pain (lifetime prevalence), neck pain (lifetime prevalence, 1-month prevalence, and doctor visit), and thoracic spine pain (doctor visit) outcome measures. None of the included local spinopelvic parameters could be identified as an associated factor with measures of spinal pain. Conclusions. The orientation of gross body segments with respect to the gravity line appear superior to local spinopelvic features in terms of clinical importance, at least in the current pre-PHV cohort. Opportunities may exist for postural subgrouping strategies to begin with global alignment parameters in order to gain further insight in the relationship between sagittal alignment and the relative risk of developing spinal pain/seeking medical consultation for this pain

MMP-2 mediates Purkinje cell morphogenesis and spine development in the mouse cerebellum

Matrix metalloproteinase-2 (MMP-2) is a highly studied proteolytic enzyme, involved in many detrimental and beneficial functions throughout the body, and also active in the central nervous system (CNS). MMP-2 is profoundly expressed in the developing cerebellum and was recently reported to modulate granule cell proliferation by affecting cell cycle kinetics in cerebella of postnatal day 3 mouse pups. In this report, a two-dimensional difference gel electrophoresis proteomics study was implemented at this postnatal stage and revealed 16 differentially expressed proteins between MMP-2-deficient (MMP-2(-/-)) and wild-type cerebella. Among those, collapsin response mediator protein 1 (CRMP1) could be identified as the most significant differential protein between the two genotypes. Western blot experiments confirmed this finding and further disclosed a significant increase in phosphorylated CRMP1 expression in MMP-2(-/-) cerebella. Strikingly, subsequent immunohistochemical and microscopic analyses revealed an aberrant Purkinje cell (PC) dendritogenesis, possibly related to upregulated (phospho-) CRMP1 levels in these neonatal MMP-2(-/-) animals. Further, detailed morphometric analyses showed persistent PC morphological changes in MMP-2(-/-) mice, from the neonatal stage until adulthood. These were characterized by a reduced growth of PC somata, reduced dendritic tree sizes, and a decreased dendritic arborization. During development, the observed defects were accompanied by a temporarily disturbed parallel fiber and climbing fiber synaptic input on the PCs, while in adult MMP-2(-/-) animals, an increased PC spine density and reduced spine lengths were noted. The observed PC abnormalities might contribute to the mild defects in motor performance, i.e. balance and coordination, detected in adult MMP-2(-/-) mice. Overall, these findings indicate the importance of MMP-2 in CNS development and dendritogenesis, and highlight the importance of a correct developmental wiring for adult brain morphology and function.status: publishe

Reduced information processing speed as primum movens for cognitive decline in MS

Background: Cognitive impairment affects half of the multiple sclerosis (MS) patient population and is an important contributor to patients' daily activities. Most cognitive impairment studies in MS are, however, cross-sectional or/and focused on the early disease stages. Objective: We aim to assess the time course of decline of different cognitive domains. Methods: We collected neuropsychological data on 514 MS patients to construct Kaplan-Meier survival curves of the tests included in the Neuropsychological Screening Battery for MS (NSBMS) and the Symbol Digit Modalities Test (SDMT). Cox-proportional hazard models were constructed to examine the influence of MS onset type, age at onset, gender, depression and level of education on the time course, expressed as age or disease. Results: Survival curves of tests focusing on information processing speed (IPS) declined significantly faster than tests with less specific demands of IPS. Median age for pathological decline was 56.2 years (95% CI: 54.4-58.2) on the SDMT and 63.9 years (95% CI: 60-66.9) on the CLTR, a memory task. Conclusion: In conclusion, IPS is the cognitive domain not only most widely affected by MS but it is also the first cognitive deficit to emerge in MS

An aberrant cerebellar development in mice lacking matrix metalloproteinase-3

Cell-cell and cell-matrix interactions are necessary for neuronal patterning and brain wiring during development. Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of remodelling the pericellular environment and regulating signaling pathways through cleavage of a large degradome. MMPs have been suggested to affect cerebellar development, but the specific role of different MMPs in cerebellar morphogenesis remains unclear. Here, we report a role for MMP-3 in the histogenesis of the mouse cerebellar cortex. MMP-3 expression peaks during the second week of postnatal cerebellar development and is most prominently observed in Purkinje cells (PCs). In MMP-3 deficient (MMP-3(-/-)) mice, a protracted granule cell (GC) tangential migration and a delayed GC radial migration results in a thicker and persistent external granular layer, a retarded arrival of GCs in the inner granular layer, and a delayed GABAergic interneuron migration. Importantly, these neuronal migration anomalies, as well as the consequent disturbed synaptogenesis on PCs, seem to be caused by an abnormal PC dendritogenesis, which results in reduced PC dendritic trees in the adult cerebellum. Of note, these developmental and adult cerebellar defects might contribute to the aberrant motor phenotype observed in MMP-3(-/-) mice and suggest an involvement of MMP-3 in mouse cerebellar development.status: publishe

Persistent impact of in utero irradiation on mouse brain structure and function characterized by MR imaging and behavioral analysis

Prenatal irradiation is known to perturb brain development. Epidemiological studies revealed that radiation exposure during weeks 8-15 of pregnancy was associated with an increased occurrence of mental disability and microcephaly. Such neurological deficits were reproduced in animal models, in which rodent behavioral testing is an often used tool to evaluate radiation-induced defective brain functionality. However, up to now, animal studies suggested a threshold dose of around 0.30 Gray (Gy) below which no behavioral alterations can be observed, while human studies hinted at late defects after exposure to doses as low as 0.10 Gy. Here, we acutely irradiated pregnant mice at embryonic day 11 with doses ranging from 0.10 to 1.00 Gy. A thorough investigation of the dose-response relationship of altered brain function and architecture following in utero irradiation was achieved using a behavioral test battery and volumetric 3D T2-weighted magnetic resonance imaging (MRI). We found dose-dependent changes in cage activity, social behavior, anxiety-related exploration, and spatio-cognitive performance. Although behavioral alterations in low-dose exposed animals were mild, we did unveil that both emotionality and higher cognitive abilities were affected in mice exposed to ≥0.10 Gy. Microcephaly was apparent from 0.33 Gy onwards and accompanied by deviations in regional brain volumes as compared to controls. Of note, total brain volume and the relative volume of the ventricles, frontal and posterior cerebral cortex, cerebellum, and striatum were most strongly correlated to altered behavioral parameters. Taken together, we present conclusive evidence for persistent low-dose effects after prenatal irradiation in mice and provide a better understanding of the correlation between their brain size and performance in behavioral tests.Verreet T., Rangarajan J.R., Quintens R., Verslegers M., Lo A.C., Govaerts K., Neefs M., Leysen L., Baatout S., Maes F., Himmelreich U., D'Hooge R., Moons L., Benotmane M.A., ''Persistent impact of in utero irradiation on mouse brain structure and function characterized by MR imaging and behavioral analysis'', Frontiers in behavioral neuroscience, vol. 10, article 83, May 2016.status: publishe