Cortical lesions and cognitive impairment in multiple sclerosis
Cortical lesions and cognitive impairment in multiple sclerosis
F.Rinaldi ?M.Calabrese ?P.Grossi ?M.Puthenparampil ?P.Perini ?P.Gallo
Published online:16July 2010óSpringer-Verlag 2010
Abstract Multiple sclerosis (MS)is a chronic in?am-matory and degenerative disease of the central nervous system.In the last decade,pathological and magnetic res-onance imaging (MRI)studies have shown that a signi?-cant portion of in?ammatory lesions are located in the grey matter,especially in the cerebral cortex,of MS patients.Cortical in?ammatory lesions (CL)can be demonstrated in vivo in MS patients by double inversion recovery (DIR)MRI sequence.Neuropsychological de?cits constitute a major clinical aspect of MS,being demonstrated in a per-centage ranging from 40to 65%of patients,and have been shown to be associated with cortical demyelination and atrophy.Recent DIR studies in MS patients having dif-ferent clinical forms of the disease have disclosed that CL burden not only correlates with the severity of physical disability,but is also one of the major structural changes associated with disease-related cognitive impairment.Keywords Multiple sclerosis áCognitive impairment áCortical lesions
Introduction
Since the extraordinarily telling remark on the cognitive impairment observed in multiple sclerosis (MS)patients made by Charcot,i.e.,‘‘In most of the patients affected by
multi-locular sclerosis […]there is a marked enfeeblement of the memory;conceptions are formed slowly;the intel-lectual and emotional faculties are blunted in their totality’’(Charcot 1877),the presence of various degrees of cogni-tive dysfunctions has been largely documented in MS.Cognitive de?cits may affect from 40to 65%of MS patients,and signi?cantly contribute to their disability [1,2].Indeed,cognitive dysfunction disrupts lives,life-styles,employment status,and yearly earnings of MS patients,has detrimental effects on personal,occupational,and social functioning,thereby affecting overall quality of life.Although more frequent and severe in the progressive forms of MS,a cognitive impairment can be present since the early stages of the disease [1,2].MS affects various aspects of cognitive functioning,including attention and concentration,information processing ef?ciency,executive functions,processing speed,and long-term memory.Pro-cessing speed,visual learning and memory seem to be the most commonly affected in MS.Overt dementia is rare in MS,and the more common clinical presentation is one of speci?c and subtle cognitive de?cits that can vary sub-stantially among patients [1,2].
Magnetic resonance imaging (MRI)has been largely applied to investigate the radiological abnormalities asso-ciated with cognitive dysfunction in MS [1,3].Although the decline in cognitive performance was ascribed to white matter (WM)and subcortical pathology,the strength of the relationship between WM lesion load and cognitive impairment was modest.Moreover,brain atrophy measures were found to correlate only moderately with MS-related cognitive impairment [4–6].Other MRI studies,aimed at evaluating the extent of brain tissue loss on a regional basis,have disclosed that neocortical volume loss was more closely associated with cognitive decline than whole-brain atrophy [7,8].
F.Rinaldi and M.Calabrese have equally contributed to the work.F.Rinaldi (&)áM.Calabrese áP.Grossi áM.Puthenparampil áP.Perini áP.Gallo
Department of Neurosciences,The Multiple Sclerosis Centre of Veneto Region,University Hospital of Padova,Via Giustiniani,5,35128Padua,Italy e-mail:francyrinaldi@https://www.sodocs.net/doc/0214262323.html,
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Neurol Sci (2010)31(Suppl 2):S235–S237DOI 10.1007/s10072-010-0368-4
The cortical involvement in MS is probably a quite complex and heterogeneous phenomenon since it may result from several pathological processes,like meningeal in?ammation,neuronal injury,Wallerian or transsynaptic degeneration,and overall from local demyelinating lesions [9,10].Indeed,MS is characterized by an extensive cor-tical in?ammation,with a relevant number of focal lesions (cortical lesions,CL)located within the cerebral cortex of patients[9–11].In the past few years,a large effort was devoted to the development of MRI techniques capable of visualizing at least a portion of CL in vivo.Recently,the application of double inversion recovery(DIR)sequences convincingly demonstrated that CL are a frequent?nding in patients with MS[12,13].DIR imaging allowed an average increase of152%in CL detection per patient when compared with FLAIR.Moreover,in comparison with T2-weighted sequences,DIR showed a500%increase in detection of CL[14].In previous studies on large cohorts of MS patients,we found that CL could be demonstrated in the early disease stages[12],were associated with critical symptoms,such as epilepsy[15],were inversely correlated with the‘‘benign’’course of the disease[16]and could be detected at clinical onset in MS patients having no lesions in the WM,as disclosed by conventional MRI sequences [17].Moreover,CL were found to correlate with cortical atrophy in primary progressive MS[18],and to play an important role in determining the clinical course of the disease[19].The hypothesis that CL could be also an additional pathological substrate for MS-related cognitive dysfunction remained to be proved.
CL as a substrate of cognitive dysfunction in MS Roosendaal and colleagues[20]demonstrated that CL, detected by DIR imaging,might have a signi?cant impact on MS-related cognitive https://www.sodocs.net/doc/0214262323.html,ing the Letter Digit Substitution Test to assess processing speed of visual information and the Location Learning Test(LLT)to evaluate visuospatial memory,their study showed,in13 MS patients,that CL increased signi?cantly over a time period of3years and were associated with a worse per-formance on neuropsychological measures at follow-up. More speci?cally,they observed a signi?cant relationship at follow-up between hippocampal lesion number and the LLT delay score,which could be understood in terms of the heavy involvement of the hippocampus in visuospatial memory.Main limitations of the study were the relatively low number of subjects and the use of a cognitive test battery limited to only two cognitive domains.
In a different way,we quanti?ed the extent of CL detectable on DIR images in70patients affected from relapsing–remitting MS(RRMS),in order to improve our understanding of their relative contribution to disease-related cognitive impairment[21].Furthermore,in our study,neuropsychological assessment was performed using the Rao Brief Repeatable Battery of Neuropsychological Tests,that includes tests of verbal immediate and delayed recall memory[Selective Reminding Test(SRT)and SRT-Delayed Recall],spatial immediate and delayed recall memory(10/36Spatial Recall Test and10/36Spatial Recall Test-Delayed),sustained attention,concentration, and speed of information processing(Paced Auditory Serial Addition Test at3s and Symbol Digit Modalities Test),and verbal?uency on semantic stimulus(Word List Generation).Twenty-four patients(34.3%)were classi?ed as cognitively impaired[i.e,they scored2standard devi-ations(SDs)below the mean normative values in C1 cognitive test]and46patients(65.7%)were classi?ed as cognitively unimpaired.T2hyperintense WM lesion vol-ume and contrast-enhancing lesion number were not dif-ferent between cognitively impaired and cognitively unimpaired patients.CL were detected in18of24cogni-tively impaired patients(75.0%)(see Fig.1)and44of46 cognitively unimpaired patients(95.7%)(P=0.01),but cognitively impaired patients had a signi?cantly higher CL volume(P\0.001).The best correlation was found between CL load(number and volume)and tests for sus-tained attention(SDMT,PASAT-3),test for speed of information processing(PASAT-3),and global cognitive impairment.A multivariate analysis revealed signi?cant contributions from CL volume and,at a lower level,
age Fig.1Cortical lesions(DIR sequence)in one MS patient with cognitive impairment
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and grey matter(GM)atrophy as independent predictors of cognitive impairment.Finally,we observed that RRMS patients with cognitive de?cits had higher CL load and cortical atrophy than those having normal cognitive per-formance.The multivariate analysis further revealed that only CL volume and neocortical volume loss were inde-pendent predictors of cognitive decline in these patients.
Our results are in agreement with previous pathological [22]and neuroimaging[7]studies,which demonstrated a signi?cant cortical pathology in cognitively impaired RRMS patients.Considering the con?icting observations on the role played by subcortical WM damage in deter-mining the cognitive decline in MS,our data further strengthen the notion that the overall burden of WM lesions does not fully account for the severity of cognitive impairment in MS and indicate the CL burden as one of the major structural changes associated to MS-related cogni-tive dysfunction.
Con?ict of interest statement The authors declare that they have no con?ict of interest related to the publication of this article. References
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