Oral D-Aspartate enhances synaptic plasticity reserve in progressive multiple sclerosis.

BACKGROUND: Synaptic plasticity reserve correlates with clinical recovery after a relapse in relapsing-remitting forms of multiple sclerosis (MS) and is significantly compromised in patients with progressive forms of MS. These findings suggest that progression of disability in MS is linked to reduced synaptic plasticity reserve. D-Aspartate, an endogenous aminoacid approved for the use in humans as a dietary supplement, enhances synaptic plasticity in mice. OBJECTIVE: To test whether D-Aspartate oral intake increases synaptic plasticity reserve in progressive MS patients. METHODS: A total of 31 patients affected by a progressive form of MS received either single oral daily doses of D-Aspartate 2660 mg or placebo for 4 weeks. Synaptic plasticity reserve and trans-synaptic cortical excitability were measured through transcranial magnetic stimulation (TMS) protocols before and after D-Aspartate. RESULTS: Both TMS-induced long-term potentiation (LTP), intracortical facilitation (ICF) and short-interval ICF increased after 2 and 4 weeks of D-Aspartate but not after placebo, suggesting an enhancement of synaptic plasticity reserve and increased trans-synaptic glutamatergic transmission. CONCLUSION: Daily oral D-Aspartate 2660 mg for 4 weeks enhances synaptic plasticity reserve in patients with progressive MS, opening the path to further studies assessing its clinical effects on disability progression.

Nerve growth factor is elevated in the CSF of patients with multiple sclerosis and central neuropathic pain.

Central neuropathic pain (CNP) is common and disabling among patients with multiple sclerosis (MS). The pathological mechanisms underlying CNP in MS are not well understood. We explored whether NGF is implicated in the pathogenesis of CNP in MS. We measured NGF concentration in the CSF of 73 patients affected by MS, 15 with and 58 without CNP and 14 controls. We found increased levels of NGF in the CSF of patients with CNP compared to patients without and to controls. This finding supports the hypothesis that NGF plays a role in MS related CNP.

Cerebrospinal fluid lactate is associated with multiple sclerosis disease progression.

BACKGROUND: Altered cerebrospinal fluid (CSF) levels of lactate have been described in neurodegenerative diseases and related to mitochondrial dysfunction and neuronal degeneration. We investigated the relationship between CSF lactate levels, disease severity, and biomarkers associated with neuroaxonal damage in patients with multiple sclerosis (MS). METHODS: One-hundred eighteen subjects with relapsing-remitting multiple sclerosis (RRMS) were included, along with one-hundred fifty seven matched controls. CSF levels of lactate, tau protein, and neurofilament light were detected at the time of diagnosis. Patients were followed-up for a mean of 5 years. Progression index (PI), multiple sclerosis severity scale (MSSS), and Bayesian risk estimate for multiple sclerosis (BREMS) were assessed as clinical measures of disease severity and progression. Differences between groups and correlation between CSF lactate, disease severity and CSF biomarkers of neuronal damage were explored. RESULTS: CSF lactate was higher in RRMS patients compared to controls. A negative correlation was found between lactate levels and disease duration. Patients with higher CSF lactate concentration had significantly higher PI, MSSS, and BREMS scores at long-term follow-up. Furthermore, CSF lactate correlated positively and significantly with CSF levels of both tau protein and neurofilament light protein. CONCLUSIONS: Measurement of CSF lactate may be helpful, in conjunction with other biomarkers of tissue damage, as an early predictor of disease severity in RRMS patients. A better understanding of the alterations of mitochondrial metabolic pathways associated to RRMS severity may pave the way to new therapeutic targets to contrast axonal damage and disease severity.

RANTES correlates with inflammatory activity and synaptic excitability in multiple sclerosis.

BACKGROUND: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. OBJECTIVE: To assess the role of RANTES in the regulation of cortical excitability. METHODS: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. RESULTS: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1ß. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. CONCLUSION: RANTES correlates with inflammation and synaptic excitability in MS brains.

CB1 receptor affects cortical plasticity and response to physiotherapy in multiple sclerosis.

OBJECTIVES: Therapeutic effects of physical therapy in neurologic disorders mostly rely on the promotion of use-dependent synaptic plasticity in damaged neuronal circuits. Genetic differences affecting the efficiency of synaptic plasticity mechanisms could explain why some patients do not respond adequately to the treatment. It is known that physical exercise activates the endocannabinoid system and that stimulation of cannabinoid CB1 receptors (CB1Rs) promotes synaptic plasticity in both rodents and humans. We thus tested whether CB1R genetic variants affect responsiveness to exercise therapy. METHODS: We evaluated the effect of a genetic variant of the CB1R associated with reduced receptor expression (patients with long AAT trinucleotide short tandem repeats in the CNR1 gene) on long-term potentiation (LTP)-like cortical plasticity induced by transcranial magnetic theta burst stimulation (TBS) of the motor cortex and, in parallel, on clinical response to exercise therapy in patients with multiple sclerosis. RESULTS: We found that patients with long AAT CNR1 repeats do not express TBS-induced LTP-like cortical plasticity and show poor clinical benefit after exercise therapy. CONCLUSIONS: Our results provide the first evidence that genetic differences within the CB1R may influence clinical responses to exercise therapy, and they strengthen the hypothesis that CB1Rs are involved in the regulation of synaptic plasticity and in the control of spasticity in humans. This information might be of great relevance for patient stratification and personalized rehabilitation treatment programs.

Growth factors and synaptic plasticity in relapsing-remitting multiple sclerosis.

During multiple sclerosis (MS) inflammatory attacks, and in subsequent clinical recovery phases, immune cells contribute to neuronal and oligodendroglial cell survival and tissue repair by secreting growth factors. Animal studies showed that growth factors also play a substantial role in regulating synaptic plasticity, and namely in long-term potentiation (LTP). LTP could drive clinical recovery in relapsing patients by restoring the excitability of denervated neurons. We recently reported that maintenance of synaptic plasticity reserve is crucial to contrast clinical deterioration in MS and that the platelet-derived growth factor (PDGF) may play a key role in its regulation. We also reported that a Hebbian form of LTP-like cortical plasticity, explored by paired associative stimulation (PAS), correlates with clinical recovery from a relapse in MS. Here, we explored the role of PDGF in clinical recovery and in adaptive neuroplasticity in relapsing-remitting MS (RR-MS) patients. We found a correlation between the cerebrospinal fluid (CSF) PDGF concentrations and the extent of clinical recovery after a relapse, as full recovery was more likely observed in patients with high PDGF concentrations and poor recovery in subjects with low PDGF levels. Consistently with the idea that PDGF-driven synaptic plasticity contributes to attenuate the clinical consequences of tissue damage in RR-MS, we also found a striking correlation between CSF levels of PDGF and the amplitude of LTP-like cortical plasticity explored by PAS. CSF levels of fibroblast growth factor, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor did not correlate with clinical recovery nor with measures of synaptic transmission and plasticity.

Interleukin-1ß promotes long-term potentiation in patients with multiple sclerosis.

The immune system shapes synaptic transmission and plasticity in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS). These synaptic adaptations are believed to drive recovery of function after brain lesions, and also learning and memory deficits and excitotoxic neurodegeneration; whether inflammation influences synaptic plasticity in MS patients is less clear. In a cohort of 59 patients with MS, we found that continuous theta-burst transcranial magnetic stimulation did not induce the expected long-term depression (LTD)-like synaptic phenomenon, but caused persisting enhancement of brain cortical excitability. The amplitude of this long-term potentiation (LTP)-like synaptic phenomenon correlated with the concentration of the pro-inflammatory cytokine interleukin-1ß (IL-1ß) in the cerebrospinal fluid. In MS and EAE, the brain and spinal cord are typically enriched of CD3(+) T lymphocyte infiltrates, which are, along with activated microglia and astroglia, a major cause of inflammation. Here, we found a correlation between the presence of infiltrating T lymphocytes in the hippocampus of EAE mice and synaptic plasticity alterations. We observed that T lymphocytes from EAE, but not from control mice, release IL-1ß and promote LTP appearance over LTD, thereby mimicking the facilitated LTP induction observed in the cortex of MS patients. EAE-specific T lymphocytes were able to suppress GABAergic transmission in an IL-1ß-dependent manner, providing a possible synaptic mechanism able to lower the threshold of LTP induction in MS brains. Moreover, in vivo blockade of IL-1ß signaling resulted in inflammation and synaptopathy recovery in EAE hippocampus. These data provide novel insights into the pathophysiology of MS.

Synaptic plasticity and PDGF signaling defects underlie clinical progression in multiple sclerosis.

Neuroplasticity is essential to prevent clinical worsening despite continuing neuronal loss in several brain diseases, including multiple sclerosis (MS). The precise nature of the adaptation mechanisms taking place in MS brains, ensuring protection from disability appearance and accumulation, is however unknown. Here, we explored the hypothesis that long-term synaptic potentiation (LTP), potentially able to minimize the effects of neuronal loss by providing extra excitation of denervated neurons, is the most relevant form of adaptive plasticity in stable MS patients, and it is disrupted in progressing MS patients. We found that LTP, explored by means of transcranial magnetic theta burst stimulation over the primary motor cortex, was still possible, and even favored, in stable relapsing-remitting (RR-MS) patients, whereas it was absent in individuals with primary progressive MS (PP-MS). We also provided evidence that platelet-derived growth factor (PDGF) plays a substantial role in favoring both LTP and brain reserve in MS patients, as this molecule: (1) was reduced in the CSF of PP-MS patients, (2) enhanced LTP emergence in hippocampal mouse brain slices, (3) was associated with more pronounced LTP in RR-MS patients, and (4) was associated with the clinical compensation of new brain lesion formation in RR-MS. Our results show that brain plasticity reserve, in the form of LTP, is crucial to contrast clinical deterioration in MS. Enhancing PDGF signaling might represent a valuable treatment option to maintain brain reserve and to attenuate the clinical consequences of neuronal damage in the progressive phases of MS and in other neurodegenerative disorders.

Short interval intracortical facilitation correlates with the degree of disability in multiple sclerosis.

BACKGROUND: The Expanded Disability Status Scale (EDSS) is the most widely used measure of disability in MS, however because of its limitations surrogate markers of clinical disability progression are of high interest. Transcranial magnetic stimulation (TMS) measures of demyelination and cortical excitability correlate with disability levels in MS. OBJECTIVE: Aim of this study was testing whether paired pulse (pp) TMS represents a reliable surrogate marker to measure clinical disability in MS. METHODS: ppTMS measures of intracortical synaptic transmission such as short interval intracortical inhibition (SICI), long interval intracortical inhibition (LICI), short interval intracortical facilitation (SICF) and intracortical facilitation (ICF) were collected from 74 patients affected by MS. Correlation of EDSS scores with ppTMS measures was analyzed. RESULTS: EDSS scores correlated with patient's age, disease duration, Motor Evoked Potentials latency and thresholds and SICF measures but not with age of onset, SICI, ICF and LICI. CONCLUSIONS: These findings support a possible use of SICF and MEP latency as surrogate markers of disability in MS. Further research is warranted to determine the role of SICF in the follow up of disease progression and to validate its use as an endpoint in multiple sclerosis clinical trials.

Transcranial direct current stimulation ameliorates tactile sensory deficit in multiple sclerosis.

BACKGROUND: Deficit of tactile sensation in patients with MS is frequent and can be associated with interference with daily life activities. Transcranial direct current stimulation (tDCS) showed to increase tactile discrimination in healthy subjects. OBJECTIVE: In the present study, we investigated whether tDCS may be effective in ameliorating tactile sensory deficit in MS patients. METHODS: Patients received sham or real anodal tDCS of the somatosensory cortex for 5 consecutive days in a randomized, double blind, sham-controlled study. Discrimination thresholds of spatial tactile sensation were measured using the grating orientation task (GOT). As secondary outcomes we also measured subjective perception of tactile sensory deficit through a visual analog scale (VAS), quality of life and overall disability to evaluate the impact of the treatment on patients daily life. Evaluations were performed at baseline and during a 4-week follow-up period. RESULTS: Following anodal but not sham tDCS over the somatosensory cortex, there was a significant improvement of discriminatory thresholds at the GOT and increased VAS for sensation scores. Quality of life, and disability changes were not observed. CONCLUSION: Our results indicate that a five day course of anodal tDCS is able to ameliorate tactile sensory loss with long-lasting beneficial effects and could thus represent a therapeutic tool for the treatment of tactile sensory deficit in MS patients.