Background:
Previous studies evidenced a link between metabolic dysregulation, inflammation, and neurodegeneration in multiple sclerosis (MS).
Objectives:
To explore whether increased adipocyte mass ...expressed as body mass index (BMI) and increased serum lipids influence cerebrospinal fluid (CSF) inflammation and disease severity.
Methods:
In this cross-sectional study, 140 consecutive relapsing-remitting (RR)-MS patients underwent clinical assessment, BMI evaluation, magnetic resonance imaging scan, and blood and CSF collection before any specific drug treatment. The CSF levels of the following cytokines, adipocytokines, and inflammatory factors were measured: interleukin (IL)-6, IL-13, granulocyte macrophage colony-stimulating factor, leptin, ghrelin, osteoprotegerin, osteopontin, plasminogen activator inhibitor-1, resistin, and Annexin A1. Serum levels of triglycerides, total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C) were assessed.
Results:
A positive correlation emerged between BMI and Expanded Disability Status Scale score. Obese RR-MS patients showed higher clinical disability, increased CSF levels of the proinflammatory molecules IL-6 and leptin, and reduced concentrations of the anti-inflammatory cytokine IL-13. Moreover, both the serum levels of triglycerides and TC/HDL-C ratio showed a positive correlation with IL-6 CSF concentrations.
Conclusion:
Obesity and altered lipid profile are associated with exacerbated central inflammation and higher clinical disability in RR-MS at the time of diagnosis. Increased adipocytokines and lipids can mediate the negative impact of high adiposity on RR-MS course.
Theta-burst stimulation (TBS) is a technique that elicits long-lasting changes in the excitability of human primary motor cortex (M1). Tonic contraction of the target muscle modifies the aftereffects ...of TBS, whereas interactions between phasic muscle contraction and the aftereffects of TBS are unknown. In this paper, we investigated whether phasic voluntary movements influence TBS-induced changes in M1 excitability. We examined whether a brief sequence of phasic finger movements performed by healthy humans before both intermittent TBS (iTBS) and continuous TBS (cTBS) influences TBS-induced aftereffects. Ten healthy subjects underwent iTBS and cTBS. To evaluate the TBS-induced aftereffects on M1 excitability, single TMS pulses were given over the FDI motor area before (T0) and 5 (T1), 15 (T2), and 30 min (T3) after TBS. To find out whether finger movements influenced the TBS-induced aftereffects, we tested motor-evoked potentials (MEPs) size by single TMS pulses at T0, immediately after movements, and at T1-T3. We also measured the kinematic variables mean amplitude and mean peak velocity of the movements. When no phasic voluntary movements preceded TBS, iTBS elicited facilitatory and cTBS elicited inhibitory aftereffects on MEP size. Conversely, movements performed before TBS elicited significant changes in the direction of the TBS-induced aftereffects. iTBS produced inhibitory instead of facilitatory aftereffects and cTBS produced facilitatory instead of inhibitory aftereffects. Finger movements alone had no effects on MEPs size tested with single-pulse TMS. Peripheral electrical stimulation had no effect on iTBS-induced aftereffects. Repeated phasic finger movements interfere with TBS-induced aftereffects probably by modulating mechanisms of brain metaplasticity.
Specific proinflammatory and anti-inflammatory molecules could represent useful cerebrospinal fluid (CSF) biomarkers to predict the clinical course of multiple sclerosis (MS). The proinflammatory ...molecule interleukin (IL)-6 has been investigated in the pathophysiology of MS, and has been associated in previous, smaller studies to increased disability and disease activity. CSF IL-6 detectability in MS 2 This is a provisional file, not the final typeset article Here, we wanted to further address IL-6 as a possible CSF biomarker of MS by investigating its detectability in a large cohort of 534 MS patients and in 100 individuals with other non-inflammatory neurological diseases. In these newly diagnosed patients, we also explored correlations between IL-6 detectability, MS phenotypes and disease characteristics.We found that IL-6 was more frequently detectable in the CSF of MS patients compared with their control counterparts, as significant differences emerged between patients with clinically isolated syndrome, relapsing remitting, secondary progressive and primary progressive MS, compared to noninflammatory controls. IL-6 was equally present in the CSF of all MS phenotypes. In MS patients, IL-6 detectability was found to signal clinically and/or radiologically defined disease activity, among all other clinical characteristics.Our results add further evidence that CSF proinflammatory cytokines could be useful for the identification of those MS patients who are prone to increased prospective disease activity. In particular, IL-6 could represent an interesting prognostic biomarker of MS, as also demonstrated in other diseases where CSF IL-6 was found to identify patients with worse disease severity.
Elevated levels of specific proinflammatory molecules in the cerebrospinal fluid (CSF) have been associated with disability progression, enhanced neurodegeneration and higher incidence of mood ...disorders in people with multiple sclerosis (MS). Studies in animal models of MS suggest that preventive exercise may play an immunomodulatory activity, with beneficial effects on both motor deficits and behavioral alterations. Here we explored the impact of lifestyle physical activity on clinical presentation and associated central inflammation in a large group of newly diagnosed patients with MS. Furthermore, we addressed the causal link between exercise-mediated immunomodulation and mood symptoms in the animal setting.
A cross-sectional study was conducted on 235 relapsing-remitting MS patients at the time of the diagnosis. Patients were divided into 3 groups (“sedentary”, “lifestyle physical activity” and “exercise”) according to the level of physical activity in the six months preceding the evaluation. Patients underwent clinical, neuropsychological and psychiatric evaluation, magnetic resonance imaging and lumbar puncture for diagnostic purposes. The CSF levels of proinflammatory and anti-inflammatory cytokines were analyzed and compared with a group of 80 individuals with non-inflammatory and non-degenerative diseases. Behavioral and electrophysiological studies were carried out in control mice receiving intracerebral injection of IL-2 or vehicle. Behavior was also assessed in mice with experimental autoimmune encephalomyelitis (EAE), animal model of MS, reared in standard (sedentary group) or running wheel-equipped (exercise group) cages.
In exercising MS patients, depression and anxiety were reduced compared to sedentary patients. The CSF levels of the interleukin-2 and 6 (IL-2, IL-6) were increased in MS patients compared with control individuals. In MS subjects exercise was associated with normalized CSF levels of IL-2. In EAE mice exercise started before disease onset reduced both behavioral alterations and striatal IL-2 expression. Notably, a causal role of IL-2 in mood disorders was shown. IL-2 administration in control healthy mice induced anxious- and depressive-like behaviors and impaired type-1 cannabinoid (CB1) receptor-mediated neurotransmission at GABAergic synapses, mimicking EAE-induced synaptic dysfunction.
Our results indicate an immunomodulatory effect of exercise in MS patients, associated with reduced CSF expression of IL-2, which might result in reduced mood disorders. These data suggest that exercise in the early stages may act as a disease-modifying therapy in MS although further longitudinal studies are needed to clarify this issue.
Abstract Introduction Recent studies have suggested that the cerebellum may be involved in the pathophysiology of resting tremor in patients with Parkinson's disease (PD). The aim of the study was to ...investigate the effects of cerebellar continuous theta burst stimulation (cTBS) on cerebello-thalamo-cortical connectivity and resting tremor in PD patients. Methods Thirteen PD patients and ten healthy subjects underwent two experimental sessions: (i) ‘real’ cTBS, delivered over the cerebellar hemisphere and (ii) ‘sham’ cerebellar cTBS, delivered over the neck muscles. The two sessions were performed at least one week apart. The effects of ‘real’ and ‘sham’ cerebellar cTBS were quantified as excitability changes in the contralateral primary motor cortex or as possible changes in resting tremor in the ipsilateral hand. Primary motor cortex excitability was assessed by recording the input/output curve of the motor-evoked potentials from the contralateral first dorsal interosseous muscle. Results Resting tremor was rated clinically and objectively assessed by means of kinematic techniques. ‘Real’ cerebellar cTBS, though not ‘sham’ cerebellar cTBS, reduced the excitability in the contralateral primary motor cortex both in healthy subjects and in patients with PD. There was no significant change in rest tremor severity, as assessed by a clinical examination or kinematic techniques, after either ‘real’ or ‘sham’ cerebellar cTBS in patients. Lastly, there was no correlation between individual changes in M1 excitability and clinical or kinematic measures of resting tremor in patients. Conclusion The cerebello-thalamo-cortical connectivity, as tested by cTBS, is not predominantly involved in the generation of resting tremor in PD.
Background:
Individual genetic variability may influence the course of multiple sclerosis (MS). The interleukin (IL)-8C>T rs2227306 single nucleotide polymorphism (SNP) regulates IL-8 activity in ...other clinical conditions; however, its role in MS has never been investigated.
Objectives:
To explore the association between IL-8 SNP rs2227306, cerebrospinal fluid (CSF) IL-8 concentrations, clinical, and radiological characteristics in a group of newly diagnosed MS patients.
Methods:
In 141 relapsing-remitting (RR)-MS patients, rs2227306 polymorphism, CSF levels of IL-8, clinical, and demographical characteristics were determined. In 50 patients, structural magnetic resonance imaging (MRI) measures were also assessed.
Results:
An association between CSF IL-8 and Expanded Disability Status Scale (EDSS) at diagnosis was found in our set of patients (r = 0.207, p = 0.014). CSF IL-8 concentrations were significantly higher in patients carrying the T variant of rs2227306 (p = 0.004). In the same group, a positive correlation emerged between IL-8 and EDSS (r = 0.273, p = 0.019). Finally, a negative correlation between CSF levels of IL-8 and cortical thickness emerged in rs2227306T carriers (r = −0.498, p = 0.005).
Conclusion:
We describe for the first time a role of SNP rs2227306 of IL-8 gene in regulating the expression and the activity of this inflammatory cytokine in MS.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelinating white matter lesions and neurodegeneration, with a variable clinical ...course. Brain network architecture provides efficient information processing and resilience to damage. The peculiar organization characterized by a low number of highly connected nodes (hubs) confers high resistance to random damage. Anti-homeostatic synaptic plasticity, in particular long-term potentiation (LTP), represents one of the main physiological mechanisms underlying clinical recovery after brain damage. Different types of synaptic plasticity, including both anti-homeostatic and homeostatic mechanisms (synaptic scaling), contribute to shape brain networks. In MS, altered synaptic functioning induced by inflammatory mediators may represent a further cause of brain network collapse in addition to demyelination and grey matter atrophy. We propose that impaired LTP expression and pathologically enhanced upscaling may contribute to disrupting brain network topology in MS, weakening resilience to damage and negatively influencing the disease course.
The endocannabinoid system (ECS) has been recently recognized as a prominent promoter of the emotional homeostasis, mediating the effects of different environmental signals including rewarding and ...stressing stimuli. The ECS modulates the rewarding effects of environmental stimuli, influencing synaptic transmission in the dopaminergic projections to the limbic system, and mediates the neurophysiological and behavioral consequences of stress. Notably, the individual psychosocial context is another key element modulating the activity of the ECS. Finally, inflammation represents an additional factor that could alter the cannabinoid signaling in the CNS inducing a "sickness behavior," characterized by anxiety, anhedonia, and depressive symptoms. The complex influences of the ECS on both the environmental and internal stimuli processing, make the cannabinoid-based drugs an appealing option to treat different psychiatric conditions. Although ample experimental evidence shows beneficial effects of ECS modulation on mood, scarce clinical indication limits the use of cannabis-based treatments. To better define the possible clinical indications of cannabinoid-based drugs in psychiatry, a number of issues should be better addressed, including genetic variability and psychosocial factors possibly affecting the individual response. In particular, better knowledge of the multifaceted effects of cannabinoids could help to understand how to boost their therapeutic use in anxiety and depression treatment.
Background:
Synaptic plasticity, the basic mechanism of clinical recovery after brain lesion, can also remarkably influence the clinical course of multiple sclerosis (MS). Physical rehabilitation ...represents the main treatment option to promote synaptic long-term potentiation (LTP) and to enhance spontaneous recovery of neurological deficits.
Objectives:
To overview the role of pharmacological treatment and physical rehabilitation in modulating LTP and enhancing clinical recovery in MS.
Results:
Drug-induced LTP enhancement can be effectively used to promote functional recovery, alone or combined with rehabilitation. Also, as inflammatory cytokines alter synaptic transmission and plasticity in MS, pharmacological resolution of inflammation can positively influence clinical recovery. Finally, physical exercise could be an independent factor able to preserve or enhance LTP reserve both influencing signaling pathways involved in plasticity induction and maintenance, and decreasing inflammation.
Future directions:
Better knowledge of LTP determinants may be useful to design specific strategies to promote recovery after a relapse and to reduce the progressive neurological deterioration in MS patients.
In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively influencing the disease course. In the present study, we aimed to explore the influence of the ...proinflammatory cytokine IL-1β on peculiar features of associative Hebbian synaptic plasticity, such as input specificity, using the paired associative stimulation (PAS). In 33 relapsing remitting-MS patients and 15 healthy controls, PAS was performed on the abductor pollicis brevis (APB) muscle. The effects over the motor hot spot of the APB and abductor digiti minimi (ADM) muscles were tested immediately after PAS and 15 and 30 min later. Intracortical excitability was tested with paired-pulse transcranial magnetic stimulation (TMS). The cerebrospinal fluid (CSF) levels of IL-1β were calculated. In MS patients, PAS failed to induce long-term potentiation (LTP)-like effects in the APB muscle and elicited a paradoxical motor-evoked potential (MEP) increase in the ADM. IL-1β levels were negatively correlated with the LTP-like response in the APB muscle. Moreover, IL-1β levels were associated with synaptic hyperexcitability tested with paired-pulse TMS. Synaptic hyperexcitability caused by IL-1β may critically contribute to alter Hebbian plasticity in MS, inducing a loss of topographic specificity.
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