Maja Ukmar

A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis

OBJECTIVE (a) To establish whether the cognitive decline of the early phase of relapsing-remitting multiple sclerosis depends on the progression of the burden of disease, or on the loss of brain parenchyma, or is influenced by both; (b) to monitor the loss of brain parenchyma in the early phase of the disease; and (c) to examine its possible relation with the progression of physical disability. METHODS For 2 years 53 patients with clinically definite relapsing-remitting multiple sclerosis with disease duration 1–5 years and expanded disability status scale⩽5.0 at baseline were monitored. The neuropsychological performances, the psychological functioning, the neurological impairment, and the disability have been assessed at baseline and after 2 years. Patients also underwent PD/T2 and T1 weighted brain MRI. T2 and T1 lesion volumes were measured by a semiautomatic technique. Quantification of brain parenchymal volumes was obtained using a highly reproducible computerised interactive program. The relation between cognitive impairment and MRI findings has been investigated by partial correlation and stepwise multiple regression analyses excluding the effects of age, education, anxiety, depression, and total days of steroid use. RESULTS In the 2 years of the study the mean change for T2 and T1 lesion volumes and brain parenchymal volumes were +1.7 ml (95% confidence interval (95% CI) 1.3–2.2, p=0.005, (29.8%); +0.2 ml, 95% CI 0.15–0.26, p=0.004, (25%); and –32.3 ml, 95% CI 24.2–42.3, p<0.0001, (2.7%), respectively. Overall, 14 patients (26.4%) were judged to be cognitively impaired at baseline and 28 (52.8%) at the end of the follow up. Of the 18 neuropsychological tests and subtests employed in the study, patients with multiple sclerosis failed 5.8 (SD 2.3) tests at the baseline and 8.4 (SD 2.9) (p<0.0001) tests at the end of the study. When the cognitive changes were examined in individual patients, five (9.4%) of them were considered cognitively improved, 33 (62.3%) remained stable, and 15 (28.3%) worsened over 2 years. T2 and T1 volume changes in improved, stable, and worsened patients did not show any significant difference, whereas brain parenchymal volume decrease in cognitively worsened patients was significantly greater (−66 ml (5.4%), 95% CI 37–108.9, p=0.0031). The cognitive impairment was independently predicted over 2 years only by the change of brain parenchymal volumes (R=0.51, p=0.0003). Ten patients (18.9%), who worsened by one or more points in the EDSS during the follow up period had significant decreases in brain parenchymal volumes (−99 ml (8%), 95% CI 47.6–182.3, p=0.005). At the end of the study the loss of brain parenchyma correlated significantly with change in EDSS (r= 0.59, p<0.0001). CONCLUSIONS In the early phase of relapsing-remitting multiple sclerosis the cognitive deterioration relies more on the development of brain parenchymal volume atrophy than on the extent of burden of disease in the brain. The loss of brain parenchymal volume underlies the progressive accumulation of physical disability from the initial phase of the disease, which becomes more demonstrable only if studied with longer observation periods. Probably, the main pathological substrate of brain atrophy in the early stage of the disease is early axonal loss, which causes the progression of neurological deficits and the development of cognitive impairment. These data support the debated opinion that disease modifying therapy should be initiated as early as possible.

Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS

Background: IV methylprednisolone (IVMP) has been used to treat relapses in patients with relapsing-remitting (RR) MS, but its effect on disease progression is not known. Furthermore, there are no data on the impact of IVMP on T1 black holes or whole-brain atrophy. Objective: To determine the effect of IVMP on MRI measures of the destructive pathology in patients with RR-MS and secondarily to determine the effect of IVMP on disability progression in patients with RR-MS. Methods: The authors conducted a randomized, controlled, single-blind, phase II clinical trial of IVMP in patients with RR-MS. Eighty-eight patients with RR-MS with baseline Expanded Disability Status Scale (EDSS) scores of ≤5.5 were randomly assigned to regular pulses of IVMP (1 g/day for 5 days with an oral prednisone taper) or IVMP at the same dose schedule only for relapses (IVMP for relapses) and followed without other disease-modifying drug therapy for 5 years. Pulsed IVMP was given every 4 months for 3 years and then every 6 months for the subsequent 2 years. Patients had quantitative cranial MRI scans at study entry and after 5 years and standardized clinical assessments every 4 to 6 months. Results: Eighty-one of 88 patients completed the trial as planned, and treatment was well tolerated. Baseline demographic, clinical, and MRI measures were well matched in the two study arms. Patients on the pulsed IVMP arm received more MP than patients on the control arm of the study (p < 0.0001). Mean change in T1 black hole volume favored pulsed IVMP therapy (+1.3 vs +5.2 mL; p < 0.0001), as did mean change in brain parenchymal volume (+2.6 vs −74.5 mL; p = 0.003). There was no significant difference between treatment arms in the change in T2 volume or annual relapse rate during the study. However, there was significantly more EDSS score worsening in the control group, receiving IVMP only for relapses. There was a 32.2% reduction (p ≤ 0.0001) in the probability of sustained EDSS score worsening in the pulsed MP arm compared with the relapse treatment arm. At the end of the study, EDSS was better in the pulsed MP group (1.7 vs 3.4; p < 0.0001). Prolonged treatment with pulsed IVMP was safe and well tolerated; only two patients dropped out for toxic side effects over 5 years. Conclusions: In patients with RR-MS, treatment with pulses of IVMP slows development of T1 black holes, prevents or delays whole-brain atrophy, and prevents or delays disability progression. A phase III study of IVMP pulses is warranted.

Depression and anxiety in multiple sclerosis. A clinical and MRI study in 95 subjects

Abstract The aim of the present study was to investigate the relationship between involvement of specific areas of the brain and the occurrence of depression and anxiety in patients with multiple sclerosis. We studied 95 patients (62 women and 33 men, mean age 39.5 years, SD 11.2) with definite MS, 97 patients (65 women and 32 men, mean age 40.7, SD 11.9) suffering from chronic rheumatoid diseases and 110 healthy subjects (71 women and 39 men, mean age 40.1, SD 12.7). The disability, the independence, the cognitive performances, the depressive and anxiety symptoms were assessed. The diagnosis of major depression was made according to the DSM-IV. The patients with multiple sclerosis underwent a 1.5 Tesla magnetic resonance examination including T1 and T2 weighted images. Calculation of regional and total lesion loads and brain volumes were performed. The number (%) of subjects with a diagnosis of major depression was 18 (18.9) among MS cases, 16 (16.5) among controls with chronic disease (p=NS), and 4 (3.6) among healthy volunteers (p < 0.0001). The Hamilton Depression and Anxiety rating scales median scores were 5 and 18, respectively in the MS patients, 5 (p= NS) and 14 (p= NS) in the chronic rheumatoid diseases controls, and 3 (p= < 0.0001) and 6 (p= < 0.0001) in the healthy controls. Both severity of depressive symptoms and diagnosis of major depression correlated, albeit weakly, with right frontal lesion load (r=0.22, p=0.035, and r=0.23, p=0.026, respectively) and right temporal brain volume (r=0.22, p=0.005 and r=0.22, p=0.036, respectively). The severity of depression was related significantly also with total temporal brain volume (r=0.26, p=0.012), right hemisphere brain volume (r=0.25, p=0.015), disability (r=0.30, p=0.003) and independence of MS cases (r=−0.26, p=0.01). The anxiety did not correlate significantly with any of the measures of regional and total lesion loads and brain volume or with any of the considered clinical variables. The similar frequency of depression and severity of depressive symptoms in MS patients and in chronic disease patients, the significant difference in this respect with the normal controls, and the significant correlation between depression and the disability measures would suggest a psychological reaction to the impact of the disease but the relationship between depression and the alterations in the frontal and temporal lobes of the right hemisphere supports, on the contrary, the causative role of organic brain damage. The lack of any significant association between symptoms of anxiety and either MRI abnormalities or clinical variables led us to the opinion that anxiety is a reactive response to the psychosocial pressure put on the patients.

What is the role of motor simulation in action and object recognition? Evidence from apraxia

An important issue in contemporary cognitive neuroscience concerns the role of motor production processes in perceptual and conceptual analysis. To address this issue, we studied the performance of a large group of unilateral stroke patients across a range of tasks using the same set of common manipulable objects. All patients (n = 37) were tested for their ability to demonstrate the use of the objects, recognize the objects, recognize the corresponding object-associated pantomimes, and imitate those same pantomimes. At the group level we observed reliable correlations between object use and pantomime recognition, object use and object recognition, and pantomime imitation and pantomime recognition. At the single-case level, we document that the ability to recognize actions and objects dissociates from the ability to use those same objects. These data are problematic for the hypothesis that motor processes are constitutively involved in the recognition of actions and objects and frame new questions about the inferences that are merited by recent findings in cognitive neuroscience.

MRI techniques and cognitive impairment in the early phase of relapsing-remitting multiple sclerosis.

Abstract Correlation studies between various conventional and non-conventional MRI parameters and cognitive impairment in the early stages of multiple sclerosis (MS) are lacking, although it is known that a number of patients with early MS have mild cognitive impairment. Our aim was to explore whether this cognitive impairment is dependent on the extent and severity of the burden of disease, diffuse microscopic brain damage or both. We studied 63 patients with clinically definite relapsing-remitting (RR) MS, duration of disease 1–10 years and Expanded disability status scale scores ≤ 5.0. Mean age was 35.4 years, mean duration of disease 5.8 years and median EDSS score 1.5. Neuropsychological performance, psychological function, neurological impairment and disability were assessed. The patients also underwent MRI, including magnetisation-transfer (MT) studies. We quantified the lesion load on T2- and T1-weighted images, the magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT) and the brain parenchymal fraction (BPF). No significant difference was found between lesion loads in patients with and without cognitive impairment. In 15 patients (23.8 %) with overall cognitive impairment, median BPF and average NABT MTR were significantly lower than those in patients without cognitive impairment (0.868 vs 0.892, P = 0.02 and 28.3 vs 29.7 P = 0.046, respectively). Multiple regression analysis models demonstrated that the only variables independently correlated with cognitive impairment were: BPF (R = 0.89, P = 0.001) and average NABT MTR (R = 0.76, P = 0.012). Our findings support the hypothesis that, cognitive decline in patients with MS, a low disability score and short duration of disease is directly associated with the extent and severity of diffuse brain damage. The loss of brain parenchyma did not correlate with the severity of microscopic damage in the NABT, indicating that the two processes could be distinct in the early stages of the disease.

Evaluation of white matter damage in patients with Alzheimer’s disease and in patients with mild cognitive impairment by using diffusion tensor imaging

PurposeThe objective of this study was to evaluate white matter tissue damage in patients with Alzheimer’s disease (AD) and in patients with mild cognitive impairment (MCI) using diffusion tensor imaging (DTI).Materials and methodsForty-seven subjects were evaluated: 14 patients with AD, 15 with MCI and 18 healthy volunteers. All subjects were studied using conventional magnetic resonance imaging (MRI) and DTI (32 directions) with a 1.5 T magnet. Fractional anisotropy (FA) was measured in the following regions: frontal, occipital, parietal and temporal white matter and in the genu and splenium of the corpus callosum. The results were compared between the different groups and correlated with the Mini-Mental State Evaluation (MMSE) scores.ResultsA statistically significant difference was obtained between controls and MCI patients (p<0.007) and between controls and AD patients (p<0.05) with regard to FA of the white matter in the splenium. A statistically significant difference was obtained between controls and AD patients with regard to FA in the genu (p<0.016). Moreover, there was a statistically significant difference between controls and AD patients considering the genu (p<0.016) and the frontal white matter on the right side (p<0.024). The MMSE scores correlated with the FA values measured in the genu, the splenium and frontal white matter on the right side. No significant differences were identified between patients with AD and those with MCI.ConclusionsDTI could be of value in the early detection of white-matter damage in patients with MCI and AD. The DTI values correlate with the neuropsychological tests.RiassuntoObiettivoValutare mediante risonanza magnetica (RM) con tensori di diffusione (DTI) le alterazioni della sostanza bianca in soggetti con malattia di Alzheimer (AD) e in soggetti con mild cognitive impairment (MCI).Materiali e metodiSono stati valutati 47 soggetti: 14 pazienti con diagnosi di AD, 15 pazienti con diagnosi di MCI e 18 soggetti sani di controllo. Gli esami di RM sono stati eseguiti con un magnete da 1,5 T mediante sequenze convenzionali e una sequenza pesata in diffusione con tensori applicati secondo 32 direzioni. È stata valutata l’anisotropia frazionaria (FA) a livello della sostanza bianca frontale, parietale, occipitale e temporale nonché a livello dello splenio e del ginocchio del corpo calloso. I risultati ottenuti sono stati confrontati tra i tre gruppi e con il MMSE test.RisultatiÈ emersa una differenza statisticamente significativa a livello dello splenio per quanto riguarda la FA tra i soggetti con MCI ed i controlli (p<0,007) e tra soggetti con AD ed i controlli (p<0,05), a livello del ginocchio tra i controlli e i soggetti con AD (p<0,016) e a livello della sostanza bianca frontale destra fra controlli e soggetti con AD (p<0,024). La FA è risultata correlare con il MMSE a livello del ginocchio, dello splenio e della sostanza bianca a livello frontale destro. Dal confronto fra i soggetti con MCI ed il gruppo con AD non è emersa alcuna differenza statisticamente significativa.ConclusioniL’utilizzo dei tensori di diffusione nei pazienti con AD e MCI consente una precoce valutazione del danno della sostanza bianca. I valori di DTI correlano con i test neuropsicologici.

I nterferon beta-1a slows progression of brain atrophy in relapsing-remitting multiple sclerosis predominantly by reducing gray matter atrophy

Background Brain atrophy, as assessed by magnetic resonance imaging (MRI), has been correlated with disability in patients with multiple sclerosis (MS). Recent evidence indicates that both white matter (WM) and gray matter (GM) are subject to atrophy in patients with MS. Although neurological deficiencies in MS are primarily due to loss of WM, the clinical significance of GM atrophy has not been fully explored in MS. Methods We have undertaken a three-year, open-label study, comparing 26 patients who elected to receive intramuscular interferon beta-1a (IFN β-1a) therapy, with 28 patients who elected not to receive therapy. Both groups had quantitative cranial MRI scans at study entry and after three years, and standardized clinical assessments every six months. Brain parenchymal fraction (BPF), GM fraction (GMF), and WM fraction (WMF) percent changes were calculated, and T2- and T1-lesion volumes (LVs) assessed. Results After three years, mean percent (%) change in BPF favored the IFN β-1a treatment group (IFN β-1a —1.3% versus the control group —2.5%, P=0.009), as did the mean percent change in GMF (+0.2 versus —1.4%, P=0.014), and the mean percent change in T1-LV (—9.3 versus +91.6%, P=0.011). At the end of the study, there was a significant within-patient decrease in BPF for both groups (P=0.02 for the IFN β-1a treatment group, and P<0.001 for the control group), a significant within-patient decrease in WMF for the IFN β-1a treatment group (P=0.01), and a significant decrease in GMF for the control group (P=0.013) when compared with baseline. Conclusion Over a three-year period, treatment with IFN β-1a significantly slowed the progression of whole-brain and GM atrophy, and of T1-hypointense LV accumulation, when compared with the control group. Multiple Sclerosis 2007; 13: 490-501. http://msj.sagepub.com

Depressive symptoms and MRI changes in multiple sclerosis.

To determine whether changes in specific regions of the brain can contribute to the development of depression in patients with multiple sclerosis (MS). We prospectively studied 90 patients with clinically definite MS. Disability, independence, cognitive performances, and depressive and anxiety symptoms have been assessed at baseline and 2 years later. At these two time‐points, patients underwent a 1.5‐T magnetic resonance examination of the brain including T1‐ and T2‐weighted images. Calculation of regional and total lesion loads (LL) have been performed by a semiautomatic technique; total and regional brain volumes have been calculated by a fully automatic highly reproducible computerized interactive program. Measurements of LL did not show any significant difference between depressed and non‐depressed patients. Brain atrophy was significantly more conspicuous in the left frontal lobe (P=0.039), in both frontal lobes (P=0.046) and showed a trend towards a difference in the right frontal lobe (P=0.056), in the right temporal lobe (P=0.057) and in both temporal lobes (P=0.072) of depressed patients. Disability, independence and cognitive performances were similar in depressed and non‐depressed patients (P=NS). Spearman correlation analysis and multiple‐regression analysis demonstrated that the severity of the depressive symptoms score was associated both with the disability score and the right temporal brain volume. Destructive lesions in the right temporal lobe can contribute to the severity of depression in patients with MS but the influence of the severity of neurological impairment should be taken into account.

Olfactory dysfunction and extent of white matter abnormalities in multiple sclerosis: a clinical and MR study

Background: The relative contribution to the olfactory dysfunction of the lesions in the specific brain regions involved in olfaction compared with the lesions scattered all over the rest of the brain has not been fully clarified yet in patients with multiple sclerosis (MS). The concurrent use of Magnetic Resonance Imaging (MRI) and a standardized test of odor identification ability now permits to study the relation between smell loss and the extent of white matter abnormalities. Methods: We tested the olfactory function of 40 patients with definite MS and of 40 age-sex- and smoking-habit-matched healthy controls by using the Cross Cultural Smell Identification Test. We measured also the lesion load on T2-weighted images in the inferior-frontal and temporal lobes and in the rest of the brain in MS patients. Therefore, we tried to correlate measures of lesion load and smell test scores. Results: A robust correlation was demonstrated between MR measures of lesion load in the white matter of the olfactory brain region and smell loss (r=70.739, P50.0001). A significant relationship has been found even after taking potential confounding factors, such as sex, age, disease duration, disability, anxiety and depression, into account (r=70.90, P50.0001). Conclusions: Our findings show, in MS patients with stable neurological impairment and no recent disease exacerbation, a correlation between smell loss and the lesion load in the regions of the brain involved in olfaction and support the theory that the extent and severity of MRI abnormalities in specific brain regions are related to the presence of selective neurologic and neuropsychologic impairment.

Persistent aura without infarction: decription of the first case studied with both brain SPECT and perfusion MRI

To the best of our knowledge, persistent visual symptoms, lasting months or years without evidence of infarction, a rare complication of migraine with aura, has been reported in only 20 patients. We report the case of a 43-year-old woman with a 31-year history of migraine with typical visual aura. At presentation, she experienced a visual aura in her right hemifield followed by a pulsating headache. The visual symptoms persisted. There were no abnormal findings on neurological and ophthalmological examinations, EEG, visual evoked potentials (VEPs), brain computed tomography and magnetic resonance imaging (MRI). Both brain single photon emission compted tomography (SPECT) and brain perfusion MRI revealed decreased left fronto-parieto-occipital and right occipital blood perfusion. A perfusion MRI, performed 7 months after symptom onset and almost complete extinction of symptoms, was normal. As previously reported, we demonstrated a cortical hypoperfusion by SPECT in a case of persistent visual aura. For the first time this finding was confirmed by perfusion MRI.