Cognitive disorders in multiple sclerosis

Forty to sixty percent of patients with multiple sclerosis (MS) have cognitive dysfunction. The frequency of cognitive disturbances according to the clinical form is not completely understood and the natural history of these disorders has not been extensively studied. Cognitive deficits can be detected in early stages of the disease. Their frequency increases from clinically isolated syndromes, to relapsing-remitting and secondary progressive MS. Cognitive abnormalities are frequently observed also in primary progressive MS. The most frequently impaired functions are information processing speed, attention and memory. Dementia is uncommon but may disclose the disease. Diffuse cerebral injury, assessed by magnetic resonance imaging, contributes to cognitive dysfunction in MS, probably by interrupting connecting fibers between neuronal networks involved in these cognitive functions. Compensatory mechanisms may occur at early stages but they are limited by extension of brain injury.     

Cognition in the early stage of multiple sclerosis

Objective Cognitive dysfunctions may contribute to limitation of everyday activities of patients with multiple sclerosis (MS). Recent studies have demonstrated that 45 to 65% of MS-patients are cognitively impaired. The profile of MS-related cognitive dysfunctions varies greatly. It includes memory and learning deficits, attention deficits, executive dysfunctions and visuo-spatial deficits. Most studies of cognition in MS examined patients in later stages, often including MS-patients with marked physical disabilities. Studies of cognitive dysfunctions in the early stage of the disease are rare. This study specifically aimed at evaluating and characterizing cognitive impairments in the early stage of MS, and determining specific patterns of cognitive dysfunction. Methods 21 MS patients, experiencing their first neurological symptoms not more than two years previously, and 22 healthy controls were compared. A comprehensive neuropsychological test-battery was used to evaluate MS-related cognition. The battery consisted of memory and learning tests, executive functioning tests and a visuo spatial functioning test. A computerized attention test-battery was also included, which assess accuracy and speed of test responses. In addition depression and intellectual capabilities were assessed. Results Compared with healthy controls, MS-patients in the early stage of the disease performed significantly lower on each neuropsychological assessment, except for verbal short-term memory. In particular, MS-patients showed a lengthened reaction time for simple and focused attention (19–38%), impaired non-verbal memory function (RVDLT recognition: 33%) and a planning deficit (24%). Associations between information processing speed and disease course and the employment situation were additionally found. However, patients did not have clinically relevant depression rates on the ADS-L and visuo spatial abilities remain preserved. Conclusion Our findings revealed discrete cognitive dysfunction in MS-patients within the early stage of the disease. Received in revised form: 18 January 2006     

Cognitive impairment in patients with Parkinson disease

Parkinson disease is a progressive neurodegenerative disorder resulting in motor symptoms and cognitive deficits. Neuropsychological studies have suggested that patients with Parkinson disease exhibit a broad range of cognitive deficits even in the early stages of the disease. In this review, we discuss the neuropsychological evidence for cognitive impairment in patients with Parkinson disease, outlining the different domains of cognitive disturbance. First, we review previous findings on executive dysfunction, which is associated with a disruption in frontostriatal circuitry mainly driven by dopaminergic dysmodulation. Executive dysfunction is the core symptom in the cognitive deficits in Parkinson disease. Second, we focus on impairment in different domains of memory function, such as short-term and long-term memory. Third, we discuss the pattern of cognitive deficits in visuospatial ability, ranging from basic perceptual processes to rather complex motor skills. Next, we summarize the profile of cognitive deficits in language, although previous findings are mixed and hence this topic is relatively controversial. Finally, we introduce several recent findings on social cognitive deficits, which is a new area of research that has emerged in the past decade. We also discuss the possible neural mechanisms underlying each domain of cognitive deficits in patients with Parkinson disease.     

Cognition in multiple sclerosis: relevance of lesions,brain atrophy and proton MR spectroscopy

The overall burden of brain MRI-visible lesions does not fully account for cognitive impairment in multiple sclerosis (MS). Several MRI studies have highlighted the importance of brain damage in the normal-appearing brain tissue. Brain atrophy (global, cortical, white and deep grey matter) is related to cognitive deficits in MS patients and this holds true since the earliest disease stages. Non-conventional MRI techniques such as proton MR spectroscopy have related metabolic changes in specific brain areas to specific cognitive deficits. Overall, data provided by MRI support the notion that cognitive disturbances need to be considered for a more complete clinical characterisation of patients with MS, including those with “benign” MS.     

Cognitive dysfunction in different stages in multiple sclerosis – presentation of 3 cases

Journal of Neurology - Although multiple sclerosis (MS) is a physically disabling disease, many patients also suffer from cognitive dysfunction in all stages of the disease. Recent studies have...     

Behavioural abnormalities contribute to functional decline in Huntington's disease

The independent and relative contributions of motor, cognitive, and behavioural deficits to functional decline in patients with Huntington's disease are examined. Twenty two patients with Huntington's disease were assessed with rating scales for motor dysfunction, cognitive measures of executive functions, and behavioural measures of apathy, executive dysfunction, and disinhibition. Their functional status was assessed with informant based and clinician based ratings of activities of daily living (ADL). A composite apathy/executive dysfunction behavioural index was strongly related to decline in ADL independently and after controlling for motor and cognitive deficits. These results suggest that behavioural dysfunction contributes to functional decline in patients with Huntington's disease and may impede their ability to utilise motor or cognitive skills that remain available in the early stages of the disease.     

Awareness of deficit in multiple sclerosis

The present study examined awareness of deficits among individuals with multiple sclerosis (MS). A total of 74 pairs of persons with MS and their significant others participated. Awareness of cognitive deficit was measured by discrepancy scores between patient reports of their cognitive abilities and objective test results. Awareness of functional deficit was measured by the discrepancy between the patient and significant other reports of the functional abilities of the patient. Results suggest that about one third of MS patients have diminished awareness of their cognitive and/or functional deficits. Unawareness of deficit was more common among patients with secondary-progressive MS than among those with relapse-remitting MS. Executive dysfunction was strongly associated with unawareness of cognitive deficits but not unawareness of functional deficits. Unawareness of cognitive deficits and unawareness of functional deficits appear to be tapping different aspects of unawareness of deficit.     

Visual object recognition in multiple sclerosis

Deficits in tasks measuring visual processing have been earlier reported in studies of MS. Yet, the nature and severity of visual-processing deficits in MS remains unclear. We used a new method in order to measure the different stages of visual processing in object recognition: shape recognition, familiarity recognition, semantic categorization, and identification with naming. Six two-choice reaction-time tasks were presented to 30 MS patients and 15 healthy controls. The patients were divided into cognitively preserved and cognitively deteriorated study groups according to their cognitive status. The purpose was to find out whether deficits at specific stages of visual processing can be found in cognitively deteriorated MS patients. Cognitively deteriorated MS patients did not perform as well as cognitively preserved MS patients or healthy controls. They were slower already at the early stage of visual processing where discrimination of whole objects from scrambled ones was required. They also had higher error rates in tasks requiring object familiarity detection and object identification with naming. Thus, cognitively deteriorated MS patients had difficulties in visual shape recognition and semantic-lexical processing. However, variation of performances was large within both of the patient groups indicating that even patients without a generalized cognitive decline may have deficits in some stages of the visual processing. We suggest that because of the heterogeneity of the patients, every single case needs to be examined separately in order to identify the possible deficits in visual processing.     

Cognitive deficits in experimental autoimmune encephalomyelitis: neuroinflammation and synaptic degeneration

Multiple sclerosis (MS) is characterized by auto-reactive T cells that respond to central nervous system (CNS)-based antigens and affect motor, sensory as well as behavioral and cognitive functions. Cognitive deficits are now considered an early manifestation of the disease in MS patients. However, the pathophysiology responsible for the cognitive symptoms in MS remains unclear. Increasing evidence from a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE), suggests a correlation between the synaptopathy induced by microglia activation in the early phase of the disease and cognitive dysfunction. In particular, EAE causes deficits in hippocampal-dependent learning and memory that are associated with early microglial activation, synaptic loss and neurodegeneration. Interestingly, inflammatory cytokines released from infiltrating lymphocytes or activated microglia are able to alter synaptic transmission. Increased glutamate-mediated transmission and loss of GABAergic inputs were observed in EAE. They may thus underlie cognitive dysfunction in this model and in MS.     

Treatment options of cognitive impairment in multiple sclerosis

Multiple sclerosis (MS) is a progressive disease of the CNS, characterized by the production of widespread lesions in the brain and spinal cord. Inflammatory demyelination has traditionally been seen as the main disease process in MS; however, axonal damage or loss is increasingly being documented to occur early in the disease. Cognitive deficits can occur independently of physical disability, which complicates their identification and recognition. More recently, cortical demyelination has been identified among possible causes of cognitive impairment in MS. Neuropsychological studies have consistently demonstrated that 40–65% of patients with MS experience cognitive dysfunction, particularly in recent memory, information processing speed, and sustained attention. Early detection of cognitive impairment is essential to enable therapeutic intervention to alleviate symptoms or prevent further cognitive decline, although how best to manage MS-related cognitive impairment is currently unclear. Treatment strategies for cognitive impairment in MS are still in their infancy. This article will summarize several pharmacological attempts to enhance cognitive performances in people with MS.     

Neuropsychological performance in patients with mild multiple sclerosis

Although changes in cognitive function in patients with multiple sclerosis (MS) have been reported, these changes have been traditionally associated with the later stages of the disease. In the current study, a comprehensive neuropsychological battery was administered to MS patients (N = 86) in whom the disease progression was relatively mild and in remission and a demographically well-matched control group (N = 46). Besides the expected differences in tests of motor function, the two groups also differed on a number of cognitive tests with no motor demands. The two cognitive functions that appear impaired were learning and memory. Given that similar deficits have been found in MS patients with more severe symptoms, it is argued that changes in cognitive function can occur in the mild stages of the disease.     

Funktionelle Bildgebung kognitiver Prozesse bei M.-Huntington-Patienten und präsymptomatischen Mutationsträgern

Cognitive deficits are among the core symptoms of patients with Huntington's disease (HD). While impaired attention, visuospatial processing, and memory can be observed during early stages of the illness, HD patients exhibit deficits in executive function on tests requiring planning, problem solving, and cognitive flexibility with progression of the disease. Cognitive dysfunction is already present in individuals who carry the HD gene mutation but remain presymptomatic for motor and cognitive disturbances. This review provides an overview and a discussion of functional neuroimaging findings on cognitive dysfunction in patients with HD and presymptomatic HD gene mutation carriers. In HD patients, currently available evidence suggests a functional deficit of multiple cortical and subcortical regions extending beyond volumetric abnormalities. Early dysfunction of lateral prefrontal and cingulate regions has been shown in individuals with presymptomatic HD, while compensatory responses of posterior brain regions may occur closer to the onset of manifest clinical symptoms. While functional neuroimaging techniques may substantially contribute to defining neurodegenerative disease phenotypes and to identifying neural biomarkers in presymptomatic individuals, the extant data on cognitive function in HD patients and HD gene carriers however is sparse and has to be expanded through further studies.     

Acetylcholinesterase inhibitors in cognitive impairment in Huntington’s disease: A brief review

Huntington’s disease (HD) is a neurodegenerative disease associated with cognitive deficits. Cognitive dysfunction may be present in the early stages of the disease, even before the onset of motor symptoms. The cognitive dysfunction includes executive dysfunction, psychomotor symptoms, visuospatial deficits, perceptual deficits, memory loss and difficulty learning new skills. Acetylcholinesterase inhibitors have shown good effect in the treatment of other types of dementia and it is postulated that it might delay cognitive decline in HD. We reviewed the evidence for Acetylcholinesterase inhibitors in the treatment of cognitive decline and dementia associated with Huntington’s disease. We identified 6 articles that investigated the role of Acetylcholinesterase inhibitors for treatment of cognitive deficits in Huntington’s disease. Following the review, the authors concluded that there is limited evidence for the use of Acetylcholinesterase inhibitors for cognitive impairment in HD.     

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.     

Assessment and rehabilitation of cognitive impairment in multiple sclerosis

Patients with multiple sclerosis (MS) have a substantial risk of cognitive dysfunction, even in the earliest stages of the disease, where there is minimum physical disability. Despite the high prevalence rates and the significant impact of cognitive dysfunction on quality of life in this population, cognitive functions are not routinely assessed due to the high cost and time consumption. This article provides an overview of the current state of knowledge related to cognition in MS and on the optimal approach to neuropsychological assessment of this population. It then focuses on the pharmacological and other treatment options available for MS patients with, or at risk for developing, cognitive impairment. The available immune-modulating agents may reduce the development of new lesions and therefore prevent or minimize the progression of cognitive decline. However, there is currently insufficient evidence concerning the efficiency of symptomatic treatment in MS. There is also currently no optimal non-pharmacological treatment strategy for cognitive decline in MS, as the studies published to date report heterogeneous results. Nevertheless, non-pharmacological treatments such as cognitive rehabilitation may benefit some MS patients. As cognition is increasingly recognized as a major feature of MS, its assessment and rehabilitation will become a greater priority.     

Multiple sclerosis-related cognitive changes: a review of cross-sectional and longitudinal studies

Prevalence estimates of cognitive impairment in multiple sclerosis (MS) range from 40% to 65%, depending on the research setting. Cognitive dysfunction virtually encompasses all the disease stages and types of clinical course, although it is generally less frequent in relapsing-remitting (RR) patients compared with secondary progressive (SP) patients, and tends to be less frequent in primary progressive (PP) patients. Moreover, it causes role limitations in work and social life, independently of the degree of physical disability. Relatively little is known about the evolution of cognitive impairment in MS, particularly starting from the early stages of the disease. Controlled studies, however, have clearly shown that cognitive deterioration tends to progress over time. Among clinical predictors, incipient cognitive decline seems to be the major risk factor for further deterioration in the short-term. In the long-term, the likelihood increases that also patients with initial cognitive preservation may deteriorate. As for magnetic resonance imaging (MRI), there are consistent, albeit moderate, correlations between the progression of cognitive impairment and increasing brain lesion load and brain atrophy. The aim of this paper is to provide a review of existing cross-sectional and longitudinal studies on cognitive deterioration in MS.     

White matter lesions and cognitive deficits: relevance of lesion pattern?

Magnetic resonance imaging (MRI) permits efficient visualization of white matter lesions (WML). A growing body of literature deals with the correlation of WML and cognitive dysfunction with conflicting results. We studied the influence of lesion pattern as well as size by analyzing MRI and psychometric test performance in 2 patient collectives with different WML patterns. 22 patients with myotonic dystrophy (MD) and mainly subcortical WML werecompared with 39 patients with multiple sclerosis (MS) and mainly periventricular lesions. 73% of MD patients had WML, the extent of which correlated with cognitive deficits. Severely impaired patients had psychometric findings compatible with "subcortical" dementia. In MS the extent of WML alone did not correlate significantly with cognitive deficits. Significant cognitive dysfunction was observed with extension of WML to areas of white matter immediately underlying cortex, but not with exclusively periventricular lesions. Cerebral atrophy had less impact. Comparison of MD and MS indicates that WML immediately subjacent to cortex are likely to cause significant cognitive deficits, whereas extensive periventricular demyelination may cause no major dysfunction. This may relate to early disturbance of associative fibers by subcortical lesions. Our results emphasize the significance of pattern as well as total extent of WML. Myotonic dystrophy is a useful model to study the effect of subcortical lesions, due to a typical lesion pattern unusual in other conditions.     

Functional imaging of cognition in Parkinson's disease

PURPOSE OF REVIEW: Cognitive deficits that occur even early in the course of Parkinson's disease have received increasing attention in current imaging research. The exact physio-pathological processes mediating the deficits and the complex relationship of cognitive signs and antiparkinsonian treatment are not well understood. A clearer understanding of these mechanisms could potentially influence treatment choices, drug development and, ultimately, patient care. RECENT FINDINGS: Abnormal networks identified in studies of resting state metabolism in Parkinson's disease represent metabolic markers for remote effects of striato-nigral degeneration. These metabolic changes include subcortico-cortical networks, in particular cognitive cortico-striato-pallidal-thalamocortical loops. Recent brain studies focus on intervention-related brain changes. They illustrate different task-specific changes in brain activation with deep brain stimulation and with levodopa. Variable results of stimulation can be attributed to different effects on segregated cortico-striato-pallidal-thalamocortical loops during stimulation. By contrast, the heterogeneity observed in studies with levodopa possibly reflects the disease-stage and task-specific effects of levodopa. A decline in caudate dopamine modulated basal ganglia outflow appears to contribute to executive dysfunction and to brain activation changes in these loops at early Parkisnon's disease stages, while mesocortical degeneration mediated increases of inefficient dorsolateral prefrontal cortex activation may display a feature of more advanced disease stages only. SUMMARY: Despite evidence for the role of dopamine and cortico-striato-pallidal-thalamocortical loops in cognition, the specific contributions of mesocortical dopamine depletion and striatal dysfunction with downstream consequences on the loops remain to be separated. Additionally, more research is needed into the role of non-dopaminergic pathology in cognitive decline in Parkinson's disease.     

Comparison of neuropsychological impairment and vocational outcomes in systemic lupus erythematosus and multiple sclerosis patients

Systemic lupus erythematosus (SLE) and multiple sclerosis (MS) are chronic immunologic diseases that can cause cognitive dysfunction. MS is a central nervous system (CNS) disease characterized by demyelination and progressive brain atrophy. SLE is an autoimmune disease capable of damaging multiple organ systems, including the CNS. Cognitive disturbances are seen in both SLE and MS. The present study is concerned with understanding the similarities and differences between the cognitive profiles of SLE and MS as well as the relationship between cognitive impairment and vocational disability in these patients. We examined 47 SLE patients, 47 MS patients, and 44 healthy controls. The groups were well matched on demographics and the patient groups were also matched on disease duration and severity. Group comparisons revealed that generative verbal fluency and visual-spatial memory are more profoundly affected in MS than SLE; whereas depression, fatigue, and working memory deficits are similarly involved in both diseases. Logistic regression analysis revealed that executive function, in particular, was predictive of vocational outcomes in SLE and MS patients.     

Pathophysiology of cognitive impairment in multiple sclerosis

Only in the last decade has significant progress been reached in understanding the pathophysiology of cognitive impairment in multiple sclerosis (MS). Edema, inflammation, demyelination and axonal loss may have different consequences on nerve fiber conduction, causing temporal disorganization or disruption of the inputs travelling along the intrahemispheric and interhemispheric connections among associative areas as well as between cortical and subcortical structures involved in mental functions.Neuropsychological, electrophysiological, metabolic and magnetic resonance imaging (MRI) studies have provided converging evidence that the most common type of cognitive dysfunction observed in MS patients, the so-called subcortical dementia, is an almost invariable complication of the advanced phases of the disease. In these phases, large amounts of brain white matter may be affected by microscopic and macroscopic lesions characterized by pronounced axonal loss.However, the acute occurence of transitory and isolated selective cognitive deficits or reversible dementia has been observed in a few patients. In these cases a pathogenetic role of the inflammatory process in cognitive changes is to be considered. In fact, antineural antibodies, proinflammatory cytokines and other neurotoxic substances may induce or regulate several critical cellular and electrophysiologic functions. Understan-ding how the cellular and humoral responses may be differently associated with acute or chronic disease evolution and with macroscopic and microscopic brain changes is essential for the formulation of a unifying pathogenetic model of cognitive impairment in MS.