Brain atrophy and lesion load as explaining parameters for cognitive impairment in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, with lesions widespread through the brain and spinal cord. An important manifestation is cognitive impairment, which, though difficult to measure, may have a major social impact. To better understand the relationship between structural tissue damage and cognitive impairment, we examined the extent and spatial distribution of brain lesions, as measured by magnetic resonance imaging (MRI), in relation to abnormal cognitive performance as measured by the Brief Repeatable Battery (BRB) in 82 MS patients. Possible confounders, like fatigue, pain and depression were also assessed. Brain MR image analysis included hyperintense T2 and hypointense T1 lesion load in the whole brain and the four lobes separately, as well as whole brain volume measurements. Cognitive impairment (defined as more than two abnormal tests) was found in 67% of the patients. Moderately strong correlations were found between the subtests of the BRB and the lesion loads in the brain regions hypothesized to be associated with that cognitive test, although these correlations were in general not much stronger than those between the subtests and the overall lesion load (due to strong interrelationships). The Spatial Recall Test correlated best with parietal lesion load; the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Task (PASAT) and the Word List Generation best with frontal, parietal and temporal lesion load; while the Verbal List Generation Test Index correlated only with atrophy. Atrophy and lesion load were the main factors determining the test scores, explaining 10-25% of the variance in the test results, and were more important than fatigue, pain and depression; only depression had a minor, but significant, additional effect on the PASAT. In conclusion, cognitive impairment in MS is moderately dependent on amount (and distribution) of structural brain damage, especially in the more physically impaired patients group.

Keywords

magnetic resonance multiple sclerosis neuropsychology

Get full access to this article

View all access options for this article.

References

Ra SM , Leo GJ , Bernardin L , Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction . Neurology 1991; 41: 685-691 .

Rao SM and Cognitive study group . A manual for the Brief Repeatable Battery of neuropsychological tests in multiple sclerosis. New York: National Multiple Sclerosis Society , 1990.

Hohol MJ , Guttmann CR , Orav J , Mackin GA , Kikinis R , Khoury SJ et al. Serial neuropsychological assessment and magnetic resonance imaging analysis in multiple sclerosis . Arch Neurol 1997; 54: 1018-1025 .

Fischer JS , Priore RL , Jacobs LD , Cookfair DL , Rudick RA , Herndon RM. Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis . Ann Neurol 2000; 48: 885-892 .

Sperling RA , Guttmann CRG , Hohol MJ , Warfield SK , Jakab M , Parente M. Regional magnetic resonance imaging lesion burden and cognitive function in multiple sclerosis-a longitudinal study . Arch Neurol 2001; 58: 115-121 .

Barak Y , Achiron A. Effect of interferon-beta-1b on cognitive functions in multiple sclerosis . Eur Neurol 2002; 47: 11-14 .

Solari A , Mancuso L , Motta A , Mendozzi L , Serrati C. Comparison of two brief neuropsychological batteries in people with multiple sclerosis . Mult Scler 2002; 8: 169-176 .

Solari A , Motta A , Mendozzi L , Pucci E , Forni M , Mancardi G et al. Computer-aided retraining of memory and attention in people with multiple sclerosis: a randomized, double-blind controlled trial . J Neurol Sci 2004; 222: 99-104 .

Poser CM , Paty DW , Scheinberg L , McDonald WI , Davis FA , Ebers GC et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols . Ann Neurol 1983; 13: 227-231 .

10.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS) . Neurology 1983; 33: 1444-1452 .

11.

Krupp LB , Larocca NG , Muirnash J , Steinberg AD. The fatigue severity scale-application to patients with multiple sclerosis and systemic lupus erythematosus . Arch Neurol 1989; 46: 1121-1123 .

12.

Schwartz JE , Jandorf L , Krupp LB. The measurement of fatigue: a new instrument . J Psychosom Res 1993; 37: 753-762 .

13.

Beck AT. Beck Depression Inventory. San Antonio, TX: The Psychological Corporation , 1987.

14.

Buschke H , Fuld PA. Evaluating storage, retention, and retrieval in disordered memory and learning . Neurology 1974; 24: 1019-1025 .

15.

Dekker R , Mulder JL , Dekker PH. Verbale Leer en Geheugen Test. Lisse: Swets en Zeitlinger , 1996.

16.

Rao SM , Hammeke TA , McQuillen MP , Khatri BO , Lloyd D. Memory disturbance in chronic progressive multiple sclerosis . Arch Neurol 1984; 41: 625-631 .

17.

Barbizet J , Cany E. Clinical and psychometrical study of a patient with memory disturbances . Int J Neurol 1968; 7: 44-54 .

18.

Smith A. Symbol digit modalities test. Los Angeles, CA: Western Psychological Services , 1973.

19.

Gronwall DM. Paced auditory serial-addition task: a measure of recovery from concussion . Percept Mot Skills 1977; 44: 367-373 .

20.

Spreen O, Benton AL. Neurosensory Center Comprehensive Examination for Aphasia (NCCEA). Victoria: University of Victoria, Neuropsychology Laboratory, 1969.

21.

van Walderveen MAA , Barkhof F , Hommes OR , Polman CH , Tobi H , Frequin SM et al. Correlating MRI and clinical disease activity in multiple sclerosis-relevance of hypointense lesions on short-TR short-TE (T1-weighted) spin-echo images . Neurology 1995; 45: 1684-1690 .

22.

Kalkers NF , Vrenken H , Uitdehaag BMJ , Polman CH , Barkhof F. Brain atrophy in multiple sclerosis: impact of lesions and of damage of whole brain tissue . Mult Scler 2002; 8: 410-414 .

23.

Boringa J , Lazeron RHC , Reuling IEW , Ader HJ , Pfennigs LEMA , Lindeboom J et al. The Brief Repeatable Battery of Neuropsychological Tests: normative values allow application in multiple sclerosis clinical practice . Mult Scler 2001; 7: 263-267 .

24.

Weinshenker BG , Bass B , Rice GPA , Noseworthy J , Carriere W , Baskerville J et al. The natural history of multiple sclerosis-a geographically based study . Brain 1989; 112: 133-146 .

25.

Weinshenker BG. Natural history of multiple sclerosis . Ann Neurol 1994; 36: S6-S11 .

26.

Franklin GM , Heaton RK , Nelson LM , Filley CM , Seibert C. Correlation of neuropsychological and MRI findings in chronic/progressive multiple sclerosis . Neurology 1988; 38: 1826-1829 .

27.

Beatty WW , Paul RH , Wilbanks SL , Hames KA , Blanco CR , Goodkin DE. Identifying multiple sclerosis patients with mild or global cognitive impairment using the Screening Examination for Cognitive Impairment (SEFCI) . Neurology 1995; 45: 718-723 .

28.

van den Burg W , van Zomeren AH , Minderhoud JM , Prange AJ , Meijer NS. Cognitive impairment in patients with multiple sclerosis and mild physical disability . Arch Neurol 1987; 44: 494-501 .

29.

Rao SM , Leo GJ , Haughton VM , St Aubin-Faubert P , Bernardin L. Correlation of magnetic resonance imaging with neuropsychological testing in multiple sclerosis . Neurology 1989; 39: 161-166 .

30.

Swirsky-Sacchetti T , Mitchell DR , Seward J , Gonzales C , Lublin F , Knobler R et al. Neuropsychological and structural brain lesions in multiple sclerosis: a regional analysis . Neurology 1992; 42: 1291-1295 .

31.

Lazeron RHC , Langdon DW , Filippi M , van Waesberghe JHTM , Stevenson VL , Boringa JBS et al. Neuropsychological impairment in multiple sclerosis patients: the role of (juxta)cortical lesion on FLAIR . Mult Scler 2000; 6: 280-285 .

32.

Christodoulou C , Krupp LB , Liang Z , Huang W , Melville P , Roque C et al. Cognitive performance and MR markers of cerebral injury in cognitively impaired MS patients . Neurology 2003; 60: 1793-1798 .

33.

Nocentini U , Rossini PM , Carlesimo GA , Graceffa A , Grasso MG , Lupoi D et al. Patterns of cognitive impairment in secondary progressive stable phase of multiple sclerosis: correlations with MRI findings . Eur Neurol 2001; 45: 11-18 .

34.

Foong J , Rozewicz L , Quaghebeur G , Davie CA , Kartsounis LD , Thompson AJ et al. Executive function in multiple sclerosis. The role of frontal lobe pathology . Brain 1997; 120: 15-26 .

35.

Rovaris M , Filippi M , Falautano M , Minicucci L , Rocca MA , Martinelli V et al. Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis . Neurology 1998; 50: 1601-1608 .

36.

Comi G , Filippi M , Martinelli V , Sirabian G , Visciani A , Campi A et al. Brain magnetic resonance imaging correlates of cognitive impairment in multiple sclerosis . J Neurol Sci 1993; 115: S66-S73 .

37.

Benedict RHB , Bakshi R , Simon JH , Priore R , Miller C , Munschauer F. Frontal cortex atrophy predicts cognitive impairment in multiple sclerosis . J Neuropsychiatr Clin Neurosci 2001; 14: 44-51 .

38.

Arnett PA , Rao SM , Bernardin L , Grafman J , Yetkin FZ , Lobeck L. Relationship between frontal lobe lesions and Wisconsin Card Sorting Test performance in patients with multiple sclerosis . Neurology 1994; 44: 420-425 .

39.

Corbetta M , Miezin FM , Dobmeyer S , Shulman GL , Petersen SE. Selective and divided attention during visual discriminations of shape, color, and speed: functional anatomy by positron emission tomography . J Neurosci 1991; 11: 2383-2402 .

40.

Wojciulik E , Kanwisher N. The generality of parietal involvement in visual attention . Neuron 1999; 23: 747-764 .

41.

Lazeron RHC , Rombouts SARB , De Sonneville LMJ , Barkhof F , Scheltens P. A paced visual serial addition test for fMRI . J Neurol Sci 2003; 213: 29-34 .

42.

Beatty WW , Goodkin DE , Hertsgaard D , Monson N.

Clinical and demographic predictors of cognitive performance in multiple sclerosis. Do diagnostic type, disease duration, and disability matter?

Arch Neurol 1990; 47: 305-308 .

43.

De Sonneville LMJ , Boringa JB , Reuling IEW , Lazeron RHC , Ader HJ , Polman CH. Information processing characteristics in subtypes of multiple sclerosis . Neuropsychologia 2002; 40: 1751-1765 .

44.

Zakzanis KK. Distinct neurocognitive profiles in multiple sclerosis subtypes . Arch Clin Neuropsychol 2000; 15: 115-136 .

45.

Huijbregts SCJ , Kalkers NFM , De Sonneville LMJ , de Groot VM , Reuling IEW , Polman CHM. Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS . Neurology 2004; 63: 335-339 .

46.

Lezak MD. Neuropsychological assessment, third edition. New York, Oxford: Oxford University Press , 1995.

47.

Haxby JV , Grady CL , Ungerleider LG , Horwitz B. Mapping the functional neuroanatomy of the intact human brain with brain work imaging . Neuropsychologia 1991; 29: 539-555 .

48.

Parks RW , Loewenstein DA , Dodrill KL , Barker WW , Yoshii F , Chang JY et al. Cerebral metabolic effects of a verbal fluency test-a PET scan study . J Clin Exp Neuropsychol 1988; 10: 565-575 .