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Biomedical subjects

G Comi

Publications and source records attributed to G Comi.

At least 91 records · Page 5Linked to original sources
PubMed2001

Magnetization transfer and diffusion tensor MR imaging of the optic radiations and calcarine cortex from patients with Leber's hereditary optic neuropathy.

Optic nerve abnormalities are easily detectable in patients with Leber's hereditary optic neuropathy (LHON), using magnetic resonance imaging (MRI). However, the presence of structural changes in the optic radiations and calcarine cortex of these patients is still an unresolved issue. In this study, we obtained magnetization transfer (MT) and diffusion tensor (DT) MRI to investigate the integrity of these structures in patients with LHON. Dual echo, MT- and DT-MRI scans of the brain were obtained from 10 men with LHON and 10 healthy sex- and age-matched controls. After image co-registration, we obtained MT ratio (MTR), average diffusivity (D) and fractional anisotropy (FA) maps. MTR, D and FA values for the white matter of the optic radiations and MTR and D values for the calcarine cortex were obtained using a region of interest (ROI) analysis. No macroscopic abnormalities were detected in any of the scans from LHON patients and controls. No statistically significant differences of MTR, D or FA values were found for any of the regions studied in LHON patients and healthy controls. Our results suggest that, in patients with LHON, the optic radiations and the calcarine cortex are spared from structural damage, both at a macroscopic and a microscopic level.

Adult↗
PubMed2001

Correlates of MS disability assessed in vivo using aggregates of MR quantities.

OBJECTIVES: To assess the magnitude of the correlations between disability and composite MRI scores in patients with MS. METHODS: T2- and T1-weighted MRI, magnetization transfer imaging, diffusion tensor imaging, and MRS imaging scans of the brain from 23 patients with MS were obtained. T2 lesion volume, T1 lesion volume, brain magnetization transfer ratio, average brain diffusivity (D), and brain N-acetylaspartate/creatine ratio were measured. RESULTS: The correlations between the Expanded Disability Status Scale (EDSS) score and each of the MR quantities taken in isolation were not significant, with the exception of the correlation between EDSS and the NAA/creatine ratio (r = -0.50; p = 0.01). In contrast, three of the composite MR scores computed using regression models were strongly correlated with the EDSS scores (r range, 0.58 to 0.73; p range, 0.004 to 0.0001). The model that included T2 and T1 lesion volumes and brain D explained 34% of the EDSS variance; the model that included T2 and T1 lesion volumes and brain N-acetylaspartate/creatine ratio explained 36% of the EDSS variance; the model that included T1 lesion volume, brain D, and brain N-acetylaspartate/creatine ratio explained 53% of the EDSS variance. CONCLUSIONS: The results suggest that multiparametric MR models have the potential to provide powerful measures to monitor MS evolution.

Adult↗
PubMed2001

Delivery to the central nervous system of a nonreplicative herpes simplex type 1 vector engineered with the interleukin 4 gene protects rhesus monkeys from hyperacute autoimmune encephalomyelitis.

Systemic administration of antiinflammatory molecules to patients affected by immune-mediated inflammatory demyelinating diseases of the central nervous system (CNS) has limited therapeutic efficacy due to the presence of the blood-brain barrier (BBB). We found that three of five rhesus monkeys injected intrathecally with a replication-defective herpes simplex virus (HSV) type 1-derived vector engineered with the human interleukin 4 (IL-4) gene were protected from an hyperacute and lethal form of experimental autoimmune encephalomyelitis induced by whole myelin. The intrathecally injected vector consistently diffused within the CNS via the cerebrospinal fluid and infected ependymal cells, which in turn sustained in situ production of IL-4 without overt immunological or toxic side effects. In EAE-protected monkeys, IL-4-gene therapy significantly decreased the number of brain as well as spinal cord inflammatory perivenular infiltrates and the extent of demyelination, necrosis, and axonal loss. The protective effect was associated with in situ downregulation of inflammatory mediators such as tumor necrosis factor alpha (TNF-alpha) and monocyte chemoattractant protein 1 (MCP-1), upregulation of transforming growth factor beta (TGF-beta), and preservation of BBB integrity. Our results indicate that intrathecal delivery of HSV-1-derived vectors containing antiinflammatory cytokine genes may play a major role in the future therapeutic armamentarium of inflammatory CNS-confined demyelinating diseases and, in particular, in the most fulminant forms where conventional therapeutic approaches have, so far, failed to achieve a satisfactory control of the disease evolution.

Animals↗
PubMed2001

Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.

BACKGROUND: Interferon beta reduces activity in multiple sclerosis as measured clinically and by magnetic resonance imaging (MRI). We assessed the effect of interferon beta-1a on the occurrence of relapses in patients after first presentation with neurological events, who are at high risk of conversion to clinically definite multiple sclerosis. METHODS: Eligible patients had had a first episode of neurological dysfunction suggesting multiple sclerosis within the previous 3 months and had strongly suggestive brain MRI findings. Patients were randomly assigned interferon beta-1a 22 microg or placebo subcutaneously once weekly for 2 years. Neurological and clinical assessments were done every 6 months and brain MRI every 12 months. Analyses excluded one patient assigned placebo who received no study injections. FINDINGS: 241 (78%) of 308 randomised patients received study treatment for 2 years; 278 (90%) remained in the study until termination. 57 (85%) of 67 who stopped therapy did so after conversion to clinically definite multiple sclerosis. Fewer patients developed clinically definite multiple sclerosis in the interferon group than in the placebo group (52/154 [34%] vs 69/154 [45%]; p=0.047). The time at which 30% of patients had converted to clinically definite multiple sclerosis was 569 days in the interferon group and 252 in the placebo group (p=0.034). The annual relapse rates were 0.33 and 0.43 (p=0.045). The number of new T2-weighted MRI lesions and the increase in lesion burden were significantly lower with active treatment. INTERPRETATION: Interferon beta-1a treatment at an early stage of multiple sclerosis had significant positive effects on clinical and MRI outcomes.

Adolescent↗
PubMed2001

The role of non-conventional MR techniques to study multiple sclerosis patients.

Conventional magnetic resonance imaging (MRI) lacks pathological specificity to the heterogeneous substrates of multiple sclerosis (MS) lesions and is not able to detect subtle, disease-related changes in the normal-appearing white matter (NAWM). As a consequence, the correlation between MRI findings and the long-term evolution of MS is moderate at best. To overcome the limitations of conventional MRI, new quantitative magnetic resonance (MR) techniques, such as cell-specific imaging, magnetization transfer imaging (MTI), proton magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI) and functional MR imaging (fMRI) have all been recently applied to the study of MS. These techniques should provide more accurate and pathologically specific estimates of the MS lesion burden than conventional MR and should improve our understanding of the mechanisms leading to MS-related irreversible disability.

Humans↗
PubMed2001

Diffusion tensor magnetic resonance imaging in multiple sclerosis.

OBJECTIVES: To quantify, using diffusion tensor imaging (DTI), the tissue damage in lesions and normal-appearing white matter (NAWM) from a large cohort of patients with MS and to investigate the magnitude of the correlation between DTI-derived metrics and clinical disability. METHODS: Dual-echo and DTI scans were obtained from 78 patients with relapsing-remitting, secondary progressive, or primary progressive MS and from 20 normal control participants. Post-contrast T1-weighted images were also obtained from the patients. After creating mean diffusivity (D) and fractional anisotropy (FA) images and image coregistration, D and FA values were measured for 4846 lesions (3207 nonenhancing T1-isointense, 1511 nonenhancing T1-hypointense, and 128 enhancing), 497 NAWM areas from patients, and 160 white matter areas from the controls. RESULTS: The average lesion D was higher and the average lesion FA was lower than the corresponding quantities of the NAWM (p < 0.001). The values of enhancing and nonenhancing lesions were not different, whereas enhancing lesions had lower FA (p < 0.001). T1-hypointense lesions had higher D and lower FA than T1-isointense lesions (p < 0.001). NAWM of patients had higher and lower FA than white matter of controls (p = 0.01). Significant correlations were found between T1 and T2 lesion volume and and FA of lesions and NAWM. In the overall patient sample, a moderate correlation was also found between lesion D and the Expanded Disability Status Scale score (r = 0.28, p = 0.01). However, the r value of this correlation was 0.48 in patients with secondary progressive MS, whose disability was also correlated with average lesion FA (r = -0.50). CONCLUSIONS: The results of this study show that DTI is able to identify MS lesions with severe tissue damage and to detect changes in the NAWM. They also indicate that DTI-derived measures are correlated with clinical disability, especially in patients with secondary progressive MS, thus suggesting a role for DTI in monitoring advanced phases of the disease.

Adult↗
PubMed2001

Magnetization transfer and diffusion tensor MR imaging of basal ganglia from patients with multiple sclerosis.

Although post-mortem studies have shown that lesions of multiple sclerosis (MS) can be detected in the basal ganglia, conventional T2-weighted magnetic resonance (MR) imaging is poorly sensitive for detecting such abnormalities. This study was performed to investigate whether magnetization transfer (MT) and diffusion tensor MR imaging are able to detect in vivo basal ganglia changes in patients with MS. After image coregistration, MT ratio (MTR) and mean diffusivity (&Dmacr;) maps were obtained and MTR and &Dmacr; values of the putamen, head of the caudatus and thalamus measured from 31 patients with clinically definite MS and 14 age- and sex-matched healthy volunteers using region of interest analysis. Although we found slightly decreased MTR and increased &Dmacr; in the basal ganglia from patients compared to controls, suggesting increased extra-cellular water and reduced amount of 'barriers' restricting water molecular motion in the basal ganglia of patients with MS, none of the differences was statistically significant. These data suggest that the more sophisticated MR probes of tissue disruption and cellular integrity are no more sensitive than current conventional imaging for detecting basal ganglia abnormalities in patients with MS.

Adult↗
PubMed2001

Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy.

This multicenter, randomized, double-blind, crossover trial compared a six week course of oral prednisolone tapering from 60 mg to 10 mg daily with intravenous immunoglobulin (IVIg) 2.0 g/kg given over one to two days for treating chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Twenty-four of the thirty-two randomized patients completed both treatment periods. Both treatments produced significant improvements in the primary outcome measure, change in an 11-point disability scale two weeks after randomization. There was slightly, but not significantly, more improvement after IVIg than with prednisolone, the mean difference between the groups in change in disability grade being 0.16 (95% CI = -0.35 to 0.66). There were also slightly, but not significantly, greater improvements favoring IVIg in the secondary outcome measures: time to walk 10 meters after two weeks and improvement in disability grade after six weeks. Results may have been biased against IVIg by the eight patients who did not complete the second arm of the trial. A serious adverse event (psychosis) attributable to treatment occurred in one patient while on prednisolone and in none with IVIg.

Administration, Oral↗
PubMed2001

Fatigue in multiple sclerosis is associated with abnormal cortical activation to voluntary movement--EEG evidence.

Converging evidence is consistent with the view that fatigue in Multiple Sclerosis is independent from pyramidal tract involvement, suggesting a possible involvement of frontal areas. During voluntary movement, changes of the EEG rhythms can be observed over sensorimotor areas. Event-related desynchronization (ERD) of the 10 and 20 Hz frequency bands occurs during motor planning and execution and is followed after movement termination by event-related synchronization (ERS), expressing cortical idling or inhibition. We evaluated the pattern of cortical activation to voluntary movement in MS patients complaining of fatigue assessed using the Fatigue Severity Scale. Fifteen MS patients complaining of fatigue, 18 MS patients without fatigue, and 14 normal controls were studied. The two patients groups were similar for age, sex, disease duration, and were not disabled (score <1.5 at the Expanded Disability Status Scale). Twenty-nine channel EEG was recorded during about 60 self-paced extensions of the right thumb. The onset latency and amount of the contralateral sensorimotor (C3 electrode) 10 and 18--22 Hz ERD were similar in the three groups. ERD was more widespread anteriorly in the fatigue group compared with normal controls (P < 0.01 over Fz electrode). Postmovement contralateral sensorimotor 18--22 Hz ERS was significantly lower in fatigue MS patients compared with normal subjects (P < 0.005) and with nonfatigue MS patients (P = 0.02). These findings are consistent with a central origin of fatigue in MS and indicate cortical dysfunction even during a simple motor task, resulting in hyperactivity during movement execution and failure of the inhibitory mechanisms intervening after movement termination.

Adult↗
PubMed2001

Physiopathology and treatment of fatigue in multiple sclerosis.

Fatigue is a common symptom of patients with multiple sclerosis (MS). It is reported by about one-third of patients, and for many fatigue is the most disabling symptom. Fatigue may be associated with motor disturbances and/or mood disorders, which makes it very difficult to determine whether the fatigue is an aspect of these features or a result per se of the disease. Although peripheral mechanisms have some role in the pathogenesis of fatigue, in MS there are clear indications that the more important role is played by "central" abnormalities. Neurophysiological studies have shown that fatigue does not depend on involvement of the pyramidal tracts and implicate impairment of volitional drive of the descending motor pathways as a physiopathological mechanism. Metabolic abnormalities of the frontal cortex and basal ganglia revealed by positron-emission tomography and correlations between fatigue and magnetic resonance imaging lesion burden support this hypothesis. Some recent studies also suggest that pro-inflammatory cytokines contribute to the sense of tiredness. No specific treatments are available. Management strategies include medications, exercise, and behavioural therapy; in most cases a combined approach is appropriate.

Antidepressive Agents↗
PubMed2001

Sporadic failure of botulinum toxin treatment in usually responsive patients with adductor spasmodic dysphonia.

Botulinum toxin (BT) injections into vocalis (thyroarytenoid) muscle is currently considered the first-choice treatment for adductor spasmodic dysphonia, producing improvement for an average period of 3 months. In our experience, sporadic failure of BT efficacy can occur even in patients usually responsive to this therapy. The reasons for these episodes have not been clarified. In a retrospective, open trial, we investigated the effect toxin preparation (Botox or Dysport) and injection monitoring (electromyography or laryngoscopy) on the success rate of BT treatment. We studied 15 patients with adductor dysphonia usually responsive to BT therapy. BT was administered into the vocalis muscle in 112 and 36 injections under electromyographic or laryngoscopic guidance, respectively. Botox and Dysport were used in 106 and 42 sessions, respectively. In 29% of all injections, no subjective or objective changes, nor side effects were observed. Failure rate did not differ using electromyographic (28.6%) or laryngoscopic (30.5%) guidance. Failure rates with Botox and Dysport were 30.2% and 26.2%, respectively, but this difference was not statistically significant. These data suggest that treatment failure may occur regardless of the method of injection and of the drug preparation used, possibly due to mislocalisation of vocal folds.

Adult↗
PubMed2001

Clinical and MRI assessment of brain damage in MS.

Cognitive impairment in multiple sclerosis (MS), generally in the form of the so-called subcortical dementia, results predominantly by the disruption of communication among cortical and subcortical areas, consequent to white matter damage. Studies with conventional magnetic resonance imaging (MRI) demonstrated that cognitive impairment in MS patients is related to lesion burden, although the strength of this correlation is weak. This can be partially explained by the poor pathological specificity of conventional MRI techniques and by damage in the normal-appearing white matter (NAWM). This interpretation is supported by studies using non-conventional MRI techniques, more specific to the heterogeneous substrates of MS pathology, such as the assessment of hypointense lesion load on T1-weighted scans and the measurement of the magnetization transfer ratio (MTR) of whole brain, MS lesions and NAWM. Other factors, such as the site of MS lesions and the presence of active inflammation, also seem to play an important role.

Brain↗
PubMed2001

A PET study with [11-C]raclopride in Parkinson's disease: preliminary results on the effect of amantadine on the dopaminergic system.

Amantadine has been proved to be beneficial in Parkinson's disease. Although it is still uncertain which neurochemical events are modified at therapeutic doses, an increase in dopaminergic tone secondary to NMDA receptor blockade and a direct inhibition of the glutamatergic overactivity have been suggested to be involved in its clinical effects. The aim of this study was to evaluate the effects of amantadine on the dopaminergic system by measuring the in vivo binding of [11-C]raclopride to D2 dopamine receptors in the basal ganglia of 6 patients with idiopathic Parkinson's disease. Each patient underwent a PET study, before and after 14 days of treatment with amantadine (200 mg/day). Repeated treatment with therapeutic doses of amantadine induced a moderate increase in the in vivo binding of [11C]raclopride in the putamen of PD patients. This observation indicates that in PD patients, 200 mg/day amantadine does not produce an increase in extracellular levels of dopamine sufficiently to inhibit raclopride binding or that, if present, is it masked by a concurrent increase in receptor availability, as recently reported in rat striatum.

Aged↗
PubMed2001

The ependymal route to the CNS: an emerging gene-therapy approach for MS.

The systemic administration of anti-inflammatory molecules to patients affected by immune-mediated inflammatory demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis, has limited therapeutic efficacy owing to the presence of the blood-brain barrier. The delivery of drugs to the CNS using a nonreplicative viral vector engineered with genes encoding anti-inflammatory cytokines might represent an alternative therapeutic strategy. Here, we propose accessing the CNS through the ependymal-leptomeningeal route. This approach is based on the injection of nonreplicative vectors into the cerebrospinal fluid space. These vectors are able to infect the ependymal and leptomeningeal cells consistently and without side effects, and in turn, produce the 'therapeutic' product of the transgene in the CNS for extended periods of time. This strategy could represent an alternative treatment for inflammatory neurological disorders when systemic immunosuppressive therapies fail to control the evolution of disease satisfactorily.

Blood-Brain Barrier↗
PubMed2001

Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria.

The gene products involved in mammalian mitochondrial DNA (mtDNA) maintenance and organization remain largely unknown. We report here a novel mitochondrial protein, Twinkle, with structural similarity to phage T7 gene 4 primase/helicase and other hexameric ring helicases. Twinkle colocalizes with mtDNA in mitochondrial nucleoids. Screening of the gene encoding Twinkle in individuals with autosomal dominant progressive external ophthalmoplegia (adPEO), associated with multiple mtDNA deletions, identified 11 different coding-region mutations co-segregating with the disorder in 12 adPEO pedigrees of various ethnic origins. The mutations cluster in a region of the protein proposed to be involved in subunit interactions. The function of Twinkle is inferred to be critical for lifetime maintenance of human mtDNA integrity.

Amino Acid Sequence↗