Cognitive Deficits In Multiple Sclerosis Research Articles

Cuprizone treatment induces demyelination and astrocytosis in the mouse hippocampus

Memory impairment is outstanding within the spectrum of cognitive deficits in multiple sclerosis (MS) patients. Demyelination has been reported in the hippocampus formation of MS patients. The degree of hippocampus lesions in MS strongly correlates with progression of cognitive dysfunction. Because no appropriate animal model for the study of hippocampus demyelination has been established, we used the cuprizone mouse model to investigated demyelination in young adult and aged mice. The myelin status was analyzed by classical histological staining, immunocytochemistry for proteolipoprotein, and electron microscopy. Oligodendrocyte, astroglial, and microglia markers were studied. Cuprizone intoxication induced an almost complete demyelination of distinct hippocampus subregions to a similar extent in young adult and aged male mice. Demyelination was pronounced in a subset of white and gray matter areas, i.e., the stratum lacunosum moleculare containing the perforant path, medial alveus, stratum pyramidale in the cornu ammonis 2/3 region, and hilus region. Besides demyelination, affected areas displayed hypertrophic and hyperplastic astrocytosis. No significant effect on microglia invasion was detected at any investigated time point (0, 3, 5, and 7 weeks). We conclude that cuprizone-induced demyelination provides an adequate animal model to investigate appropriate therapy strategies for the prevention of hippocampus demyelination.

Cognitive impairment in multiple sclerosis

Multiple sclerosis (MS) is a progressive disease of the CNS that is characterised by widespread lesions in the brain and spinal cord. MS results in motor, cognitive, and neuropsychiatric symptoms, all of which can occur independently of one another. The common cognitive symptoms include deficits in complex attention, efficiency of information processing, executive functioning, processing speed, and long-term memory. These deficits detrimentally affect many aspects of daily life, such as the ability to run a household, participate fully in society, and maintain employment--factors that can all affect the overall quality of life of the patient. The increased use of neuroimaging techniques in patients with MS has advanced our understanding of structural and functional changes in the brain that are characteristic of this disease, although much remains to be learned. Moreover, examination of efforts to treat the cognitive deficits in MS is still in the early stages.

Short-latency afferent inhibition predicts verbal memory performance in patients with multiple sclerosis

The pathogenesis of cognitive deficits in multiple sclerosis (MS) patients is the subject of debate. A causative role of grey matter impairment has been suggested. Acetylcholinesterase inhibitors have been proposed in the treatment of cognitive impairment in MS. Short-latency afferent inhibition (SAI) is a cortical phenomenon assessed by a transcranial magnetic stimulation protocol that provides an in vivo index of central cholinergic function. We recruited 20 consecutive relapsing-remitting or secondary progressive MS patients showing normal upper limb somatosensory and motor evoked potentials. SAI of the left-hand motor cortex from median nerve stimuli was tested. A matched group of 20 healthy subjects was also assessed. All patients underwent neuropsychological assessment with Rao's Brief Repeatable Battery (BRB). Multiple regression was performed on the number of failed tests and on scores of single BRB tests as dependent variables with Extended Disability Status Scale (EDSS) score, SAI, age, gender and disease duration as regressors. Patients with impaired SAI, were reassessed after a single oral dose of rivastigmine. SAI was a significant predictor of the score in tests that assess verbal memory. EDSS score and age were found as predictors of the other BRB tests. SAI was significantly improved by oral rivastigmine. Our data confirm that cognitive impairment in MS is multifactorial. The performances in the subdomain of verbal memory are predicted by SAI. These results favour the hypothesis of grey matter involvement and suggest a role of acetylcholine dysfunction in the pathogenesis of some aspects of cognitive deficits in MS.

Multiple Sclerosis, Cannabinoids, and Cognition

Multiple Sclerosis, Cannabinoids, and Cognition

Extensive Hippocampal Demyelination in Multiple Sclerosis

Memory impairment is especially prominent within the spectrum of cognitive deficits in multiple sclerosis (MS), and a crucial role for hippocampal pathology may therefore be expected in this disease. This study is the first to systematically assess hippocampal demyelination in MS. Hippocampal tissue samples of 19 chronic MS cases and 7 controls with non-neurologic disease were stained immunohistochemically for myelin proteolipid protein. Subsequently, number, location, and size of demyelinated lesions were assessed. Furthermore, the specimens were stained for HLA-DR to investigate microglia/macrophage activity. An unexpectedly high number of lesions (n = 37) was found in 15 of the 19 MS cases. Mixed intrahippocampal-perihippocampal lesions, which were more often found in cases with cognitive decline, were large and did not respect anatomical borders. Moderate microglial activation was frequently observed at the edges of these mixed lesions. Isolated intrahippocampal lesions were also frequently found. These were smaller than the mixed lesions and had a specific anatomical predilection: the cornu ammonis 2 subregion and the hilus of the dentate gyrus were consistently spared. Microglial activation was rare in isolated intrahippocampal lesions. Our results indicate that hippocampal demyelination is frequent and extensive in MS and that anatomical localization, size, and inflammatory activity vary for different lesion types.

De la psychométrie au handicap neuropsychologique dans la sclérose en plaques. Proposition d’une batterie de dépistage en langue française et facteurs de risque cognitifs

Cognitive deficit in multiple sclerosis (MS) is a frequent early feature in the disease course, which conditions patients' overall disability. The goals of this study were to validate a reproducible brief screening battery written in French and to examine cognitive risk profiles in patients with a mild physical disability.Cognitive performances of 40 patients with EDSS <4.5 were compared with those of a control group. The study was completed with an analysis of socio-demographic, clinical and psychological variables (questionnaires).Three tests were discriminative with satisfactory predictive values (positive: 88 percent; negative: 96 percent) and a time duration <30 minutes: PASAT (hard condition), backward digit span, learning stage of California Verbal Learning Test. Four variables were associated with cognitive deficit: educational level <11 years, age >40 years, pathological laughing-crying, unemployment.Our brief battery is an easy and reproducible tool. Completed with warning signs indicating the need for neuropsychological screening, this tool provides the practitioner with a global means of assessing disease activity and potentially therapeutic efficacy.

The Neurobiology of Mental Illness

The Neurobiology of Mental Illness

Treating cognitive deficits in multiple sclerosis

[In] most of the patients affected by multi-locular sclerosis, there is marked enfeeblement of the memory. — —Charcot (1877) Neuropsychological studies have consistently demonstrated that 40 to 65% of patients with multiple sclerosis (MS) experience cognitive dysfunction, particularly in recent memory, information processing speed, and sustained attention.1 Cognitive deficits occur in all MS subtypes, are evident at the earliest stages of MS, and tend to worsen over time.1,2⇓ Deficits correlate with lesion burden and brain atrophy. Localized lesions lead to specific deficits (e.g., frontal lesions associated with executive dysfunction).1 Deficits in cognition can have a deleterious effect on activities of daily living that appear to be independent of severity of physical disability.3 Despite its high prevalence and impact on quality of life, there are currently no proven symptomatic pharmacologic treatments for this problem. Disease modifying therapies (DMT) may reduce the development of new lesions and therefore prevent or minimize the progression of cognitive decline (although actual improvements are also possible if inflammatory mediators are causing reversible dysfunction). Cognitive tests have been used to evaluate the effects of DMT in clinical trials with mixed results.4,5⇓ Only a handful of open label or small controlled studies have evaluated symptomatic treatments for cognitive deficits in MS. Initial studies of 4-aminopyridine, amantadine, and pemoline have been largely negative. Even though MS is not known to have primary cholinergic deficits, there are reasons …

Working memory deficits in multiple sclerosis: a controlled study with auditory P600 correlates

Background: Recently, the P600 component of event related potentials, a waveform that is conceived to be generated and/or modulated by basal ganglia and cingulate area has been considered an index...

The utility of computerized neuropsychological assessment of cognitive dysfunction in patients with relapsing-remitting multiple sclerosis.

Traditional paper-and-pencil neuropsychological batteries used to document cognitive deficits in multiple sclerosis (MS) patients lack timing precision. This makes it difficult to accurately measure psychomotor slowing, a central cognitive symptom of MS. Additionally, traditional batteries lack multiple alternate forms necessary to control for practice effects when assessing cognition over time. Finally such batteries are lengthy and expensive. Computerized neuropsychological batteries address many of these shortcomings. They measure response time more precisely, require less administration time, include alternate forms, and are ideal for rapid screening/triage. Although there are normative data on the reliability and validity of computerized measures, there have been no controlled validation studies with MS patients. The current study was designed to validate a computerized neuropsychological battery (ANAM) for use with relapsing-remitting (RR) MS patients. Prior to initiation of interferon-beta-1a (Avonex) treatment, subjects participated in a neuropsychological evaluation consisting of traditional and computerized measures. Moderate-to-high correlations were found between computerized and traditional measures. Computerized tests accurately predicted performance on key traditional tests. The battery was also concordant with traditional measures in identifying RR MS patients with and without neurocognitive impairment. Findings are discussed with respect to increased accuracy and accessibility of neuropsychological evaluations for MS patients.

Trastornos neuropsiquiátricos en la esclerosis múltiple

Neuropsychological investigations over the past 20 years have shown the high prevalence of cognitive dysfunction in multiple sclerosis, although there are still large gaps. In this article we review current concepts regarding the different types of neuropsychiatric disorders, their physiopathology, diagnosis and treatment.We present a classification of the most important types of cognitive and psychiatric alterations in multiple sclerosis, and their physiopathology. We review the methods used in diagnosis, follow up and assessment of these patients. Finally, we analyze the current treatment available for each of these disorders.Although considerable advances have been made in understanding the neuropsychological disorders occurring in multiple sclerosis, there are still many questions to be answered. There is a need for a unified, agreed, validated battery of neuropsychological tests for the study of specific cognitive deficits in multiple sclerosis so that results may be compared. There is also a lack of biological markers which would help in diagnosis and prognosis. Finally the design and carrying out of clinical trials in the search for specific, effective drugs for the treatment of neuroconductual disorders of multiple sclerosis is necessary.

Event-related auditory evoked potentials and multiple sclerosis

Long latency event-related auditory evoked potentials, particularly the P300 wave, constitute an objective electrophysiological index of cognitive function. For this reason, these potentials have been studied in a series of 101 patients with multiple sclerosis (MS), classified according to McAlpine's criteria into definite, probable and possible cases. The patients were also classified as depressed or non-depressed according to the DSM-III and Research Diagnostic Criteria. They were also subjected to a battery of psychometric tests. In the patient population the N200 and P300 latencies were increased, as were the P200 latencies, when compared with a control population. This electrophysiological pattern had previously been observed in other conditions characterised by subcortical lesions. Partial correlations (at constant disease duration) between the disability score and the cognitive deficit were found to be significant. Patients with an increased P300 latency had a greater disability and the P300 latency was significantly correlated with the duration of the illness. The N200 and P300 latencies were increased in depressed MS subjects, but this increase did not reach the level of significance. Depression was more frequent in the more severely handicapped patients. This suggests that the origin of the depression seen in multiple sclerosis is only partly organic, and that it is one of the factors contributing to the subcortical cognitive deficit in multiple sclerosis. Progressive forms of the disease exhibited the most profound cognitive deficit, and the most marked increase in P300 latency.

Anatomical and functional correlates of cognitive deficit in multiple sclerosis

This brief article reviews the present state of knowledge concerning the relationship between structural and functional cerebral abnormalities and the cognitive deficits associated with multiple sclerosis. Currently available neuroimaging techniques have substantially contributed to a better understanding of the latter, suggesting that cortical-subcortical disconnection is the most likely cause of the cognitive disturbance. Longitudinal studies are needed to determine the natural history of the cognitive deficit and its relationship to the cerebral changes detected by neuroimaging techniques.

Neuropsychology and multiple sclerosis: Diagnostic and rehabilitative approaches

The frequency of cognitive deficits in multiple sclerosis (MS) patients is rather high and the estimates vary between 43% and 72% depending on the patient samples studied as well as on the methods of cognitive assessment. Despite the great impact of cognitive dysfunction on several aspects of the quality of life, the importance of accurate assessment and rehabilitation of neuropsychological deficits in MS patients has long been ignored. In this article, we first describe tests for the assessment of impairments, disabilities and handicaps. We emphasize that after screening with brief assessment instruments, detailed testing of the basic target deficits is mandatory for the planning of special cognitive training programs. Second, the correlation of certain cognitive deficit patterns with important magnetic resonance imaging (MRI) variables such as total lesion area, size of the corpus callosum and specific lesion location is outlined in detail. Third, some recommendations are made with regard to general rehabilitation principles such as restitution, compensation and adaptation as well as for special rehabilitation techniques including cognitive retraining of basic deficits and/or training of activities of daily living. Finally, we emphasize that there is a need for the development of tailor-made neuropsychological rehabilitation techniques for MS patients, which take into account the course and stage of the disease as well as the specific psychosocial problems of the individual patient.