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Cerebral amyloid angiopathy A microvascular link between parenchymal and vascular dementia.

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EDITORIALS
Cerebral Amyloid
Angiopathy: A
Microvascular Link Between
Parenchymal and Vascular
Dementia?
Why should cerebral amyloid (congophilic) angiopathy
(CAA) be of interest to neuroscientists? This peculiar
cerebral microvascular lesion is one in which arteriolar
media, including its smooth muscle cell (SMC) component, is gradually replaced by fibrillar amyloid
(Fig).1 The end result of this process is the presence,
within cerebral cortex, of markedly weakened arterial
walls, which frequently give rise to (lobar) cerebral
hemorrhages.2,3 Less often, severe CAA is associated
with ischemic brain lesions and granulomatous angiitis.4,5 That CAA is most common and severe in patients with Alzheimer disease (AD) has been well documented in many studies.6 In this issue of the Annals,
Grabowski and colleagues present clinicopathologic details of an Iowa family with autosomal dominant inheritance of a phenotype characterized by progressive
aphasic dementia; in one patient who came to necropsy, there was evidence for severe CAA.7 Of interest
is that the clinical and neuropathologic syndrome is
linked to a mutation (causing a substitution of asparagine for aspartic acid) at codon 694 of the gene that
encodes the amyloid precursor protein (APP), from
which A␤ is cleaved.
The APP codon 694 mutation represents the third
APP codon in a row, mutations in which determine a
phenotype that includes CAA. A Gln-for-Glu substitution at residue 22 of A␤ (APP codon 693) is linked to
hereditary cerebral hemorrhage with amyloidosis,
Dutch type (HCHWA-D), a disease in which lobar cerebral hemorrhages and ischemic brain lesions occur in
the context of overwhelming meningeal and neocortical
CAA.8,9 Although parenchymal amyloid deposits are
seen in HCHWA-D brain, neurofibrillary degeneration
of neurons is rare and does not appear to correlate with
the severity of either microvascular or parenchymal A␤
deposition.10 In nearby Belgium, patients with an APP
codon 692 missense mutation manifest massive brain
parenchymal and microvascular A␤ deposition, the latter sometimes causing brain hemorrhage, although only
a small number of patients with this disease have been
studied at autopsy.11
The new “Iowa kindred” will have to be carefully
studied using rigorous clinical, neuropsychologic, neuroimaging, and neuropathologic tools, the latter to es-
tablish how constant the CAA phenotype is among
other family members. In the patient whose brain is
described, the morphologic features of CAA were remarkably similar to those noted in HCHWA-D, including radially disposed amyloid fibrils and secondary
calcification of (some) affected cerebral microvascular
walls.9,12
But can predominantly microvascular (arteriolar and
capillary) amyloid deposition lead to dementia and, if
so, by what mechanism? The lessons to be learned
from patients with HCHWA-D and this newly described family suggest that the answer to the first question is, overwhelmingly, “yes.” A major mechanism
causing dementia in Dutch patients appears to be the
presence of ischemic brain infarcts and residua of encephalic bleeds.8 –10,12 Retrospective clinicopathologic
correlative studies using autopsy material have also
shown that cerebrovascular “events” or lesions in individuals with HCHWA-D are a function of the severity
of microvascular degeneration linked directly to the
presence of CAA.13 Interestly, the single patient from
the Iowa kindred examined at necropsy showed widespread abundant neurofibrillary tangles and frequent
A␤1– 40-immunoreactive senile plaques, both of which
almost certainly contributed to this individual’s dementia syndrome. Small brain infarcts at the cortex–white
matter junction are also described, and leukoencephalopathy was noted, ie, the neuropathologic picture
showed some features that have been described in patients (lacking CAA) with a relatively “pure” ischemic
vascular dementia.14
Patients with a dementia syndrome consistent with AD
on occasion have predominantly A␤-immunoreactive
CAA as the overwhelming brain lesion present on neuropathologic evaluation. Does this simply represent a
microvascular variant of AD resulting from extensive
A␤ deposition mainly in capillary and arterial walls
(rather than neuropil), or is it a distinctive disease process?15 The existence of such cases should be viewed as
an opportunity to explore heterogeneous mechanisms
of CNS “amyloidogenesis,” some resulting in parenchymal and others in vascular A␤ deposition.16 Nor is
A␤ the only protein that has been implicated in CAA
pathogenesis. In CAA associated with AD, gamma
trace (cystatin C) is known to be a major constituent
of affected arterial walls.17 Comparatively rare forms of
familial CAA (fCAA) are associated with arterial medial
deposition of unique proteins, the most recently identified one being “ABri,” found in a British kindred of
familial dementia linked to a mutation of a gene on
chromosome 13.18 Thus, an understanding of CAA
may tell us a great deal about novel mechanisms of A␤
deposition and toxicity in the central nervous system,
but it might tell us even more about the many types of
cerebral microvascular disease characterized by progressive injury and loss of SMCs within the arteriolar me-
© 2001 Wiley-Liss, Inc.
691
Brain Research Institute and Neuropsychiatric
Research Institute
UCLA Medical Center
Los Angeles, CA
References
Fig. (A) A relatively normal arteriole in a nondemented patient. The vessel has been cut at an angle. Perivascular clearing is an artefact of tissue preparation. Arrows indicate arteriolar media with a relatively normal complement of smooth
muscle cells (SMCs). (B) An arteriole with severe cerebral
amyloid angiopathy, by contrast. Medial SMCs have been replaced by fibrillar amyloid. However, a relatively normal endothelial cell (arrow) is seen adjacent to the lumen. Hematoxylin and eosin. ⫻405 (A), ⫻375 (B).
dia (“cerebral angiomyopathies”).19 Finally, patients
with severe CAA (including syndromes of fCAA) may
offer a unique opportunity to study injurious effects of
microvascular amyloid deposition (short of ischemic/
hemorrhagic stroke) on perivascular brain tissue.
Harry V. Vinters, MD
Departments of Pathology and Laboratory Medicine
(Neuropathology) and Neurology
692
Annals of Neurology
Vol 49
No 6
June 2001
1. Vinters HV, Secor DL, Read SL, et al. The microvasculature in
brain biopsy specimens from patients with Alzheimer’s disease:
an immunohistochemical and ultrastructural study. Ultrastruct
Pathol 1994;18:333–348.
2. Gilbert GG, Vinters HV. Cerebral amyloid angiopathy: incidence and complications in the aging brain. I. Cerebral hemorrhage. Stroke 1983;14:915–923.
3. Vinters HV. Cerebral amyloid angiopathy—a critical review.
Stroke 1987;18:311–324.
4. Cadavid D, Mena H, Koeller K, Frommelt RA. Cerebral beta
amyloid angiopathy is a risk factor for cerebral ischemic infarction. A case control study in human brain biopsies. J Neuropathol Exp Neurol 2000;59:768 –773.
5. Anders KH, Wang ZZ, Kornfeld M, et al. Giant cell arteritis in
association with cerebral amyloid angiopathy: immunohistochemical and molecular studies. Hum Pathol 1997;28:1237–
1246.
6. Greenberg SM. Cerebral amyloid angiopathy. Prospects for
clinical diagnosis and treatment. Neurology 1998;51:690 – 694.
7. Grabowski TJ, Cho HS, Vonsattel JPG, et al. Novel amyloid
precursor protein mutation in an Iowa family with dementia
and severe cerebral amyloid angiopathy. Ann Neurol 2001;49:
697–705.
8. Bornebroek M, Haan J, Maat-Schieman MLC, Van Duinen
SG, Roos RAC. Hereditary cerebral hemorrhage with
amyloidosis-Dutch type (HCHWA-D): I—a review of clinical,
radiologic and genetic aspects. Brain Pathol 1996;6:111–114.
9. Maat-Schieman MLC, van Duinen SG, Bornebroek M, et al.
Hereditary cerebral hemorrhage with amyloidosis-Dutch type
(HCHWA-D): II—a review of histopathological aspects. Brain
Pathol 1996;6:115–120.
10. Maat-Schieman MLC, Van Duinen SG, Natté R, Roos RAC.
Neuropathology of hereditary cerebral hemorrhage with
amyloidosis-Dutch type. In: Verbeek MM, de Waal RMW,
Vinters HV, eds. Cerebral amyloid angiopathy in Alzheimer’s
disease and related disorders. Dordrecht: Kluwer Academic
Publishers, 2000:223–236.
11. Roks G, Van Harskamp F, De Koning I, et al. Presentation of
amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692). Brain 2000;123:2130 –
2140.
12. Vinters HV, Natté R, Maat-Schieman MLC, et al. Secondary
microvascular degeneration in amyloid angiopathy of patients
with hereditary cerebral hemorrhage with amyloidosis, Dutch
type (HCHWA-D). Acta Neuropathol 1998;95:235–244.
13. Natté R, Vinters HV, Maat-Schieman MLC, et al. Microvasculopathy is associated with the number of cerebrovascular lesions in hereditary cerebral hemorrhage with amyloidosis,
Dutch type. Stroke 1998;29:1588 –1594.
14. Vinters HV, Ellis WG, Zarow C, et al. Neuropathologic substrates of ischemic vascular dementia. J Neuropathol Exp Neurol 2000;59:931–945.
15. Vinters HV. Cerebral amyloid angiopathy and Alzheimer’s
disease: two entities or one? J Neurol Sci 1992;112:1–3.
16. Verbeek MM, Eikelenboom P, de Waal RMW. Differences between the pathogenesis of senile plaques and congophilic angiopathy in Alzheimer disease. J Neuropathol Exp Neurol 1997;
56:751–761.
17. Vinters HV, Secor DL, Pardridge WM, Gray F. Immunohisto-
chemical study of cerebral amyloid angiopathy. III. Widespread
Alzheimer A4 peptide in cerebral microvessel walls colocalizes
with gamma trace in patients with leukoencephalopathy. Ann
Neurol 1990;28:34 – 42.
18. Frangione B, Vidal R, Rostagno A, Ghiso J. Familial cerebral
amyloid angiopathies and dementia. Alzheimer Dis Assoc Disord 2000;14(Suppl 1):S25–S30.
19. Vinters HV, Wang Z. Non-CAA angiopathies and their possible interactions with cerebral amyloid angiopathy. Amyloid: J
Protein Folding Disord 8(Suppl 1) (in press, 2001).
When Running a Stop Sign
May Be a Good Thing
Despite the remarkable discoveries regarding the molecular basis of Duchenne and Becker muscular dystrophies (DMD/BMD) and of their animal models during the past decade,1 definitive treatment has not
become available.2 Various forms of molecular therapies, such as dystrophin gene replacement or utrophin
up-regulation, are still in the preclinical stage.3 Thus, a
recent report from Barton-Davis and coworkers4 created excitement by observing a significant number a
dystrophin-positive muscle fibers in skeletal muscles of
mdx mice after a short course of systemic administration of gentamicin, an aminoglycoside antibiotic.
These authors hypothesized that gentamicin interfered
with the ability of ribosomes to recognize the pathogenic translational stop codon UAA in the dystrophin
mRNA, resulting in a “read through” and the production of stable, full-length dystrophin. In earlier studies,
the aminoglycosides’ ability to misread stop codons has
been used for negating the deleterious effects of stop
mutations of the cystic fibrosis transmembrane regulator in a bronchial cell line vitro5 and in the nasal mucosa of patients in vivo.6 More recently, in a fibroblast
cell line in vitro, heterozygous stop mutations of the
lysosomal enzyme alpha-L-iduronidase (whose deficiency causes the majority of Hurler’s syndrome cases)
were shown to be partially overridden by gentamicin.7
Howard and coworkers,8 using an elegant in vitro system, quantitated the gentamicin-induced read-through
for the three different stop codons and also showed a
modifying effect of the flanking nucleotides.
Barton-Davis et al4 suggested that, despite the relatively low frequency (about 15%) of DMD/BMD patients with a disease-causing nonsense mutation and
the notorious toxicity of aminoglycosides, this might
be a treatment for selected patients.This challenge was
taken up by Wagner et al,9 who, in this issue of the
Annals, report their study of 2 DMD and 2 BMD pa-
tients who received daily intravenous bolus injections
of 7.5 mg/kg gentamicin for 14 days. This produced a
peak gentamicin serum concentration similar to that
noted in the mdx mice.4 All patients had a nonsense
mutation of their dystrophin gene, creating a premature stop codon (2⫻ TGA, TAA, TAG). No oto- or
nephrotoxicity was noted. No full-length dystrophin
was found in the pre- and posttreatment tibialis anterior muscle biopsies in any of the 4 patients by microscopic immunocytochemistry or Western blot analysis.9
The key issue is what causes the difference between
the studies of Barton-Davis et al4 in mdx mice and
those of Wagner et al9 in properly selected DMD/
BMD patients despite the close similarity in the peak
gentamicin serum levels and the duration of treatment.
It appears likely that the difference is related to species
and possibly drug composition.
There are several relevant parameters that may differ
between mice and man. It is believed that the “readthrough” frequency induced by a subtoxic concentration of gentamicin is a relatively rare event.9 In other
words, read-through dystrophin mRNA copies may
constitute a relatively small percentage of the total
number of translated mRNA copies. Furthermore, it is
not clear whether pulsed administration of gentamicin
producing conspicuous blood level fluctuations is the
best way to maximize the read-through efficiency. In
addition, the turnover rate of dystrophin is suspected
to be slow.10 Thus, it might take more than 2 weeks of
treatment to establish a steady state of sarcolemmal
dystrophin that is not only detectable but therapeutically useful. In fact, perhaps such a steady state is never
attainable in man using subtoxic doses of gentamicin.
An important issue may be the brand and composition of gentamicin sulphate used. A given batch of
commercially available gentamicin usually contains
three major components (gentamicin C1, C1a, and
C2) that show only slight differences in their chemical
structure but differ significantly in their propensity to
induce misreading in bacterial and eukaryotic ribosomes.11,12 Thus, the different results may be attributable to different brands of gentamicin used in the
mouse and human studies cited.4,9
Where do we go from here? The first task is to repeat and verify the results of the mdx mouse experiments4 using gentamicin with a defined composition.
Importantly, in our laboratories (G.K.) no full-length
dystrophin could be induced by the same experimental
paradigm in mdx mice using gentamicin from a supplier other than Barton-Davis et al.4 To optimize gentamicin composition for misreading efficiency, Howard
and colleagues’8 in vitro paradigm may be used. Further human experiments should be delayed until some
of these issues are resolved in animal experiments.
However, even if full-length dystrophin production by
administration of aminoglycosides becomes possible in
© 2001 Wiley-Liss, Inc.
693
DMD patients, it may require high and permanent
doses close to the toxic level. A lifelong commitment to
such a schedule is a medically and ethically vexing decision even for a disease as pernicious as DMD.
George Karpati, MD
Montreal Neurological Institute
McGill University
Montreal, Quebec, Canada
Hanns Lochmuller, MD
Genzentrum
Ludwig-Maximilians-University
Munich, Germany
References
1. Karpati G, Brown RH Jr. The dawning of a new era in the
molecular biology of the muscular dystrophies. Brain Pathol
1996;6:17.
2. Allamand V, Campbell KP. Animal models for muscular
dystrophy: valuable tools for the development of therapies.
Hum Mol Genet 2000;9:2459 –2467.
3. Hartigan-O’Connor D, Chamberlain JS. Developments in gene
therapy for muscular dystrophy. Microsc Res Techn 2000;48:
223–238.
4. Barton-Davis ER, Cordier L, Shoturma DI, et al. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles
of mdx mice. J Clin Invest 1999;104:375–381.
5. Howard M, Frizell RA, Bedwell DM. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop
codon mutations. Nature Med 1996;2:467– 469.
6. Wilschanski M, Famini C, Blau H, et al. A pilot study of the
effect of gentamicin on nasal potential difference measurements
in cystic fibrosis patients carrying stop mutations. Am J Respir
Crit Care Med 2000;161:860 – 865.
7. Keeling KM, Brooks DA, Hopwood JJ, et al. Gentamicinmediated suppression of Hurler syndrome stop mutations restores a low level of ␣-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation. Hum Mol Genet
2001;10:291–299.
8. Howard MT, Shirts BH, Petros LM, et al. Sequence specificity
of aminoglycoside-induced stop condon readthrough: potential
implications for treatment of Duchenne muscular dystrophy.
Ann Neurol 2000;48:164 –169.
9. Wagner KR, Hamed S, Hadley DW, et al. Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations. Ann Neurol 2001;49:706 –711.
10. Ahmad A, Brinson M, Hodges BL, et al. Mdx mice inducibly
expressing dystrophin provide insights into the potential of gene
therapy for Duchenne muscular dystrophy. Hum Mol Genet
2000;9:2507–2515.
11. Loveless MO, Kohlhepp SJ, Gilbert DN. The influence of aminoglycoside antibiotics on the in vitro function of rat liver ribosomes. J Lab Clin Med 1984;103:294 –303.
12. Yoshizawa S, Fourmy D, Puglisi JD. Structural origins of gentamicin antibiotic action. EMBO J 1998;17:6437– 6448.
694
© 2001 Wiley-Liss, Inc.
Variants of the Guillain
Barré Syndrome: Progress
Toward Fulfilling “Koch’s
Postulates”
Reports recently published in the Annals of Neurology
reflect the extent to which research on uncommon
“variants” of the Guillain Barre syndrome has advanced1,2,3,4. Two syndromes are making parallel but
complementary advances. The Fisher syndrome (FS) of
ataxia, ophthalmoparesis, and areflexia was first described as a variant of GBS by Miller Fisher 45 years
ago5. The history of the axonal forms dates to the report by Feasby and colleagues 15 years ago, and the
motor form of axonal GBS was described and given the
designation acute motor axonal neuropathy (AMAN)
only seven years ago6,7. Partly because they are uncommon in the U.S. and Europe, both the Fisher syndrome and AMAN were initially controversial. The
AMAN story has been clarified largely by studies from
Asia, especially Japan and northern China, where the
syndrome is relatively frequent7-13. In spite of their
youth, understanding of the pathogenesis of these variants now outstrips the most frequent form of GBS in
the U.S., acute inflammatory demyelinating polyneuropathy (AIDP).
The unifying hypothesis of pathogenesis being tested
in the variant syndromes is molecular mimicry,
whereby an antecedent infection generates an immune
response to antigenic targets in the organism that are
shared by normal tissue components. In this formulation the immune system “sees” and attacks the
shared antigenic moieties innocently expressed by an
element of the nerve fiber, either axon or Schwann
cell. The most frequently recognized antecedent infection in AMAN and FS is Campylobacter jejuni2,11,14-16.
Both syndromes are strongly associated with specific
anti-ganglioside antibodies. In AMAN these antibodies
are against GM1, GD1a, GalNAc-GD1a, and
GM1b2,11,12,17-19, while in FS the association is with
GQ1b20,21. Lipopolysaccharides of C. jejuni isolates
from patients with AMAN and FS carry relevant
ganglioside-like moieties16,22-24. Pathological studies in
AMAN indicate a non-inflammatory, antibodymediated, complement-dependent mode of injury to
motor axons10. In this context the critical missing
link– the data needed to satisfy Witebsky’s postulates
(the equivalent of Koch’s postulates for an autoimmune pathogenetic sequence) – is induction of clinical
and pathological disease by passive transfer of anti-
ganglioside antibodies produced by infection with relevant C. jejuni isolates.
This goal has been partly reached in a series of studies on FS, using in vitro muscle-nerve preparations as a
model for motor nerve terminal transmission1,3,25.
Plomp et al. have shown that anti-GQ1b antibody
containing sera, IgG fractions, and a human derived
monoclonal anti-GQ1b exert a complement-dependent
temporary increase in spontaneous neurotransmitter release, followed by block of evoked release resulting in
paralysis1. This effect has been reproduced with a set of
monoclonal antibodies cross-reactive with GQ1b made
by immunizing with the LPS from C. jejuni isolates
from GBS and FS patients25. Buchwald and colleagues
have produced complementary data, differing in the
role of the complement3. Moreover, the observation
that the ganglioside GQ1b is enriched in cranial occulomotor nerves provides a satisfying explanation for the
association of anti-GQ1b antibodies and ophthalmoplegia seen in FS26.
In this issue of Annals, Yuki et al. report a new animal model of axonal injury induced by immunization
with a mixture of bovine brain gangliosides or purified
GM14. The Yuki group has played a key role in developing the concept of molecular mimicry in GBS, and
the present article moves closer the goal of developing
a robust model of AMAN. The notable observations
include the fact that the antibody responses to ganglioside GM1 were closely associated with axonal and
motor injury, that all animals with clinical and pathological disease showed antiganglioside antibody class
switching from IgM to IgG, and that, as in AMAN,
inflammation was absent in the injured nerves. An important issue regarding this model that needs further
study relates to the presence of a significant number of
degenerating fibers in the adjuvant immunized control
animals.
Putting these studies into perspective requires some
background information on anti-GM1 antibody associated clinical syndromes, fine specificities of these antibodies, and distribution of GM1 ganglioside in peripheral nerves. Antibodies to GM1 were among the
first to be described in patients with GBS and they are
usually associated with predominantly motor neuropathies. Anti-GM1 antibodies have attracted controversy
because they can be associated with several neuropathic
syndromes. IgM anti-GM1 antibodies are present in a
significant proportion of patients with multifocal motor neuropathy, a disorder which appears to involve
initial demyelination of motor fibers27,28. Anti-GM1
antibodies, particularly of the IgG class, are present in
some patients with AMAN, but also some AIDP cases.
The specificity of anti-GM1 antibodies also varies
among different patients; some antibodies specifically
recognize GM1, others recognize the Gal(b1-3)GalNAc
moiety shared by GM1, GD1b, and some peripheral
nerve glycoproteins29,30. Although anti-GM1 antibodies are associated with predominant motor syndromes,
this ganglioside is present in motor and sensory neurons, axons, and associated myelin31-33.
With the availability of an animal model with selective motor nerve fiber injury we are closer to understanding several fundamental questions regarding molecular mimicry, anti-ganglioside antibodies, and the
pathogenesis of different variants of GBS including
AMAN. Some of these issues are also relevant to
antibody-mediated neural damage in general: 1) What
are the mechanisms underlying generation of IgG antiganglioside antibodies after enteric infection, and why
is this response triggered in only a very small proportion of patients after an inciting infection? 2) Why are
certain fibers preferentially damaged, for example motor fibers in AMAN or oculomotor fibers in FS? 3)
Since gangliosides such as GM1 are expressed by both
axon and myelin in myelinated fibers, why are axons or
myelin primarily injured in AMAN or AIDP? 4) Are
gangliosides the target antigens, or do anti-ganglioside
antibodies crossreact with other glycoconjugates? 5)
What are the mechanisms of anti-ganglioside antibody
mediated nerve fiber injury? Does this nerve fiber injury require complement? 6) What determines the PNS
susceptibility? The CNS is also enriched in gangliosides
but generally is spared in conditions associated with
anti-ganglioside antibodies (a possible exception is the
association of anti-GQ1b antibody with Bickerstaff’s
encephalitis). 7) Why and how do anti-ganglioside antibodies selectively cross the blood-nerve barrier and access the endoneurial space? Do inflammatory T cells
contribute to this selective breakdown of the blood tissue barrier?
While these and other issues remain, there is an
irony in the fact that 30 years ago it appeared that
AIDP was going to be one of the first autoimmune
diseases to be fully understood in terms of immunopathogenesis. Yet now, while the pathogenesis of AIDP
remains uncertain, we are well along in understanding
and modeling the mechanisms leading to two “minor”
variants of the Guillain Barre syndrome.
Kazim A. Sheikh1, John W. Griffin1-3
Departments of Neurology1, Neuroscience2, and
Pathology3
Johns Hopkins Hospital
Baltimore, Maryland
References
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2. Ho TW, Willison HJ, Nachamkin I, et al. Anti-GD1a anti-
Editorial: Sheikh and Griffin: GBS Variants
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Yuki N, Yamada M, Koga M, et al. Animal model of axonal
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Hafer-Macko C, Hsieh S-T, Li CY, Ho TW, Sheikh K, Cornblath DR, et al. Acute motor axonal neuropathy: an antibodymediated attack on axolemma. Ann Neurol 1996; 40:635– 644.
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Annals of Neurology
Vol 49
No 6
June 2001
19. Yuki N, Ho TW, Tagawa Y, et al. Autoantibodies to GM1b
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20. Chiba A, Kusunoki S, Shimizu T, Kanazawa I. Serum IgG antibody to ganglioside GQ1b is a possible marker of Miller
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21. Willison HJ, Veitch J, Patterson G, Kennedy PGE. Miller
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ganglioside. J Neurol Neurosurg Psychiatry 1993;56:204 –206.
22. Yuki N, Handa S, Taki T, et al. Cross-reactive antigen between
nervous tissue and a bacterium elicits Guillain-Barre syndrome:
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23. Sheikh KA, Nachamkin I, Ho TW, et al. C. jejuni lipopolysaccharides in Guillain-Barre syndrome: molecular mimicry and
host susceptibility. Neurology 1998;51:371–378.
24. Nachamkin I, Ung H, Moran AP, et al. Ganglioside GM1
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