[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.211.82.105. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Figure 1.
Typical transverse T1-weighted magnetic resonance images and illustrative examples of the cross-sectional version of the Structural Imaging Evaluation of Normalized Atrophy software (SIENAX) output of a healthy control subject (A and B, respectively) and a patient with relapsing-remitting multiple sclerosis (RRMS) (C and D, respectively) of similar age. Loss of brain volume is seen in the RRMS patient.

Typical transverse T1-weighted magnetic resonance images and illustrative examples of the cross-sectional version of the Structural Imaging Evaluation of Normalized Atrophy software (SIENAX) output of a healthy control subject (A and B, respectively) and a patient with relapsing-remitting multiple sclerosis (RRMS) (C and D, respectively) of similar age. Loss of brain volume is seen in the RRMS patient.

Figure 2.
Box plots comparing magnetic resonance measurements of normalized brain volume (NBV) of the healthy control subjects (HCs) and patients with relapsing-remitting multiple sclerosis (RRMS) without (RRMSϵ4−; n = 58) and with (RRMSϵ4+; n = 18) the apolipoprotein E ϵ4 allele. The NBV values of RRMSϵ4+ patients are significantly (P = .01) lower than those of the HC and RRMSϵ4− groups. In each box, the horizontal line represents the median; the box length shows the range within which the central 50% of values fall, with the box edges at the first and third quartiles; and the limit lines represent the range of values.

Box plots comparing magnetic resonance measurements of normalized brain volume (NBV) of the healthy control subjects (HCs) and patients with relapsing-remitting multiple sclerosis (RRMS) without (RRMSϵ4−; n = 58) and with (RRMSϵ4+; n = 18) the apolipoprotein E ϵ4 allele. The NBV values of RRMSϵ4+ patients are significantly (P = .01) lower than those of the HC and RRMSϵ4− groups. In each box, the horizontal line represents the median; the box length shows the range within which the central 50% of values fall, with the box edges at the first and third quartiles; and the limit lines represent the range of values.

Figure 3.
Box plots comparing magnetic resonance measurements of normalized brain volume (NBV) of the healthy control subjects (HC) and patients with relapsing-remitting multiple sclerosis (RRMS) without (RRMSϵ4−) and with (RRMSϵ4+) the apolipoprotein E ϵ4 allele. In this case, from the whole group of RRMS patients, only those with short disease duration (<3 years) and absence of disability (Expanded Disability Status Scale score, <2) are selected (22 patients without and 8 patients with the ϵ4 allele). The NBV values of the HCs are from a subgroup of 12 subjects age matched with patient subgroups (mean age, 30 years in each group). The NBV values of the RRMSϵ4+ group are significantly (P = .04) lower than those of the HC and RRMSϵ4− groups. In each box, the horizontal line represents the median; the box length shows the range within which the central 50% of values fall, with the box edges at the first and third quartiles; and the limit lines represent the range of values.

Box plots comparing magnetic resonance measurements of normalized brain volume (NBV) of the healthy control subjects (HC) and patients with relapsing-remitting multiple sclerosis (RRMS) without (RRMSϵ4−) and with (RRMSϵ4+) the apolipoprotein E ϵ4 allele. In this case, from the whole group of RRMS patients, only those with short disease duration (<3 years) and absence of disability (Expanded Disability Status Scale score, <2) are selected (22 patients without and 8 patients with the ϵ4 allele). The NBV values of the HCs are from a subgroup of 12 subjects age matched with patient subgroups (mean age, 30 years in each group). The NBV values of the RRMSϵ4+ group are significantly (P = .04) lower than those of the HC and RRMSϵ4− groups. In each box, the horizontal line represents the median; the box length shows the range within which the central 50% of values fall, with the box edges at the first and third quartiles; and the limit lines represent the range of values.

Demographic and Clinical Information Relative to the Whole Group of RRMS Patients and the Subgroup of ϵ4-Negative and ϵ4-Positive Patients*
Demographic and Clinical Information Relative to the Whole Group of RRMS Patients and the Subgroup of ϵ4-Negative and ϵ4-Positive Patients*
1.
Mahley  RW Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science.1988;240:622-630.
PubMed
2.
Boyles  JKZoellner  CDAnderson  LJ  et al A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J Clin Invest.1989;83:1015-1031.
PubMed
3.
Nicoll  JARoberts  GWGraham  DI Apolipoprotein E ϵ4 allele is associated with deposition of amyloid beta-protein following head injury. Nat Med.1995;1:135-137.
PubMed
4.
Chapman  JKorczyn  ADKarussis  DMMichaelson  DM The effects of APOE genotype on age at onset and progression of neurodegenerative diseases. Neurology.2001;57:1482-1485.
PubMed
5.
Teasdale  GMNicoll  JAMurray  GFiddes  M Association of apolipoprotein E polymorphism with outcome after head injury. Lancet.1997;350:1069-1071.
PubMed
6.
Evangelou  NJackson  MBeeson  DPalace  J Association of the APOE ϵ4 allele with disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry.1999;67:203-205.
PubMed
7.
Chapman  JVinokurov  SAchiron  A  et al APOE genotype is a major predictor of long-term progression of disability in MS. Neurology.2001;56:312-316.
PubMed
8.
Masterman  TZhang  ZHellgren  D  et al APOE genotypes and disease severity in multiple sclerosis. Mult Scler.2002;8:98-103.
PubMed
9.
Fazekas  FStrasser-Fuchs  SSchmidt  H  et al Apolipoprotein E genotype related differences in brain lesions of multiple sclerosis. J Neurol Neurosurg Psychiatry.2000;69:25-28.
PubMed
10.
Enzinger  CRopele  SStrasser-Fuchs  S  et al Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E ϵ4 allele. Arch Neurol.2003;60:65-70.
PubMed
11.
Schmidt  SBarcellos  LFDeSombre  K  et al Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. Am J Hum Genet.2002;70:708-717.
PubMed
12.
Losseff  NAWang  LLai  HM  et al Progressive cerebral atrophy in multiple sclerosis: a serial MRI study. Brain.1996;119(pt 6):2009-2019.
PubMed
13.
Brex  PAJenkins  RFox  NC  et al Detection of ventricular enlargement in patients at the earliest clinical stage of MS. Neurology.2000;54:1689-1691.
PubMed
14.
Simon  JHJacobs  LDCampion  MK  et alMultiple Sclerosis Collaborative Research Group (MSCRG) A longitudinal study of brain atrophy in relapsing multiple sclerosis. Neurology.1999;53:139-148.
PubMed
15.
Rudick  RAFisher  ELee  JCSimon  JJacobs  LMultiple Sclerosis Collaborative Research Group Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology.1999;53:1698-1704.
PubMed
16.
Fox  NCJenkins  RLeary  SM  et al Progressive cerebral atrophy in MS: a serial study using registered, volumetric MRI. Neurology.2000;54:807-812.
PubMed
17.
Smith  SMZhang  YJenkinson  M  et al Accurate, robust and automated longitudinal and cross-sectional brain change analysis. Neuroimage.2002;17:479-489.
PubMed
18.
Miller  DHBarkhof  FFrank  JAParker  GJThompson  AJ Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain.2002;125(pt 8):1676-1695.
PubMed
19.
De Stefano  NIannucci  GSormani  MP  et al MR correlates of cerebral atrophy in patients with multiple sclerosis. J Neurol.2002;249:1072-1077.
PubMed
20.
Poser  CMPaty  DWScheinberg  L  et al New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol.1983;13:227-231.
PubMed
21.
Kurtzke  JF Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology.1983;33:1444-1452.
PubMed
22.
Sorbi  SNacmias  BForleo  P  et al ApoE allele frequencies in Italian sporadic and familial Alzheimer's disease. Neurosci Lett.1994;177:100-102.
PubMed
23.
Smith  SM Fast robust automated brain extraction. Hum Brain Mapp.2002;17:143-155.
PubMed
24.
Zhang  YBrady  MSmith  S Segmentation of brain MR images through a hidden Markov random field model and the expectation maximization algorithm. IEEE Trans Med Imaging.2001;20:45-57.
PubMed
25.
De Stefano  NMatthews  PMFilippi  M  et al Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology.2003;60:1157-1162.
PubMed
26.
Hogh  POturai  ASchreiber  K  et al Apoliprotein E and multiple sclerosis: impact of the ϵ-4 allele on susceptibility, clinical type and progression rate. Mult Scler.2000;6:226-230.
PubMed
27.
Fazekas  FStrasser-Fuchs  SKollegger  H  et al Apolipoprotein E ϵ4 is associated with rapid progression of multiple sclerosis. Neurology.2001;57:853-857.
PubMed
28.
Waxman  SG Molecular remodeling of neurons in multiple sclerosis: what we know, and what we must ask about brain plasticity in demyelinating diseases. Adv Neurol.1997;73:109-120.
PubMed
29.
Cifelli  AMatthews  PM Cerebral plasticity in multiple sclerosis: insights from fMRI. Mult Scler.2002;8:193-199.
PubMed
30.
White  FNicoll  JARoses  ADHorsburgh  K Impaired neuronal plasticity in transgenic mice expressing human apolipoprotein E4 compared to E3 in a model of entorhinal cortex lesion. Neurobiol Dis.2001;8:611-625.
PubMed
31.
O'Brien  JTPaling  SBarber  R  et al Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia. Neurology.2001;56:1386-1388.
PubMed
32.
Evangelou  NEsiri  MMSmith  SPalace  JMatthews  PM Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol.2000;47:391-395.
PubMed
33.
Peterson  JWBo  LMork  SChang  ATrapp  BD Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol.2001;50:389-400.
PubMed
34.
Yasuda  MMori  EKitagaki  H  et al Apolipoprotein E ϵ4 allele and whole brain atrophy in late-onset Alzheimer's disease. Am J Psychiatry.1998;155:779-784.
PubMed
35.
Bigler  EDLowry  CMAnderson  CVJohnson  SCTerry  JSteed  M Dementia, quantitative neuroimaging, and apolipoprotein E genotype. AJNR Am J Neuroradiol.2000;21:1857-1868.
PubMed
36.
Doody  RSAzher  SNHaykal  HADunn  JKLiao  TSchneider  L Does APO ϵ4 correlate with MRI changes in Alzheimer's disease? J Neurol Neurosurg Psychiatry.2000;69:668-671.
PubMed
37.
Hashimoto  MYasuda  MTanimukai  S  et al Apolipoprotein E ϵ4 and the pattern of regional brain atrophy in Alzheimer's disease. Neurology.2001;57:1461-1466.
PubMed
38.
den Heijer  TOudkerk  MLauner  LJvan Duijn  CMHofman  ABreteler  MM Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes. Neurology.2002;59:746-748.
PubMed
39.
Mori  ELee  KYasuda  M  et al Accelerated hippocampal atrophy in Alzheimer's disease with apolipoprotein E ϵ4 allele. Ann Neurol.2002;51:209-214.
PubMed
40.
Klunk  WEPanchalingam  KMcClure  RJStanley  JAPettegrew  JW Metabolic alterations in postmortem Alzheimer's disease brain are exaggerated by Apo-E4. Neurobiol Aging.1998;19:511-515.
PubMed
Original Contribution
April 2004

Influence of Apolipoprotein E ϵ4 Genotype on Brain Tissue Integrity in Relapsing-Remitting Multiple Sclerosis

Author Affiliations

From the Department of Neurological and Behavioral Sciences, University of Siena, Siena, Italy (Drs De Stefano, Mortilla, and Federico); the Neurology Unit, Hospital of Empoli, Empoli, Italy (Drs Bartolozzi and Guidi), and the Department of Neurology, University of Florence, Florence, Italy (Drs Nacmias, Zipoli, Siracusa, Sorbi, and Amato).

Arch Neurol. 2004;61(4):536-540. doi:10.1001/archneur.61.4.536
Abstract

Background  Recent clinical and imaging studies have raised the hypothesis that patients with multiple sclerosis (MS) and the apolipoprotein E (ApoE) ϵ4 allele may have a more severe disease course than those without the ApoE ϵ4 allele. This seems to be related to more extensive tissue destruction and less efficient neuronal maintenance and repair in ApoE ϵ4 carriers.

Objective  To evaluate the influence of different ApoE genotypes on brain tissue integrity in patients with relapsing-remitting MS (RRMS).

Design  We determined the ApoE genotype in 76 RRMS patients. Conventional T1-, T2-, and proton density–weighted magnetic resonance (MR) images were obtained for each patient and in a group of demographically matched healthy control subjects. On conventional T1-weighted MR images, an automated analysis tool was used to obtain total brain volumes normalized for head size (NBVs). Total brain lesion load was estimated on proton density– and T2-weighted MR images.

Results  From the whole group of RRMS patients, we identified 18 with and 58 without the ϵ4 allele. Both patient groups were not significantly different in age, age of disease onset, clinical disability, and disease duration. Carriers of the ϵ4 allele showed significantly (P = .01) lower NBVs than controls and non–ϵ4 allele carriers. When a similar analysis was performed on only those patients with both very short disease duration and absence of clinical disability, NBV values were still significantly lower in RRMS patients with the ϵ4 allele than in those without it (P = .02) and in controls (P = .007). In contrast, RRMS patients with different ApoE genotypes did not show significant differences in values of total brain T2-weighted lesion volumes.

Conclusions  The presence of significant NBV decreases only in the group of RRMS patients with the ApoE ϵ4 genotype provides new evidence that links ApoE ϵ4–related impaired mechanisms of cell repair and severe tissue destruction in MS. Results of the present study suggest that this negative influence of the ApoE ϵ4 genotype might be active from the earliest disease stages.

Apolipoprotein E (ApoE) is a ubiquitous apolipoprotein involved in the metabolism of cholesterol.1 It has been suggested that ApoE-dependent uptake of lipoproteins may play an important role in the development, maintenance, and response to injury of the central nervous system.2,3 Apolipoprotein E is expressed in humans in 3 isoforms coded by the alleles ϵ2, ϵ3, and ϵ4 and is abundantly present in the brain. In many recent studies, the genotype ϵ4 has been consistently associated with severe neurodegeneration and seems to constitute a risk factor in several neurological disorders.4,5 This seems to be related to more extensive tissue destruction and less efficient neuronal maintenance and repair in ApoE ϵ4 carriers.

Recently, clinical and imaging studies have raised the hypothesis that in multiple sclerosis (MS), as in many neurological disorders, patients with the ApoE ϵ4 allele may have a more severe disease course than those without the allele. More specifically, the presence of the ϵ4 allele in the ApoE genotype of patients with MS seems to be related to poorer recovery after relapses,6 faster disease progression,7 higher frequency of severe disease form,8 and higher T1-weighted lesion load and axonal damage seen on magnetic resonance (MR) images.9,10 In MS, in contrast to what has been described in patients with other neurological disorders,4 the presence of the ϵ4 allele seems to have little or no effect on the age of disease onset, and its deleterious effect seems to be evident only late in the course of the disease.4,11 However, whether significant differences in brain tissue damage between MS patients with and without the ϵ4 allele can be detected at early disease stages has not been fully evaluated by previous studies.

Cerebral tissue loss can be quantitatively assessed from conventional T1-weighted MR images with the aid of software allowing automatic or semiautomatic computed measurements of total brain volume.1217 With the use of these methods, visually undetectable brain atrophy can be found and seems to be relevant in MS patients from the earliest disease stages.18 Because brain atrophy in MS should be interpreted as the consequence of destructive pathological changes (ie, demyelination, gliosis, and axonal damage) that occur in lesions and normal-appearing brain,18,19 measures of cerebral volumes normalized for head size can represent a reliable marker of adverse outcome of this disease. Thus, measurements of brain atrophy can discriminate the real disease-modifying effect of the ApoE genotype in MS.

With this background, we performed conventional brain MR imaging on a group of patients with relapsing-remitting MS (RRMS), assessed their ApoE genotype, and used an automated method for computing analysis of total brain volumes (Structural Imaging Evaluation of Normalized Atrophy [SIENA]17) to evaluate the influence of the ApoE genotype on tissue destruction in the whole group of patients and in a subgroup of them with minimal disease duration and no clinical disability.

METHODS
STUDY POPULATION

We studied 76 consecutive patients (50 women and 26 men aged 18-55 years [mean ± SD age, 34.5 ± 8 years]) with RRMS.20 When MR images were obtained, none of the RRMS patients had been treated with corticosteroids for at least 1 month, and 7 of the 76 were being treated with interferon beta. A neurological evaluation (which included the rating of disability using the Expanded Disability Status Scale [EDSS]21) was performed by an experienced observer on each patient within 24 hours of the performance of the MR examination. A population of 22 demographically matched healthy control subjects (HCs; 14 women and 8 men aged 25-56 years [mean ± SD age, 34.9 ± 8 years]) was also studied for comparisons. The HCs were recruited from laboratory and hospital workers and included in the study if they had a negative history for neurological disorders and no abnormalities on conventional brain MR images. Before study initiation, local ethical committee approval and written informed consent were obtained from all the subjects.

ApoE GENOTYPE

The ApoE genotype was determined in all RRMS patients through standard polymerase chain reaction and restriction analyses using the method previously described.22

MR EXAMINATIONS AND ANALYSIS

All RRMS patients and HCs were examined using the same MR protocol. We used a transverse dual-echo, turbo spin-echo sequence (repetition time/echo time 1/echo time 2, 2075/30/90 milliseconds; 256 × 256 matrix; 1 signal average; 250-mm field of view) yielding proton density (PD)– and T2-weighted images with 50 contiguous 3-mm slices acquired parallel to the line connecting the anterior and posterior commissures. Subsequently, a T1-weighted sequence (repetition time/echo time, 35/10 milliseconds; 256 × 256 matrix; 1 signal average; 250-mm field of view) was performed. This sequence yielded image volumes of 50 slices, 3-mm thick, oriented to match the PD/T2-weighted acquisition exactly.

Classification of T2-weighted lesion volume (LV) was performed in each patient by a single observer by means of a user-supervised thresholding technique. The observer was unaware of the subjects' identities. Lesion borders were determined primarily on PD-weighted images, but information from T2- and T1-weighted images were also considered, as the software used (MEDx; Sensor Systems Inc, Sterling, Va) offered the ability to toggle between the PD-, T2-, and T1-weighted images. This provided the operator with convenient access to the information in both data sets while defining lesions and facilitating the discrimination of cerebrospinal fluid from periventricular plaques. The value of total brain LV was calculated by multiplying lesion area by slice thickness and was reproducible to about 5% in serial measurements.

On T1-weighted MR images, normalized volumes of the whole of the brain parenchyma were measured using a method for brain volume measurement (the cross-sectional version of the SIENA software17 [SIENAX]) (Figure 1). SIENAX uses a method to extract the brain and skull from the MR images, as previously described.23 A tissue segmentation program24 is then used to segment the extracted brain image into brain tissue, cerebrospinal fluid, and background, yielding an estimate of total brain tissue volume. The original MR images are registered to a canonical image in a standardized space (using the skull image to provide the scaling cue), a procedure that provides a spatial normalization factor for each subject. The estimate of brain tissue volume for a subject is then multiplied by the normalization factor to yield the normalized brain volume (NBV).

STATISTICAL ANALYSIS

We compared measures relative to the whole RRMS patient group with those of the HC group using the nonparametric Mann-Whitney test. Differences among RRMS patients with different ApoE genotypes and HCs were assessed using analysis of variance followed by pairwise post-hoc comparison using the Tukey Honestly Significant Difference procedure to account for multiple comparisons. The same statistical procedure was also used after grouping the RRMS patients with different ApoE genotypes by short disease duration (<3 years) and absence of clinical disability (EDSS score, <2). Values were considered significant at the level of .05 or less. Unless otherwise indicated, data are expressed as mean ± SD.

RESULTS

In agreement with the results of previous studies,17,19,25 mean NBV values of the whole group of RRMS patients were significantly lower than those of the HC group (1574 ± 65 cm3 [RRMS group] vs 1610 ± 37 cm3[HCs]; P = .01) (Figure 1).

In the group of 76 RRMS patients, we identified 18 carriers of the ϵ4 allele (14 with the genotype ApoE ϵ3/ϵ4, 3 with the genotype ApoE ϵ4/ϵ4, and 1 with the genotype ApoE ϵ2/ϵ4) and 58 subjects without the ϵ4 allele (10 with the genotype ApoE ϵ2/ϵ3 and 48 with the genotype ApoE ϵ3/ϵ3). The 2 patient groups showed no significant differences in age, age at disease onset, disease duration, and EDSS score (Table 1).

In the RRMS patients grouped by their ApoE genotype, we found that MS patients with the ϵ4 allele showed significantly (P = .01) lower values of NBV than HCs and patients without the ϵ4 allele (1553 ± 50 cm3 [RRMS ϵ4-positive group] vs 1581 ± 68cm3 [RRMS ϵ4-negative group]vs 1610 ± 37 cm3 [HCs]) (Figure 2). In contrast, the 2 groups of MS patients with different ApoE genotypes did not show significant differences in values of total brain T2-weighted LV (3.6 ± 2.8 cm3 [RRMS ϵ4-positive group] vs 4.4 ± 3.8 cm3[RRMS ϵ4-negative group]; P = .54).

Similar analyses were also performed selecting a subgroup of MS patients with very short disease duration (<3 years) and absence of clinical disability (EDSS, <2) from the whole patient group. When patients with different ApoE genotypes of these subgroups (30 subjects, 8 with the ϵ4 allele and 22 without the ϵ4 allele) were compared with 12 age-matched HCs (mean age, 30 years in each group), NBV values were still significantly lower in RRMS patients with the ϵ4 allele than in MS patients without the ϵ4 allele (P = .02) and HCs (P = .007) (1561 ± 41 cm3 [RRMS ϵ4-positive group] vs 1609 ± 56 cm3 [RRMS ϵ4-negative group] vs 1618 ± 42 cm3 [HCs]) (Figure 3).

COMMENT

Although there is lack of general consensus on this matter,8 several recent clinical studies have reported on the disease-modifying effect of the ApoE genotype in MS.68,26,27 This is based on the frequent observation that the presence the ϵ4 allele in the genotype of MS patients is associated with greater severity and faster progression of the disease. In agreement with this are recent MR studies showing increased "black holes"9 and decreased values of N-acetylaspartate10 (both reliable surrogate markers of tissue/axonal damage or loss) in brains of MS patients who carry the ϵ4 allele compared with those who do not have the ϵ4 allele in their ApoE genotype. The present study, by showing that cerebral volumes are significantly lower in RRMS patients with the ϵ4 allele than in those without the ϵ4 allele and HCs, adds to previous work reporting further evidence that links ApoE genotypes to the degree of tissue damage in brains or MS patients. This suggests that the ϵ4 allele may have a real, deleterious effect on MS prognosis.

The differences in brain tissue damage between MS patients who carry and do not carry the ϵ4 allele do not coincide, in our study, with significant differences in age at disease onset, disease duration, and clinical disability between the 2 patient groups. As reported by previous studies, MS patients with the ApoE ϵ4 allele do not seem to have a higher risk for development of the disease than those carrying the ApoE ϵ3 allele,4 and the deleterious effect of the ApoE ϵ4 allele seems to become evident later, when the cerebral abnormality develops and impaired repair efficiency results in more pronounced loss of brain function.4 However, on the basis of our results and those of previous9 MR studies, we can speculate that in ϵ4 carriers with MS, the potential functional impairment due to a more prominent tissue destruction is not initially clinically evident. Instead, it is fully compensated by the adaptive mechanisms of reorganization. Clinical differences between ϵ4 and ϵ3 carriers could become evident later, when compensatory resources of the central nervous system are exhausted.28,29 Results indicating that neuronal plasticity is more impaired in transgenic mice possessing the human ApoE ϵ4 allele than in those having the ApoE ϵ3 allele30 seem to confirm this hypothesis. On the other hand, by restricting the analysis to RRMS patients with minimal disease duration (<3 years) and absence of clinical disability (EDSS score, <2), our data suggest that, although clinical differences are still absent, the ϵ4 allele links with more pronounced brain tissue damage, even at the very early stages of MS.

Cerebral atrophy occurs in most neurodegenerative disorders with a mechanism that is mostly driven by neuronal and axonal loss.31 The pathological correlates of brain atrophy in MS imply the presence of inflammation and focal demyelination and the consequent loss of brain components such as myelin and glial cells.18,19 A relevant component of atrophy, however, appears to be independent of focal demyelinating lesions and is probably the expression of the widespread neuroaxonal damage due to inflammation and/or primitive neurodegeneration.18,25,32,33 This might explain why, in our study, NBV decreases in ApoE ϵ4 carriers were not associated with more pronounced total brain T2-weighted LV and why, in a previous MS study,9 the LV was not significantly higher in ϵ4 carriers than in ϵ3 carriers.

Although our study has limitations owing to the cross-sectional design and the relatively small sample of patients, this is, to our knowledge, the first study attempting quantitative measurements of cerebral volumes in MS patients with different ApoE genotypes. Similar measurements exist in patients with Alzheimer disease with discrepant results on differences in total brain volumes between patients with different ApoE genotypes,3437 but with homogeneous findings on differences in brain regional volumes (ie, hippocampus and amygdala) between ϵ3 and ϵ4 carriers.35,3739 These results, which have been confirmed by a recent postmortem study,40 suggest a regional specificity of the effect of the ApoE ϵ4 allele in the brains of patients with Alzheimer disease. This regional specificity is very unlikely in MS (where most of the normal-appearing brain is affected by the disease32,33), making a marker such as the NBV more appropriate than other regional or tissue specific markers to assess evidence of tissue damage.

CONCLUSIONS

Our data add to previous evidence of the adverse effect of ApoE ϵ4 genotype on MS patients showing the presence of more pronounced structural brain damage in RRMS patients who carry the ϵ4 allele than in those who do not carry this allele. This structural brain damage (which is present in MS patients with the ApoE ϵ4 allele, even at the earliest disease stages) might be clinically silent while mechanisms of adaptation can compensate, but is probably responsible for the faster progression of disability observed in MS patients carrying the ApoE ϵ4 allele when central nervous system compensatory resources are exhausted. Characterization of the ApoE genotype can be helpful to explain some of the variance in disease progression in clinical studies and, perhaps, should be considered before deciding which patients should begin early treatment in MS.

Back to top
Article Information

Corresponding author and reprints: Nicola De Stefano, MD, Department of Neurological and Behavioral Sciences, Viale Bracci 2, 53100, Siena, Italy (e-mail: destefano@unisi.it).

Accepted for publication December 3, 2003.

Author contributions: Study concept and design (Drs De Stefano, Bartolozzi, Guidi, Sorbi, and Amato); acquisition of data (Drs De Stefano, Bartolozzi, Nacmias, Zipoli, Mortilla, Guidi, Siracusa, and Federico); analysis and interpretation of data (Drs De Stefano and Zipoli); drafting of the manuscript (Drs De Stefano, Nacmias, Zipoli, Mortilla, and Siracusa); critical revision of the manuscript for important intellectual content (Drs De Stefano, Bartolozzi, Guidi, Sorbi, Federico, and Amato); obtained funding (Dr Federico); administrative, technical, and material support (Drs Bartolozzi, Mortilla, Guidi, and Federico); study supervision (Drs De Stefano, Sorbi, and Amato).

This study was supported by grants from the University of Siena (Progetto Ateneo di Ricerca) and the Associazione Italiana Sclerosi Multipla (Dr De Stefano), and by a grant from MURST, Rome, Italy (Dr Federico).

We thank Sridar Narayanan for thoughtful discussion.

References
1.
Mahley  RW Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science.1988;240:622-630.
PubMed
2.
Boyles  JKZoellner  CDAnderson  LJ  et al A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J Clin Invest.1989;83:1015-1031.
PubMed
3.
Nicoll  JARoberts  GWGraham  DI Apolipoprotein E ϵ4 allele is associated with deposition of amyloid beta-protein following head injury. Nat Med.1995;1:135-137.
PubMed
4.
Chapman  JKorczyn  ADKarussis  DMMichaelson  DM The effects of APOE genotype on age at onset and progression of neurodegenerative diseases. Neurology.2001;57:1482-1485.
PubMed
5.
Teasdale  GMNicoll  JAMurray  GFiddes  M Association of apolipoprotein E polymorphism with outcome after head injury. Lancet.1997;350:1069-1071.
PubMed
6.
Evangelou  NJackson  MBeeson  DPalace  J Association of the APOE ϵ4 allele with disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry.1999;67:203-205.
PubMed
7.
Chapman  JVinokurov  SAchiron  A  et al APOE genotype is a major predictor of long-term progression of disability in MS. Neurology.2001;56:312-316.
PubMed
8.
Masterman  TZhang  ZHellgren  D  et al APOE genotypes and disease severity in multiple sclerosis. Mult Scler.2002;8:98-103.
PubMed
9.
Fazekas  FStrasser-Fuchs  SSchmidt  H  et al Apolipoprotein E genotype related differences in brain lesions of multiple sclerosis. J Neurol Neurosurg Psychiatry.2000;69:25-28.
PubMed
10.
Enzinger  CRopele  SStrasser-Fuchs  S  et al Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E ϵ4 allele. Arch Neurol.2003;60:65-70.
PubMed
11.
Schmidt  SBarcellos  LFDeSombre  K  et al Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. Am J Hum Genet.2002;70:708-717.
PubMed
12.
Losseff  NAWang  LLai  HM  et al Progressive cerebral atrophy in multiple sclerosis: a serial MRI study. Brain.1996;119(pt 6):2009-2019.
PubMed
13.
Brex  PAJenkins  RFox  NC  et al Detection of ventricular enlargement in patients at the earliest clinical stage of MS. Neurology.2000;54:1689-1691.
PubMed
14.
Simon  JHJacobs  LDCampion  MK  et alMultiple Sclerosis Collaborative Research Group (MSCRG) A longitudinal study of brain atrophy in relapsing multiple sclerosis. Neurology.1999;53:139-148.
PubMed
15.
Rudick  RAFisher  ELee  JCSimon  JJacobs  LMultiple Sclerosis Collaborative Research Group Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology.1999;53:1698-1704.
PubMed
16.
Fox  NCJenkins  RLeary  SM  et al Progressive cerebral atrophy in MS: a serial study using registered, volumetric MRI. Neurology.2000;54:807-812.
PubMed
17.
Smith  SMZhang  YJenkinson  M  et al Accurate, robust and automated longitudinal and cross-sectional brain change analysis. Neuroimage.2002;17:479-489.
PubMed
18.
Miller  DHBarkhof  FFrank  JAParker  GJThompson  AJ Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain.2002;125(pt 8):1676-1695.
PubMed
19.
De Stefano  NIannucci  GSormani  MP  et al MR correlates of cerebral atrophy in patients with multiple sclerosis. J Neurol.2002;249:1072-1077.
PubMed
20.
Poser  CMPaty  DWScheinberg  L  et al New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol.1983;13:227-231.
PubMed
21.
Kurtzke  JF Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology.1983;33:1444-1452.
PubMed
22.
Sorbi  SNacmias  BForleo  P  et al ApoE allele frequencies in Italian sporadic and familial Alzheimer's disease. Neurosci Lett.1994;177:100-102.
PubMed
23.
Smith  SM Fast robust automated brain extraction. Hum Brain Mapp.2002;17:143-155.
PubMed
24.
Zhang  YBrady  MSmith  S Segmentation of brain MR images through a hidden Markov random field model and the expectation maximization algorithm. IEEE Trans Med Imaging.2001;20:45-57.
PubMed
25.
De Stefano  NMatthews  PMFilippi  M  et al Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology.2003;60:1157-1162.
PubMed
26.
Hogh  POturai  ASchreiber  K  et al Apoliprotein E and multiple sclerosis: impact of the ϵ-4 allele on susceptibility, clinical type and progression rate. Mult Scler.2000;6:226-230.
PubMed
27.
Fazekas  FStrasser-Fuchs  SKollegger  H  et al Apolipoprotein E ϵ4 is associated with rapid progression of multiple sclerosis. Neurology.2001;57:853-857.
PubMed
28.
Waxman  SG Molecular remodeling of neurons in multiple sclerosis: what we know, and what we must ask about brain plasticity in demyelinating diseases. Adv Neurol.1997;73:109-120.
PubMed
29.
Cifelli  AMatthews  PM Cerebral plasticity in multiple sclerosis: insights from fMRI. Mult Scler.2002;8:193-199.
PubMed
30.
White  FNicoll  JARoses  ADHorsburgh  K Impaired neuronal plasticity in transgenic mice expressing human apolipoprotein E4 compared to E3 in a model of entorhinal cortex lesion. Neurobiol Dis.2001;8:611-625.
PubMed
31.
O'Brien  JTPaling  SBarber  R  et al Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia. Neurology.2001;56:1386-1388.
PubMed
32.
Evangelou  NEsiri  MMSmith  SPalace  JMatthews  PM Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol.2000;47:391-395.
PubMed
33.
Peterson  JWBo  LMork  SChang  ATrapp  BD Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol.2001;50:389-400.
PubMed
34.
Yasuda  MMori  EKitagaki  H  et al Apolipoprotein E ϵ4 allele and whole brain atrophy in late-onset Alzheimer's disease. Am J Psychiatry.1998;155:779-784.
PubMed
35.
Bigler  EDLowry  CMAnderson  CVJohnson  SCTerry  JSteed  M Dementia, quantitative neuroimaging, and apolipoprotein E genotype. AJNR Am J Neuroradiol.2000;21:1857-1868.
PubMed
36.
Doody  RSAzher  SNHaykal  HADunn  JKLiao  TSchneider  L Does APO ϵ4 correlate with MRI changes in Alzheimer's disease? J Neurol Neurosurg Psychiatry.2000;69:668-671.
PubMed
37.
Hashimoto  MYasuda  MTanimukai  S  et al Apolipoprotein E ϵ4 and the pattern of regional brain atrophy in Alzheimer's disease. Neurology.2001;57:1461-1466.
PubMed
38.
den Heijer  TOudkerk  MLauner  LJvan Duijn  CMHofman  ABreteler  MM Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes. Neurology.2002;59:746-748.
PubMed
39.
Mori  ELee  KYasuda  M  et al Accelerated hippocampal atrophy in Alzheimer's disease with apolipoprotein E ϵ4 allele. Ann Neurol.2002;51:209-214.
PubMed
40.
Klunk  WEPanchalingam  KMcClure  RJStanley  JAPettegrew  JW Metabolic alterations in postmortem Alzheimer's disease brain are exaggerated by Apo-E4. Neurobiol Aging.1998;19:511-515.
PubMed
×