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Figure 1.
Outcome at 1 month measured by the modified Rankin scale and Barthel Index. All data are percentages of patients; comparisons are all with ϵ3/ϵ3 patients.

Outcome at 1 month measured by the modified Rankin scale and Barthel Index. All data are percentages of patients; comparisons are all with ϵ3/ϵ3 patients.

Figure 2.
Outcome at 3 months measured by the modified Rankin scale and Barthel Index. All data are percentages of patients; comparisons are all with ϵ3/ϵ3 patients.

Outcome at 3 months measured by the modified Rankin scale and Barthel Index. All data are percentages of patients; comparisons are all with ϵ3/ϵ3 patients.

Table 1. 
Baseline Characteristics of Patients With Ischemic Stroke*
Baseline Characteristics of Patients With Ischemic Stroke*
APOE Genotype Distribution Among Patients With Ischemic Stroke
APOE Genotype Distribution Among Patients With Ischemic Stroke
Table 2. 
Stroke Severity and Apolipoprotein E Genotype*
Stroke Severity and Apolipoprotein E Genotype*
Table 3. 
Predictors of 3-Month Functional Outcome Derived From a Multivariate Analysis*
Predictors of 3-Month Functional Outcome Derived From a Multivariate Analysis*
1.
Laskowitz  DTHorsburgh  KRoses  AD Apolipoprotein E and the CNS response to injury. J Cereb Blood Flow Metab. 1998;18465- 471Article
2.
Strittmatter  WJWeisgraber  KHHuang  DY  et al.  Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993;908098- 8102Article
3.
Saunders  AMStrittmatter  WJSchmechel  D  et al.  Association of apolipoprotein E allele ϵ4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993;431467- 1472Article
4.
Meyer  MRTschanz  JTNorton  MC  et al.  APOE genotype predicts when—not whether—one is predisposed to develop Alzheimer disease. Nat Genet. 1998;19321- 322Article
5.
Nicoll  JARoberts  GWGraham  DI Apolipoprotein E ϵ4 allele is associated with deposition of amyloid beta-protein following head injury. Nat Med. 1995;1135- 137Article
6.
Teasdale  GMNicoll  JRMurray  GFiddes  M Association of apolipoprotein E polymorphism with outcome after head injury. Lancet. 1997;3501069- 1071Article
7.
Friedman  GFroom  PSazbon  L  et al.  Apolipoprotein E-ϵ4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology. 1999;52244- 248Article
8.
Jordan  BDRelkin  NRRavdin  LDJacobs  ARBennett  AGandy  S Apolipoprotein E ϵ4 associated with chronic traumatic brain injury in boxing. JAMA. 1997;278136- 140Article
9.
Alberts  MJGraffagnino  CMcClenny  C  et al.  ApoE genotype and survival from intracerebral haemorrhage [letter]. Lancet. 1995;346575Article
10.
McCarron  MOMuir  KWWeir  CJ  et al.  The apolipoprotein E ϵ4 allele and outcome in cerebrovascular disease. Stroke. 1998;291882- 1887Article
11.
Laskowitz  DTSheng  HBart  RDJoyner  KARoses  ADWarner  DS Apolipoprotein E–deficient mice have increased susceptibility to focal cerebral ischemia. J Cereb Blood Flow Metab. 1997;17753- 758Article
12.
Sheng  HLaskowitz  DTMackensen  GB  et al.  Apolipoprotein E deficiency worsens outcome from global cerebral ischemia in the mouse. Stroke. 1999;301118- 1124Article
13.
Horsburgh  KKelly  SMcCulloch  JHiggins  GARoses  ADNicoll  JAR Increased neuronal damage in apolipoprotein E deficient mice following global ischaemia. Neuroreport. 1999;10837- 841Article
14.
Sheng  HXLaskowitz  DTBennett  E  et al.  Apolipoprotein E isoform–specific differences in outcome from focal ischemia in transgenic mice. J Cereb Blood Flow Metab. 1998;18361- 366Article
15.
Brott  TAdams  HP  JrOlinger  CP  et al.  Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20864- 870Article
16.
Bamford  JSandercock  PDennis  MBurn  JWarlow  C Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet. 1991;3371521- 1526Article
17.
Wenham  PRPrice  WHBlandell  G Apolipoprotein E genotyping by one-stage PCR [letter]. Lancet. 1991;3371158- 1159Article
18.
Mahoney  FIBarthel  DW Functional evaluation: the Barthel Index. Md State Med J. 1965;1461- 65
19.
Rankin  J Cerebral vascular accidents in patients over the age of 60, II: prognosis. Scot Med J. 1957;2200- 215
20.
van Swieten  JCKoudstaal  PJVisser  MCSchouten  HJvan Gijn  J Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19604- 607Article
21.
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;3331581- 1587Article
22.
McCarron  MONicoll  JAR High frequency of apolipoprotein E ϵ2 allele is specific for patients with cerebral amyloid angiopathy-related haemorrhage. Neurosci Lett. 1998;24745- 48Article
23.
Ferrucci  LGuralnik  JMPahor  M  et al.  Apolipoprotein E ϵ2 allele and risk of stroke in the older population. Stroke. 1997;282410- 2416Article
24.
Couderc  RMahieux  FBailleul  SFenelon  GMary  RFermanian  J Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease: a case-control study. Stroke. 1993;24661- 664Article
25.
Mahieux  FBailleul  SFenelon  RCouderc  RLaruelle  PGunel  M Prevalence of apolipoprotein E phenotypes in patients with acute ischemic stroke [abstract]. Stroke. 1990;21I- 115
26.
Pedro-Botet  JSenti  MNogues  X  et al.  Lipoprotein and apolipoprotein profile in men with ischemic stroke: role of lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein E polymorphism. Stroke. 1992;231556- 1562Article
27.
Margaglione  MSeripa  DGravina  C  et al.  Prevalence of apolipoprotein E alleles in healthy subjects and survivors of ischemic stroke: an Italian case-control study. Stroke. 1998;29399- 403Article
28.
Coria  FRubio  INunez  E  et al.  Apolipoprotein E variants in ischemic stroke [letter]. Stroke. 1995;262375- 2376
29.
Nakata  YKatsuya  TRakugi  H  et al.  Polymorphism of angiotensin converting enzyme, angiotensinogen, and apolipoprotein E genes in a Japanese population with cerebrovascular disease. Am J Hypertens. 1997;101391- 1395Article
30.
Hachinski  VGraffagnino  CBeaudry  M  et al.  Lipids and stroke: a paradox resolved. Arch Neurol. 1996;53303- 308Article
31.
Kessler  CSpitzer  CStauske  D  et al.  The apolipoprotein E and beta-fibrinogen G/A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease. Arterioscler Thromb Vasc Biol. 1997;172880- 2884Article
32.
McCarron  MODeLong  DAlberts  MJ APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis. Neurology. 1999;531308- 1311Article
33.
Wilson  PWSchaefer  EJLarson  MGOrdovas  JM Apolipoprotein E alleles and risk of coronary disease: a meta-analysis. Arterioscler Thromb Vasc Biol. 1996;161250- 1255Article
34.
Davignon  JGregg  RESing  CF Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988;81- 21Article
35.
Nathan  BPBellosta  SSanan  DA  et al.  Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science. 1994;264850- 852Article
36.
Miyata  MSmith  JD Apolipoprotein E allele–specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat Genet. 1996;1455- 61Article
37.
Laskowitz  DTMatthew  WDBennett  ER  et al.  Endogenous apolipoprotein E suppresses LPS-stimulated microglial nitric oxide production. Neuroreport. 1998;9615- 618Article
38.
Muller  WMeske  VBerlin  K  et al.  Apolipoprotein E isoforms increase intracellular CA2+ differentially through a w-agatoxin IVa-sensitive CA2+-channel. Brain Pathol. 1998;8641- 653Article
39.
Wiebers  DOAdams  HPJWhisnant  JP Animal models of stroke: are they relevant to human disease? Stroke. 1990;211- 3Article
40.
Poirier  J Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. Trends Neurosci. 1994;17525- 530Article
41.
Horsburgh  KNicoll  JA Selective alterations in the cellular distribution of apolipoprotein E immunoreactivity following transient cerebral ischaemia in the rat. Neuropathol Appl Neurobiol. 1996;22342- 349Article
42.
Fullerton  SMStrittmatter  WJMatthew  WD Peripheral sensory nerve defects in apolipoprotein E knockout mice. Exp Neurol. 1998;153156- 163Article
43.
Tomimoto  HAkiguchi  ISuenaga  T  et al.  Immunohistochemical study of apolipoprotein E in human cerebrovascular white matter lesions. Acta Neuropathol. 1995;90608- 614Article
44.
Horsburgh  KGraham  DIStewart  JNicoll  JAR Influence of apolipoprotein E genotype on neuronal damage and apoE immunoreactivity in human hippocampus following global ischemia. J Neuropathol Exp Neurol. 1999;58227- 234Article
Original Contribution
October 2000

Prospective Study of Apolipoprotein E Genotype and Functional Outcome Following Ischemic Stroke

Author Affiliations

From the Departments of Neurology (Drs McCarron, Muir, and Bone and Ms Currie) and Neuropathology (Drs McCarron, Nicoll, Brown, and Ms Stewart), Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland.

Arch Neurol. 2000;57(10):1480-1484. doi:10.1001/archneur.57.10.1480
Abstract

Background  The apolipoprotein E (APOE) ϵ4 allele is a marker of adverse outcome following head injury and intracerebral hemorrhage. Transgenic animal data in a focal cerebral ischemia model suggest that the ϵ4 allele increases infarct size and functional impairment.

Objective  To determine if APOE genotype is associated with functional recovery from ischemic stroke.

Design  Prospective study.

Setting  Stroke service at a university teaching hospital.

Patients  Patients with clinical and neuroimaging findings (computed tomography or magnetic resonance imaging) compatible with an acute ischemic stroke.

Main Outcome  Functional outcome by Barthel index (BI) and modifed Rankin scale (mRS) was compared for ϵ3/ϵ3 patients vs ϵ4 carriers and vs ϵ2 carriers at 1 and 3 months. Univariate predictors of 3-month outcome were examined in a multivariate analysis.

Results  One hundred eighty nine patients were enrolled: 100 women, 89 men (mean ± SD age, 69.4 ± 11.0 years). There were 25 ϵ2 alleles (frequency, 0.07), 292 ϵ3 alleles (0.77), and 61 ϵ4 alleles (0.16). Baseline National Institutes of Health Stroke Scale scores and Oxfordshire Community Stroke Project classifications were similar in all groups (ϵ3/ϵ3, ϵ4, and ϵ2 carriers). One-month (BI, P = .64; mRS, P = .59) and 3-month (BI, P = .87; mRS, P = .73) outcomes were not associated with possession of either ϵ4 or the ϵ2 allele. Baseline National Institutes of Health Stroke Scale scores (P<.001) and age (P = .002) were significant predictors of 3-month BI and mRS outcomes in multivariate analyses.

Conclusions  Although there is a robust influence of APOE polymorphism on functional recovery after some types of brain injury in humans, it does not exert a major influence on injury severity or functional recovery following ischemic stroke.

ALLELIC VARIATION in apolipoprotein E (APOE for gene; apoE for protein) influences some forms of acute and chronic brain injury.1 Interest in the effects of APOE polymorphism on the central nervous system arose in 1993 with the finding that the APOE ϵ4 allele is associated with late-onset familial2 and sporadic Alzheimer disease.3 The ϵ4 allele seems to determine not if but when an individual will develop the disease.4 In addition, possession of the ϵ4 allele is clearly established as a marker of poorer outcome following acute57 and chronic head injury8 as well as intracerebral hemorrhage.9,10 There has been less consistent evidence to demonstrate that the APOE ϵ4 allele is associated with a worse outcome following ischemic stroke.

Animal studies with APOE knockout mice have shown larger infarcts in models of focal cerebral ishemia11 and increased neuronal injury in models of global cerebral ischemia.12,13 Homozygous APOE ϵ3/ϵ3 and ϵ4/ϵ4 transgenic mice have also been assessed under transient focal cerebral ischemia conditions.14 Mice with the ϵ3/ϵ3 genotype had significantly smaller infarct volumes and better functional outcome than did ϵ4/ϵ4 mice. These results yield the testable hypothesis that human ϵ4 carriers may have a poorer outcome following ischemic stroke (as occurs in head injury) than non-ϵ4 carriers. However, no adverse effect on long-term survival could be demonstrated in a large retrospective study in patients with ischemic stroke10; instead, a modestly improved long-term survival was associated with increasing ϵ4 allele dose. This study did not, however, examine functional recovery. Survival after ischemic stroke is influenced profoundly by nongenetic factors. Because the transgenic animal data in transient focal cerebral ischemia have demonstrated such functional differences in ϵ3/ϵ3 compared with ϵ4/ϵ4 animals, we sought to determine if APOE genotype influences 1-month or 3-month functional outcome in humans following ischemic stroke.

PATIENTS AND METHODS
PATIENT SELECTION

Consecutive patients were recruited prospectively from an acute stroke unit between January 1997 and May 1998. Ischemic stroke was diagnosed when patients presented with an acute onset of a focal neurological deficit with no evidence of intracerebral hemorrhage or alternative pathologic characteristics on brain imaging. Prior to enrollment, all patients or a relative gave informed consent for the study. Clinical baseline characteristics including National Institutes of Health Stroke Scale (NIHSS) scores15 and Oxfordshire Community Stroke Project (OCSP) classifications16 were recorded at the time of admission. The study was approved by the hospital ethics committee.

APOE GENOTYPING

Apolipoprotein E genotypes were determined from whole blood samples by physicians blind to stroke classification and outcome. Leukocyte DNA was extracted and amplified by a polymerase chain reaction.17 The product was digested using the restriction enzyme HhaI, separated on a 10% polyacrylamide gel, stained with ethidium bromide, and visualized by UV light.

FOLLOW-UP

Participating patients were observed prospectively. Functional outcome was measured at 1 month and 3 months using the Barthel Index (BI)18 and modified Rankin scale (mRS),19,20 blind to APOE genotype.

STATISTICAL ANALYSIS

Differences in stroke severity using OCSP classifications and the NIHSS scores among different APOE genotype categories (ϵ3/ϵ3, ϵ2 carrying, and ϵ4 carrying patients) were assessed with a χ2 test and Mann-Whitney test, respectively. Outcome categories of the BI and mRS were defined as in the National Institute of Neurological Disorders recombinant tissue plasminogen activator trial21: ie, good (mRS, 0-1; BI 95-100); moderate (mRS, 2-3; BI, 55-90); poor (mRS, 4-5; BI, 0-50); and dead (mRS, 6). Outcome was compared between ϵ4 carriers and ϵ3/ϵ3 patients as well as between ϵ2 carriers and ϵ3/ϵ3 patients using the χ2 test. The groups were also examined as ϵ4 and non-ϵ4 carriers with outcome dichotomized as good (mRS, 0, 1, or 2; BI>55) vs all other functional categories. Differences in the distribution of potential prognostic variables (OCSP classifications and NIHSS scores; history of hypertension, stroke or transient ischemic attack, diabetes mellitus, atrial fibrillation, ischemic heart disease, peripheral vascular disease; current cigarette smoker; current infection or hyperlipidemia; use of aspirin, calcium antagonists, angiotensin-converting enzyme inhibitors; age; and possession of the ϵ2 or ϵ4 APOE alleles) were examined in a linear regression analysis using 3-month BI and mRS scores as categorical values. Variables with P<.05 on univariate analysis were then considered in a multivariate analysis by multiple linear regression.

RESULTS

One hundred eighty nine patients were enrolled and APOE genotyped. All had follow-up assessments. There were 89 men and 100 women (mean ± SD age, 69.4 ± 11.0 years; range, 28-93 years). The baseline characteristics, including the OCSP classifications are given in Table 1. The median NIHSS score on admission was 6 (interquartile range, 3-10).

The APOE alleles were in Hardy-Weinberg equilibrium. No patient had the ϵ2/ϵ2 genotype, as indicated on the tabulation below.

Fifty-eight patients (31%) carried 1 or more ϵ4 alleles and 25 (13%) had an ϵ2 allele. There was no significant difference in the age of ϵ3/ϵ3 patients (mean age, 69 years) and ϵ4 (mean age, 68 years; P = .56) or ϵ2 carrying patients (mean age, 73 years; P = .11) at the time of stroke. The APOE allele frequencies were 0.07 for ϵ2 (n = 25 alleles), 0.77 for ϵ3 (n = 292), and 0.16 for ϵ4 (n = 61), a similar frequency distribution to that found in previously studied Scottish populations.22

STROKE SEVERITY

There was no statistically significant difference in baseline stroke severity among the proportion of patients in different OCSP categories for ϵ3/ϵ3 vs ϵ2 or ϵ4 carriers (Table 2). Although patients possessing an ϵ4 allele had greater median NIHSS scores on admission to the hospital than ϵ3/ϵ3 carriers, the difference was also not statistically significant (P = .10).

OUTCOME

One-month outcome (Figure 1) was not statistically different in ϵ4 carriers and patients with the ϵ3/ϵ3 genotype for either BI (P = .64) or mRS (P = .59) scores. Similarly, there were no significant differences between ϵ2 carriers and ϵ3/ϵ3 patients (mRS, P = .19; BI, P = .87).

The results were unchanged at 3 months (Figure 2). In addition, dichotomizing around end points that signify functional independence (mRS<3 and BI>55) yielded no statistically significant differences between ϵ4 (n = 58) and non-ϵ4 carriers (n = 131) (mRS, P = .37; BI, P = .61) or for ϵ2 carriers compared with non-ϵ2 carriers (mRS, P = .19; BI, P = .32). Excluding ϵ2/ϵ4 heterozygotes (in case of divergent functional effects) from the analyses did not alter any of the results.

Univariate analyses showed that OCSP categories (P<.001), NIHSS scores (P<.001), and age (P = .002) were significantly associated with an adverse 3-month (BI) outcome. Scores for the NIHSS and age remained significant in a multivariate analysis of 3-month BI and mRS outcomes (Table 3).

COMMENT

Although APOE polymorphism has emerged as an important determinant of outcome following head injury58 and intracerebral hemorrhage,9,10 the findings of this prospective outcome study and a previous retrospective survival study in another population10 indicate that the ϵ4 allele does not exert a major adverse influence on baseline severity, functional outcome, or survival following ischemic stroke. These contrasting findings from different types of brain injury suggest that the association of the ϵ4 allele with outcome may be insult specific.

Previous case-control and cohort studies have examined APOE genotype as a possible genetic predisposition to ischemic stroke.2331 Some studies have implicated the ϵ2 allele,24,25 some the ϵ4 allele,2527 and others have reported neutral findings.2831 A recent meta-analysis of case-control studies found a small significant overrepresentation of the ϵ4 allele in ischemic stroke patients compared with age- and sex-matched controls.32 The ϵ4 allele is also overrepresented in coronary heart diseasϵ33 and is thought to be more atherogenic than other APOE alleles.34 Individuals with the ϵ3/ϵ4 and ϵ4/ϵ4 genotypes seem to carry excess risk compared with control subjects in both coronary heart diseasϵ33 and ischemic stroke.32 Although the results of the current study demonstrated fewer lacunar infarcts in ϵ4 carriers (29% vs 42%) and higher median NIHSS scores compared with ϵ3/ϵ3 patients (7 vs 5), neither of these was statistically significant, supporting the findings of a larger study that demonstrated no difference in APOE allele frequencies between patients with lacunar and cortical ischemic events.10

Properties of apoE that are potentially relevant to brain injury (neurotrophic,35 antioxidant,36 immunomodulatory,37 and intracellular calcium effects38) have been identified under in vitro conditions. Although some of these are isoform specific (neurotrophic,35 antioxidant,36 and intracellular calcium changes38), the relevance in vivo of differing mechanisms has not been clearly defined. Consequently, in head injury and intracerebral hemorrhage (conditions for which possession of the ϵ4 allele seems to almost double the risk of a poor prognosis6,10), it is not known whether ϵ4 carriers incur more severe injury or have defective repair mechanisms compared with non-ϵ4 carriers. In the present study, baseline NIHSS scores and OCSP categories were used to assess stroke severity. Similar findings in each of the major APOE genotype groupings (ϵ3/ϵ3, ϵ4, and ϵ2 carriers) suggest that ischemic insult severity in stroke is not associated with APOE genotype.

The outcome findings of our study question how reliably one can extrapolate data from animal models of stroke to humans.39 Brain apoE changes have been well described in different animal models of brain injury,1,40 including cerebral ischemia.41 The results have suggested that injury either causes neuronal expression of apoE or increases neuronal uptake of apoE.41 This has led to the description of apoE as an "injury factor."42 In one focal ischemic model, infarct volume and hemiparesis severity were significantly worse in transgenic ϵ4/ϵ4 mice compared with ϵ3/ϵ3 mice.14 It remains unclear if APOE genotype influences the size of human infarct volume in different types of ischemic stroke. Tomimoto et al43 have demonstrated that apoE-immunoreactive axons in humans are accompanied by apoE-positive macrophages in the periphery of infarcts, although APOE genotypes were not examined in this small study. However, a recent semiquantitative assessment of neuronal damage following global ischemia in humans failed to demonstrate an APOE genotype influence.44

The follow-up functional assessments in our study provided a means, albeit crude, of measuring repair. The neutral results suggest that the different apoE isoforms do not reflect major differences in repair mechanisms following cerebral ischemia in humans. A trend toward better functional outcome in ϵ2 carriers vs either the ϵ3/ϵ3 or ϵ4+ groups was present, but must be interpreted with caution since only 13% of the population (n = 25 patients) possessed an ϵ2 allele. Furthermore, survival and 3-month placement following ischemic stroke in a cohort of 640 patients10 were not associated with the APOE ϵ2 allele.

Although ischemic stroke is a heterogeneous condition, the number of patients in our study is much greater than in those studies of head injury58 or intracerebral hemorrhage9,10 (equally heterogeneous conditions) that demonstrated an influence of APOE ϵ4 on outcome. This supports the conclusion that APOE genotype does not contribute to major clinically significant differences in either injury severity or functional outcome in ischemic stroke. Our results indicate that associations between APOE genotype and outcome in humans may be insult specific.

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Article Information

Accepted for publication February 23, 2000.

Mark O. McCarron, MD, MA, MRCP, is supported by a Patrick Berthoud Fellowship, Kent, England.

Reprints: Keith Muir, MD, MRCP, MSc, Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 4TF, Scotland (e-mail: k.muir@clinmed.gla.ac.uk).

References
1.
Laskowitz  DTHorsburgh  KRoses  AD Apolipoprotein E and the CNS response to injury. J Cereb Blood Flow Metab. 1998;18465- 471Article
2.
Strittmatter  WJWeisgraber  KHHuang  DY  et al.  Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993;908098- 8102Article
3.
Saunders  AMStrittmatter  WJSchmechel  D  et al.  Association of apolipoprotein E allele ϵ4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993;431467- 1472Article
4.
Meyer  MRTschanz  JTNorton  MC  et al.  APOE genotype predicts when—not whether—one is predisposed to develop Alzheimer disease. Nat Genet. 1998;19321- 322Article
5.
Nicoll  JARoberts  GWGraham  DI Apolipoprotein E ϵ4 allele is associated with deposition of amyloid beta-protein following head injury. Nat Med. 1995;1135- 137Article
6.
Teasdale  GMNicoll  JRMurray  GFiddes  M Association of apolipoprotein E polymorphism with outcome after head injury. Lancet. 1997;3501069- 1071Article
7.
Friedman  GFroom  PSazbon  L  et al.  Apolipoprotein E-ϵ4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology. 1999;52244- 248Article
8.
Jordan  BDRelkin  NRRavdin  LDJacobs  ARBennett  AGandy  S Apolipoprotein E ϵ4 associated with chronic traumatic brain injury in boxing. JAMA. 1997;278136- 140Article
9.
Alberts  MJGraffagnino  CMcClenny  C  et al.  ApoE genotype and survival from intracerebral haemorrhage [letter]. Lancet. 1995;346575Article
10.
McCarron  MOMuir  KWWeir  CJ  et al.  The apolipoprotein E ϵ4 allele and outcome in cerebrovascular disease. Stroke. 1998;291882- 1887Article
11.
Laskowitz  DTSheng  HBart  RDJoyner  KARoses  ADWarner  DS Apolipoprotein E–deficient mice have increased susceptibility to focal cerebral ischemia. J Cereb Blood Flow Metab. 1997;17753- 758Article
12.
Sheng  HLaskowitz  DTMackensen  GB  et al.  Apolipoprotein E deficiency worsens outcome from global cerebral ischemia in the mouse. Stroke. 1999;301118- 1124Article
13.
Horsburgh  KKelly  SMcCulloch  JHiggins  GARoses  ADNicoll  JAR Increased neuronal damage in apolipoprotein E deficient mice following global ischaemia. Neuroreport. 1999;10837- 841Article
14.
Sheng  HXLaskowitz  DTBennett  E  et al.  Apolipoprotein E isoform–specific differences in outcome from focal ischemia in transgenic mice. J Cereb Blood Flow Metab. 1998;18361- 366Article
15.
Brott  TAdams  HP  JrOlinger  CP  et al.  Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20864- 870Article
16.
Bamford  JSandercock  PDennis  MBurn  JWarlow  C Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet. 1991;3371521- 1526Article
17.
Wenham  PRPrice  WHBlandell  G Apolipoprotein E genotyping by one-stage PCR [letter]. Lancet. 1991;3371158- 1159Article
18.
Mahoney  FIBarthel  DW Functional evaluation: the Barthel Index. Md State Med J. 1965;1461- 65
19.
Rankin  J Cerebral vascular accidents in patients over the age of 60, II: prognosis. Scot Med J. 1957;2200- 215
20.
van Swieten  JCKoudstaal  PJVisser  MCSchouten  HJvan Gijn  J Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19604- 607Article
21.
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;3331581- 1587Article
22.
McCarron  MONicoll  JAR High frequency of apolipoprotein E ϵ2 allele is specific for patients with cerebral amyloid angiopathy-related haemorrhage. Neurosci Lett. 1998;24745- 48Article
23.
Ferrucci  LGuralnik  JMPahor  M  et al.  Apolipoprotein E ϵ2 allele and risk of stroke in the older population. Stroke. 1997;282410- 2416Article
24.
Couderc  RMahieux  FBailleul  SFenelon  GMary  RFermanian  J Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease: a case-control study. Stroke. 1993;24661- 664Article
25.
Mahieux  FBailleul  SFenelon  RCouderc  RLaruelle  PGunel  M Prevalence of apolipoprotein E phenotypes in patients with acute ischemic stroke [abstract]. Stroke. 1990;21I- 115
26.
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