Дисертації з теми "MULTIPLE SCLEROSIS, MRI, COGNITIVE IMPAIRMENT"

La sclerosi multipla (SM) è il prototipo delle malattie demielinizzanti, in cui la patologia della sostanza grigia e bianca (GM/WM) contribuisce alla compromissione di diversi domini cognitivi tra cui l’attenzione, la velocità di elaborazione mentale, la memoria, le funzioni esecutive e visuospaziali, così come molti aspetti della cognizione sociale. L’obiettivo principale del presente studio di risonanza magnetica (MRI) era di indagare l’effetto della SM sulla cognizione e sulla struttura del cervello, combinando indagini neuropsicologiche e morfologiche. Abbiamo mirato ad analizzare i cambiamenti delle principali funzioni cognitive nel tempo in pazienti ambulatoriali con SM recidivante-remittente (SMRR) lieve e iniziale rispetto ai soggetti sani, e correlato questi risultati ai cambiamenti di volume regionale nella GM. Abbiamo inoltre esplorato l’impatto della SM su molti aspetti della cognizione sociale, dell’umore, della fatica, del benessere psicologico e della qualità della vita di questi pazienti tra l’inizio e la fine dello studio. Il primo risultato MRI importante riguardava l’identificazione di un pattern di atrofia temporale destra (giro temporale inferiore e polo temporale medio) nel gruppo SMRR rispetto ai controlli normali, che è rimasto invariato tra la valutazione basale e il follow-up. Dopo un anno, è emersa una considerevole atrofia della GM profonda dell’emisfero destro (amigdala, globo pallido e putamen) e del cervelletto (14.2%), mentre scompariva nel putamen e nell’insula dell’emisfero sinistro. Inoltre, fattori quali il sesso, l’età e la velocità di elaborazione (cioè, il Symbol Digit Modalities Test) erano in grado di predire il volume della GM dei pazienti a un anno. Per quanto riguarda la valutazione cognitiva, i risultati primari evidenziavano che una grande percentuale (circa il 50%) del gruppo SMRR era significativamente compromessa rispetto ai controlli in prove riguardanti memoria a breve ed a lungo termine, velocità di elaborazione, funzioni visuospaziali ed esecutive, ed emozioni negative (tristezza e rabbia). I pazienti mostravano inoltre sintomi di disagio psicologico (somatizzazione, ossessività-compulsività, ostilità e problemi interpersonali). Queste difficoltà tendevano ad appiattirsi nel tempo nel gruppo SMRR. Mentre la memoria a lungo termine, le abilità visive percettive e spaziali e l’attribuzione della rabbia sembravano migliorare, i deficit di memoria di lavoro, velocità di elaborazione e inibizione dell’interferenza, e il riconoscimento della tristezza rimanevano stabili dopo un anno. Al follow-up, anche le caratteristiche di disagio psicologico si erano attenuate, ma emergevano nuovi sintomi depressivi. In conclusione, i nostri risultati hanno evidenziato che vi era un declino cognitivo minimo ma significativo nel gruppo SMRR. Il pattern di atrofia temporale riscontrato nei pazienti rispetto ai controlli poteva rendere conto dei loro deficit iniziali. Dopo un anno, la significativa riduzione dei volumi cerebellari e delle strutture GM profonde poteva inoltre spiegare perché le difficoltà primarie nella memoria e nel riconoscimento della tristezza erano rimaste stabili, mentre le altre erano diminuite. Tutti questi deficit non erano significativamente correlati ad altri fattori, come l’umore, la fatica e le caratteristiche cliniche della malattia. Sebbene le prestazioni in alcune misure esecutive siano probabilmente migliorate a causa dell’effetto della pratica, al follow-up di un anno la memoria di lavoro e la velocità di elaborazione erano ancora compromesse, dimostrando che la progressione a breve termine della malattia ha un impatto clinicamente significativo su queste capacità. Anche gli aspetti emozionali e comportamentali erano migliorati nel tempo, suggerendo che la gestione sanitaria precoce e il trattamento farmacologico possono contribuire al benessere e alla qualità della vita delle persone con SM.
Multiple sclerosis (MS) is the prototype of demyelinating diseases, in which both gray and white matter (GM/WM) pathology contribute to impairment of several cognitive domains including attention, mental processing speed, memory, executive and visuospatial functions, as well as many aspects of social cognition. Such deficits have been reported in all stages and subtypes of the disease, and result in significant, negative consequences for mood and quality of life of people with MS. The main goal of the current magnetic resonance imaging (MRI) study was to investigate the effect of MS on cognition and brain structure, by combining neuropsychological and morphological investigations. More precisely, we aimed to analyze changes of main cognitive functions over time in mild and early relapsing-remitting MS (RRMS) outpatients compared to healthy subjects, and correlated these findings to GM regional volume changes. We were also interested to explore the impact of MS on many aspects of social cognition, mood, fatigue, psychological well-being, and quality of life of these patients between the beginning and the end of the study. The first important MRI result was the identification of a right temporal atrophy pattern (inferior temporal gyrus and middle temporal pole) in the RRMS group compared to normal controls, which was unchanged between the baseline and follow-up. After one year, a considerable atrophy in deep GM of right hemisphere (amygdala, globus pallidus and putamen) and cerebellum (14.2%) emerged, while disappeared in the left putamen and insula. In addition, the GM volume of the patients at one year was predicted by sex, age, and processing speed (i.e., Symbol Digit Modalities Test). As for the cognitive evaluation, primary results highlighted that a large proportion (about 50%) of the RRMS group was significantly impaired compared with controls on short- and long-term memory, processing speed, visuospatial and executive functions, and negative emotions (sadness and anger). Patients also showed symptoms of psychological distress (somatization, obsessive-compulsiveness, hostility, and interpersonal problems). These impairments in the RRMS group tended to flatten over time. While long-term memory, perceptual and spatial visual skills, and the anger attribution seemed to improve; deficits in working memory, processing speed and interference inhibition, and the recognition of sadness remained stable after one year. At the follow-up, characteristics of psychological distress were also reduced, but new depressive symptoms emerged. In conclusion, our results highlighted that there was a minimal but significant cognitive impairment in the RRMS group. After one year, a significant reduction in the cerebellar and deep GM structure volumes could also explain why primary deficits in memory and recognition of sadness remained stable, while the others decreased. All these impairments were not significantly related to other factors, such as mood, fatigue and clinical features of the disease. Although performance in some executive measures probably improved due to ‘practice effect’, working memory and processing speed were still impaired at one-year follow-up, proving that the short-term progression of the disease has a clinically meaningful impact on these abilities. Even emotional-behavioral aspects had improved over time, leading to a better adaptation to the disease by patients. Early management of healthcare taking-charge and pharmacological treatment, which occur at the initial stage of the disease, may also contribute to the well-being and quality of life of people with MS.

Cognitive impairment strongly affects people with multiple sclerosis (MS). It comprises multifactorial symptoms and no consistent treatments are available to date. Although cognitive impairment has been observed in all stages of the disease, the majority of studies mainly focused on a specific clinical phenotype (primarily relapsing-remitting MS) or did not differentiate between MS subtypes. Advanced magnetic resonance imaging (MRI) techniques are providing useful measures of functional and structural abnormalities in patients with MS, allowing to overcome the limits of conventional MRI. This thesis wished to improve the understanding of the mechanisms responsible for the accumulation of cognitive dysfunction in patients with relapse-onset MS by combining different advanced structural and functional MRI techniques. First, we applied functional MRI (fMRI) to assess brain functional reorganization in relation to different cognitive tasks (face encoding and N-back) in patients with the main relapse-onset clinical phenotypes. We also explored the relationship between functional network alterations and clinical, cognitive, behavioural and structural MRI measures of disease-related damage. Our results provide new evidence for the debate about adaptive/maladaptive functional reorganization in MS, specifically in relation to the clinical and cognitive characteristics of MS phenotypes. Second, the investigation of resting state default mode network (DMN) functional connectivity enabled us to highlight that different modulations of DMN recruitment lead to different clinical profiles and manifestations. Moreover, functional connectivity of specific DMN areas (hippocampi) was found to be central for the assessment of important cognition-related aspects, such as depression. Finally, by applying voxel-wise MRI methods (VBM and TBSS) we explored the extent and distribution of brain GM atrophy and WM microstructural alterations in adult MS patients according to their age of disease onset, and we made some assumptions about the possible presence of pathophysiological mechanisms related to age of MS onset, that suggests a preserved reserve for structural plasticity that could modulate the structural and functional brain organization, in order to preserve or slow-down MS-related dysfunction. To conclude, the application of advanced MRI techniques allowed us to improve our knowledge on neuropsychological features in patients with relapse-onset MS.

During this PhD research course, different advanced MRI techniques were applied in pediatric multiple sclerosis (MS) patients to characterize the neuroanatomical substrates of cognitive impairment, to explore the complex interplay between gray matter (GM) maturational processes and disease-related damage and to unravel in vivo potential pathogenetic mechanisms. In details, inefficient regulation of the functional interaction between different areas of sustained attention system due to abnormal white matter (WM) integrity was identified as a potential substrate of cognitive impairment in pediatric MS patients. In a longitudinal setting, we observed that pediatric MS patients experienced failures in GM development in several cortical and sub-cortical regions, as well as GM atrophy progression in most of these regions. These abnormalities were only partially related to focal MS lesions, thus suggesting the existence of early neurodegenerative processes independent from WM lesions. Furthermore, higher IQ, a proxy of cognitive reserve in pediatric patients, resulted as a protective factor against GM damage, being associated with reduced deviations from age-expected volumes of specific GM regions at baseline and during the follow-up. Focusing on the thalamus, we observed a trend toward thalamic atrophy and we detected significant microstructural abnormalities as assessed by using different quantitative MRI measure (fractional anisotropy, mean diffusivity and T1/T2-weighted ratio). Segmenting the thalamus and thalamic WM into concentric bands originating from CSF/thalamus interface, we observed significant microstructural abnormalities in bands nearest to CSF and in those closest to WM. Moreover, the abnormalities detected at CSF/thalamus interface correlated with cortical thickness reduction, while those at thalamus/WM interface with WM lesion volume. These findings support the hypothesis of heterogeneous pathological processes, including retrograde degeneration from WM lesions and CSF-mediated damage, leading to thalamic microstructural abnormalities, likely preceding macroscopic tissue loss. In a longitudinal setting, we identified several predictors of disease course and prognosis in pediatric MS patients. Shorter time to first relapse was predicted by optic nerve lesions, while longer time was predicted by high-efficacy treatment exposure. Lesion location at baseline MRI scan together with disease activity during the first 2 years of disease significantly accounted for annualized relapse rate over 9-year of follow-up. The involvement of clinically eloquent sites (such as the optic nerve, brainstem, and spinal cord) at baseline, together with disability and MRI activity during the first 2 year of disease were found as significant predictors of 9-year disability. Finally, analyzing data from the Italian MS Register, we showed that compared to post-pubertal, pre-pubertal onset pediatric MS patients took longer time from disease onset to convert to secondary progressive phenotype and to reach irreversible Expanded Disability Status Scale scores of 3, 4, and 6. These findings highlight a different natural history of pre- vs post-pubertal onset pediatric MS, pointing towards the existence of specific pathophysiological mechanisms, combined with a greater capacity of recovery to counteract damage, in younger pediatric MS patients.
Durante questo corso di dottorato di ricerca, sono state applicate diverse tecniche avanzate di risonanza magnetica (RM) in pazienti pediatrici con sclerosi multipla (SM) per caratterizzare i substrati neuroanatomici del deterioramento cognitivo, per esplorare la complessa interazione tra i processi maturativi della sostanza grigia (SG) e il danno correlato alla malattia e per individuare in vivo potenziali meccanismi patogenetici. Un’inefficiente regolazione dell'interazione funzionale tra diverse aree del sistema dell’ attenzione sostenuta a causa del danno macro- e micro-strutturale della sostanza bianca (SB) è stata identificata come un potenziale substrato del deterioramento cognitivo nei pazienti pediatrici con SM. In un setting longitudinale, abbiamo osservato che i pazienti pediatrici con SM vanno incontro ad alterazioni dello sviluppo della SG in diverse regioni corticali e sottocorticali ed a progressiva atrofia nella maggior parte di queste regioni. Queste anomalie apparivano solo parzialmente correlate alle lesioni focali tipiche della SM, suggerendo così l'esistenza di processi neurodegenerativi precoci, indipendenti dalle lesioni della SB. Inoltre, un QI più elevato, misura indiretta della riserva cognitiva nei pazienti pediatrici, è risultato un fattore protettivo contro il danno della SG, essendo associato a minor deviazione dai volumi attesi per età di specifiche regioni di SG. Focalizzandoci sul talamo, abbiamo osservato una tendenza all'atrofia di questa struttura ed abbiamo rilevato anomalie microstrutturali utilizzando diverse misure quantitative di RM (anisotropia frazionaria, diffusività media e rapporto T1/T2). Segmentando il talamo e la SB talamica in bande concentriche partendo dall'interfaccia liquor/talamo, abbiamo osservato anomalie microstrutturali nelle bande più vicine al liquor e in quelle più vicine alla SB. Inoltre, le alterazioni rilevate all'interfaccia liquor/talamo correlavano con la riduzione dello spessore corticale, mentre quelle all’interfaccia talamo/SB con il volume delle lesioni della SB. Questi risultati supportano l'ipotesi di processi patologici eterogenei: degenerazione retrograda da lesioni della SB e danno mediato dal liquor, che portano ad anomalie microstrutturali talamiche precedenti la perdita di sostanza. In un setting longitudinale, abbiamo identificato diversi predittori del decorso di malattia e della prognosi nei pazienti pediatrici con SM. Un intervallo tempo più breve tra l’esordio di malattia e la prima ricaduta appariva associato alla presenza di lesioni del nervo ottico, mentre un intervallo più lungo all'esposizione al trattamento. La localizzazione delle lesioni alla prima RM insieme all'attività di malattia durante i primi 2 anni correlava con il tasso di recidiva annualizzato in 9 anni di follow-up. Il coinvolgimento di siti clinicamente eloquenti (come il nervo ottico, il tronco cerebrale e il midollo spinale) insieme alla disabilità ed all'attività neuroradiologica durante i primi 2 anni di malattia sono stati individuati come predittori della disabilità a 9 anni. Infine, analizzando i dati del Registro Italiano Sclerosi Multipla, abbiamo dimostrato che rispetto ai pazienti pediatrici con SM ad esordio post-pubere, i pazienti con SM con esordio pre-pubere impiegano più tempo dall'insorgenza della malattia per convertire al fenotipo secondariamente progressivo e per raggiungere più elevati livelli di disabilità. Questi risultati evidenziano una diversa storia naturale della SM pediatrica pre- e post-pubere che indica l'esistenza di meccanismi fisiopatologici specifici ed una maggiore capacità di recupero nei pazienti pediatrici più giovani.

Cognitive impairment is common in multiple sclerosis (MS), with as many as 70% of patients with MS affected. Individuals with MS who experience cognitive deficits are less likely to be employed, and may have more difficulty performing independent activities of daily living. Most commonly, deficits are observed in processing speed, complex attention, and memory. Because lesion location varies widely among individuals, no clear pattern of cognitive dysfunction in MS has emerged. However, a number of risk and protective factors may influence the likelihood of individuals to develop and/or express dysfunction, though the contribution of each to specific domains of cognition has not been fully explored. Recently, support for the cognitive reserve hypothesis (i.e., enriching life experiences protect against cognitive decline despite disease burden) has emerged in the MS literature. The current study investigated the contributions of cognitive reserve to learning and memory functioning in MS and the interaction of cognitive reserve variables and risk factors known to impact cognitive functioning in individuals with MS. Finding revealed cognitive reserve protects against decline in the domains of processing speed and complex attention. Furthermore, indirect protective effects of cognitive reserve through these domains were observed for verbal learning and memory. Finally, in line with previous literature, cognitive dysfunction predicted employment status of the current sample. Clinical implications and future directions for intervention efforts are discussed.

Ten people with multiple sclerosis (MS) who felt they had cognitive difficulties because of their MS were investigated. This study had multiple aims. Firstly, to explore the subjective experience of cognitive deficits. Secondly, to assess whether or not there was objective evidence of cognitive difficulties on neuropsychological testing, and whether this was commensurate with a pattern of subcortical dementia. Thirdly, to determine whether their magnetic resonance imaging (MRI) scans replicated the patterns of atrophy frequently reported in MS patients with cognitive difficulties. And finally, to investigate the psychological well-being of the subjects. In depth neuropsychiatric interviews, psychiatric and psychological inventories, a comprehensive neuropsychological battery, and MRI investigations were done. The mean Full Scale Intelligence Quotient (FSIQ) fell within the superior range, at the 89th percentile. On tests of general intelligence, mental state examinations, there was little or no indication of cognitive deterioration. However, on sophisticated neuropsychological testing, there was convincing evidence of cognitive problems. Magnetic resonance imaging lesions were atypical of the reported research on cognitively compromised MS patients.

Cognitive impairment is an important contributor to disability in multiple sclerosis (MS), one of the most common chronic neurological condition affecting young adults. The clinical presentation of cognitive changes in MS is unique given the progressive nature of the disease and the interaction between cognitive impairments and other MS symptoms. Appropriate evaluation of cognitive deficits is an important issue in assessment for persons with MS. The main objectives of this study are to provide a modern approach to assess stability, unidimentionality and item hierarchy of the Perceived Deficits Questionnaire (PDQ) for persons with MS and to estimate the extend to which there are gender differences in the associations of mood and fatigue with perceived cognitive function and with tested cognitive capacity in persons diagnosed with MS. A center-stratified sample of 185 persons with MS was assembled and participants were evaluated on both perceived and measured cognitive function, as well as other clinical aspects of the disease. To develop an interval-like measure, Rasch analysis was performed, which helped to identify the item hierarchy of PDQ, to confirm the factor structure, item fit and redundancy, unidimensionality, as well as to examine item stability. As a result, an 11-item questionnaire, the PDQ-Rasch was developed. Cognitive function was measured in two ways. The PDQ was used to assess self- perceptions and the PASAT was used to measure processing speed. Multiple linear regression models were used to identify correlates of perceived cognition and measured cognition. PDQ was explained by depressed mood, fatigue, female gender and pain. Furthermore, mood had a stronger effect among women than men on PDQ. PASAT was predicted by physical function and pain.
Les déficits cognitifs contribuent de façon importante à l'handicap relié à la sclérose en plaque (SP), une des conditions neurologiques chroniques les plus communes chez les jeunes adultes. La présentation clinique des changements cognitifs chez les personnes atteintes de SP est unique en raison de la nature progressive de la maladie et de l'interaction entre les déficits cognitifs et les autres symptômes de la SP. Une évaluation adéquate des changements cognitifs est donc importante dans l'évaluation des personnes atteintes de la SP. L'objectif principal de cette étude est d'évaluer la stabilité, l'unidimensionalité et la hiérarchie des items de la mesure de perception du fonctionnement cognitif (Questionnaire sur les Déficits Perçus, PDQ), ainsi que d'explorer les différences de gendre dans les associations entre l'humeur, la fatigue et le fonctionnement cognitif chez les personnes atteintes de la SP. La perception du fonctionnement cognitif, le fonctionnement cognitif, ainsi que d'autres aspects cliniques ont été mesurés sur un échantillon, stratifié par centre, de 185 personnes atteintes de la SP. L'analyse Rasch a été effectuée d'identifier la hierarchie des items du PDQ, de confirmer la structure factorielle, la redondance des items, l'unidimensionalité, ainsi que pour examiner la stabilité des items. Un questionnaire de 11 items, le PDQ-Rasch, a été développé. Des modèles de régression linéaire ont servis à identifier les corrélations entre les habilités cognitives perçues (PDQ) et les habiletés cognitives mesurées (par le PASAT). Les résultats du PDQ ont été expliqués par une humeur dépressive, la fatigue, le sexe féminin, et la douleur. De plus, l'humeur avait un effet plus fort sur les femmes que sur les hommes, dans les résultats du PDQ. Les résultats du PASAT ont été prédits par le fonctionnement physique et la douleur.

The primary objective of this study was to assess cognitive functioning in participants with relapsing remitting multiple sclerosis (RRMS) using the MicroCog and to compare their performance to that of a demographically matched, healthy control group. It was hypothesized that as a group, participants with RRMS would have worse cognitive function than healthy controls on all Level 1, 2, and 3 Index scores of the MicroCog. Twenty-six participants with RRMS and twenty-nine sex and education matched healthy controls were administered the MicroCog (Standard Form) along with measures of depression and clinical status, and paper-pencil tests of processing speed (Symbol Digit Modalities Test; SDMT and Paced Auditory Serial Addition Test; PASAT). A series of ANCOVAs with depression as a covariate was performed to determine between group differences for each MicroCog Level 3 Index score (General Cognitive Proficiency (GCP) and General Cognitive Functioning (GCF)), Level 2 Index score (Information Processing Accuracy (IPA) and Information Processing Speed (IPS)), and Level 1 Index score (Attention/Mental Control, Memory, Reasoning/Calculation, Spatial Processing, and Reaction Time). Pearson's and point biserial r correlations were calculated in order to assess the degree to which Level 2 and 3 Index scores correlated with clinical and demographic factors (sex, disease duration, depression, and clinical status) and to correlate the MicroCog IPS index score with traditional measures of processing speed. Eight RRMS and two control participants met criteria for cognitive impairment on the MicroCog. ANCOVA results indicated there were significant differences between RRMS and control performance for two MicroCog scores (GCF and IPS). There were not significant differences for GCP, IPS, and all Level 1 scores. A post-hoc analysis performed for the same hypothesis with a group of age equivalent participants suggested a significant RRMS by depression interaction for Level 3 scores. RRMS was not predictive of Level 2 scores after controlling for depression in the age equivalent sample. Correlations for clinical and demographic factors with cognitive outcomes indicated significant relationships for clinical status and depression. There was not a significant relationship detected for disease duration or sex. MicroCog and processing speed measures were significantly related. Post-hoc analyses supported that the criterion validity of the MicroCog is comparable to other cognitive screening tools in RRMS. The results and limitations of our study are discussed, in addition to recommendations for future research.

Les troubles mnésiques sont fréquents dans la sclérose en plaques (SEP) mais leurs substrats anatomique et biologique sont mal connus. L’objectif de cette thèse translationnelle était de comprendre les mécanismes physiopathologiques des troubles mnésiques à la phase précoce de la SEP, avec pour perspective de trouver de nouvelles cibles thérapeutiques et de définir de nouveaux marqueurs d’imagerie. Nous avons réalisé une analyse neuropsychologique et IRM de patients atteints de forme précoce de SEP et nous avons étudié des souris à la phase précoce d’une encéphalomyélite auto-immune expérimentale (EAE, le modèle animal de la SEP) avec une combinaison d’expériences comportementales, d’IRM, histologiques, électrophysiologiques et pharmacologiques. Nous avons démontré que l’atteinte hippocampique était précoce dans l’histoire de la maladie et qu’elle était corrélée au déclin mnésique des patients atteints de SEP. Nous avons identifié chez les souris EAE que la structure et la fonction du gyrus denté étaient plus vulnérables que les autres sous-champs de l’hippocampe au stade précoce de la maladie et nous avons transposé cette découverte à la pathologie humaine en démontrant une perte des capacités de pattern separation chez des patients atteints de forme précoce de SEP. Du point de vue mécanistique, nous avons démontré que l’activation microgliale précoce était responsable de l’atteinte du gyrus denté et des troubles mnésiques dans l’EAE et que cette cascade physiopathologique pouvait être prévenue grâce à un traitement par minocycline. Du point de vue de l’imagerie, nous avons également démontré que l’atteinte microstructurale de l’hippocampe ainsi que la neurodégénérescence précoce du gyrus denté pouvaient être étudiées in vivo en tenseur de diffusion (DTI). Nous travaillons à la mise en place de méthode encore plus spécifique par l’imagerie de densité neuritique et d’orientation/dispersion (NODDI). Nos résultats relient l’atteinte mnésique précoce de la SEP à une neurodégénérescence sélective du gyrus denté. Ce processus physiopathologique peut être prévenu en inhibant l’activation microgliale chez les souris EAE et peut être étudié in vivo grâce au DTI chez la souris comme chez l’homme, offrant d’évidentes perspectives cliniques dans la prise en charge des patients atteints de SEP
Memory impairment is frequent in multiple sclerosis (MS) but its anatomical and biological substrates are poorly understood. The objective of this translational thesis was to understand the pathophysiological mechanisms of early memory impairment in MS, to find new potential therapeutic targets and to define new imaging biomarkers related to memory impairment. We used neuropsychological and MRI experiments in patients with early MS and we explored experimental autoimmune encephalomyelitis (EAE) mice (a mouse model of MS) at the early stage of the disease with a combination of behavioral, in vivo MRI, histological, electrophysiological and pharmacological approaches. In patients with MS, we demonstrated that hippocampal damage occurs early during the course of the disease and that it correlates with memory impairment. In EAE-mice, we identified that dentate gyrus structure and function are more vulnerable than other hippocampal subfields at the early stage of the disease and we translated this finding back to humans by demonstrating loss of pattern separation performances in patients with early MS. From a mechanistic point of view, we demonstrated that early microglial activation causes dentate gyrus disruption and memory impairment in EAE-mice and that this pathophysiological cascade can be prevented with minocycline. From the imaging point of view, we demonstrated that hippocampal microstructural damage and early dentate gyrus degeneration can be monitored in vivo with diffusion tensor imaging (DTI). We are currently developing more specific imaging approaches with optimization of the Neurite Orientation Dispersion and Density Imaging (NODDI) to assess hippocampal subfields. Our results link early memory impairment in MS to a selective disruption of the dentate gyrus. We were able to prevent this neurodegenerative process with microglial inhibitors in EAE-mice and to capture these features non-invasively with DTI in both humans and rodents, paving the way toward new clinical perspectives in MS

Multiple sclerosis is the most common cause of non-traumatic disability in young adults. In addition to the physical disability associated with the condition there exists significant non-motor symptoms. Cognitive dysfunction in multiple sclerosis is common and presents significant morbidity for patients. There is mounting evidence for neuroplasticity playing a role in limiting the functional impact of pathology in MS. However, the degree to which neuroplasticity can ameliorate the impact of cognitive dysfunction and the potential that exists for structured cognitive rehabilitation are largely unknown. Aims To explore the feasibility and efficacy of computerised, home-based cognitive rehabilitation in patients with multiple sclerosis using neuropsychological assessment and advanced structural and functional magnetic resonance imaging. Methods 38 patients with MS and evidence of cognitive impairment as defined as scores below the 5th centile for normative data on the Brief International Cognitive Assessment for MS test battery were enrolled in an open-design randomised, controlled, exploratory trial of computerised cognitive rehabilitation. Neuropsychological and MRI data were obtained at baseline (time 1) as well as immediately following a 6-week intervention period (time 2) and after an addition twelve week follow up period (time 3). Changes in cortical activations were explored using a visual n-back fMRI paradigm and microstructural changes were explored using quantitative magnetisation transfer imaging. Patients were randomly assigned to undergo 45-minutes of computerised cognitive rehabilitation (RehaCom software, n = 19) three times weekly for six weeks or to a control condition (natural history DVDs, n = 19). Results The n-back fMRI task was associated with robust cortical activations in known working memory networks. The spatial extent and magnitude of the activations were greater for the 2-back than the 1-back condition. At time 3 significant increases in activation were seen in both the 1-back and 2-back conditions in the treatment group relative to controls. In the 1-back task, increased activation was seen in the left frontal and right temporo-parietal regions (p < 0.05 FWEcorr). In the more demanding 2-back task, there was increased activation in the bilateral prefrontal cortex and right temporoparietal regions relative to control group at time 2 (p < 0.05 FWEcorr). No significant changes were observed on quantitative magnetisation transfer imaging. Compared to time 1, a significantly higher proportion of patients in the treatment group showed 10% or greater improvement in the Symbol Digits Modality Test (SDMT) at time 2 (x2 = 0.008) however no significant difference in cognitive performance was seen between the groups at time 3. Quality of life outcome measures did not significantly differ between the groups. Conclusion This study supports the hypothesis that home-based, computerised cognitive rehabilitation may be a feasible and effective approach to improving cognitive performance in patients with MS. The alterations in cortical activation in attention and executive centres are likely to represent more efficient neural processing. The changes at the microstructural level that underpin this adaptation may be beyond the resolution of current imaging techniques. Improvements in quality of life as a result of cognitive rehabilitation may result from improved work place or social performance, which may occur over a longer timeframe. Quality of life outcome measures may need to be conducted over a longer period of follow up.

Basée sur une approche en neuropsychologie et neuroimagerie, cette étude visait à (i)caractériser le déficit du voyage mental dans le temps (VMT : mémoire autobiographique et projection future) chez des patients atteints de sclérose en plaques de forme rémittente et (ii) à améliorer leur performance. Nous avons montré que le déficit du VMT s’accompagne de changements d’activations cérébrales spontanés dans des régions clés du réseau cérébral du VMT, en comparaison de sujets sains. Par ailleurs, l’utilisation d’un programme de facilitation cognitive a permis une amélioration significative des fonctions étudiées, non attribuable à un effet « placebo » ou d’apprentissage. Le bénéfice clinique s’est traduit par une augmentation de l’activité cérébrale dans des régions cérébrales clés du réseau, mais distinctes selon la direction temporelle.Les huit expériences ont ainsi démontré que le déficit du VMT entraîne une plasticité cérébrale spontanée et que intervention cognitive est efficace et sous-tendue par des processus cérébraux détectables
Based on a double approach in clinical neuropsychology and neuroimaging, the aim of thepresent thesis was twofold: (i) to study relapsing-remitting multiple sclerosis (RR-MS)patients presenting with autobiographical memory (AM) and episodic future thinking (EFT) impairment, and (ii) to improve AM and EFT functioning in the same patients.Thus, we showed a deficit in both AM and EFT in RR-MS patients, which was expressed by spontaneous brain activity changes in key brain regions of the AM and EFT networks,relatively to healthy controls. Then, we documented that the use of a mental visual imagery (MVI)-based facilitation programme led to AM and EFT improvement, which was notattributable to nursing or learning effects. This clinical benefit was accompanied with anincreased reliance on distinct key brain regions of the core AM and EFT network.Overall, we documented the effectiveness of cognitive facilitation for AM and EFT, and the occurrence of spontaneous and induced brain plasticity changes during AM and EFT performance in RR-MS patients, which were sustained by both common and distinct cerebral mechanisms

La sclérose en plaques est une maladie inflammatoire du système nerveux central, ayant plusieurs phénotypes cliniques, caractérisée par la coexistence de phénomènes inflammatoires focaux et d’une neurodégénérescence diffuse, dont la physiopathologie est actuellement inconnue. L’apparition de troubles cognitifs marque un tournant évolutif pour les patients, est en lien avec la progression de la maladie, et notamment l’atrophie cérébrale. Néanmoins le statut cognitif de certains patients reste préservé malgré la progression de la maladie. Le concept de réserve cognitive rendrait compte de cette absence de corrélation entre statut cognitif et lésions cérébrales en lien de la maladie, mais ses bases physiologiques sont à l’heure actuelle inconnues. Trois techniques d’imagerie : L’étude de la perfusion cérébrale en arterial spin labelling, de la vasoréactivité cérébrale grâce à l’inhalation d’un gaz enrichi en CO2, et des anomalies de substance blanche cérébrale en tenseur de diffusion sont utilisées dans ce manuscrit pour répondre aux questions suivantes :- Existe-t-il des anomalies vasculaires pouvant expliquer la neurodégénérescence diffuse observée dans la sclérose en plaques, et notamment dans les formes progressives ?- Existe-t-il en tenseur de diffusion des anomalies de certains faisceaux de substance blanche qui serait corrélées au statut cognitif ou au phénotype clinique des patients? La réserve cognitive est-elle médiée par des phénomènes de plasticité de la substance blanche dans la sclérose en plaques?
Multiple sclerosis in an inflammatory and dysimmune condition of the central nervous system, with different clinical patterns. This disease involves patchy area of demyelination and of a diffuse axonal loss and neurodegeneration. The pathophysiology of this diffuse neurodegeneration remains currently unknown. The apparition of a cognitive impairment dramatically changes the clinical prognosis in patients. This cognitive impairment seems to be linked to a diffuse dysconnexion of normal appearing white matter, and to grey matter atrophy. Cognitive reserve could explains a lack of correlation between the cognitive status in patients and the cerebral lesion load due to the disease. Anatomical basis of cognitive reserve are unclear. Three methods of imaging : arterial spin labelling, measure of the cerebral vasoreactivity with the inhalation of a gas enriched in dioxid, and diffusion tensor imaging are employed to answer to these questions in multiple sclerosis : Are there vascular abnormalities related to neurodegeneration, in particular in progressive forms of multiple sclerosis? Could we find white matter differences in tracts related to cognitive impairment or clinical form in patients? Is Cognitive reserve linked to a cerebral white matter plasticity in this condition ?

La esclerosis múltiple (EM) es una enfermedad inflamatoria, desmielinizante y neurodegenerativa del sistema nervioso central y principal causa de discapacidad en el adulto joven. Aunque su causa es desconocida, se ha observado que se desarrolla en personas con una susceptibilidad genética que se exponen a ciertos factores medioambientales. En la historia natural de la enfermedad, las alteraciones cognitivas son frecuentes y se manifiestan en un 40 a 65% de pacientes. Están presentes desde fases iniciales de la enfermedad, hasta las formas progresivas de la misma. Estas alteraciones hacen que los pacientes tengan dificultades para mantener el empleo y que sean dependientes para las actividades diarias. Por esto, es necesaria una evaluación neuropsicológica que permita realizar adaptaciones en el trabajo o desarrollar programas de estimulación cognitiva. Existen varias pruebas para estudiar las alteraciones cognitivas en la EM, sin embargo, muchas requieren de personal especializado y un mínimo de 10 minutos para su aplicación. La presente tesis doctoral plantea que la presencia de deterioro cognitivo es un evento precoz en la evolución de la EM y que puede ser detectado tanto mediante pruebas cognitivas de cribado cómo por estudios neurofisiológicos. La tesis doctoral consta de dos estudios sobre la evaluación cognitiva de pacientes con EM. En el primero, se comparan el SDMT y el PASAT, dos pruebas de cribado de deterioro cognitivo para conocer cuál de las dos es más sensible y específica para detectar alteraciones cognitivas en un seguimiento de un año. En el segundo, se compara el rendimiento de pacientes con EM en fases iniciales de la enfermedad con un grupo control, mediante potenciales relacionados con eventos. En el primer estudio se incluyeron 237 pacientes y 57 controles. Todos los participantes se valoraron inicialmente con una batería neuropsicológica extensa. Después de un año, 196 pacientes se exploraron nuevamente. Los resultados mostraron que el SDMT es más sensible y específico que el PASAT para detectar deterioro cognitivo y que además tiene mejor correlación con el resto de pruebas administradas. Así mismo, se observó que el SDMT es un test más fácil y rápido de administrar y que además puede ser contestado por todas los sujetos. Por otro lado, el PASAT requiere repetir varias veces las instrucciones, haciendo la prueba más larga y se encontró que un 5.3% de los controles no la quiso contestar. En el segundo estudio, se incluyeron 27 pacientes con EM en fases iniciales y 31 controles. Se valoró el sistema de monitorización del desempeño a través de la negatividad relacionada con el error (ERN), que es un potencial cerebral relacionado con eventos que se observa después de un error de comportamiento. También se realizó una exploración neuropsicológica completa. No se observaron diferencias entre los grupos en la mayoría de pruebas neuropsicológicas ni en la tarea ODDBALL auditiva. En la tarea de STOP el desempeño conductual de los pacientes y los controles fue similar, sin embargo, la amplitud de la ERN asociada con los errores de STOP fue significativamente mayor en los pacientes. Esto se observó ya que después de la presentación de una señal de STOP, los errores de comisión estaban asociados con un aumento en la onda negativa. Este hallazgo indica que los pacientes con EM en fases iniciales utilizan áreas cerebrales más extensas para mantener el mismo rendimiento cognitivo que los controles sanos. Los resultados de esta tesis doctoral apoyan, por un lado, la utilización del SDMT como prueba de cribado de deterioro cognitivo en la EM y, por otro, sugieren la presencia de mecanismos compensatorios cerebrales en etapas iniciales de la enfermedad, cuando las alteraciones cognitivas no se manifiestan en una exploración neuropsicológica.
Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative central nervous system disease and is the principal cause of disability in young adults. Even though its aetiology is unknown, it has been observed that it develops in people with genetic susceptibility that is exposed to certain environmental factors. In the natural history of the disease, cognitive impairment is frequent and may be present in 40 to 65% of the patients. It can be observed from the initial phases of the disease until the progressive forms of MS. Patients with cognitive impairment have difficulties to maintain their job and they usually need help in the activities of daily living. Therefore, a neuropsychological assessment is needed in order to make adaptations in patient’s jobs or to develop cognitive stimulation programs. There are different tests to evaluate cognitive impairment in MS patients, nevertheless, many of them require specialized personnel and minimum 10 minutes to be administrated. This doctoral thesis suggests that the presence of cognitive impairment is a common event in MS evolution that can be detected with cognitive screening tests as well as with neurophysiological studies. The doctoral thesis consists of two studies regarding cognitive evaluation of MS patients. The first one, compares the SDMT and the PASAT, two known screening tests for cognitive impairment in MS, in order to assess which one is more sensitive and specific to detect cognitive impairment after one-year follow-up. The second one, compares cognitive performance of MS patients in early stages of the disease and a control group, using event related potentials. In the first study 237 patients and 57 healthy subjects were included. All participants were assessed at baseline with a comprehensive neuropsychological battery. After one year, 196 patients were assessed a second time. The results showed that the SMDT is more sensitive and specific than the PASAT to detect cognitive impairment and it also has a better correlation with the other tests that were administered. It was also observed that the SDMT is easier and faster to administer than the PASAT and in addition, all the subjects were able to answer it. On the other hand, instructions to answer the PASAT needed to be repeated several times, making the test longer and we found that 5.3% of controls didn’t want to answer it. In the second study, 27 patients with MS in initial phases of the disease and 31 controls were included. The performance monitoring system through the error-related negativity (ERN), that is an event-related brain potential observed following behavioural errors was evaluated. A comprehensive neuropsychological evaluation was also performed. No differences between groups were observed in most of the neuropsychological tests or on the auditory ODDBALL task. In the STOP task behavioural performance of patients and controls was similar, nevertheless, the amplitude of the ERN associated with STOP errors was significantly higher in the patients group. This was observed because after de STOP signal presentation, commission errors were associated with an increase in the negative wave. This finding indicates that patients in early stages of MS use larger brain areas in order to maintain the same cognitive performance than healthy controls. The results of this doctoral thesis support the SDMT as screening test of cognitive impairment in MS patients and suggest the presence of compensatory cerebral mechanisms in the early stages of the disease, when cognitive impairment is not yet observed in a neuropsychological assessment.

Multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the central nervous system, representing the most common non-traumatic cause of disability in young adults. Magnetic Resonance Imaging (MRI) in MS represents a fundamental tool for the diagnostic workup, disease monitoring over time and also for treatment response. The focal lesions of cerebral white matter (WM), detected by conventional MRI are distinctive signs of the disease and show a certain relationship with clinical disability, especially in the long term. The involvement of gray matter (GM) is evident from the beginning of the disease and includes focal (i.e., cortical lesions) and diffuse pathology (i.e., atrophy). Both represent an important burden of disease and are associated with physical and cognitive disability. Cognitive impairment (CI) is estimated to affect 40-70% of MS patients. It tends to worsen over time, but might be relevant even at earliest stages and is primarily characterized by reduced information processing speed, visual learning, working and long-term memory and executive functioning. The overall relationship between CI and lesion load was found to be weak-to-moderate, leading to the hypothesis that cannot be adequately explained by conventional MRI, limited to the detection of macroscopic brain damage. In the last years, novel imaging techniques, including diffusor tensor imaging (DTI), have provided further insights into the understanding of CI in people with MS, highlighting the importance of the subtle brain damage in the normal appearing white matter, since the early stage and outside the focal lesions . My PhD research project is divided into three cross-sectional studies, enclosed in the present thesis and conducted from the Novembre 2016 to June 2019 at the Quantitative Neuroimaging Laboratory (QNL), Department of Medicine, Surgery and Neuroscience of University of Siena. Aims of this work were achieved by quantitatively assessing MR-derived brain volumes (Jim 7.0, Xinapse System; Structural Image Evaluation, using Normalization, of Atrophy [SIENAX]) as well as microstructural WM damage (DTI and derived indices such as fractional anisotropy [FA], mean diffusivity [MD], axial [AXD], and radial diffusivity [RD]) in different groups of relapsingremitting MS. More specifically, the first and the second studies are focused on a new DTI-derived MRI marker, named Peak Width of Skeletonized Mean Diffusivity (PSMD) and its role in detecting the diffuse WM microstructural damage in Multiple Sclerosis, taking into account also the correlations between brain structures changes and cognitive measures (assessed through the validated Italian translation of Rao Brief Repeatable Battery [BRB]) and its feasibility in the clinical practice. In the third and last study we reported the preliminary results about the relevance of cognitive reserve (CR) on the association between cognitive impairment and WM microstructural damage in mild disability MS.

Η γνωστική έκπτωση εμφανίζεται στο 40-70% των ασθενών με ΠΣ, επηρεάζει σημαντικά την ποιότητα ζωής τους και έχει συσχετισθεί τόσο με τη σωματική αναπηρία, όσο και με διάφορες απεικονιστικές παραμέτρους, όπως ο συνολικός όγκος βλαβών και δείκτες ατροφίας του εγκεφάλου. Μέθοδοι: Στην παρούσα μελέτη συμμετείχαν 80 ασθενείς με ΠΣ (50 με υποτροπιάζουσα-RRMS, 30 με δευτεροπαθώς προϊούσα-SPMS). Κατεγράφησαν δημογραφικά δεδομένα και η κλίμακα αναπηρίας EDSS. Παράλληλα, έγινε νευροψυχολογική εκτίμηση με το υπολογιστικό πρόγραμμα CNS-VS καθώς και με τη δοκιμασία οπτικονοητικής ιχνηλάτησης (TMT A και Β) και λεκτικής ροής. Μελετήθηκε η επίδραση στην καθημερινή λειτουργικότητα των ασθενών (κλίμακα IADL, ικανότητα για εργασία) και υπολογίσθηκε ο συνολικός όγκος βλαβών, η ατροφία μεσολοβίου, ατροφία θαλάμων και η διάταση της 3ης κοιλίας. Χρησιμοποιήθηκε επίσης ομάδα 31 υγιών μαρτύρων για τις νευροψυχολογικές δοκιμασίες και ξεχωριστή ομάδα 51 υγιών μαρτύρων για τα απεικονιστικά δεδομένα. Αποτελέσματα: Παρατηρήθηκε έκπτωση των γνωστικών λειτουργιών στο 38% των ασθενών με RRMS και στο 80% των ασθενών με SPMS. Οι ασθενείς μας, εμφάνισαν συχνότερα χαμηλές επιδόσεις στο χρόνο αντίδρασης (83,33% SPMS/ 58% RRMS), στη δοκιμασία TMT Β (76,67% SPMS/ 34% RRMS), στην ψυχοκινητική ταχύτητα (66,67% SPMS/ 20% RRMS), στη δοκιμασία TMT Α (63,33% SPMS/ 34% RRMS), στη δοκιμασία φωνολογικής λεκτικής ροής (50% SPMS/ 30% RRMS) και στη μνήμη (40% SPMS/ 16% RRMS). Στους ασθενείς με RRMS, η γνωστική έκπτωση εμφάνισε ασθενή συσχέτιση τόσο με τη σωματική αναπηρία, όσο και με τη διάρκεια της νόσου και το συνολικό όγκο βλαβών (p<.05). Αντίθετα, ισχυρή συσχέτιση παρατηρήθηκε μεταξύ της γνωστικής έκπτωσης και των δεικτών ατροφίας του εγκεφάλου (p<.001) Παράλληλα, η κλίμακα IADL εμφάνισε ισχυρή συσχέτιση με τη μνήμη, την ψυχοκινητική ταχύτητα, την ταχύτητα επεξεργασίας και με όλους τους δείκτες ατροφίας (p<.001). Στους ασθενείς με SPMS ανευρέθη ασθενή συσχέτιση μεταξύ γνωστικής έκπτωσης και πάχους 3ης κοιλίας (p<.05). Στο σύνολο των ασθενών με ΠΣ, συνυπολογίζοντας ως συμμεταβλητές την ηλικία, το φύλο, τα έτη εκπαίδευσης και τη διάρκεια της νόσου, η χαμηλή ψυχοκινητική ταχύτητα και οι χαμηλές επιδόσεις στη δοκιμασία TMT B αποτελούν τους πλέον ευαίσθητους δείκτες πρόβλεψης αυξημένης σωματικής αναπηρίας (p=.004 για ψυχοκινητική ταχύτητα και p=.007 για TMTB) και έκπτωσης καθημερινής λειτουργικότητας (p=.001 για ψυχοκινητική ταχύτητα), ενώ η έκπτωση της σύνθετης μνήμης (p=.002) και η χαμηλή επίδοση στη δοκιμασία TMT Β (p=.004) αποτελούν τους πλέον ευαίσθητους προγνωστικούς δείκτες της ανικανότητας των ασθενών για εργασία. Στο σύνολο των ασθενών με ΠΣ, η ατροφία των θαλάμων αποτελεί τον καλύτερο προγνωστικό δείκτη χαμηλής επίδοσης στη δοκιμασία TMT Β (p=.000) και έκπτωσης της σύνθετης μνήμης (p=.000), ενώ η ατροφία τοu μεσολοβίου αποτελεί τον πλέον ευαίσθητο δείκτη πρόβλεψης μειωμένης ψυχοκινητικής ταχύτητας (p=.000). Συμπεράσματα: Παρόλο που η έκπτωση των γνωστικών λειτουργιών είναι παρούσα από τα αρχικά στάδια της νόσου, είναι συχνότερη, πλέον έκδηλη και βαρύτερη στη χρόνια προιούσα ΠΣ. Δεν ανευρέθη διαφορετικό πρότυπο έκπτωσης γνωστικών λειτουργιών μεταξύ ασθενών με RRMS και ασθενών με SPMS. Το σφαιρικό αυτό πρότυπο, χαρακτηρίζεται από έκπτωση στην ταχύτητα επεξεργασίας πληροφοριών, ακολουθούμενο από ελλειμματικές εκτελεστικές λειτουργίες και έκπτωση της σύνθετης μνήμης. Η έκπτωση των καθημερινών δραστηριοτήτων είναι πολύ βαρύτερη στην SPMS, σε σύγκριση με την RRMS . Η επιφάνεια του μεσολοβίου και των θαλάμων αναδείχθηκαν οι πλέον ευαίσθητοι δείκτες στο διαχωρισμό των ασθενών με RRMS από SPMS. Παρατηρούμε δηλαδή, ότι παρόλο που η ατροφία είναι παρούσα από τα αρχικά στάδια της νόσου, με την πάροδο των ετών αυξάνεται σημαντικά. Η ψυχοκινητική ταχύτητα, η μνήμη και η δοκιμασία ΤΜΤ Β έχουν τη μεγαλύτερη προβλεπτική ικανότητα για την εξέλιξη της νόσου, τόσο σε επίπεδο σωματικής αναπηρίας, όσο και καθημερινής λειτουργικότητας. Οι δείκτες ατροφίας παρουσίασαν την ισχυρότερη συσχέτιση με τη γνωστική έκπτωση και την έκπτωση στην καθημερινή λειτουργικότητα. Από τους δείκτες αυτούς, η ατροφία των θαλάμων και του μεσολοβίου φαίνεται να έχουν την ικανότητα να προβλέψουν τη γνωστική έκπτωση στο σύνολο των ασθενών με ΠΣ.
Cognitive decline is present in 40%-70% of patients with MS and affects their quality of life. It has been significantly correlated with physical disability as well as with total lesion load and atrophy measures on MRI. Methods: In the present study, we evaluated 80 patients with MS (50 with RRMS, 30 with SPMS). We studied their demographic characteristics and assessed them clinically with EDSS. All patients underwent thorough Neuropsychological assessment with a computerized cognitive screening battery (CNS-VS) as well as with Trail Making Test A and B and verbal fluency task. We evaluated their everyday activities with the Instrumental Activities of Daily Living Scale, and we calculated the total lesion volume, thalamic atrophy, corpus callosum atrophy and 3rd ventricle width as apeared on the MRI. In addition, 31 healthy individuals underwent the same Neuropsychological assessment and 51 healthy individuals had brain MRI scans for comparison with our patients. Results: We found 38% of our RRMS patients and 80% of our SPMS patients to have cognitive deficits. More frequently affected measures were reaction time (83,33% SPMS/ 58% RRMS), TMT B(76,67% SPMS/ 34% RRMS), psychomotor speed (66,67% SPMS/ 20% RRMS), TMT A (63,33% SPMS/ 34% RRMS), phonological verbal fluency task (50% SPMS/ 30% RRMS) and memory (40% SPMS/ 16% RRMS). In our RRMS patients, cognitive impairment had a weak correlation with physical disability and total MR lesion load (p<.05) and a strong correlation with all atrophy measures (p<.001). Moreover, IADL were highly correlated with psychomotor speed, processing speed, memory and all MR atrophy measures (p<.001). On the other hand, our SPMS cognitively impaired patients had only a weak correlation with 3rd ventricle width (p<.05). When taking our MS patients as a single group and using as covariates age, sex, years of education and disease duration, we found that low psychomotor speed (p=.004) and poor performance on TMT B (p=.007) were the most sensitive predictors of increased physical disability, whereas psychomotor speed predicted impaired every day activities (p=.001). Employment status was predicted by impaired composite memory (p=.002) and poor performance on TMT B (p=.004). Thalamic atrophy was the most sensitive indicator for poor performance on TMT B (p=.000) and impaired memory (p=.000), while corpus callosum atrophy was the best indicator for slow psychomotor speed (p=.000). Conclusions: Although cognitive impairment is present from the early stages of MS, it is much commoner, more pronounced and severe at the progressive stage of MS. In the present study, we were not able to find a different pattern of cognitive decline between RRMS and SPMS patients. We observed a global pattern, consisting of impairment in information processing speed, followed by executive dysfunction and memory deficits. As disease progresses, everyday activities are affected more severely. Comparison of RRMS and SPMS patients revealed statistical significant difference in the surface of corpus callosum and thalami, indicating that although atrophy is present form the early stages of the disease, it is more prominent in the progressive stage. Psychomotor speed, composite memory and TMT B are the best predictors of EDSS and every day activities impairment (IADL). All of our MR atrophy measures had a strong correlation with cognitive decline and impaired every day activities. It seems that thalamic atrophy and corpus callosum atrophy are the best predictors of cognitive decline in our MS patients.

A number of reports suggests that multiple sclerosis (MS) leads to certain changes in psychosocial functioning. Whether these changes are the direct result of specific symptoms of MS such as: physical impairments, depression or deficits in cognitive function, is not yet clear. Few studies have examined the relative effects of each of these symptoms on various measures of social and vocational activities. Therefore, the purpose of this study was to determine: 1) in a sample of MS patients in the early stages of a relapsing-remitting disease course, the prevalence of cognitive impairment and depression; 2) whether these two dimensions were independent of physical disability; and 3) whether cognitive impairment, depression, or physical disability was most predictive of the decline of psychosocial functioning. In order to discover whether each of the symptoms existed within the sample, the MS group was divided according to cutting scores established by the performance of the normal control group. First, a group of MS patients who were cognitively impaired was identified by scoring lower than the fifth percentile of the normals' scores on the Word Fluency Test. Thirty seven patients (20%) of the MS group scored in the impaired range. Validation of this impairment was assessed by performance on other neuropsychological tests. Neither disease-related nor demographic variables could account for the deficit. Similarly, a group of patients with a high level of depressive symptoms was identified by using the ninety-fifth percentile of the normals' scores on the Beck Depression Inventory (BDI) as a cut-off. Thirty eight (21%) patients were classified as depressed according to the above criterion. Finally, those patients with highest levels of physical disability (top 20%) were identified from their scores on the Kurtzke EDSS. Thirty four (19%) of the MS group were considered physically impaired. Of the total MS sample, only 11% were impaired on a combination of two or more dimensions. The dependent variable for the final question, psychosocial functioning, was assessed by activity in the work force (employed vs unemployed), level of social/recreational activity, and outlook for the future (either optimistic or pessimistic). The results of this investigation suggest four things. First, cognitive impairment does exist in the early stages of MS and is independent of disease-related or demographic variables. Second, evidence for depressed mood was also found in a portion of this sample. Third, these observed symptoms as well as degree of physical disability are independent phenomena in the early stages of the disease. Fourth, being cognitively impaired is related to both a decrease in vocational and recreational activities and a greater pessimism towards the future. If a MS patient is depressed, it is more likely that he or she is unemployed and also less socially active. Interestingly, the degree of physically disability does not seem to be related to these three areas of psychosocial functioning.

Recent reviews (Peyser & Poser, 1986; Rao, 1986) suggest that Multiple Sclerosis results in cognitive impairments in the areas of learning and memory, abstract reasoning, information processing efficiency, and, often, visual-spatial ability. Whether this pattern applies to the individual with MS is unclear. Due to the disseminated distribution of MS neuropathology, patients may undergo idiosyncratic cognitive changes dependent upon the site of white matter lesions. The present study explored this question using cluster analysis on the neuropsychological data from a group of mildly disabled MS patients (n = 177) and a well-matched control group (n=89). In a group of MS patients who were identified with unequivocal cognitive impairment, the resultant clusters indicated that MS does not result in a characteristic pattern of impairment. Two clusters were obtained that resembled the pattern described in the literature, while the majority of patients clustered into groups with specific deficits in one or two areas, with normal performance in others. In order to identify associations between cluster groups and lesion sites, frequency tables were constructed for the presence of a lesion on Magnetic Resonance Imaging in 24 brain sites. An association was obtained between two lesion sites and two cognitive tests. Visual-spatial impairment, as assessed by the Benton Visual Retention test, was associated with lesions in the genu of the corpus callosum and with more lesions throughout the corpus callosum. Impaired performance on Paired Associates, a test of learning and memory for novel verbal associations, was associated with a lesion in the deep white matter of the left parietal lobe. The results support the hypothesis that MS results in multiple patterns of cognitive impairment depending on the individual placement of white matter lesions. Identifying and characterizing the heterogeneity of the impairment may greatly increase our understanding of the role of myelin in cognition and the functions of white matter tracts in the brain.