[Show abstract][Hide abstract] ABSTRACT: Background:
Depression is common in patients with multiple sclerosis (MS), although the brain mechanisms of this psychiatric condition in MS are poorly understood. Specifically, it remains to be determined whether depression in MS is related to altered activity and functional connectivity patterns within limbic circuits.
Seventy-seven MS patients with variable levels of depression (as assessed via the Beck Depression Inventory) underwent functional magnetic resonance imaging while performing an emotional processing task. To conduct the functional connectivity analyses, the bilateral amygdala and hippocampus, two areas critically involved in the pathophysiology of depression, were chosen as 'seed' regions. Multiple regression models were used to assess how depression in MS patients was correlated with the activity and functional connectivity patterns within the limbic system.
Depression scores in MS patients were negatively correlated: (1) with the activity in the subgenual cingulate cortex; (2) with the functional connectivity between the hippocampus and orbitofrontal cortex as well as the dorsolateral prefrontal cortex, and (3) with the functional connectivity between the amygdala and dorsolateral prefrontal cortex.
Our study showed that individual differences in depression in MS patients were significantly associated with altered regional activity and functional connectivity patterns within the limbic system.
Full-text · Article · Oct 2015 · Multiple Sclerosis
[Show abstract][Hide abstract] ABSTRACT: Magnetic Resonance Imaging (MRI) techniques provided evidences into the understanding of cognitive impairment (CIm) in Multiple Sclerosis (MS).
To investigate the role of white matter (WM) and gray matter (GM) in predicting long-term CIm in a cohort of MS patients.
303 out of 597 patients participating in a previous multicenter clinical-MRI study were enrolled (49.4% were lost at follow-up). The following MRI parameters, expressed as fraction (f) of intracranial volume, were evaluated: cerebrospinal fluid (CSF-f), WM-f, GM-f and abnormal WM (AWM-f), a measure of lesion load. Nine years later, cognitive status was assessed in 241 patients using the Symbol Digit Modalities Test (SDMT), the Semantically Related Word List Test (SRWL), the Modified Card Sorting Test (MCST), and the Paced Auditory Serial Addition Test (PASAT). In particular, being SRWL a memory test, both immediate recall and delayed recall were evaluated. MCST scoring was calculated based on the number of categories, number of perseverative and non-perseverative errors.
AWM-f was predictive of an impaired performance 9 years ahead in SDMT (OR 1.49, CI 1.12-1.97 p = 0.006), PASAT (OR 1.43, CI 1.14-1.80 p = 0.002), SRWL-immediate recall (OR 1.72 CI 1.35-2.20 p<0.001), SRWL-delayed recall (OR 1.61 CI 1.28-2.03 p<0.001), MCST-category (OR 1.52, CI 1.2-1.9 p<0.001), MCST-perseverative error(OR 1.51 CI 1.2-1.9 p = 0.001), MCST-non perseverative error (OR 1.26 CI 1.02-1.55 p = 0.032).
In our large MS cohort, focal WM damage appeared to be the most relevant predictor of the long-term cognitive outcome.
[Show abstract][Hide abstract] ABSTRACT: Multiple Sclerosis (MS) is a heterogeneous disease and all the approved treatments are only partially active and a variable percentage of patients are non-responders. Early detection of non-responders allows change of treatment, offers more useful therapy to the patient and allocates better a large amount of financial resources. Non-responsive patients can be divided into two subgroups: non-responders because of their pathogenesis and immuno-pharmacological non-responders. Quantification of Neutralizing antibodies (Nabs) and of biological activity of IFN-β are recognized approaches to identify immuno-pharmacological non-responders. A consistent number of studies have demonstrated that quantification of Myxovirus- induced protein A (MxA) is a valid biomarker to detect immune-pharmacological non responders after one year of treatment. Persistent high titer of Nabs and absence of biological activity predict abolition of IFN-β effects in disease activity measured through MRI, number of relapses and disability. Guidelines and flow-charts including both Nabs and MxA quantification are presented.
No preview · Article · Dec 2014 · Cytokine & Growth Factor Reviews
[Show abstract][Hide abstract] ABSTRACT: Introduction Major Depression (MD) is a common psychiatric dis-order in patients with multiple sclerosis (MS), the most frequent neurological disease in young people. 1 Approximately 50–60% of MS patients may display recurrent episodes of MD that have a negative impact on their quality of life and may lead to devastating outcomes, as death by suicide. 1 In clinical settings, MD in MS tends to be overlooked and attrib-uted to the overall neurological disability, rather than to specific brain changes; however, evidence is accumulating that MD in MS has a distinct neurobio-logical basis and does not only reflect a maladaptive psychological response to a chronic disease such as MS. Three different lines of research support this view. First, clinical studies showed that MD in MS is not necessarily associated with disease duration and severity, but might also manifest itself at early stages of the disease. 2 Second, MS-related immunological markers (e.g. T-cell activation) may not only be cor-related with motor or cognitive symptoms, but also with mood disturbances as MD. 3 Third, neuro-imaging studies revealed specific brain alterations in MS patients with MD, relative to non-depressed MS patients. Specifically, increased lesion load and reduced fractional anisotropy (FA), two measures of white-matter damage, were reported in the frontal and temporal lobes of MS patients with MD, relative to non-depressed MS patients. 4,5 Furthermore, our past functional magnetic resonance imaging Structural 'connectomic' alterations in the limbic system of multiple sclerosis patients with major depression
Full-text · Article · Dec 2014 · Multiple Sclerosis
[Show abstract][Hide abstract] ABSTRACT: Significant corpus callosum (CC) involvement has been found in relapsing–remitting multiple sclerosis (RRMS), even if conventional magnetic resonance imaging measures have shown poor correlation with clinical disability measures. In this work, we tested the potential of multimodal imaging of the entire CC to explain physical and cognitive disability in 47 patients with RRMS. Values of thickness, fractional anisotropy (FA) and mean diffusivity (MD) were extracted from 50 regions of interest (ROIs) sampled along the bundle. The relationships between clinical, neuropsychological and imaging variables were assessed by using Spearman's correlation. Multiple linear regression analysis was employed in order to identify the relative importance of imaging metrics in modeling different clinical variables. Regional fiber composition of the CC differentially explained the response variables (Expanded Disability Status Scale [EDSS], cognitive impairment). Increases in EDSS were explained by reductions in CC thickness and MD. Cognitive impairment was mainly explained by FA reductions in the genu and splenium. Regional CC imaging properties differentially explained disability within RRMS patients revealing strong, distinct patterns of correlation with clinical and cognitive status of patients affected by this specific clinical phenotype.
Full-text · Article · Nov 2014 · Clinical neuroimaging
[Show abstract][Hide abstract] ABSTRACT: We compared pre-amplification (PA) RT-PCR blood CD19 mRNA quantification with Flow Cytometry (FC), to personalize Rituximab re-treatment in Neuromyelitis Optica Spectrum Disorders (NMOSD) patients. 47 blood samples from 3NMOSD patients were studied. PA-RT-PCR quantified CD19 in all samples, and a positivity threshold was defined, whereas CD19 + B cells were under threshold in 31/47 samples by FC. In all samples where CD19 + B cells were above FC threshold, they resulted above the PA-RT-PCR threshold. CD19 mRNA was above threshold in 8 other samples, resulted negative by FC, and preceded the FC positivity in 7/8 samples by 1–3 months, showing major sensitivity.
No preview · Article · Sep 2014 · Journal of Neuroimmunology
[Show abstract][Hide abstract] ABSTRACT: In this study, we used an automated segmentation of regions of interest and co-registration to diffusion tensor imaging (DTI) images to investigate whether microstructural abnormalities occur in gray structures of the frontal-subcortical circuits in patients with amyotrophic lateral sclerosis (ALS). Twenty-four patients with probable or definite sporadic ALS and 22 healthy controls were enrolled in the study. Thirteen out of 24 ALS patients and all of the control subjects underwent a detailed neuropsychological evaluation. DTI was performed to measure mean diffusivity (MD) and fractional anisotropy in the frontal cortex, caudate, putamen, globus pallidus, thalamus, amygdala and hippocampus. MD values of ALS patients were significantly higher in the frontal cortex (P = 0.023), caudate (P = 0.01), thalamus (P = 0.019), amygdala (P = 0.012) and hippocampus (P = 0.002) compared to controls. MD of these structures significantly correlated to a variable degree with neurological disability and neuropsychological dysfunctions. The increased MD values in several cortical and subcortical gray structures and their correlations with neuropsychological variables substantiate a multisystemic degeneration in ALS and suggest that dysfunctions of frontal-subcortical circuits could play a pivotal role in frontal impairment and behavioral symptoms in ALS patients.
Full-text · Article · Jan 2014 · Neurological Sciences
[Show abstract][Hide abstract] ABSTRACT: Diffusion tensor imaging (DTI) is one of the most sensitive MRI tools for detecting subtle cerebral white matter abnormalities in amyotrophic lateral sclerosis (ALS). Nowadays a plethora of DTI tools have been proposed, but very few methods have been translated into clinical practice. New Method: The aim of this study is to validate the objective measurement of fiber tracts as provided by a new unbiased and automated tractography reconstruction tool named as TRActs Constrained by UnderLying Anatomy (TRACULA). The reliability of this tract-based approach was evaluated on a dataset of 14 patients with definite ALS compared with 14 age/sex-matched healthy controls. To further corroborate these measurements, we used a well-known voxelwise approach, called tract-based spatial statistics (TBSS), on the same dataset.
TRACULA showed specific significant alterations of several DTI parameters in the corticospinal tract of the ALS group with respect to controls. Comparison with Existing Method: The same finding was detected using the well-known TBSS analysis. Similarly, both methods depicted also additional microstructural changes in the cingulum.
DTI tractography metrics provided by TRACULA perfectly agree with those previously reported in several post-mortem and DTI studies, thus demonstrating the accuracy of this method in characterizing the microstructural changes occurring in ALS. With further validation (i.e. considering the heterogeneity of other clinical phenotypes), this method has the potential to become useful for clinical practice providing objective measurements that might aid radiologists in the interpretation of MR images and improve diagnostic accuracy of ALS.
Full-text · Article · Jan 2014 · Journal of Neuroscience Methods
[Show abstract][Hide abstract] ABSTRACT: β-Interferon therapy is known to be a potential trigger of suicidal behavior, but this effect has not been previously reported for other multiple sclerosis (MS) treatments, such as, natalizumab. Here we report the case history of a 32-year-old woman affected by relapsing-remitting MS, who attempted suicide during natalizumab treatment. This case suggests that a suicidal ideation might be a rare side effect of natalizumab. Nevertheless, this case represents the first evidence of the new adverse drug reaction related to natalizumab treatment. We should alert clinicians to be aware of the possibility of paradoxical activation of suicidality during its therapeutic use. The main purpose of the present article is to use this case to review the possible relationship between suicidal behavior and drugs.
Full-text · Article · Dec 2013 · Journal of Pharmacology and Pharmacotherapeutics
[Show abstract][Hide abstract] ABSTRACT: The objective of this paper is to identify clinical or magnetic resonance imaging (MRI) predictors of long-term clinical progression in a large cohort of multiple sclerosis (MS) patients.
A total of 241 relapsing-remitting (RR) MS patients were included in a nine-year follow-up (FU) study. The reference MRIs were acquired at baseline (BL) as part of a multicenter, cross-sectional, clinical-MRI study. Volumetric MRI metrics were measured by a fully automated, operator-independent, multi-parametric segmentation method. Clinical progression was evaluated as defined by: conversion from RR to secondary progressive (SP) disease course; progression of Expanded Disability Status Scale (EDSS); achievement and time to reach EDSS 4.
We concluded that conversion from RR to SP (OR 0.79; CI 0.7-0.9), progression of EDSS (OR 0.85; CI 0.77-0.93), achievement of EDSS 4 (OR 0.8; CI 0.7-0.9), and time to reach EDSS 4 (HR 0.88; CI 0.82-0.94) were all predicted by BL gray matter (GM) volume and, except for progression of EDSS, by BL EDSS (respectively: (OR 2.88; CI 1.9-4.36), (OR 2.7; CI 1.7-4.2), (HR 3.86; CI 1.94-7.70)).
BL GM volume and EDSS are the best long-term predictors of disease progression in RRMS patients with a relatively long and mild disease.
[Show abstract][Hide abstract] ABSTRACT: Episodic memory deficits are frequent symptoms in Multiple Sclerosis and have been associated with dysfunctions of the hippocampus, a key region for learning. However, it is unclear whether genetic factors that influence neural plasticity modulate episodic memory in MS. We thus studied how the Brain Derived Neurotrophic Factor Val(66)Met genotype, a common polymorphism influencing the hippocampal function in healthy controls, impacted on brain networks underlying episodic memory in patients with Multiple Sclerosis. Functional magnetic resonance imaging was used to assess how the Brain Derived Neurotrophic Factor Val(66)Met polymorphism modulated brain regional activity and functional connectivity in 26 cognitively unimpaired Multiple Sclerosis patients and 25 age- and education-matched healthy controls while performing an episodic memory task that included encoding and retrieving visual scenes. We found a highly significant group by genotype interaction in the left posterior hippocampus, bilateral parahippocampus, and left posterior cingulate cortex. In particular, Multiple Sclerosis patients homozygous for the Val(66) allele, relative to Met(66) carriers, showed greater brain responses during both encoding and retrieval while the opposite was true for healthy controls. Furthermore, a robust group by genotype by task interaction was detected for the functional connectivity between the left posterior hippocampus and the ipsilateral posterior cingulate cortex. Here, greater hippocampus-posterior cingulate cortex connectivity was observed in Multiple Sclerosis Met(66) carriers relative to Val(66) homozygous during retrieval (but not encoding) while, again, the reverse was true for healthy controls. The Val(66)Met polymorphism has opposite effects on hippocampal circuitry underlying episodic memory in Multiple Sclerosis patients and healthy controls. Enhancing the knowledge of how genetic factors influence cognitive functions may improve the clinical management of memory deficits in patients with Multiple Sclerosis.
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) is a demyelinating disease affecting the central nervous system, frequently associated with cognitive impairments. Damages of the cerebellum are very common features of patients with MS, although the impact of this clinical factor is generally neglected. Recent evidence from our group demonstrated that MS patients with cerebellar damages are characterized by selective cognitive dysfunctions related to attention and language abilities. Here, we aimed at investigating the presence of neuroanatomical abnormalities in relapsing-remitting MS patients with (RR-MSc) and without (RR-MSnc) cerebellar signs. Twelve RR-MSc patients, 14 demographically, clinically, and radiologically, matched RR-MSnc patients and 20 controls were investigated. All patients underwent neuropsychological assessment. After refilling of FLAIR lesions on the 3D T1-weighted images, VBM was performed using SPM8 and DARTEL. A correlation analysis was performed between VBM results and neuropsychological variables characterizing RR-MSc patients. Despite a similar clinical status, RR-MSc patients were characterized by more severe cognitive damages in attention and language domains with respect to RR-MSnc and controls. With respect to controls, RR-MSnc patients were characterized by a specific atrophy of the bilateral thalami that became more widespread (including motor cortex) in the RR-MSc group (FWE < 0.05). However, consistent with their well-defined neuropsychological deficits, RR-MSc group showed atrophies in the prefrontal and temporal cortical areas when directly compared with RR-MSnc group. Our results demonstrated that RR-MS patients having cerebellar signs were characterized by a distinct neuroanatomical profile, mainly involving cortical regions underpinning executive functions and verbal fluency.
Full-text · Article · Dec 2012 · Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: Objective:
Recent evidence suggests that intermediate-length polyglutamine (PolyQ) expansions in the ataxin-2 (ATXN-2) gene are a risk factor for amyotrophic lateral sclerosis (ALS). This work was undertaken with the aim to investigate the frequency of ataxin-1 (ATXN-1) and ATXN-2 PolyQ expansions in a cohort of patients with sporadic ALS (sALS) and patients with familial ALS (fALS) from southern Italy.
We assessed the PolyQ lengths of ATXN-1 and ATXN-2 in 405 patients with sALS, 13 patients with fALS, and 296 unrelated controls without history of neurodegenerative disorders.
We found significantly higher intermediate PolyQ expansions ≥ 32 for ATXN-1 alleles and ≥ 28 for ATXN-2 alleles in the sALS cohort (ATXN-1: ALS, 7.07% vs controls, 2.38%; p = 0.0001; ATXN-2: ALS, 2.72% vs controls, 0.5%; p = 0.001). ATXN-1 CAT and ATXN-2 CAA interruptions were detected in patients with ALS only. Age at onset, site of onset, and sex were not significantly related to the ATXN-1 or ATXN-2 PolyQ repeat length expansions.
Both ATXN-1 and ATXN-2 PolyQ intermediate expansions are independently associated with an increased risk for ALS.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: . Although a growing body of evidence has highlighted the role of cognitive rehabilitation (CR) in the management of cognitive dysfunctions in multiple sclerosis (MS), there is still no evidence for a validated therapeutic approach. OBJECTIVE: . We propose a new therapeutic strategy characterized by a computer-based intensive attention training program in MS patients with predominant attention deficits. We aim to investigate the effectiveness of our rehabilitation procedure, tailored for those with impaired abilities, using functional magnetic resonance imaging (fMRI). METHODS: . Using a double-blind randomized controlled study, we enrolled 12 MS patients, who underwent a CR program (experimental group), and 11 age-gender-matched MS patients, who underwent a placebo intervention (control group). fMRI was recorded during the execution of a cognitive task broadly used for assessing attention abilities in MS patients (paced visual serial addition test). RESULTS: . Significant effects were detected both at a phenotypic and at an intermediate phenotypic level. After CR, the experimental group, in comparison with the control group, showed a specific enhanced performance in attention abilities as assessed by the Stroop task with an effect size of 0.88, which was associated with increased activity in the posterior cerebellar lobule and in the superior parietal lobule. CONCLUSIONS: . Our study demonstrates that intensive CR tailored for those with impaired abilities affects neural plasticity and improves some aspects of cognitive deficits in MS patients. The reported neurophysiological and behavioral effects corroborate the benefits of our therapeutic approach, which might have a reliable application in the clinical management of cognitive deficits in MS.
Full-text · Article · Nov 2012 · Neurorehabilitation and neural repair
[Show abstract][Hide abstract] ABSTRACT: An increased R2 recovery component of the blink reflex (R2-BRrc) has been commonly observed in Parkinson disease, cranio-cervical dystonia, and dystonic tremor, while the BRrc was reported normal in patients with essential tremor (ET). We studied BRrc in patients with ET associated with resting tremor (rET) in comparison with patients with ET.
This was a cross-sectional study investigating R2-BRrc at interstimulus intervals (ISI) of 100, 150, 200, 300, 400, 500, and 750 msec in 14 patients with rET, 14 patients with ET, and 16 healthy controls. To compare individual patients, we calculated an R2 recovery index in each subject as the mean of R2 area ratio values at ISIs of 150, 200, 300, 400, and 500 msec. All patients and controls underwent DAT-SPECT.
Patients with rET differed from those with ET for the presence of resting tremor associated in several cases (36%) with a subtle arm dystonia. DAT-SPECT was normal in all patients and controls. All patients with rET (with and without dystonia) had an increased R2-BRrc while all patients with ET had a normal BRrc comparable to that of control subjects. The R2 recovery index was abnormal in all patients with rET but in none of the patients with ET.
Patients with rET showed increased R2-BRrc, suggesting that this form of tremor may be a dystonic tremor rather than a subtype of ET. BRrc helps to correctly diagnose DAT-negative patients with resting tremor also in the absence of overt dystonic posturing.
[Show abstract][Hide abstract] ABSTRACT: Consistent findings have shown that the cerebellum is critically implicated in a broad range of cognitive processes including executive functions. Of note, cerebellar symptoms and a number of cognitive deficits have been widely reported in patients with multiple sclerosis (MS). This study investigated for the first time the role of cerebellar symptoms in modulating the neural networks associated with a cognitive task broadly used in MS patients (Paced Visual Serial Addition Test (PVSAT)). Twelve relapsing-remitting (RR) MS patients with prevalent cerebellar signs and symptoms (RR-MSc), 15 RR-MS patients without cerebellar manifestation (RR-MSnc) and 16 matched-healthy controls were examined during functional magnetic resonance imaging (fMRI). We tested whether the RR-MSc patients displayed abnormal activations within "cognitive" cerebellar regions and other areas typically engaged in working memory and tightly connected with the cerebellum. Despite similar behavioral performances during fMRI, RR-MSc patients displayed, relatively to both RR-MSnc patients and controls, significantly greater responses in the left cerebellar Crus I/Lobule VI. RR-MSc patients also displayed reduced functional connectivity between the left cerebellar Crus I and the right superior parietal lobule (FWE<.05). These results demonstrated that the presence of the cerebellar signs drastically impacts on the neurofunctional networks underlying working memory in MS. The altered communication between the cerebellum and a cortical area implicated in short-term buffering and storage of relevant information, offer new insights into the pathophysiological mechanisms of cognition in MS.
Full-text · Article · Aug 2012 · Experimental Neurology
[Show abstract][Hide abstract] ABSTRACT: Neuromyelitis optica (NMO) is a severely disabling autoimmune disorder of the central nervous system, which predominantly affects the optic nerves and spinal cord. In a majority of cases, NMO is associated with antibodies to aquaporin-4 (AQP4) (termed NMO-IgG).
In this study, we evaluated a new multiparametric indirect immunofluorescence (IIF) assay for NMO serology.
Sera from 20 patients with NMO, 41 patients with multiple sclerosis (MS), 30 healthy subjects, and a commercial anti-AQP4 IgG antibody were tested in a commercial composite immunofluorescence assay ("Neurology Mosaic 17"; Euroimmun, Germany), consisting of five different diagnostic substrates (HEK cells transfected with AQP4, non-transfected HEK cells, primate cerebellum, cerebrum, and optic nerve tissue sections).
We identified AQP4 specific and non-specific fluorescence staining patterns and established positivity criteria. Based on these criteria, this kit yielded a high sensitivity (95%) and specificity (100%) for NMO and had a significant positive and negative likelihood ratio (LR+ = ∞, LR- = 0.05). Moreover, a 100% inter- and intra-laboratory reproducibility was found.
The biochip mosaic assay tested in this study is a powerful tool for NMO serology, fast to perform, highly sensitive and specific for NMO, reproducible, and suitable for inter-laboratory standardization as required for multi-centre clinical trials.
[Show abstract][Hide abstract] ABSTRACT: Glatiramer acetate (GA) in multiple sclerosis acts through the induction of GA-specific T-helper 2 cells. Nevertheless, the phenomenon is not universal in patients, explaining individual differences in clinical response.
The objective of this article was to categorize GA-treated patients.
An enhanced quantitative PCR assay was used for measuring ex-vivo GA-induced IFNγ and IL4 mRNA responses in mononuclear cells from 23 healthy donors, 27 untreated patients, 33 short-term (≤6 months) and 77 long-term (>6 months) GA-treated patients. Thresholds for IFNγ and IL4 transcriptional response were calculated by ROC analysis and long-term treated patients were compared in terms of prognostic stratification.
Thresholds for IFNγ and IL4 transcriptional response were calculated at 5.36 and 1.41 relative expression (RE). Finally, 67% of long-term treated patients scored above both response thresholds. These patients had a higher proportion of relapse-free subjects (74% vs 40% when compare to patients who scored below both thresholds) and a significantly better relapse-free survival rate (p=0.006; CI 0.29-0.75). The negative predictive value to predict adverse clinical outcome was 79% (CI 0.63-0.90), meaning that by a positive response, there is a 79% chance that the patient will not experience a negative outcome at 3 years.
Our enhanced quantitative PCR assay produced clinically significant results for GA-treated patients. As such, if patients have a positive response, it means they have less chance of a relapse, while patients with a negative response have a greater probability of a worse outcome.
No preview · Article · May 2012 · Multiple Sclerosis