Functional connectivity changes within specific networks parallel the clinical evolution of multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), the location of focal lesions does not always correlate with clinical symptoms, suggesting disconnection as a major pathophysiological mechanism. Resting-state (RS) functional magnetic resonance imaging (fMRI) is believed to reflect brain functional connectivity (FC) within specific neuronal networks. OBJECTIVE: RS-fMRI was used to investigate changes in FC within two critical networks for the understanding of MS disabilities, namely, the sensory-motor network (SMN) and the default-mode network (DMN), respectively, implicated in sensory-motor and cognitive functions. METHODS: Thirty-four relapsing-remitting (RR), 14 secondary progressive (SP) MS patients and 25 healthy controls underwent MRI at 3T, including conventional images, T1-weighted volumes, and RS-fMRI sequences. Independent component analysis (ICA) was employed to extract maps of the relevant RS networks for every participant. Group analyses were performed to assess changes in FC within the SMN and DMN in the two MS phenotypes. RESULTS: Increased FC was found in both networks of MS patients. Interestingly, specific changes in either direction were observed also between RR and SP MS groups. CONCLUSIONS: FC changes seem to parallel patients' clinical state and capability of compensating for the severity of clinical/cognitive disabilities.

Anatomical brain connectivity can assess cognitive dysfunction in multiple sclerosis.

BACKGROUND: Brain disconnection plays a major role in determining cognitive disabilities in multiple sclerosis (MS). We recently developed a novel diffusion-weighted magnetic resonance imaging (DW-MRI) tractography approach, namely anatomical connectivitity mapping (ACM), that quantifies structural brain connectivity. OBJECTIVE: Use of ACM to assess structural connectivity modifications in MS brains and ascertain their relationship with the patients' Paced-Auditory-Serial-Addition-Test (PASAT) scores. METHODS: Relapsing-remitting MS (RRMS) patients (n = 25) and controls (n = 25) underwent MRI at 3T, including conventional images, T1-weighted volumes and DW-MRI. Volumetric scans were coregistered to fractional anisotropy (FA) images, to obtain parenchymal FA maps for both white and grey matter. We initiated probabilistic tractography from all parenchymal voxels, obtaining ACM maps by counting the number of streamlines passing through each voxel, then normalizing by the total number of streamlines initiated. The ACM maps were transformed into standard space, for statistical use. RESULTS: RRMS patients had reduced grey matter volume and FA, consistent with previous literature. Also, we showed reduced ACM in the thalamus and in the head of the caudate nucleus, bilaterally. In our RRMS patients, ACM was associated with PASAT scores in the corpus callosum, right hippocampus and cerebellum. CONCLUSIONS: ACM opens a new perspective, clarifying the contribution of anatomical brain disconnection to clinical disabilities in MS.

Infratentorial lesion volume correlates with sensory functional system in multiple sclerosis patients: a 3.0-Tesla MRI study.

PURPOSE: This study sought to correlate lesion volume in infratentorial areas using 3.0-T proton-density (PD)-weighted images with disability scales and appropriate functional system scores in patients with multiple sclerosis (MS). MATERIALS AND METHODS: We examined 20 consecutive patients (13 women and 7 men) with a median age of 47 years (range 26-70). Neurological examination included the Expanded Disability Status Scale and its functional systems, the Barthel Index (BI) and the Rivermead Mobility Index (RMI). MRI scans were performed on a system operating at 3.0 T using a quadrature birdcage head coil. Acquired images imported as Digital Imaging and Communication in Medicine (DICOM) files, and the region of interest (ROI) files were converted to Neuroimaging Informatics Technology Initiative (NIfTI) format and normalised to the Montreal Neurological Institute (MNI) standard template. An automated segmentation algorithm was used to distinguish between supratentorial and infratentorial areas. Normalisation to the magnetisation-prepared rapid acquisition with gradient echo (MPRAGE) T1-weighted sequence allowed lesion volume estimation in the different anatomical areas. RESULTS: A significant correlation was found between infratentorial lesion volume and the sensory functional system score (rho=0.76, p=0.002). No significant correlation was found between supratentorial lesion volume and Expanded Disability Status Scale (EDSS), RMI and BI scores. CONCLUSIONS: The described method, by means of anatomical assignment of MS lesions, allows detection of significant correlation coefficients between clinical and MRI lesion burden in MS patients at the infratentorial level.

Investigation of quantitative magnetisation transfer parameters of lesions and normal appearing white matter in multiple sclerosis.

The aim of this study was to use quantitative magnetisation transfer (MT) imaging to assess the different pathological substrates of tissue damage in multiple sclerosis (MS) and examine whether the MT parameters may be used to explain the disability in relapsing remitting (RR) MS. Thirteen patients with RRMS and 14 healthy controls were prescribed conventional MRI and quantitative MT imaging at 3.0 T. A two-pool model of MT (where A refers to the free pool and B to the macromolecular pool) was fitted to the data yielding a longitudinal relaxation rate R(A), a relative size F of macromolecular pool, transverse relaxation times T(2) (A) and T(2) (B) for the two pools and a forward exchange rate RM(0) (B). The MT ratio (MTR) was also computed. The mean MT parameters of the normal appearing white matter (NAWM) and of lesions in patients, and of white matter in controls were estimated. MT parameters were significantly different between lesions and NAWM in patients, and between the NAWM and the white matter of controls (with the exception of T(2) (B) and the MTR). Two models were investigated using ordered logistic regression, with the expanded disability status scale (EDSS) as the dependent variable. In the first one, mean NAWM MT parameters and lesion load were entered as explanatory variables; in the second one, mean MT variables within lesions and lesion load were entered as explanatory variables. Unexpectedly, T(2) (B) was the parameter most significantly associated with EDSS in NAWM. This parameter might represent a weighted average of the relaxation times of spins with different molecular environments, and therefore its variation could indicate a change in the balance between subpopulations of macromolecular spins. Conversely, in lesions, RM(0) (B), T(2) (B), F, R(A), and lesion load significantly predicted disability only when combined together. This might reflect the complex interaction between demyelination, remyelination, gliosis, inflammation and axonal loss taking place within lesions.

An exploration of anger phenomenology in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients are often emotionally disturbed. We investigated anger in these patients in relation to demographic, clinical, and mood characteristics. PATIENTS AND METHODS: About 195 cognitively unimpaired MS patients (150 relapsing-remitting and 45 progressive) were evaluated with the State Trait Anger Expression Inventory, the Chicago Multiscale Depression Inventory, and the State Trait Anxiety Inventory. The patients' anger score distribution was compared with that of the normal Italian population. Correlation coefficients among scale scores were calculated and mean anger scores were compared across different groups of patients by analysis of variance. RESULTS: Of the five different aspects of anger, levels of withheld and controlled Anger were respectively higher and lower than what is expected in the normal population. Although anger was correlated with anxiety and depression, it was largely independent from these mood conditions. Mean anger severity scores were not strongly influenced by individual demographic characteristics and were not higher in more severe patients. CONCLUSIONS: The presence of an altered pattern of anger, unrelated to the clinical severity of MS, suggests that anger is not an emotional reaction to disease stress. An alteration of anger mechanisms might be a direct consequence of the demyelination of the connections among the amygdale, the basal ganglia and the medial prefrontal cortex.

An Italian experience in the ICF implementation in rehabilitation: preliminary theoretical and practical considerations.

PURPOSE: The International Classification of Functioning, Disability and Health (ICF) in its complete form cannot be adopted in clinical rehabilitative practice due to its complexity and size. Ongoing international research is aimed at validating and verifying the reliability of simplified instruments derived from the ICF (ICF Core Sets). An Italian multicentre study was recently conducted with these aims. The purpose of this article is to present some qualitative considerations on ICF Core Sets implementation. METHOD: A brief schedule purposely built to assess the difficulties encountered by the health professionals who administered the ICF Core Sets were sent them via e-mail. Due to the small size of the sample, a qualitative analysis was performed. RESULT: The main difficulties which emerged were: (i) To clearly translate the ICF categories' contents in a language easily understandable especially by patients with low education and concrete cognitive style, (ii) the process of assigning the qualifier to the given category, particularly with the 'Activity and Participation' and 'Environmental factors' components, and (iii) the influence of evaluators' different professional backgrounds on interview performance. CONCLUSION: Since the classification was designed to uniform language and to promote homogeneous ways of evaluation in extremely different healthcare and social contexts, more studies are necessary to improve reliability and to identify the best methods of using the ICF in daily clinical practice.

The effects of left- versus right-hemisphere lesions on the sensitivity to intra- and interconceptual semantic relationships.

Studies on split-brain, normal and brain-damaged subjects suggest differences in the processing of semantic relationships by the two hemispheres. Various authors have conceived of this distinction in terms of the paradigmatic/syntagmatic dissociation, and the connotative and denotative meanings of words, and as reflecting different types of links between words. Drews has suggested that a left-hemisphere lesion would affect the processing of intraconceptual relationships, while a right-hemisphere lesion would impair the processing of interconceptual relationships. The goal of this study was to test this hypothesis, using a number of intra- and interconceptual semantic relationships. Pairs of common words were submitted to left-hemisphere brain-damaged and right-hemisphere brain-damaged subjects. The task required subjects to indicate whether or not there was any relationship between the words. The results only partially support the hypothesis. The right/left opposition applied to only one of three types of intraconceptual relationships (whole-part relation) and to one of two types of interconceptual relationship (same location relation). This partially unexpected result is discussed in reference to other studies.

Interhemispheric transfer time in a patient with a partial lesion of the corpus callosum.

The interhemispheric transfer time (ITT) of basic visuo-motor integration was investigated in a patient who had a lesion of the corpus callosum that spared the splenium and rostrum. Overall, 4291 simple reaction times were collected during unimanual responses to tachistoscopically presented lateralized simple visual stimuli at 4 degrees, 6 degrees and 10 degrees. Despite retaining some abilities that typically require the integration of information between hemispheres (e.g. haptic naming, tachistoscopic lateralized consonant reading) the patient performed similarly to completely callosotomized patients in a basic visuo-motor ITT task (overall 25.5 ms) at any eccentricity. These findings suggest that specific callosal channels mediate the basic visuo-motor ITT and these do not include the rostrum and/or the splenium of the corpus callosum.

Impaired apoptosis in mitogen-stimulated lymphocytes of patients with multiple sclerosis.

We investigated the sensitivity to cell death of peripheral blood mononuclear cells (PBMCs) from patients with multiple sclerosis (MS). PBMCs from MS patients, following PHA stimulation, were less sensitive to cell death than those from healthy donors (mean +/- s.e.m., 22.5 +/- 1.9 in MS patients vs 36.5 +/- 2.8 in healthy controls; p = 0.0003). However, when Fas-agonist antibody was added, the increase in respect to apoptosis induced by mitogen alone was even higher in MS patients than in controls. In addition, PHA-activated PBMCs from MS patients showed higher surface expression of Fas than controls, while Bcl-2 expression was decreased. This finding raised the question of whether an impaired generation of apoptotic signals may be contributing to the immune component of MS.

Defective Fas ligand production in lymphocytes from MS patients.

In the present transectional study, Fas ligand (Fas-L) levels, either in membrane or in soluble form, in cells from multiple sclerosis (MS) patients were investigated. Expression of Fas was evaluated after PHA stimulation of peripheral blood mononuclear cells from MS patients with relapsing-remitting or secondary-progressive disease, and in healthy donors. There was statistically significant decreased expression (p = 0.001), as well as release of Fas-L, (p = 0.045) in lymphocytes from MS patients, in comparison with healthy donors. Moreover, levels of Fas-L production were inversely correlated with the EDSS scores of patients in an highly significant way. Impairment of Fas-L release in stimulated PBMC from MS patients might influence the ability to eliminate autoreactive clones in vivo.

Can the pattern of neuropsychological improvement obtained with cholinergic drugs be used to infer a cholinergic mechanism in other nootropic drugs?

1. Enhancement of episodic memory and reduction of intrusion errors are considered as the most characteristic outcome of cholinergic drugs administration in AD patients. 2. Since the nootropic drugs Piracetam and Oxiracetam are deemed to act through a cholinergic mechanism, we checked whether AD patients treated with these drugs would show the same pattern of neuropsychological improvement. 3. Results were negative, since (a) episodic memory showed a similar degree of improvement both in patients treated with these drugs and in patients treated with placebo; (b) the number of intrusions tended to increase, rather than to decrease, after the treatment period.

Demyelinating plaques in relapsing-remitting and secondary-progressive multiple sclerosis: assessment with diffusion MR imaging.

BACKGROUND AND PURPOSE: Conventional MR imaging does not provide specific information that can be reliably associated with the pathologic substrate and clinical status of patients with multiple sclerosis (MS). Our goals were 1) to determine whether the orientationally averaged water diffusion coefficient () can be used to distinguish between plaques of different severity in these patients and 2) to assess possible correlations between values and disease duration, Expanded Disability Status Scale (EDSS) score, and signal intensity on T1-weighted MR images. METHODS: Twenty patients (10 with relapsing-remitting MS and 10 with secondary-progressive MS) and 11 healthy volunteers underwent a combined conventional and diffusion-weighted MR study of the brain. , a parameter that is proportional to the trace of the diffusion tensor, was computed by averaging the apparent diffusion coefficients measured in the x, y, and z directions. measurements were obtained for selected areas of white matter plaques. Differences in among the three groups were tested using analysis of variance. RESULTS: was significantly higher (1.445 +/- 0.129 x 10(-3) mm2/s) in secondary-progressive lesions than in relapsing-remitting lesions (0.951 +/- 0.08), and both values were higher than in normal white matter (0.732 +/- 0.02). There was a significant negative correlation between and the degree of hypointensity on T1-weighted images, and a positive correlation between and both EDSS score and disease duration. CONCLUSION: Our findings suggest that is useful for distinguishing MS lesions of different severities, which are associated with different degrees of clinical disability.

Cognitive improvement in clinical trials with nootropic drugs: when can it be expected and how to clarify its meaning.

In order to have a correct evaluation of the activity of a nootropic drug, the criteria adopted for the choice of patients to be included in the clinical trials and the methods used to clarify the meaning of changes observed on cognitive tasks are reported. The results of a clinical trial with the nootropic oxiracetam carried out in line with the above-mentioned criteria and methods are related.

A callosal disconnection syndrome of vascular origin.

OBJECTIVE: To study the after-effects of a selective lesion of the corpus callosum on the capacity in transferring spatial information on arm posture derived from kinesthesia and vision. DESIGN: Neuropsychological and psychophysical evaluations of a patient with callosal damage. SETTING: Institute of Neurology, University of "Tor Vergata", Rome, Italy and Research Centre, IRCCS "S. Lucia", Rome, Italy. PATIENT: P.V., a 59 years old man suffering from a vascular lesion of the left half of corpus callosum and left callosal radiations. MEASURES: Sensori-motor and cognitive tasks. Exo- and egocentric pointing abilities tasks. RESULTS: Impairments due to a disconnection between the two cerebral hemispheres were pointed out. About pointing abilities, errors were greater when each hand pointed to the remembered location of the other hand. Errors decreased dramatically with eyes open for right hand pointing to remembered location of left and right hand, and left hand pointing to remembered location of left hand. Open eyes left hand pointing to remembered location of right hand remained as poor as with eyes closed. CONCLUSIONS: The results appear compatible with the following network: visual information from striate and extrastriate cortex is passed forward to parietal cortex bilaterally (even in PV due to the splenium sparing). Kinesthetic information from parietal cortex of left and right hemisphere converge on a single visuokinesthetic center, lateralized to the left hemisphere. Information about limb position in three-dimensional space is then encoded in body-centered coordinates and passed forward to motor and premotor cortex in the frontal lobe. These frontal regions are those disconnected in PV.

[The pattern of neuropsychologic compromise in patients with Parkinson disease]. / Profilo di compromissione neuropsicologica in pazienti affetti da morbo di Parkinson.

We carried out a neuropsychological study on cognitive impairment in 57 subjects affected by idiopathic Parkinson's Disease (P.D.) and 32 subjects affected by Alzheimer's Disease (A.D.). First, we found two different subgroups of parkinsonian patients, the first one with dementia and the second one without dementia. We clearly identified these two distinct subclinical entities regardless of mean age, age of onset, duration of treatment; on the contrary, the type of treatment seems to play a specific role on the appearance of dementia in P.D., anticholinergics being assumed almost exclusively by demented parkinsonian patients (chi square c. Yates = 422; p less than 0.05). Second, we showed two distinct patterns of cognitive impairment between P.D. with dementia and A.D. In fact, cognitive impairment is consistently more evident in Alzheimer patients than in parkinsonian ones with dementia; in addition, demented parkinsonians show a pattern of impairment similar to that exhibited by patients affected by frontal lobe lesions. This result supports neuroanatomical and neurochemical data on the involvement of the whole dopaminergic system in P.D. and the role played by the ventro-medial tegmental area projecting to the frontal cortex. In conclusion, our study, identifying a specific pattern of cognitive impairment in P.D., well-differenciated from demented patients of different aetiology, suggests beneficial effects with dopaminergic agonists in these patients; in fact, these agents, acting on the second neuron, may stimulate the prefrontal region that is probably involved in the cognitive impairment of parkinsonian patients.

Cognitive dysfunction in patients with relapsing-remitting multiple sclerosis.

Cognitive dysfunction is considered one of the clinical markers of multiple sclerosis (MS). However, in the literature there are inconsistent reports on the prevalence of cognitive dysfunction, and separate data for the relapsing-remitting (RR) type of the disease are not always presented. In this study, we submitted 461 RRMS patients to a battery of neuropsychological tests to investigate their impairment in various cognitive domains. As a consequence of the exclusion criteria, the sample is not fully representative of the entire population of RRMS patients. In this selected sample, when only the eight scores of a core battery (Mental Deterioration Battery) were considered (with respective cutoffs), it emerged that 31% of the patients were affected by some degree of cognitive deficit. In particular, 15% had mild, 11.2% moderate and 4.8% had severe impairment. Information processing speed was the most frequently impaired area, followed by memory. When two other tests (SDMT and MCST) were added and cognitive domains were considered, it emerged that 39.3% of the patients were impaired in two or more domains. When four subgroups were obtained by means of cluster analysis and then compared, it emerged that information processing speed and memory deficits differentiated the still cognitively unimpaired from the mildly impaired MS patients. Significant associations were found between cognitive and clinical characteristics. However, due to the large sample size, clinically irrelevant relationships may also have emerged. Even with the limitations imposed by the sample selection and the possible underestimation of the prevalence and severity of cognitive dysfunction, these results seem to provide further evidence that information processing speed deficit may be an early and important marker of cognitive impairment in MS patients.

Cognitive functions in adult Down's syndrome.

Cognitive profiles of performances were obtained from a selected group of adult Down syndrome (DS) subjects (n = 20; mean age: 34.5 years; s.d.: 7.7) by means of an ad hoc neuropsychological battery. With the aim of examining, from a neuropsychological point of view, the modifications that increasing age produces in this group of patients, cognitive performances of younger DS subjects (mean age: 28 years; s.d.: 4.77) were compared with analogous performances obtained by the older ones (mean age: 39.8 years; s.d.: 5.11). Subsequently, to clarify qualitative aspects of cognitive patterns in the subgroups of young and old DS subjects, two different groups of control patients were utilised. Neuropsychological data collected from a group of adult mentally retarded subjects were compared with cognitive performances demonstrated by young DS subjects, while the old group of DS subjects was analyzed in comparison with a group of patients affected by initial form of Alzheimer disease (AD). Altogether, the results of our study do not seem to support, from a neuropsychological point of view, the hypothesis that mental decline observed in DS subjects reproduces the cognitive patterns of impairment observed in AD patients.

Contralateral and ipsilateral disorders of visual attention in patients with unilateral brain damage.

To explain the prevalence of unilateral spatial neglect in patients with right brain damage, Heilman et al have suggested that the attentional neurons of the right parietal lobe might have bilateral receptive fields, whereas the homologous cells of the left hemisphere would have strictly contralateral receptive fields. One implication of this theory is that patients with right brain damage should show a prevalence of disorders of visual attention not only in the half space contralateral to the damaged hemisphere, but also in the ipsilateral one. To check this theory, 50 control subjects, 102 right and 125 left brain-damaged patients were given a drawing completion task in which patients were requested to complete the missing parts of a star, a cube and a house. Omissions of lines lying on the sides of the models contralateral and ipsilateral to the damaged hemisphere were taken separately into account. Results did not confirm the hypothesis, since right brain-damaged patients failed to complete the contralateral sides of the models much more frequently than patients with left brain injury, but no difference was found between the two hemispheric groups when ipsilateral disorders of visual attention were taken into account. Furthermore, no correlation was found between omissions of lines lying on the sides of the models contralateral and ipsilateral to the damaged hemisphere. This finding suggests that contralateral and ipsilateral disorders of visual attention are not due to the same mechanism in right brain-damaged patients. The alternative hypothesis viewing ipsilateral disorders as resulting from a widespread lowering of general attention (and only contralateral neglect reflecting a specific disorder of visual attention) was supported by results obtained on a verbal memory test, used to evaluate the general cognitive and attention level of the patients. Patients with clear-cut ipislateral inattention obtained very low scores on this test, whereas patients with severe contralateral neglect, but not ipislateral inattention scored within the normal range on the verbal memory test.

Differential aspects of cognitive impairment in patients suffering from Parkinson's and Alzheimer's disease: a neuropsychological evaluation.

Neuropsychological profiles of cognitive impairment demonstrated by a group of Parkinson patients and by a group of Alzheimer patients both affected by a comparable level of mental deterioration were obtained by means of a neuropsychological battery. The results pointed out differential patterns of cognitive impairment exhibited by the two pathological groups. Particularly, Alzheimer's patients appear to be mainly impaired in mnesic functions, while Parkinsonian subjects show a pattern of performances indicative of a prevalent impairment of the functions underlied by frontal lobes. These data are in agreement with the hypothesis that different anatomical-functional cerebral structures are mainly involved in determining cognitive deterioration in the two diseases.

Defective concept formation in parkinsonians is independent from mental deterioration.

An extensive neuropsychological battery (the Mental Deterioration Battery) was utilized to distinguish, within a sample of 24 idiopathic Parkinsonians, those showing signs of diffuse mental deterioration (n = 9) from those without deterioration (n = 15). Performances of control subjects on a wide range of tests exploring mnesic, visuo-constructive, linguistic and general intellectual functions (n = 21) did not differ from analogous performances of Parkinsonians without signs of diffuse mental deterioration. The Wisconsin Card Sorting Test was then used to verify the hypothesis that a selective impairment of cognitive functions subsumed by the integrity of frontal lobes could be demonstrated in Parkinsonian patients. Our results provide evidence that in this task, defective performances are obtained by Parkinsonians and even by patients without signs of diffuse cognitive impairment. These findings seem to confirm that a deficit in concept formation, maintenance and shifting is largely independent of the dementia frequently noticed in Parkinson's disease.