M. Mortilla

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.

Relevance of cognitive deterioration in early relapsing-remitting MS: a 3-year follow-up study

Objective: To assess longitudinally cognitive functioning in relapsing—remitting multiple sclerosis (RRMS) patients and its relationship with clinical and MRI variables. Methods: Early RRMS patients and matched healthy controls were assessed in parallel in three testing sessions over 3 years, using the Rao’s Brief Repeatable Battery of Neuropsychological Tests. Patients also underwent an MRI analysis of T2-weighted lesion volume (T2LV), number of gadolinium-enhanced lesions and whole brain atrophy. Forty-nine RRMS patients (mean age 36.9 ± 8.9 years; mean disease duration 2.9 ± 1.7 years, mean Expanded Disability Status Scale, 1.7 ± 0.7) and 56 healthy controls were recruited. Results: At baseline, cognitive impairment was detected in 15 patients (30.6%). After 3 years, cognitive functioning worsened in the 29.3% of patients, whereas Expanded Disability Status Scale progression was observed in only three patients. The most sensitive test to detect cognitive deterioration over time was the Symbol Digit Modalities Test (SDMT). Only the presence of moderate cognitive impairment at baseline predicted further cognitive deterioration (p = 0.03). Among MRI variables, T2LV showed a weak to moderate relationship with some cognitive tasks. Conclusions: Over a 3-year period cognitive deterioration can be expected in approximately one-third of MS patients with relatively short disease duration. The SDMT is particularly suitable for longitudinal assessment of MS-related cognitive changes.

Imaging brain damage in first-degree relatives of sporadic and familial multiple sclerosis.

Our objective was to assess brain damage in first‐degree relatives of patients with sporadic and familial multiple sclerosis (MS).

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

Abstract 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.

Neocortical volume decrease in relapsing–remitting multiple sclerosis with mild cognitive impairment

The aim of the study was to assess neocortical changes and their relevance to cognitive impairment in early relapsing-remitting multiple sclerosis (RRMS). Conventional magnetic resonance was acquired in 41 RRMS patients and 16 demographically matched normal controls (NC). An automated analysis tool was used to obtain measures of cortical brain volumes normalized for head size. Neuropsychological performance of MS patients was assessed through the Raos Brief Repeatable Battery. We identified 18 cognitively preserved (MS-cp) and 23 cognitively impaired (MS-ci) MS patients. Values of normalized cortical volumes (NCV) in the whole MS sample were lower than those in the NC group (p=0.01). MS-ci patients showed NCV values lower (p=0.02) than did both MS-cp patients and NC. Moreover, we found a positive correlation 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 significantly decreased in patients who scored lower on a greater number of tests (r=-0.58, p<0.01) in the MS-ci group. Only MS-ci patients had cortical atrophy significantly correlated with a poorer neuropsychological performance. Grey matter pathology may contribute to the development of cognitive impairment in MS from the earliest stages of the disease.

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 (1H-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 cm3). They were mostly distributed in the frontal and parietal regions, with the highest probability in the corona radiata. On 1H-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.

Imaging axonal damage in multiple sclerosis by means of MR spectroscopy

Abstract 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.

Altered hexokinase activity in skin cultured fibroblasts and leukocytes from Alzheimer's disease patients

Changes in the activity of brain glycolytic enzymes have been reported in Alzheimers dementia. In this paper we studied the activity of the rate-limiting glycolytic enzymes, namely phosphofructokinase, lactate dehydrogenase and hexokinase in skin cultured fibroblasts and leukocytes from familial and sporadic Alzheimers disease patients and unaffected relatives. Phosphofructokinase and lactate dehydrogenase activities were similar in all groups studied. The activity of hexokinase was reduced in some patients with the familial dominant form of Alzheimers disease whilst it was normal in sporadic cases. These results suggest that Alzheimers disease may be an heterogeneous disorder and that a modification on the catalytic activity of hexokinase may play a role in the pathogenesis of the disease in at least a subgroup of patients.

Evidence of diffuse brain pathology and unspecific genetic characterization in a patient with an atypical form of adult-onset Krabbe disease

Sirs: Krabbe disease (KD) is a rare autosomal recessive disorder due to a diminished activity of the lysosomal enzyme galactocerebrosidase (GALC) [7, 13]. The demonstration of a severe deficiency in GALC activity in leukocytes or fibroblasts is the basis for diagnosis. The human GALC gene (mapped to chromosome 14q24.3– q32.1, see [14] for details) has been cloned, and a number of KD-causing mutations have been identified. Recent studies have reported an unusual, slowly progressive adult form of KD characterized by spastic paraparesis and magnetic resonance imaging (MRI) findings of bilateral corticospinal tract demyelination [11, 12]. It has been suggested that the new homozygous point mutation T1835C (L618S) found in the GALC gene of one of these patients [11] is characteristic of this form of late-onset KD. We describe a 44-year-old woman who was hospitalized because of slowly progressive gait disturbance. There was no family history of neurological disease. Her birth and delivery were uncomplicated, and development milestones were normal. She did not have neurological symptoms until the age of 42 years, when she began to complain of an unsteadiness of gait. Neurological examination showed mild spastic paraparesis with increased muscle tone in the legs. All deep-tendon reflexes were symmetrically brisk, with bilateral Babinski sign. Sense of joint position and sensation to light touch and pinprick were normal, while vibration sense was mildly decreased in the legs. Mental functions were normal. Blood laboratory examinations showed an iron deficiency anemia. Urine tests were normal. Electromyography and nerve conduction studies showed evidence of demyelinating sensorimotor neuropathy. A sural nerve biopsy specimen revealed mild signs of demyelination, with the presence of inclusions within Schwann’s cells on electron microscopy. The activity of a number of lysosomal enzymes was screened in the patient’s cultured skin fibroblasts [15], and only the GALC activity was decreased (0.26 nmol h–1 mg–1 protein, <10% of the normal mean). DNA was isolated from cultured cells as previously described [10]. The patient was found to be heterozygous for two previously reported mutations: G > A at cDNA position 809 (G270D) and 1026del10. The first mutation, G > A at cDNA position 809 (G270D), has been identified previously in other patients with adult-onset KD [3, 6, 14]. The second mutation, previously identified in another Italian patient with infantile KD [14], consists of a 10 basepair deletion starting in exon 10 at nucleotide 1026. This results in a frame shift and premature stop codon and most likely would not produce any active enzyme since there would be no production of the 30-kDa subunit necessary for activity. Combined brain proton MRI and magnetic resonance spectroscopic imaging (MRSI) was performed using a Philips Gyroscan NT operating at 1.5 T. Multislice spin-echo images were obtained in coronal and transverse planes perpendicular and parallel to the anterior commissure (AC) and posterior commissure (PC) line, LETTER TO THE EDITORS J Neurol (2000) 247 :226–228

Diffuse structural and metabolic brain changes in Fabry disease.

AbstractObjectivesTo assess structural and metabolic brain changes in subjects affected by Fabry disease (FD) or carrying the disease mutation.BackgroundFD is an X–linked metabolic disorder due to α-galactosidase A deficiency, which leads to storage of glycosphingolipids in many tissues and organs. Previous MR studies have shown structural and metabolic brain abnormalities in FD patients. It is not clear, however, whether tissue damage can be seen in both the brains of hemizygous and heterozygous and whether quantitative MR metrics are useful to monitor disease evolution.Design/MethodsWe studied 4 males and 4 females with FD. Each subject underwent brain proton MRI/MR spectroscopic imaging (MRSI) examinations to obtain measures of total brain volumes, total brain lesion volumes, magnetization transfer ratios (MTr) in WM and central brain levels of N–acetylaspartate (NAA) to creatine (Cr). A second MR examination was performed in five subjects after 2 years.ResultsFocal WM lesions were found in 2 males and 1 female. The MTr values were always low in the WM lesions of FD subjects (p < 0.001) and also were low in the normal–appearing WM of 2 affected males. Total brain volumes were never decreased in FD subjects. Brain NAA/Cr values were significantly (p = 0.005) lower in FD subjects than in normal controls and correlated closely with Rankin scale measures (r = –0.79). On follow–up examinations, no significant MR changes were found. However, the small changes in NAA/Cr correlated closely with changes in Rankin scores (r = –0.86).ConclusionsSubtle structural and metabolic tissue damage can extend beyond WM lesions in FD subjects. Diffuse brain NAA/Cr decrease can be found in FD subjects in relation to the degree of their CNS involvement and its evolution over time.