Peak width of skeletonized mean diffusivity (PSMD) and cognitive functions in relapsing-remitting multiple sclerosis.

Peak width of skeletonized mean diffusivity (PSMD) is a new MRI marker, which has shown clinical relevance in some neurological conditions and, in preliminary data, in multiple sclerosis (MS). We aimed here to investigate, in a group of relapsing-remitting MS (RRMS) patients, the relationship between PSMD and cognitive performances, in comparison with other MRI measures. RRMS patients (n = 60) and normal controls (n = 15) underwent a 3 T MRI examination. MRI-based white matter (WM) lesion volume, microstructural integrity (assessed with Tract-Based Spatial Statistics of diffusion tensor imaging [DTI] images) and brain volumes (i.e., total brain, grey matter [GM] and WM) were computed. In addition, PSMD was calculated through "skeletonization" of WM tracts and diffusion histograms. Cognition was evaluated with Rao's Brief Repeatable Battery (BRB), which incorporated tests of verbal and visual memory, attention, concentration, information processing speed and verbal fluency. PSMD closely correlated with symbol digit modalities test (SDMT) (r = -0.70, p < 0.001) and, to a lesser extent, with verbal and visual memory tests. Multiple regression analysis showed that PSMD explained SDMT variance (R2 = 0.54, p < 0.001) more than other MRI measures. Results point out the relevance of microstructural damage, as assessed by PSMD, as a reliable marker of cognition in MS, especially in explaining dysfunction in information processing speed.

Role of Whole-Body MR with DWIBS in child's Bartonellosis.

Cat-scratch disease (CSD) is a zoonosis in children, result of infection by Bartonella henselae, a gram-negative bacillus. Infection is generally characterized by regional and self-limited lymphadenopathy after exposure to a scratch or bite from a cat. Rarely, B. henselae is cause of fever of unknown origin (FUO), with dissemination to various organs, most often involving the reticuloendothelial system (liver, spleen, bone marrow), mimicking an inflammatory rather than a lymphoproliferative disease. Whole-body Magnetic Resonance Imaging (WBMRI), in association with diffusion-weighted imaging (DWIBS), allows a comprehensive evaluation of pediatric patients, without the risks inherent to ionizing radiation. It is a rapid and sensitive method for detecting and monitoring multifocal lesions such as proliferative or inflammatory and infectious processes. We report a case of systemic CDS in an immunocompetent young boy with fever of unknown origin, without history of cat contact, investigated by WBMRI.

Structural and metabolic brain abnormalities in preclinical cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy.

OBJECTIVE: To assess, by using quantitative MRI metrics, structural and metabolic brain abnormalities in subjects with preclinical cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). BACKGROUND: Brain MRI abnormalities have been occasionally reported in preclinical CADASIL subjects. However, very little is known as to when the brain tissue damage starts to accumulate, what brain regions are primarily involved and whether the brain damage is significant in subjects who have no overt clinical manifestations of the disease. METHODS: Twelve subjects (mean age 40 years; range 26-55 years; males/females 6/6) with genetically proven CADASIL and no clinical signs of the disease underwent conventional MRI and proton MR spectroscopic imaging ((1)H-MRSI) to measure white matter (WM) lesion volume (LV), global and regional cerebral volumes, and WM levels of N-acetylaspartate (NAA) normalised to creatine (Cr). MR values were compared with those of 13 age- and sex-matched healthy controls. RESULTS: All preclinical CADASIL showed WM lesions (range 0.2 to 26 cm(3)). They were mostly distributed in the frontal and parietal regions, with the highest probability in the corona radiata. On (1)H-MRSI examination, NAA/Cr values were lower in preclinical CADASIL than in HC, particularly in the corona radiata (p<0.01). Normalised brain and cortical volumes were also lower in preclinical CADASIL than in HC (p<0.01), particularly in the frontal cortex. CONCLUSIONS: The pathological process occurring in CADASIL leads to damage of WM and neocortex much before the evidence of clinical symptoms. At this preclinical stage, this seems to take place prevalently in the frontal brain region.

Communication of information to patients with inflammatory bowel disease: A European Collaborative Study in a multinational prospective inception cohort.

BACKGROUND AND AIMS: Communication to patients of information about their disease has become increasingly important in modern medicine, and particularly with chronic nonfatal disorders like inflammatory bowel disease (IBD), but the subject is not adequately researched or understood. METHODS: We studied the media and preferences for communication of information in a multi-national community-based inception cohort of European and Israeli patients with IBD and 10 years follow-up, using structured questionnaires categorizing demographics, disease status, current and preferred sources of information, use of electronic media, role of patients' associations, and satisfaction level. RESULTS: The 917 patients completing the questionnaire were derived from northern (60%) and southern (40%) countries. The mean age was 48.3 years (62% under 50 years); 51% were males; 67% had ulcerative colitis, 33% Crohn's disease. Sixty-six percent of patients designated the specialist as their primary source of information, 77% indicated satisfaction with their current information, and 65% reported not receiving information about medical treatment in the past year. Patient concerns were about new research into their illness (64%), medical treatments (58%), risks and complications (51%) and genetics (42%). Preferred sources of information were paper bulletin (76%), electronic media (30%) and international organization (79%). Diagnosis (ulcerative colitis or Crohn's disease), gender, education level and country impacted significantly on patients' choices. CONCLUSIONS: In providing health care information to patients with IBD their individual attitudes and preferences must be considered. There should be greater roles for IBD patients' associations and international IBD-research organizations, and an increasing use of electronic media.

MR Imaging in Anderson-Fabry Disease: What Are We Expected to Find?

Anderson-Fabry disease (FD) is a genetic disorder of glycosphingolipid metabolism that can involve CNS and is easily detectable with MRI. We reviewed 32 MRI performed in ten patients to detect an eventual specific pattern of the disease suggesting that finding vascular lesions in young adults must be addressed to diagnose different pathologies including FD.

Neocortical volume decrease in relapsing-remitting MS patients with mild cognitive impairment.

OBJECTIVE: To assess neocortical changes and their relevance to cognitive impairment in early relapsing-remitting (RR) multiple sclerosis (MS). METHODS: Conventional MR was acquired in 41 patients with RR MS and 16 demographically matched normal control subjects (NCs). An automated analysis tool was used with conventional T1-weighted MRI to obtain measures of cortical brain volumes normalized for head size. Neuropsychological performance of MS patients was assessed using the Rao Brief Repeatable Battery. Relationship between volumetric MR measures and neuropsychological scores was assessed. RESULTS: Neuropsychological assessment allowed for the identification of 18 cognitively preserved (MS-cp) and 23 cognitively impaired (MS-ci) MS patients. The whole MS sample showed lower values of normalized cortical volumes (NCVs) than did the NC group (p = 0.01). Upon grouping of MS patients according to cognitive performance, NCV values were lower (p = 0.02) in MS-ci patients than in both MS-cp patients and NCs. Moreover, there were positive correlations between NCV values and measures of verbal memory (r = 0.51, p = 0.02), verbal fluency (r = 0.51, p = 0.01), and attention/concentration (r = 0.65, p < 0.001) in MS-ci patients. Furthermore, NCV values were decreased in patients who scored lower on a greater number of tests (r = -0.58, p < 0.01) in the MS-ci group. None of the neuropsychological measures correlated to NCV values in the MS-cp patient group. CONCLUSIONS: Cortical atrophy was found only in cognitively impaired patients and was significantly correlated with a poorer performance on tests of verbal memory, attention/concentration, and verbal fluency. Gray matter pathology may contribute to the development of cognitive impairment in MS from the earliest stages of the disease.

Brain study using magnetic resonance imaging and proton MR spectroscopy in pediatric onset systemic lupus erythematosus.

OBJECTIVE: The aim of the present study was to assess and monitor brain damage in patients with pediatric onset systemic lupus erythematosus (SLE) using non-invasive techniques such as magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-MRS). METHODS: Twenty-four SLE patients, both symptomatic or asymptomatic for central nervous system (CNS) involvement, and 20 controls were examined. Each individual underwent a diagnostic MRI using a 1.5 T Philips ACS-NT scanner including transverse T2-weighted (T2W) spin echo, transverse FLuid Attenuated Inversion Recovery (FLAIR), and sagittal T2W turbo spin echo 5 mm slices. In addition, single voxel proton MR spectroscopy localized on the supraventricular region was performed in all patients and controls. Patients were re-examined after one year. RESULTS: 75% of SLE patients had clinical CNS involvement; 46% showed abnormal MRI (3 of them, in the absence of neurologic signs); 4 SLE patients showed N-acetylaspartate/Creatine (NAA/Cr) ratios significantly lower than the controls. Among 5 SLE patients examined at the onset of the disease, 1 had MRI alterations and another showed a decrease of NAA/Cr values. Three patients with relapses showed a correlation between the course of the disease and the NAA/Cr ratios. CONCLUSION: MRI and H-MRS are non-invasive techniques that might be useful, in some cases, in detecting CNS involvement in SLE patients and monitoring the disease course and efficacy of pharmacological treatment.

Functional reorganization of motor cortex increases with greater axonal injury from CADASIL.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small-artery disease that clinically involves only the brain. Particularly early in the disease, patients can show substantial or complete recovery after individual strokes. Cortical functional reorganization may contribute to limiting disability with such ischemic injury. We sought to test whether the extent of any functional changes in the motor cortex increases with greater brain axonal injury from CADASIL. METHODS: Functional MRI (fMRI) was used to characterize cortical activation during a simple hand-tapping task. Disease-associated pathology in subcortical white matter was assessed with the use of conventional fluid-attenuated inversion recovery (FLAIR) MRI and MR spectroscopic imaging for measurement of N-acetyl aspartate decreases, a relatively specific measure of axonal injury. RESULTS: There was evidence for variable but substantial hyperintense white matter signal in all of the patients with FLAIR imaging. With the use of fMRI, the brain regions activated during motor tasks were similar for the 9 CADASIL patients and 7 controls, except that most (6 of 9) patients showed primary motor cortex activation both ipsilateral and contralateral to the hand moved, a finding in only 1 of 7 healthy controls. Ipsilateral motor cortex activation increased (r=-0.77, P<0.05) and motor cortex activation lateralization index decreased (r=0.68, P<0.02) with greater white matter injury (as assessed from decreases in the relative N-acetyl aspartate concentration) in a region of interest including descending motor fibers of the corticospinal pathway. CONCLUSIONS: The extent of functional reorganization of motor cortex increases with increasing axonal injury, consistent with an adaptive role for these changes. Increased functional recruitment of cortex ipsilateral to the limb moved therefore may contribute to limiting motor impairment from the subcortical injury of CADASIL.

Severe metabolic abnormalities in the white matter of patients with vacuolating megalencephalic leukoencephalopathy with subcortical cysts. A proton MR spectroscopic imaging study.

Vacuolating megalencephalic leukoencephalopathy (VML) with subcortical cysts is a neurodegenerative disorder clinically characterized by megalencephaly with onset in the first year of life, progressive ataxia, spasticity and relatively spared cognitive function. Conventional MRI findings consist of diffusely abnormal cerebral white matter with subcortical cysts. Recent single-voxel proton MR spectroscopy studies have shown mild metabolic abnormalities in the white matter. We report here a combined proton MR imaging and MR spectroscopic imaging (1H-MRSI) study on 2 new, unrelated patients with this rare disorder. 1H-MRSI examinations, which can provide simultaneously metabolic information from many different brain regions, showed inhomogeneous decreases in all normally detected metabolites with significant widespread decreases in the ratio of N-acetylaspartate to creatine+phosphocreatine and concomitant small increases in lactate in the white matter of both hemispheres. Metabolic abnormalities were milder in the frontal white matter and more severe in the posterior white matter. The 1H-MRSI pattern of the gray matter was normal in both patients. In one patient, a subsequent 1H-MRSI examination (performed 3 years after the first) confirmed the presence of widespread decreases in the ratio of N-acetylaspartate to creatine+phosphocreatine in the white matter. We conclude that severe metabolic abnormalities can be found in the white matter of VML patients. This suggests that, despite the apparently mild clinical course, a severe neurodegenerative process may occur in the white matter of these patients.

Magnetic resonance imaging and spectroscopic changes in brains of patients with cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare disorder due to an inherited defect in the metabolic pathway of cholesterol. Early diagnosis of the disease is particularly important as patients benefit from therapy with chenodeoxycholic acid. Although the disease is clinically characterized by the concomitant presence of tendon xanthomas, juvenile cataracts and progressive neurological impairment, clinical features may vary greatly. Neuroradiological studies have suggested that the bilateral abnormality of the dentate nuclei could be typical of this disease. However, this finding has been seen inconsistently on conventional MRI. The dynamic of the CNS pathology in CTX is complex, and whether demyelination or axonopathy has primary importance in the pathogenesis of CTX pathology is not known. To clarify both neuroradiological and pathological issues, we performed combined brain MRI and spectroscopy examinations on 12 CTX patients. On conventional MRIs, bilateral hyperintensities of the dentate nuclei were clearly seen in nine out of 12 patients on T(2) -weighted MRIs, but were evident in all patients using a FLAIR sequence. On proton magnetic resonance (MR) spectroscopy, significant decreases in N: -acetylaspartate resonance intensities (P: <0.0001) and increases in lactate MR signals (P<0.05) were found in the group of CTX patients in large volumes of interest localized above the lateral brain ventricles and in the cerebellar hemispheres. Cerebral values of N -acetylaspartate resonance intensities showed a close correlation with patients' disability (Spearman rank correlation = -0.78, P<0.005). These results suggest that MR abnormalities in the dentate nuclei may be evident consistently in patients with CTX. Proton MR spectroscopy data demonstrated widespread axonal damage (as shown by the decrease in N -acetylaspartate) and diffuse brain mitochondrial dysfunction (as shown by the increase in brain parenchymal lactate) in patients with CTX. The close correlation seen between values of the putative axonal marker N-acetylaspartate and patients' disability scores suggests that proton MR spectroscopy can provide a useful measure of disease outcome in CTX.

Proton MR spectroscopy to assess axonal damage in multiple sclerosis and other white matter disorders.

Proton MR spectroscopy allows in vivo measurement of N-acetylaspartate in white matter, providing a biochemical index of axonal integrity. Several recent studies of patients with multiple sclerosis and other white matter disorders have shown both transient and sustained decreases in N-acetylaspartate in white matter lesions and in brain regions appearing normal on conventional MRI. These data have emphasised that a substantial amount of axonal damage or loss (presumably secondary to myelin pathology) is consistently present in most of these disorders. Recent post-mortem studies support these results. In contrast to changes seen with conventional MR imaging, decreases in N-acetylaspartate have shown a close correlation with changes in neurological status. This suggests that axonal damage may be more relevant than demyelination for determining chronic functional impairments in primary white matter diseases. Thus, serial measurement of brain N-acetylaspartate with proton MR spectroscopy can provide a reliable and clinically-relevant monitor of disease evolution. As pathological changes responsible for long-term morbidity are logically important targets for therapeutic agents, early treatment directed at axonal protection should be useful in these disorders.

Imaging axonal damage in multiple sclerosis by means of MR spectroscopy.

Axonal damage in multiple sclerosis has become an important issue. This has been emphasized by recent in vivo proton magnetic resonance (MR) spectroscopy and in vitro pathology studies that have found axonal damage in both lesions and the surrounding normal-appearing white matter. In particular, proton MR spectroscopy, by monitoring levels of N-acetylaspartate (a putative marker of axonal integrity), has been particularly illuminating, as the extent of axonal injury associated with white matter inflammation and demyelination had not been well appreciated from classical pathology studies. Recent MR data demonstrate that cerebral axonal damage begins and contributes to disability from the earliest stages of the disease. This implies that the apparently primary role of axonal damage and loss in the pathogenesis of the disease should be given due importance, and argues for the early treatment of multiple sclerosis with agents directed not only against inflammation, but also towards axonal protection.

Proton magnetic resonance spectroscopy of the brain in dementia.

Proton magnetic resonance spectroscopy (MRS) allows accurate and noninvasive biochemical assay of living tissues. In vivo measurements provided by MRS have greatly enhanced our understanding of the pathophysiology of dementia. Increases in choline and myo-inositol (markers of membrane turnover) have been demonstrated in several studies on patients with Alzheimer's disease (AD), suggesting the presence of a significant cellular membrane (and glial) pathology in this disorder. Large decreases in brain N-acetylaspartate (NAA) (a marker of neuroaxonal integrity) are commonly seen in AD as well as in other forms of dementia in cerebral gray and white matter, indicating the presence of significant axonal damage. Since greater NAA decreases have been demonstrated in brains of patients with clinically more severe disease, NAA could provide an index relevant to patients' clinical status. Brain metabolic changes can be independent of abnormalities detected by conventional magnetic resonance imaging (MRI), since proton MRS may show a normal metabolic pattern in patients with mild neurological impairment and severe MRI abnormalities. However, quantitative measurements of regional brain volumes can be useful in the diagnosis of dementia. Thus, proton MRS, alone or combined with new quantitative magnetic resonance techniques, can provide sensitive indices able to monitor disease progresson or effects of drug therapy.

No evidence of linkage between schizophrenia and D2 dopamine receptor gene locus in Italian pedigrees.

Our purpose was to test the dopamine D2 receptor gene (DRD2), the tyrosine hydroxylase (TH) gene and the monoamino oxydase A (MAO-A) gene for linkage to schizophrenia and bipolar disorders. We have analyzed seven Italian families with schizophrenia and four families with bipolar disorders for a total of 68 individuals; 32 individuals were affected. Diagnoses were made using the structured clinical interview Schedule for Affective Disorders and Schizophrenia, Lifetime version (SADS-L). The results of our study provide no evidence of linkage between alleles at D2 dopamine receptor loci and schizophrenia or bipolar disorders. The markers TH gene and MAO-A gene give slightly positive or negative results suggesting the utility of further analysis on more informative families.

Visual "disappearing phenomenon" can reliably predict the nonadenomatous nature of rectal and rectosigmoid diminutive polyps at endoscopy.

Previous studies have failed to differentiate adenomatous from nonadenomatous diminutive polyps according to their gross macroscopic features at endoscopy. We prospectively evaluated the prevalence, distribution, and predictive value of a recently described morphologic feature-the "disappearing phenomenon"-in diminutive polyps of the distal 20 cm of the large bowel by studying 218 polyps in 90 consecutive patients. Disappearance was graded as complete, incomplete, or absent. Overall, complete disappearance was noted in 93 (43.1%) polyps, with a significantly higher prevalence in the middle and lower rectum (p < .05) and among smaller, paler, and smooth-surface polyps (p < .001). Incomplete disappearance was detected in both nonadenomas (23.1%) and adenomas (15.8%), but, more importantly, complete disappearance occurred in none of the 19 observed adenomas compared with 93 of 199 nonadenomas. Multiple logistic regression analysis revealed that disappearance was the strongest predictor (p < .001) of nonadenomatous histology among considered morphologic criteria. When complete disappearance was used to predict histologic type of diminutive polyps, its sensitivity was 100% and its specificity was 46.7%. In conclusion, the disappearing phenomenon represents a reliable visual marker for identifying nonadenomatous rectal and rectosigmoidal diminutive polyps at endoscopy. Diminutive polyps that disappear completely upon insufflation are invariably nonadenomatous and should not require endoscopic biopsy or removal.

Assessment of genetic polymorphisms in DNA from formalin fixed neurological tissues.

The ability to analyze the genotype of deceased affected members of pedigrees segregating inherited neurological diseases considerably augments the informativeness of such pedigrees. This information has direct application in attempts to isolate disease genes by positional cloning strategies, and for genetic counselling. We show that the genotype at polymorphic simple sequence repeat loci can be determined from genomic DNA isolated from 10 micron thick paraffin embedded, formalin fixed neurological tissues. The critical constraint on this method is the size of the template target bearing the simple sequence repeat, which should ideally be less than 165 base pairs.

Molecular genetics of Alzheimer's disease in Italian families.

We screened 11 families from different regions of Italy by direct sequencing of exon 17 of the APP gene. Two unrelated families carried the APP717 mutation segregating with the disease. These two families originate from two Italian regions which are considered genetically separate. Published studies have demonstrated the presence of the APP717 Val-->Ile mutation in kindreds of British or Japanese origin with early onset familial Alzheimer's disease. These data suggest that the APP717 mutation is not confined to islander families which may share common founders. From the molecular genetic point of view we also did linkage analysis. Several families, in fact, have not shown a linkage with chromosome 21 and the resolution of this dilemma required investigation of those pedigrees both with additional markers from chromosome 21 and with markers from other chromosomes.