Deleterious functional consequences of perfluoroalkyl substances accumulation into the myelin sheath.

Exposure to persistent organic pollutants during the perinatal period is of particular concern because of the potential increased risk of neurological disorders in adulthood. Here we questioned whether exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) could alter myelin formation and regeneration. First, we show that PFOS, and to a lesser extent PFOA, accumulated into the myelin sheath of postnatal day 21 (p21) mice, whose mothers were exposed to either PFOA or PFOS (20 mg/L) via drinking water during late gestation and lactation, suggesting that accumulation of PFOS into the myelin could interfere with myelin formation and function. In fact, PFOS, but not PFOA, disrupted the generation of oligodendrocytes, the myelin-forming cells of the central nervous system, derived from neural stem cells localised in the subventricular zone of p21 exposed animals. Then, cerebellar slices were transiently demyelinated using lysophosphatidylcholine and remyelination was quantified in the presence of either PFOA or PFOS. Only PFOS impaired remyelination, a deleterious effect rescued by adding thyroid hormone (TH). Similarly to our observation in the mouse, we also showed that PFOS altered remyelination in Xenopus laevis using the Tg(Mbp:GFP-ntr) model of conditional demyelination and measuring, then, the number of oligodendrocytes. The functional consequences of PFOS-impaired remyelination were shown by its effects using a battery of behavioural tests. In sum, our data demonstrate that perinatal PFOS exposure disrupts oligodendrogenesis and myelin function through modulation of TH action. PFOS exposure may exacerbate genetic and environmental susceptibilities underlying myelin disorders, the most frequent being multiple sclerosis.

[18F]DPA-714: Effect of co-medications, age, sex, BMI and TSPO polymorphism on the human plasma input function.

PURPOSE: We aimed to assess the effect of concomitant medication, age, sex, body mass index and 18-kDa translocator protein (TSPO) binding affinity status on the metabolism and plasma pharmacokinetics of [18F]DPA-714 and their influence on the plasma input function in a large cohort of 201 subjects who underwent brain and whole-body PET imaging to investigate the role of neuroinflammation in neurological diseases. METHODS: The non-metabolized fraction of [18F]DPA-714 was estimated in venous plasma of 138 patients and 63 healthy controls (HCs; including additional arterial sampling in 16 subjects) during the 90 min brain PET acquisition using a direct solid-phase extraction method. The mean fraction between 70 and 90 min post-injection ([18F]DPA-71470-90) and corresponding normalized plasma concentration (SUV70-90) were correlated with all factors using a multiple linear regression model. Differences between groups (arterial vs venous measurements; HCs vs patients; high- (HAB), mixed- (MAB) and low-affinity binders (LAB); subjects with vs without co-medications, females vs males were also assessed using the non-parametric Mann-Whitney or Kruskal-Wallis ANOVA tests. Finally, the impact of co-medications on the brain uptake of [18F]DPA-714 at equilibrium was investigated. RESULTS: As no significant differences were observed between arterial and venous [18F]DPA-71470-90 and SUV70-90, venous plasma was used for correlations. [18F]DPA-71470-90 was not significantly different between patients and HCS (59.7 ± 12.3% vs 60.2 ± 12.9%) despite high interindividual variability. However, 47 subjects exhibiting a huge increase or decrease of [18F]DPA-71470-90 (up to 88% or down to 23%) and SUV70-90 values (2-threefold) were found to receive co-medications identified as inhibitors or inducers of CYP3A4, known to catalyse [18F]DPA-714 metabolism. Comparison between cortex-to-plasma ratios using individual input function (VTIND) or population-based input function derived from untreated HCs (VTPBIF) indicated that non-considering the individual metabolism rate led to a bias of about 30% in VT values. Multiple linear regression model analysis of subjects free of these co-medications suggested significant correlations between [18F]DPA-71470-90 and age, BMI and sex while TSPO polymorphism did not influence the metabolism of the radiotracer. [18F]DPA-714 metabolism fell with age and BMI and was significantly faster in females than in males. Whole-body PET/CT exhibited a high uptake of the tracer in TSPO-rich organs (heart wall, spleen, kidneys…) and those involved in metabolism and excretion pathways (liver, gallbladder) in HAB and MAB with a strong decrease in LAB (-89% and -85%) resulting in tracer accumulation in plasma (4.5 and 3.3-fold increase). CONCLUSION: Any co-medication that inhibits or induces CYP3A4 as well as TSPO genetic status, age, BMI and sex mostly contribute to interindividual variations of the radiotracer metabolism and/or concentration that may affect the input function of [18F]DPA-714 and consequently its human brain and peripheral uptake. TRIAL REGISTRATION: INFLAPARK, NCT02319382, registered December 18, 2014, retrospectively registered; IMABIO 3, NCT01775696, registered January 25, 2013, retrospectively registered; INFLASEP, NCT02305264, registered December 2, 2014, retrospectively registered; EPI-TEP, EudraCT 2017-003381-27, registered September 24, 2018.

Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis.

BACKGROUND: Natalizumab and fingolimod are used as high-efficacy treatments in relapsing-remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. METHODS: Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. RESULTS: Overall, 5,148 relapsing-remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. CONCLUSIONS: This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

Biotherapies in multiple sclerosis: a step toward remyelination and neuroprotection?

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS), characterized by CNS-restricted inflammation with subsequent demyelination and neurodegeneration. Current disease-modifying therapies efficiently reduce relapse rate and new lesions appearance, but still fail to impact the progressive course of the disease. There is a great need for the avenue of new therapies aimed at promoting myelin repair or reducing neurodegeneration that should result in the prevention of neurological disability in this chronic disease. This review will focus on the potentials and limitations of biotherapies that are currently developed for the promotion of CNS repair in MS, either monoclonal antibodies targeting axonal growth and remyelination, or cell therapies aimed at replacing the depleted myelinating cells within the CNS. As other researches aimed at promoting neuroprotection or remyelination are following a classical pharmacological approach, they will not be described in this review, which will focus on antibody-based therapies and cell therapies.

Dramatic worsening following plasma exchange in severe post-natalizumab withdrawal multiple sclerosis relapse.

We report the case of a young woman with multiple sclerosis who discontinued natalizumab twice and experienced a severe relapse following each natalizumab withdrawal. The first relapse was successfully treated by intravenous methylprednisolone (IVMP). In contrast the second relapse was unresponsive to IVMP. Subsequent treatment by plasma exchanges (PLEX) was followed by a dramatic neurological worsening. This case suggests that PLEX after natalizumab discontinuation may increase relapse severity.

Immunosuppressive therapy is more effective than interferon in neuromyelitis optica.

To determine long-term treatment (LTT) of neuromyelitis optica (NMO), we retrospectively reviewed therapies of 26 patients with NMO followed in five French neurological departments. To assess LTT efficacy, the probability of relapse free after LTT was analysed. Patients were divided into two groups according to the first treatment receiving interferon beta (IFN Group, seven patients) or immunosuppressants (IS Group, 19 patients). The probability of relapse was significantly lower in the IS Group (P =0.0007). From our results, interferon beta is not recommended, and one of the best current therapeutic options for NMO appears to be immunosuppressants.

Age at onset determines the occurrence of the progressive phase of multiple sclerosis.

We investigated the influence of age at disease onset on timing of the progressive phase in 957 patients with multiple sclerosis (MS). Age at onset powerfully predicts the probability of developing a primary progressive form of the disease. Moreover, age at onset strongly determines the time to conversion to secondary progression for patients presenting with a relapsing form. This suggests that age at onset strongly influences the neurodegenerative component of MS.

Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study.

OBJECTIVE: To assess whether modafinil, a wakefulness-promoting agent, is useful for fatigue in patients with multiple sclerosis (MS). METHODS: Patients with MS with stable disability, and a baseline score of 45 or more on the Modified Fatigue Impact Scale (MFIS), were eligible for the 5-week randomized, double-blind, placebo-controlled, parallel group study. The initial daily dose of modafinil was 200 mg for 1 week. Depending on tolerance, the dose was increased by 100 mg every week up to 400 mg/day and remained unchanged between day 21 and day 35. The primary outcome variable was the change of MFIS score at day 35. RESULTS: A total of 115 patients with MS were enrolled in the study and in the intention to treat analysis. The mean MFIS score at baseline was 63 +/- 9 in the placebo group and 63 +/- 10 in the modafinil group. MFIS scores improved between day 0 and day 35 in both placebo-treated and modafinil-treated groups, but no significant difference was detected between the two groups. There was no major safety concern. CONCLUSIONS: There was no improvement of fatigue in patients with multiple sclerosis treated with modafinil vs placebo according to the Modified Fatigue Impact Scale.

Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival.

Endothelial differentiation gene (Edg) proteins are G-protein-coupled receptors activated by lysophospholipid mediators: sphingosine-1-phosphate (S1P) or lysophosphatidic acid. We show that in the CNS, expression of Edg8/S1P5, a high-affinity S1P receptor, is restricted to oligodendrocytes and expressed throughout development from the immature stages to the mature myelin-forming cell. S1P activation of Edg8/S1P5 on O4-positive pre-oligodendrocytes induced process retraction via a Rho kinase/collapsin response-mediated protein signaling pathway, whereas no retraction was elicited by S1P on these cells derived from Edg8/S1P5-deficient mice. Edg8/S1P5-mediated process retraction was restricted to immature cells and was no longer observed at later developmental stages. In contrast, S1P activation promoted the survival of mature oligodendrocytes but not of pre-oligodendrocytes. The S1P-induced survival of mature oligodendrocytes was mediated through a pertussis toxin-sensitive, Akt-dependent pathway. Our data demonstrate that Edg8/S1P5 activation on oligodendroglial cells modulates two distinct functional pathways mediating either process retraction or cell survival and that these effects depend on the developmental stage of the cell.

Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease.

BACKGROUND: Recently described neuronal intermediate filament inclusion disease (NIFID) shows considerable clinical heterogeneity. OBJECTIVE: To assess the spectrum of the clinical and neuropathological features in 10 NIFID cases. METHODS: Retrospective chart and comprehensive neuropathological review of these NIFID cases was conducted. RESULTS: The mean age at onset was 40.8 (range 23 to 56) years, mean disease duration was 4.5 (range 2.7 to 13) years, and mean age at death was 45.3 (range 28 to 61) years. The most common presenting symptoms were behavioral and personality changes in 7 of 10 cases and, less often, memory loss, cognitive impairment, language deficits, and motor weakness. Extrapyramidal features were present in 8 of 10 patients. Language impairment, perseveration, executive dysfunction, hyperreflexia, and primitive reflexes were frequent signs, whereas a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease (MND), and limb dystonia. Frontotemporal and caudate atrophy were common. Histologic changes were extensive in many cortical areas, deep gray matter, cerebellum, and spinal cord. The hallmark lesions of NIFID were unique neuronal IF inclusions detected most robustly by antibodies to neurofilament triplet proteins and alpha-internexin. CONCLUSION: NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND. Neuronal IF inclusions are the neuropathological signatures of NIFID that distinguish it from all other FTD variants including FTD with MND and FTD tauopathies.

Oligodendroglial expression of Edg-2 receptor: developmental analysis and pharmacological responses to lysophosphatidic acid.

Edg-2 is a member of the G-protein-coupled seven-transmembrane receptor family recently identified in oligodendrocytes. Here we show that both in vitro and in vivo, Edg-2 transcripts are not detected during early stages of oligodendroglial development, but are expressed only in mature oligodendrocytes, shortly before the onset of myelination. Lysophosphatidic acid (LPA) has been reported to be a ligand of Edg-2 receptor in different cell types. However, in oligodendroglial cultures, LPA had no effect on survival, maturation, or cytoskeleton organization. In myelinating oligodendrocyte-neuron cocultures, LPA did not influence myelinogenesis. In addition, LPA failed to induce Ca2+ mobilization and had no effect on forskolin-induced cAMP accumulation. Phosphorylation of the ERK1/ERK2 MAP kinases was the only response elicited by LPA in oligodendrocytes. Therefore, in contrast to other cell types, in which LPA exerts pleiotropic effects, Edg-2-positive postmitotic oligodendrocytes display a restricted responsiveness to LPA.

Outcome of patients with HIV-1-related cognitive impairment on highly active antiretroviral therapy.

OBJECTIVE: To examine the impact of highly active antiretroviral therapy (HAART) on the outcome of HIV-1-related cognitive impairments using a neuropsychological (NP) battery to assess separately the psychomotor, executive function and memory fields. DESIGN: A longitudinal study of HIV-1-infected patients based on serial NP tests in a Paris University Hospital. METHODS: A group of 91 HIV-1-infected patients, of whom 47 were already taking HAART at their first NP examination, were initially categorized as cognitively impaired (n = 53) or non-impaired (n = 38) and underwent one to six serial NP batteries (mean follow-up 12.3+/-8.3 months). Generalized estimating equations (GEE) were used to evaluate performance in a given NP test according to the number of days on HAART. RESULTS: Despite a 25% mortality rate among patients who had cognitive impairment at their first NP examination, GEE showed a positive relationship between the duration of HAART and cognitive performance. Performance in psychomotor tests (e.g. Purdue Pegboard dominant hand) improved continuously during the study period, while memory test performance (e.g. Grober and Buschke free recall) tended to reach a plateau. CONCLUSIONS: HAART improves subcortical cognitive functions during the first year of treatment. Distinct neuropathological mechanisms appear to underlie psychomotor and memory dysfunctions in AIDS.

Clinical and spectroscopic improvement in HIV-associated cognitive impairment.

To assess the impact of highly active antiretroviral therapy (HAART) on AIDS-associated cognitive impairment, 22 patients with AIDS with (n = 11) and without (n = 11) cognitive deficit were evaluated clinically and by MRS every 3 months for 9 months. Nineteen patients were on HAART at study entry, 21 after 2 months. Cognitively impaired patients presented with a subcorticofrontal deficit and decreased N-acetyl-aspartate in frontal white matter. These clinical and metabolic abnormalities reversed partially on HAART, whereas they remained within normal limits in cognitively unimpaired patients.

Differential expression of collapsin response mediator proteins (CRMP/ULIP) in subsets of oligodendrocytes in the postnatal rodent brain.

The family of collapsin response mediator protein/Unc-33-like protein (CRMP/Ulip), composed of four homologous members, is specifically and highly expressed in the nervous system during embryonic neuronal development and dramatically down-regulated in the adult. Members of this family have been proposed to be part of the semaphorins signal transduction pathway involved in axonal outgrowth. Here, we show by in situ hybridization and immunohistochemistry that CRMP2/Ulip2, and to a lesser extent CRMP3/Ulip4, are expressed in immature and mature oligodendrocytes, but not in astrocytes. Transcripts encoding the other CRMP/Ulip members are also detectable by RT-PCR in highly purified mature oligodendrocytes. Interestingly, in the adult, the protein CRMP2/Ulip2 is mainly detectable in subsets of oligodendrocytes distributed according to an increasing rostrocaudal gradient, with the largest number of positive cells being present in the brain stem and spinal cord. In cultures of highly purified oligodendrocytes, however, CRMP2/Ulip2 was detectable in all the cells. Addition of Sema3A in the culture medium completely inhibited the emergence of oligodendrocyte processes suggesting that, as in neurons, a Sema3A signaling pathway mediated via CRMP2/Ulip2 may be involved in the regulation of oligodendroglial process outgrowth.

[Pivotal role of axonal adhesion molecules in central nervous system myelination]. / Rola czasteczek adhezji komórowej w mielinizacji osrodkowego ukladu nerwowego.

Close relationship between neurons and oligodendrocytes seems to be of the greatest importance during oligodendrocyte maturation and myelin formation within central nervous system. Two major factors are likely to play the decisive role in CNS myelination--adhesion molecules and electrical activity. It has been shown, both in vitro and in vivo, that blocking or stimulating electrical activity may inhibit or induce myelination respectively. The fact that even in culture oligodendrocytes myelinate solely axons and not other cellular processes present within CNS as well as the finding that normal myelin sheath compaction is encountered only around axons suggest that close interaction between oligodendrocytes and neurons is required for normal myelin formation. Adhesion molecules are most likely involved in this interaction by not only bringing the axon and the glial cell close to each other but also by transducing signals to initiate myelination. The neural cell adhesion molecule (NCAM) is a candidate molecule that could regulate axon/glial cell interaction. It is abundantly present in all growing fiber tracts of the developing CNS. Since its polysialylated from (PSA-NCAM) has been shown to disappear from axonal surface as myelination progresses and that its removal increases 4 to 5 fold myelination, it is thought to be a negative factor for myelin formation. These observations may have important implications in therapeutic strategies in demyelinating disorders like multiple sclerosis.

Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule.

Many factors have been shown to promote myelination, but few have been shown to be inhibitory. Here, we show that polysialylated-neural cell adhesion molecule (PSA-NCAM) can negatively regulate myelin formation. During development, PSA-NCAM is first expressed on all growing fibers; then, axonal expression is down-regulated and myelin deposition occurs only on PSA-NCAM-negative axons. Similarly, in cocultures of oligodendrocytes and neurons, PSA-NCAM expression on axons is initially high, but decreases as myelination proceeds. Importantly, if expression of PSA-NCAM is prematurely decreased in cultures, by either antibody-mediated internalization or enzymatic removal of the PSA moieties with endoneuraminidase N (endo-N), myelination increases 4- to 5-fold. In the optic nerve, premature cleavage of PSA moieties by intravitreous injection of endo-N also induces a transient increase in the number of myelinated internodes, but does not interfere with the onset of myelination. Previously, we showed that axonal electrical activity strongly induced myelination, which could be prevented by tetrodotoxin (TTX), an action potential blocker. Interestingly, removal of PSA moieties does not reverse the inhibition of myelination by TTX. Together, this suggests that myelination is tightly controlled by both positive (electrical activity) and negative (PSA-NCAM expression) regulatory signals.

Similar subcortical pattern of cognitive impairment in AIDS patients with and without dementia.

The aim of this study was to develop a series of neuropsychological tests that define the cortical and subcortical features of cognitive impairment and the characteristics of memory in demented and mildly cognitively impaired AIDS patients. We attempted to establish a usable method to assess and determine the type and degree of cognitive impairment in individual AIDS patients. We examined 53 patients without central nervous system opportunistic infections. A short battery included two scales of global efficiency (the Mattis dementia rating scale and the Mini Mental State Examination), a psychomotor speed test, an executive control assessment and explicit memory evaluation. Patients were categorized into four groups based on their score on both the Mattis dementia rating scale and the DSM-IV criteria: (1) asymptomatic; (2) having AIDS without cognitive impairment; (3) having AIDS with mild cognitive impairment; and (4) having AIDS dementia. Patients with mildly impaired cognition demonstrated slowed thinking, abnormal initiation and conceptualization, and memory impairment. AIDS dementia patients had slower motor activity and memory recall was more severely affected. The short neuropsychological battery was able to characterize modified cognitive performances in both severely and mildly cognitively impaired AIDS patients. The subcortical pattern of the memory disorder was obvious, regardless of the degree of cognitive impairment.

[Role of axonal signals in myelination of the central nervous system]. / Rôle des signaux axonaux dans la myélinisation du système nerveux central.

The myelination of the axons of the central nervous system (CNS) is assumed by the oligodendrocytes, which depend at least in part on signals of axonal origin. The axonal influence on myelination seems to consist of the sum of positive and negative factors, which can either act on the axon or on the oligodendrocyte, allowing the neuron to decide when and where myelinization is initiated. The induction factors appear to be mediated, in some cases, by electrical activity. Among the negative factors, certain factors such as the adhesion molecule PSA-NCAM seem to act by inhibiting the adhesion between the axon and the oligodendrocytic extension. Others, such as the inhibitory signalling pathway, jagged1/Notch1, appear to trigger an inhibitory oligodendroglial signalling, therapy preventing maturation and myelination. The recent determination of the role of these axonal signals has provided a new approach to the mechanisms of normal myelination. These results could be extrapolated to the process of remyelination in human demyelinating pathologies such as multiple sclerosis, and open up new therapeutic research possibilities aimed at neuronal protection.