Logo of jnnpsycJournal of Neurology, Neurosurgery and PsychiatryVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
J Neurol Neurosurg Psychiatry. 2005 Apr; 76(4): 519–526.
PMCID: PMC1739602

Cognitive impairment as marker of diffuse brain abnormalities in early relapsing remitting multiple sclerosis


Objectives: To establish the frequency of cognitive impairment in a population based sample of patients with recently diagnosed relapsing-remitting multiple sclerosis (RRMS), and to determine the relation between cognitive abnormalities and the extent of macroscopic and microscopic tissue damage revealed by magnetic resonance imaging (MRI) and magnetisation transfer (MT) imaging.

Methods: 58 patients with RRMS consecutively diagnosed in the previous six months in Aquitaine and 70 healthy controls underwent a battery of neuropsychological tests. Lesion load and atrophy indices (brain parenchymal fraction and ventricular fraction) were measured on brain MRI. MT ratio (MTR) histograms were obtained from lesions, normal appearing white matter (NAWM), and normal appearing grey matter (NAGM). Gadolinium enhanced lesions were counted.

Results: 44 RRMS patients could be individually matched with healthy controls for age, sex, and education. Patients performed worse in tests of verbal and spatial memory, attention, information processing speed, inhibition, and conceptualisation. Measures of attention and information processing speed were correlated with lesion load, mean NAWM MTR, and the peak location of the NAGM MTR histogram in the patients. Multivariate regression analysis showed that lesion load and mean NAWM MTR were among the MR indices that were most significantly associated with impairment of attention and information processing speed in these early RRMS cases.

Conclusions: Cognitive impairment appears to be common in the early stages of RRMS, mainly affecting attention, information processing speed, memory, inhibition, and conceptualisation. The severity of these deficits reflects the extent of the lesions and the severity of tissue disorganisation outside lesions.

Full Text

The Full Text of this article is available as a PDF (105K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Mesulam MM. Large-scale neurocognitive networks and distributed processing for attention, language, and memory. Ann Neurol. 1990 Nov;28(5):597–613. [PubMed]
  • Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology. 1991 May;41(5):685–691. [PubMed]
  • Ron MA, Callanan MM, Warrington EK. Cognitive abnormalities in multiple sclerosis: a psychometric and MRI study. Psychol Med. 1991 Feb;21(1):59–68. [PubMed]
  • Heaton RK, Nelson LM, Thompson DS, Burks JS, Franklin GM. Neuropsychological findings in relapsing-remitting and chronic-progressive multiple sclerosis. J Consult Clin Psychol. 1985 Feb;53(1):103–110. [PubMed]
  • Beatty WW, Goodkin DE, Monson N, Beatty PA, Hertsgaard D. Anterograde and retrograde amnesia in patients with chronic progressive multiple sclerosis. Arch Neurol. 1988 Jun;45(6):611–619. [PubMed]
  • Feinstein A, Kartsounis LD, Miller DH, Youl BD, Ron MA. Clinically isolated lesions of the type seen in multiple sclerosis: a cognitive, psychiatric, and MRI follow up study. J Neurol Neurosurg Psychiatry. 1992 Oct;55(10):869–876. [PMC free article] [PubMed]
  • Pelosi L, Geesken JM, Holly M, Hayward M, Blumhardt LD. Working memory impairment in early multiple sclerosis. Evidence from an event-related potential study of patients with clinically isolated myelopathy. Brain. 1997 Nov;120(Pt 11):2039–2058. [PubMed]
  • Achiron A, Barak Y. Cognitive impairment in probable multiple sclerosis. J Neurol Neurosurg Psychiatry. 2003 Apr;74(4):443–446. [PMC free article] [PubMed]
  • Grant I, McDonald WI, Trimble MR, Smith E, Reed R. Deficient learning and memory in early and middle phases of multiple sclerosis. J Neurol Neurosurg Psychiatry. 1984 Mar;47(3):250–255. [PMC free article] [PubMed]
  • Lyon-Caen O, Jouvent R, Hauser S, Chaunu MP, Benoit N, Widlöcher D, Lhermitte F. Cognitive function in recent-onset demyelinating diseases. Arch Neurol. 1986 Nov;43(11):1138–1141. [PubMed]
  • Amato MP, Ponziani G, Pracucci G, Bracco L, Siracusa G, Amaducci L. Cognitive impairment in early-onset multiple sclerosis. Pattern, predictors, and impact on everyday life in a 4-year follow-up. Arch Neurol. 1995 Feb;52(2):168–172. [PubMed]
  • 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 May;44(5):494–501. [PubMed]
  • Zivadinov R, Sepcic J, Nasuelli D, De Masi R, Bragadin LM, Tommasi MA, Zambito-Marsala S, Moretti R, Bratina A, Ukmar M, et al. A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2001 Jun;70(6):773–780. [PMC free article] [PubMed]
  • Zivadinov R, De Masi R, Nasuelli D, Bragadin LM, Ukmar M, Pozzi-Mucelli RS, Grop A, Cazzato G, Zorzon M. MRI techniques and cognitive impairment in the early phase of relapsing-remitting multiple sclerosis. Neuroradiology. 2001 Apr;43(4):272–278. [PubMed]
  • Comi G, Rovaris M, Leocani L, Martinelli V, Filippi M. Assessment of the damage of the cerebral hemispheres in MS using neuroimaging techniques. J Neurol Sci. 2000 Jan 15;172 (Suppl 1):S63–S66. [PubMed]
  • 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 Feb;39(2 Pt 1):161–166. [PubMed]
  • 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 Mar;44(3 Pt 1):420–425. [PubMed]
  • Foong J, Rozewicz L, Quaghebeur G, Davie CA, Kartsounis LD, Thompson AJ, Miller DH, Ron MA. Executive function in multiple sclerosis. The role of frontal lobe pathology. Brain. 1997 Jan;120(Pt 1):15–26. [PubMed]
  • Rovaris M, Filippi M, Falautano M, Minicucci L, Rocca MA, Martinelli V, Comi G. Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis. Neurology. 1998 Jun;50(6):1601–1608. [PubMed]
  • Fulton JC, Grossman RI, Udupa J, Mannon LJ, Grossman M, Wei L, Polansky M, Kolson DL. MR lesion load and cognitive function in patients with relapsing-remitting multiple sclerosis. AJNR Am J Neuroradiol. 1999 Nov-Dec;20(10):1951–1955. [PubMed]
  • Camp SJ, Stevenson VL, Thompson AJ, Miller DH, Borras C, Auriacombe S, Brochet B, Falautano M, Filippi M, Hérissé-Dulo L, et al. Cognitive function in primary progressive and transitional progressive multiple sclerosis: a controlled study with MRI correlates. Brain. 1999 Jul;122(Pt 7):1341–1348. [PubMed]
  • Brochet B, Dousset V. Pathological correlates of magnetization transfer imaging abnormalities in animal models and humans with multiple sclerosis. Neurology. 1999;53(5 Suppl 3):S12–S17. [PubMed]
  • Rovaris M, Filippi M, Minicucci L, Iannucci G, Santuccio G, Possa F, Comi G. Cortical/subcortical disease burden and cognitive impairment in patients with multiple sclerosis. AJNR Am J Neuroradiol. 2000 Feb;21(2):402–408. [PubMed]
  • Filippi M, Tortorella C, Rovaris M, Bozzali M, Possa F, Sormani MP, Iannucci G, Comi G. Changes in the normal appearing brain tissue and cognitive impairment in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2000 Feb;68(2):157–161. [PMC free article] [PubMed]
  • Boringa JB, Lazeron RH, Reuling IE, Adèr HJ, Pfennings L, Lindeboom J, de Sonneville LM, Kalkers NF, Polman CH. The brief repeatable battery of neuropsychological tests: normative values allow application in multiple sclerosis clinical practice. Mult Scler. 2001 Aug;7(4):263–267. [PubMed]
  • Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983 Mar;13(3):227–231. [PubMed]
  • Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996 Apr;46(4):907–911. [PubMed]
  • Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983 Nov;33(11):1444–1452. [PubMed]
  • Cutter GR, Baier ML, Rudick RA, Cookfair DL, Fischer JS, Petkau J, Syndulko K, Weinshenker BG, Antel JP, Confavreux C, et al. Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain. 1999 May;122(Pt 5):871–882. [PubMed]
  • Fischer JS, Rudick RA, Cutter GR, Reingold SC. The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force. Mult Scler. 1999 Aug;5(4):244–250. [PubMed]
  • Kalkers NF, Bergers L, de Groot V, Lazeron RH, van Walderveen MA, Uitdehaag BM, Polman CH, Barkhof F. Concurrent validity of the MS Functional Composite using MRI as a biological disease marker. Neurology. 2001 Jan 23;56(2):215–219. [PubMed]
  • Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382–389. [PubMed]
  • Sharrack B, Hughes RA. The Guy's Neurological Disability Scale (GNDS): a new disability measure for multiple sclerosis. Mult Scler. 1999 Aug;5(4):223–233. [PubMed]
  • Snaith RP, Harrop FM, Newby DA, Teale C. Grade scores of the Montgomery-Asberg Depression and the Clinical Anxiety Scales. Br J Psychiatry. 1986 May;148:599–601. [PubMed]
  • Amieva Hélène, Lafont Sylviane, Auriacombe Sophie, Le Carret Nicolas, Dartigues Jean-François, Orgogozo Jean-Marc, Colette Fabrigoule. Inhibitory breakdown and dementia of the Alzheimer type: a general phenomenon? J Clin Exp Neuropsychol. 2002 Jun;24(4):503–516. [PubMed]
  • Bever CT, Jr, Grattan L, Panitch HS, Johnson KP. The Brief Repeatable Battery of Neuropsychological Tests for Multiple Sclerosis: a preliminary serial study. Mult Scler. 1995 Nov;1(3):165–169. [PubMed]
  • Vernay D, Gerbaud L, Clavelou P. Qualité de vie et sclérose en plaques. Rev Neurol (Paris) 2001 Sep;157(8-9):1139–1142. [PubMed]
  • Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology. 1999 Nov 10;53(8):1698–1704. [PubMed]
  • 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 Oct;8(5):410–414. [PubMed]
  • Dousset V, Grossman RI, Ramer KN, Schnall MD, Young LH, Gonzalez-Scarano F, Lavi E, Cohen JA. Experimental allergic encephalomyelitis and multiple sclerosis: lesion characterization with magnetization transfer imaging. Radiology. 1992 Feb;182(2):483–491. [PubMed]
  • Bobholz Julie A, Rao Stephen M. Cognitive dysfunction in multiple sclerosis: a review of recent developments. Curr Opin Neurol. 2003 Jun;16(3):283–288. [PubMed]
  • Solari A, Mancuso L, Motta A, Mendozzi L, Serrati C. Comparison of two brief neuropsychological batteries in people with multiple sclerosis. Mult Scler. 2002 Apr;8(2):169–176. [PubMed]
  • Sperling RA, Guttmann CR, Hohol MJ, Warfield SK, Jakab M, Parente M, Diamond EL, Daffner KR, Olek MJ, Orav EJ, et al. Regional magnetic resonance imaging lesion burden and cognitive function in multiple sclerosis: a longitudinal study. Arch Neurol. 2001 Jan;58(1):115–121. [PubMed]
  • Vitkovitch Melanie, Bishop Sarah, Dancey Christine, Richards Anne. Stroop interference and negative priming in patients with multiple sclerosis. Neuropsychologia. 2002;40(9):1570–1576. [PubMed]
  • Rao SM, Glatt S, Hammeke TA, McQuillen MP, Khatri BO, Rhodes AM, Pollard S. Chronic progressive multiple sclerosis. Relationship between cerebral ventricular size and neuropsychological impairment. Arch Neurol. 1985 Jul;42(7):678–682. [PubMed]
  • Kujala P, Portin R, Ruutiainen J. The progress of cognitive decline in multiple sclerosis. A controlled 3-year follow-up. Brain. 1997 Feb;120(Pt 2):289–297. [PubMed]
  • Laatu S, Hämäläinen P, Revonsuo A, Portin R, Ruutiainen J. Sematic memory deficit in multiple sclerosis; impaired understanding of conceptual meanings. J Neurol Sci. 1999 Jan 15;162(2):152–161. [PubMed]
  • Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan 29;338(5):278–285. [PubMed]
  • Lazeron RH, Langdon DW, Filippi M, van Waesberghe JH, Stevenson VL, Boringa JB, Origgi D, Thompson AJ, Falautano M, Polman CH, et al. Neuropsychological impairment in multiple sclerosis patients: the role of (juxta)cortical lesion on FLAIR. Mult Scler. 2000 Aug;6(4):280–285. [PubMed]
  • Chard DT, Griffin CM, Parker GJM, Kapoor R, Thompson AJ, Miller DH. Brain atrophy in clinically early relapsing-remitting multiple sclerosis. Brain. 2002 Feb;125(Pt 2):327–337. [PubMed]
  • McGavern DB, Murray PD, Rivera-Quiñones C, Schmelzer JD, Low PA, Rodriguez M. Axonal loss results in spinal cord atrophy, electrophysiological abnormalities and neurological deficits following demyelination in a chronic inflammatory model of multiple sclerosis. Brain. 2000 Mar;123(Pt 3):519–531. [PubMed]
  • Losseff NA, Wang L, Lai HM, Yoo DS, Gawne-Cain ML, McDonald WI, Miller DH, Thompson AJ. Progressive cerebral atrophy in multiple sclerosis. A serial MRI study. Brain. 1996 Dec;119(Pt 6):2009–2019. [PubMed]
  • Simon JH, Jacobs LD, Campion MK, Rudick RA, Cookfair DL, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, et al. A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology. 1999 Jul 13;53(1):139–148. [PubMed]
  • Ge Y, Grossman RI, Udupa JK, Wei L, Mannon LJ, Polansky M, Kolson DL. Brain atrophy in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis: longitudinal quantitative analysis. Radiology. 2000 Mar;214(3):665–670. [PubMed]
  • Filippi M, Mastronardo G, Rocca MA, Pereira C, Comi G. Quantitative volumetric analysis of brain magnetic resonance imaging from patients with multiple sclerosis. J Neurol Sci. 1998 Jun 30;158(2):148–153. [PubMed]
  • Liu C, Edwards S, Gong Q, Roberts N, Blumhardt LD. Three dimensional MRI estimates of brain and spinal cord atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1999 Mar;66(3):323–330. [PMC free article] [PubMed]
  • Fisher E, Rudick RA, Cutter G, Baier M, Miller D, Weinstock-Guttman B, Mass MK, Dougherty DS, Simonian NA. Relationship between brain atrophy and disability: an 8-year follow-up study of multiple sclerosis patients. Mult Scler. 2000 Dec;6(6):373–377. [PubMed]
  • Benedict Ralph H B, Bakshi Rohit, Simon Jack H, Priore Roger, Miller Colleen, Munschauer Frederick. Frontal cortex atrophy predicts cognitive impairment in multiple sclerosis. J Neuropsychiatry Clin Neurosci. 2002 Winter;14(1):44–51. [PubMed]
  • Bermel Robert A, Bakshi Rohit, Tjoa Christopher, Puli Srinivas R, Jacobs Lawrence. Bicaudate ratio as a magnetic resonance imaging marker of brain atrophy in multiple sclerosis. Arch Neurol. 2002 Feb;59(2):275–280. [PubMed]
  • Rovaris Marco, Iannucci Giuseppe, Falautano Monica, Possa Francesca, Martinelli Vittorio, Comi Giancarlo, Filippi Massimo. Cognitive dysfunction in patients with mildly disabling relapsing-remitting multiple sclerosis: an exploratory study with diffusion tensor MR imaging. J Neurol Sci. 2002 Mar 30;195(2):103–109. [PubMed]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Group


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...