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Association of interleukin-1 polymorphisms with Alzheimer's disease in Australia.

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LETTERS
Toxicity of ␤-Amyloid Vaccination in Patients
with Alzheimer’s Disease
Bruno Pietro Imbimbo, PhD
On January 18, 2002, Elan Corporation and American
Home Products reported their decision to temporarily suspend dosing in a phase 2a study of their experimental antiAlzheimer’s disease vaccine (AN-1792) after 4 patients
showed clinical signs of central nervous system (CNS) inflammation. AN-1792, also known as AIP-001, is a 42amino acid peptide (␤-amyloid) vaccine coupled with an immune adjuvant (QS-21), a purified saponin derivative. This
double-blind, placebo-controlled study is being conducted in
the United States and four European countries and was designed to measure the immune response to AN-1792 in patients with mild to moderate Alzheimer’s disease. To date,
approximately 360 patients have received multiple doses of
AN-1792. The presence of a virus within the cerebrospinal
fluid was reported in 1 of the 4 patients with CNS inflammation under investigation. However, the cause of inflammation remains to be determined. The 4 reported cases occurred in France, where 97 patients have received the study
drug.
Dramatic results obtained with AN-1792 in transgenic animal models of Alzheimer’s disease1 raised unprecedented
hope for an effective treatment of this devastating disorder.
The vaccine increases ␤-amyloid clearance through mechanisms not fully understood. Centrally, the vaccine appears to
activate ␤-amyloid phagocytosis by microglial monocytes.
Peripherally, serum antibodies appear to bind and sequester
␤-amyloid, thereby altering its equilibrium between the CNS
and plasma.
There are many agents and mechanisms that can result in
CNS inflammation. One explanation for the encephalitis
could be external contamination during lumbar punctures,
which are required as part of the protocol. It is unlikely that
the QS-21 adjuvant used in this trial is the source of the
viruses, as it is not of animal origin but is a highly purified
saponin derived from the bark of the Quillaja saponaria Molina tree.
Viral, bacterial, fungal, and parasitic pathogens may
breach the blood–brain barrier and enter the CNS through
paracellular or transcellular mechanisms. Recent studies appear to indicate that ␤-amyloid vaccination may alter the
permeability of the blood–brain barrier. In the mouse, the
complex formed by ␤-amyloid and immunoglobulins appears
to have a 3.9- to 4.6-fold greater permeability coefficient
than nonspecific monoclonal antibodies.2 It has been also reported that in transgenic mice the passively administered antibodies can cross the blood–brain barrier to act directly in
the CNS.3 This suggests that ␤-amyloid immunization may
cause abnormal leakage of the blood–brain barrier and increase the chance that pathogenic microorganisms will reach
the CNS.
It is also possible and perhaps more likely that the adverse
events of AN-1792 observed in patients with Alzheimer’s disease could reflect an autoimmune inflammatory response
triggered by T-lymphocyte activation after immune-system
stimulation with ␤-amyloid.4 T-cell lines specific to
␤-amyloid contain a high percentage of CD8-positive cyto-
794
© 2002 Wiley-Liss, Inc.
toxic T cells, which are capable of lysing cells that overproduce ␤-amyloid.5
It is of paramount importance to clarify the nature and
mechanism of the observed adverse effects on the CNS associated with AN-1792. As other therapeutic anti-␤-amyloid
vaccination strategies are being pursued, we urgently need to
understand if the observed toxic effects are specific to AN1792 or also occur with other immunization approaches.
Chiesi Farmaceutici, Parma, Italy
References
1. Schenk D, Barbour R, Dunn W, et al. Immunization with
amyloid-beta attenuates Alzheimer-disease-like pathology in the
PDAPP mouse. Nature 1999;400:173–177.
2. Poduslo JF, Curran GL. Amyloid beta peptide as a vaccine for
Alzheimer’s disease involves receptor-mediated transport at the
blood–brain barrier. NeuroReport 2001;12:3197–3200.
3. Bard F, Cannon C, Barbour R, et al. Peripherally administered
antibodies against amyloid beta-peptide enter the central nervous
system and reduce pathology in a mouse model of Alzheimer
disease. Nat Med 2000;6:916 –919.
4. Grubeck-Loebenstein B, Blasko I, Marx FK, Trieb I. Immunization with beta-amyloid: could T-cell activation have a harmful
effect? Trends Neurosci 2000;23:114.
5. Marx F, Blasko I, Zisterer K, Grubeck-Loebenstein B. Transfected human B cells: a new model to study the functional and
immunostimulatory consequences of APP production. Exp Gerontol 1999;34:783–795.
DOI: 10.1002/ana.10218
Further Evidence that SPG3A Gene Mutations
Cause Autosomal Dominant Hereditary
Spastic Paraplegia
Maria Muglia, PhD,1 Angela Magariello, PhD,1
Giuseppe Nicoletti, MD,1 Alessandra Patitucci, PhD,1
Anna Lia Gabriele, PhD,1 Francesca Luisa Conforti, PhD,1
Rosalucia Mazzei, PhD,1 Manuela Caracciolo, MD,1
Bonaventura Ardito, MD,2 Marcello Lastilla, MD,2
Gioacchino Tedeschi, MD,3 and Aldo Quattrone, MD1,4
Autosomal dominant hereditary spastic paraplegia is a genetically heterogeneous neurodegenerative disorder characterized
by progressive spasticity of the lower limbs.
During the past few years, eight spastic gait (SPG) loci
have been shown to be associated with the pure form of autosomal dominant hereditary spastic paraplegia, but only one
gene responsible for the SPG4 locus has been identified.1
The SPG4 gene is ubiquitously expressed in adult and fetal
tissues and encodes spastin, an ATPase of the AAA protein
family.
Very recently, the gene responsible for the SPG3A locus
was also identified. The SPG3A gene is expressed predominantly in the central nervous system, although measurable
expression has been detected in all tissues by reverse transcription polymerase chain reaction experiments.2 The coding sequence is divided into 14 exons spanning approximately 69kb. The peptide encoded by SPG3A, atlastin,
shows significant homology with several GTPases, particularly guanylate binding protein-1, a member of the dynamin
family of large GTPases. Atlastin contains three conserved
nificant linkage to the SPG3 locus on chromosome 14 was
detected with a maximum LOD score of 4.58 at D14S255.
Direct sequencing of the SPG3A gene displayed a G3 A
mutation at position 818 in exon 7 of the gene. This mutation created an amino acid change from Arg to Gln at codon
217. The variation was also confirmed by digestion with restriction enzyme TaqI, which cleaved the wild-type polymerase chain reaction product of 208bp into 145 and 63bp digestion fragments but did not cleave the corresponding
region of the SPG3A gene in our patients (Fig). Complete
cosegregation of the heterozygous mutation with the disease
was observed. This mutation was absent in 100 control chromosomes examined.
The Arg217Gln missense mutation occurred at codon
217, which encodes the R amino acid of the RD motif,
which is highly conserved in the GTPases. Most likely, this
substitution alters the active site of the GTPase, thereby
modifying its function. This is the first evidence of a mutation in the SPG3A gene that alters the RD motif of atlastin.
Indeed, the mutations previously reported (R239C in exon 7
and H258R and S259Y in exon 8) altered amino acids located on the surface of the globular N-terminal region of
atlastin, which contains the conserved GTPase domain, without disrupting GPTase motifs. These data also confirm that
mutations in the SPG3A gene cause autosomal dominant hereditary spastic paraplegia.
1
Institute of Neurological Sciences, National Research Council,
Piano Lago di Mangone-Cosenza; 2Department of Neurology,
Hospital Miulli, Acquaviva delle Fonti, Bari; 3Department of
Neurology, University of Catanzaro, Naples; and 4Institute of
Neurology, University of Catanzaro, Catanzaro, Italy
References
Fig. (a) SPG3A exon sequence analysis. Sequencing with the
forward primer shows a heterozygous missense mutation
CGA3 CAA in codon 217 of exon 7 in an affected individual
(left) but not in an unaffected subject (right). (b) TaqI restriction analysis of the 208bp fragment. The G3 A transition results in the loss of the TaqI restriction site. (lane 1) Molecular
weight standard; (lane 2) undigested fragment; (lanes 3 and 4)
affected individuals; (lanes 5 and 6) normal subjects.
motifs—P-loop (74GAFRKGKS81), DxxG (146DTQG), and
RD (217RD)—that characterize guanylate binding/GTPase
active sites.3
In this study, we report a novel mutation in a large Italian
pedigree from southern Italy with autosomal dominant uncomplicated spastic paraplegia. We included 35 individuals
from four generations: 11 affected and 24 unaffected subjects. The clinical picture was uniform and characterized by
insidiously progressive lower extremity weakness and spasticity. The mean age at onset of symptoms was 8.3 years. Sig-
1. Hazan J, Fonknechten N, Mavel D, et al. Spastin, a new AAA
protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet 1999;23:296 –303.
2. Zhao X, Alvarado D, Rainier S, et al. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic
paraplegia. Nat Genet 2001;29:326 –331.
3. Prakash B, Praefcke GJK, Renault L, et al. Structure of human
guanylate-binding protein 1 representing a unique class of GTP
binding protein. Nature 2000;403:567–571.
DOI 10.1002/ana.10185
Association of Interleukin-1 Polymorphisms with
Alzheimer’s Disease in Australia
Ross Hedley, BSc,2,5 Joachim Hallmayer, MD, PhD,6
David M. Groth, PhD,3 William S. Brooks, MD,7
Samuel E. Gandy, MD, PhD,4
and Ralph N. Martins, PhD1,5
Genetic studies indicate that the interleukin-1 (IL-1) genes
may act as genetic risk factors for Alzheimer’s disease (AD).1–5
Genes encoding two agonist proteins (IL-1␣ and IL-1␤) and
one receptor antagonist (IL-ra) are present in close proximity
at chromosome 2q13–21. The IL-1␤ ⫺511 T/T genotype has
been associated with an increased risk of late-onset Alzheimer’s
disease (LOAD),1 whereas the IL-1␣ ⫺889 T/T and IL-1␤
⫹3954 T/T genotypes apparently increase the risk of early-
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Table. Interleukin-1 Polymorphisms in Alzheimer’s Disease in Australia
Genotype (%)
n
Allele Frequency
C/C (%)
C/T (%)
T/T (%)
C
T
IL-1A ⫺889 C3T polymorphism
Controls
351
AD
221
EOAD
43
LOAD
178
153 (43.6)
98 (44.4)
24 (55.8)
74 (41.6)
168 (47.9)
94 (42.5)
17 (39.5)
77 (43.2)
30 (8.5)
29 (13.1)
2 (4.7)
27 (15.2)
0.675
0.656
0.756
0.632
0.325
0.344
0.244
0.368
IL-1B ⫹3954 C3T Polymorphism
Controls
351
AD
221
EOAD
43
LOAD
178
193 (55.0)
116 (52.5)
25 (58.2)
91 (51.1)
144 (41.0)
86 (38.9)
17 (39.5)
69 (38.8)
14 (4.0)
19 (8.6)
1 (2.3)
18 (10.1)
0.755
0.719
0.779
0.705
0.245
0.281
0.221
0.295
IL-1B ⫺511 C3T Polymorphism
Controls
351
AD
220
EOAD
43
LOAD
177
154 (43.9)
106 (48.3)
21 (48.8)
85 (48.0)
160 (45.6)
84 (38.2)
16 (37.2)
68 (38.4)
37 (10.5)
30 (13.5)
6 (14.0)
24 (13.6)
0.667
0.673
0.674
0.672
0.333
0.327
0.326
0.328
Genotype (%)
n
1.1
(%)
IL-1RN VNTR Genotypes
Controls 352 168 (47.7)
AD
221 116 (52.5)
EOAD
42
21 (50.0)
LOAD
179
95 (53.1)
Allele Frequency
1.2
(%)
1.3
(%)
1.4
(%)
2.2
(%)
2.4
(%)
1
2
3
4
144 (40.9)
76 (34.4)
16 (38.1)
60 (33.5)
2 (0.6)
0
0
0
12 (3.4)
9 (4.0)
2 (4.8)
7 (3.9)
21 (6.0)
15 (6.8)
0
15 (8.4)
5 (1.4)
5 (2.3)
3 (7.1)
2 (1.1)
0.702
0.717
0.714
0.718
0.271
0.251
0.226
0.257
0.003
0.000
0.000
0.000
0.024
0.032
0.060
0.025
IL-1A ⫺889 and IL-1B ⫹3954 Composite Analysis
Controls (n ⫽ 351)
IL-1B ⫹3954
IL-1A⫺889
C/C
C/T
T/T
AD (n ⫽ 221)
IL-1B ⫹3954
IL-1A⫺889
C/C
C/T
T/T
125 (35.6)
58 (16.5)
10 (2.9)
28 (8.0)
104 (29.6)
12 (3.4)
0
6 (1.7)
8 (2.3)
C/C
C/T
T/T
C/C
C/T
T/T
84 (38.0)
26 (11.8)
6 (2.7)
14 (6.3)
66 (29.9)
6 (2.7)
0
2 (0.9)
17 (7.7)
Logistic Regression Analysis
Factor
APOE ε4 allele
⫺889 T/T genotype
⫹3954 T/T genotype
⫺889 T/T and ⫹3954 T/T genotype
Odds Ratio
95% Confidence Interval
3.262
2.108
2.467
3.892
2.221–4.79
1.183–3.757
1.235–4.929
1.616–9.370
AD ⫽ Alzheimer’s disease; EOAD ⫽ early-onset Alzheimer’s disease; IL ⫽ interleukin; LOAD ⫽ late-onset Alzheimer’s disease.
796
Annals of Neurology
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p
⬍ 0.001
0.011
0.011
0.002
onset Alzheimer’s disease (EOAD).2,4 Dual homozygotes at
IL-1␣ ⫺889 and IL-1␤ ⫹3954 appear to have a 10-fold increased risk of AD.2 We sought associations involving various
IL-1 polymorphisms and the risk of AD in an Australian population. Apolipoprotein E genotypes, plasma ApoE levels, and
⫺491 APOE promoter polymorphisms have been reported for
this cohort in ref. 6 and citations therein.
Genotyping for 5 IL-1 polymorphisms was performed as
described2 with genomic DNA from 574 individuals, including 352 healthy controls (age: mean, 77.6 years; SD, 10.2)
and 179 LOAD and 43 EOAD patients diagnosed with National Institute of Neurological and Communicative Disorders and Stroke and The Alzheimer’s Disease and Related
Disorders Association criteria. Relationships between polymorphisms and relative risks (odds ratios) for LOAD and
EOAD were estimated with the SPSS statistical package
(SPSS, version 10.1, for Windows; SPSS, Chicago, IL).
Neither the control nor the AD group deviated from the
Hardy-Weinberg genetic equilibrium. Logistic regression analysis showed the IL-1A ⫺889 T/T genotype to be significantly
associated with LOAD (odds ratio ⫽ 2.1, confidence interval
⫽ 1.2–3.8, p ⫽ 0.011; Table), but not with EOAD ( p ⫽
0.928). The IL-1A ⫹4845 polymorphisms were completely
concordant with those at IL-1A ⫺889. The IL-1B ⫹3954
T/T genotype was more prevalent in LOAD patients than in
controls (10.7 vs 4.7%; odds ratio ⫽ 2.5, CI ⫽ 1.2– 4.9, p ⫽
0.011). Individuals with dual T/T homozygosity at both
⫺889 and ⫹3954 loci were at greatest risk (odds ratio ⫽ 3.9,
CI ⫽ 1.6 –9.3, p ⫽ 0.002). As described,2 an association of
dual T/T homozygosity at both IL-1A ⫺889 and IL-1B
⫹3954 was obvious at the individual level, with 17 of 25 dual
T/T homozygotes suffering from AD. Neither the IL-1B
⫺511 T/T genotype nor the IL-1RN Intron 2 VNTR genotype was found to be associated with AD (see Table).
We have demonstrated the existence of significant associations relating IL-1 genotypes to LOAD risk in an Australian
cohort, which have also been observed in other ethnic groups
of similar origin. The presence of the IL-1A ⫺889 and
IL-1B ⫹3954 T/T dual homozygous state was associated especially with AD, confirming the results of Griffin and colleagues.2 This line of investigation may be important in personalizing the prophylaxis or therapeutic management of AD
with anti-inflammatory drugs.7
Departments of 1Psychiatry and 2Anatomy and Human
Biology, University of Western Australia, Perth, Australia;
3
School of Biomedical Sciences, Curtin University of
Technology, Bentley, Australia; 4New York University at the
Nathan S. Kline Institute, Orangeburg, NY; 5Sir James
McCusker Alzheimer’s Disease Research Unit, Hollywood
Private Hospital, Perth, Australia; 6Department of Psychiatry
and Behavioural Sciences, Stanford University School of
Medicine, Palo Alto, CA; and 7Centre for Education and
Research on Aging, Concord Repatriation General Hospital,
Concord, New South Wales, Australia
References
1. Grimaldi LME, Casadei VM, Ferri C, et al. Association of earlyonset Alzheimer’s disease with an interleukin-1␣ gene polymorphism. Ann Neurol 2000;47:361–365.
2. Nicoll JAR, Mrak RM, Graham DI, et al. Association of
interleukin-1 gene polymorphisms with Alzheimer’s disease. Ann
Neurol 2000;47:365–368.
3. Du Y, Dodel RC, Eastwood BJ, et al. Association of an interleukin 1 alpha polymorphism with Alzheimer’s disease. Neurology 2000;55:480 – 483.
4. Rebeck GW. Confirmation of the genetic association of
interleukin-1A with early onset sporadic Alzheimer’s disease.
Neurosci Lett 2000;293:75–77.
5. Licastro F, Pedrini S, Ferri C, et al. Gene polymorphism affecting ␣1-antichymotrypsin and interleukin-1 plasma levels increases Alzheimer’s disease risk. Ann Neurol 2000;48:388 –391.
6. Laws SM, Taddei K, Martins G, et al. The ⫺491 AA polymorphism in the APOE gene is associated with increased plasma
ApoE levels in Alzheimer’s disease. NeuroReport 1999;10:
879 – 882.
7. in ‘t Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal
antiinflammatory drugs and the risk of Alzheimer’s disease.
N Engl J Med 2001;345:1515–1521.
DOI: 10.1002/ana.10196
Prion Protein Deposits Match Magnetic
Resonance Imaging Signal Abnormalities in
Creutzfeldt-Jakob Disease
Stéphane Haı̈k, MD,1 Didier Dormont, MD,2
Baptiste A. Faucheux, PhD,1 Claude Marsault, MD,2
and Jean-Jacques Hauw, MD1
Brain magnetic resonance imaging (MRI) recently became a
major tool in the diagnosis of human prion diseases, but the
lesions responsible for MRI signal abnormalities continue to
be debated. High signals on T2-weighted sequences have
been linked to astrogliosis,1 and a high signal in diffusionweighted imaging (DWI) has been explained by spongiform
change.2 We report MRI, DWI features, and neuropathological findings in areas of interest in two cases of CreutzfeldtJakob disease (CJD): a sporadic CJD and a new variant
CJD. Brain imaging pictures were compared with neuropathological data, including semiquantification of gliosis and
spongiform change, and immunohistochemistry of prion
protein (PrP) and glial markers. On fluid-attenuated inversion recovery (FLAIR) sequence, in both cases we observed a
high signal in the putamen, the caudate nucleus, the pulvinar, and the mediodorsal nucleus of the thalamus (Fig).
These areas corresponded to increased signal in DWI. Normal
signal was observed in the pallidum and the white matter.
In regions with increased signal, we also observed a dramatic accumulation of pathological PrP (PrPres) shown by
immunohistochemistry. This was not seen in brain structures
with normal signal (see Fig). In contrast, no clear-cut reinforcement of the immunostaining of glial markers (glial
fibrillary acidic protein, cell differentiation antigen CD68)
was seen at the level of the brain structures. Semiquantitative
data on spongiform change and gliosis in the different brain
areas showed no clear association between an MRI high signal and these pathological features (see Fig). Therefore, we
observed a spectacular congruence of PrP deposit localization
and MRI signal abnormalities. Gliosis, spongiform change,
or both, generally occurring together with PrPres accumulation, could also explain this observation, but several pieces of
evidence suggest that another factor contributes to modifica-
Annals of Neurology
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797
Fig. Magnetic resonance imaging (MRI) of the sporadic Creutzfeldt-Jakob disease (CJD) case: bilateral
and symmetrical high signal in the axial fluidattenuated inversion recovery sequence (central MRI
picture) of the putamen, the pulvinar, and the dorsomedial nucleus of the thalamus. High-signal areas
are seen in the same regions in diffusion-weighted
imaging (DWI) (left MRI) with an unchanged or
decreased apparent diffusion coefficient (ADC) in
the calculated ADC map (right MRI). Neuropathology of the sporadic CJD case (A–I) and of the new
variant CJD case (J–L): frontal sections corresponding to levels 1, 2, and 3 in central MRI. Anatomical limits of regions are demonstrated by a Bodian
silver impregnation coupled to Luxol fast blue (A–
C). Immunostaining of the prion protein (PrP)
shows heavily stained areas that match structures
with abnormal signals in MRI. PrP immunostaining using the monoclonal antibody 12F10 (CEA,
Saclay, France) in sporadic CJD (D–F) and in new
variant CJD (vCJD) (J–L) shows highly stained
structures corresponding to putamen (D, J), pulvinar, and dorsomedial nucleus of the thalamus and
caudate nucleus in both patients (E, F, and K, L).
No correlation is observed between brain structures
with MRI abnormal signals and immunostaining of
glial fibrillary acidic protein (G–I). Scale bar ⫽ 5
mm. Graphs: Spongiform change (empty circles) and
gliosis (full triangles) were evaluated with a semiquantitative five-grade scale (0 – 4) in different
brain regions of the sporadic CJD and vCJD cases.
No clear correlation was found between the severely
affected areas and the high signals seen in MRI.
Pal ⫽ pallidum; iPal ⫽ internal pallidum; ePal ⫽
external pallidum; Pu ⫽ putamen; Cl ⫽ claustrum;
I cor ⫽ insular cortex; Cd ⫽ caudate nucleus; md
N ⫽ dorsomedial nucleus of the thalamus; APul,
MPul, and LPul ⫽ anterior, medial, and lateral
pulvinar nucleus, respectively.
tion of the MRI signal. First, some brain areas in which a
significant gliosis occurred did not correspond to an abnormal signal in MRI. Moreover, areas with a high signal in
FLAIR corresponded to a high signal in DWI, with a decreased apparent diffusion coefficient value. These signal
modifications did probably not correspond to gliosis, which
leads to an increased apparent diffusion coefficient value.3
Second, brain regions in which spongiform change was important, such as the external pallidum in the sporadic case,
did not show any significant MRI abnormalities, whereas areas with only moderate spongiform change, such as the putamen in the same case, did exhibit a very high signal on
FLAIR and DWI. That the immunostaining of an accumulated protein in the central nervous system matches imaging
abnormalities of different brain structures almost perfectly is
remarkable. The reason a strong accumulation of PrPres leads
to abnormal signals in MRI and DWI remains unclear. A
relationship between signal abnormalities and changes in
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metal content linked to PrPres accumulation is unlikely, as
we did not observe any signal modification in the involved
brain structures on T1-weighted sequences. MRI studies of
primary brain amyloidoma suggest that large deposits of
amyloid protein compound produce an abnormal signal on
MRI, with the areas of more dense amyloid deposits having
the brighter signal.4,5 Therefore, our data suggest that the
accumulation of the hydrophobic and amyloid isoform of the
PrP could contribute to modification of the MRI signal and
DWI features in the brain of individuals affected with CJD.
This study was supported in part by the European Union Concerted
Action on Human Transmissible Spongiform Encephopathies
(Biomed 2, contract BMH4-CT98-6003, J.J.H.), the Programme
Hospitalier de Recherche Clinique (grant AOM 96-117, J.J.H.),
Groupement d’Intérêt Scientifique-Infections à Prions, and INSERM/ATC Prions.
We are grateful to the members of the Epidemiological Network for
the Creutzfeldt-Jakob survey in France.
1
Laboratoire de Neuropathologie Raymond Escourolle,
INSERM U360, Association Claude Bernard, and
2
Fédération de Neuroradiologie, Groupe Hospitalier PitiéSalpêtrière, Paris, France
References
1. Urbach H, Klisch J, Wolf HK, et al. MRI in sporadic
Creutzfeldt-Jakob disease: correlation with clinical and neuropathological data. Neuroradiology 1998;40:65–70.
2. Bahn MM, Parchi P. Abnormal diffusion-weighted magnetic resonance images in Creutzfeldt-Jakob disease. Arch Neurol 1999;
56:577–583.
3. Urbach H. Creutzfeldt-Jakob disease: analysis of the MRI signal.
NeuroReport 2000;11(17):L5– 6.
4. Lee J, Krol G, Rosenblum M. Primary amyloidoma of the brain:
CT and MR presentation. AJNR Am J Neuroradiol 1995;16:
712–714.
5. Symko SC, Hattab EM, Steinberg GK, Lane B. Imaging of cerebral and brain stem amyloidomas. AJNR Am J Neuroradiol
2000;22:1353–1356.
DOI 10.1002/ana.10195
Correction
Verbal Memory in Left Temporal Lobe Epilepsy:
Evidence for Task-Related Localization by David L.
Weintrob, MSc, Michael M. Saling, PhD, Samuel F.
Berkovic, MD, FRACP, Salvatore U. Berlangieri,
MBBS, FRACP, and David C. Reutens, MD, FRACP
The above Original Article published in the April
2002 issue of Annals of Neurology, Volume 51, Issue
4, pp. 442– 448. Corrections to the abstract and a
paragraph in the Results section were incorrectly input.
Following please find both reprinted for clarity. The
publisher regrets any inconvenience this error may have
caused.
Abstract: We explored the hypothesis that components of verbal memory are subserved by separate tem-
poral lobe structures in patients with temporal lobe epilepsy. Uptake of 18F-fluorodeoxyglucose (FDG)
measured by positron emission tomography, hippocampal volume, and memory for arbitrarily and semantically related verbal paired associates were examined in 27 patients with left temporary lobe epilepsy.
Scores from memory tests performed outside the scanner were regressed against normalized resting FDG uptake at each voxel. Significant regression was seen in
the left perirhinal cortex (Talaraich coordinates x, y, z:
⫺29, 10, ⫺34; p ⬍ 0.05) for arbitrarily related word
pairs. For semantically related paired associates, significant regression was present in the left inferior temporal gyrus (x, y, z: ⫺48, ⫺18, ⫺24; p ⬍ 0.05). In subsequent analyses, mean FDG uptake within a spherical
region of interest centered on the perirhinal peak predicted performance on both tasks. Mean FDG uptake
in a region of interest centered on the inferior temporal
peak made an additional, independent contribution to
memory for semantically related pairs. Hippocampal
volumes did not explain any additional variance in
memory scores. Our findings indicate heterogeneity in
the left temporal lobe structures mediating verbal
memory function, and support the view that the
perirhinal cortex is an important mnemonic substrate.
Hippocampal Volumetry
The mean volume of the left hippocampus was
2,291mm3 (SD ⫽ 593mm3), while that of the right
hippocampus was 3,296mm3 (SD ⫽ 598mm3). Hippocampal volumes were significantly smaller on the left
(mean difference ⫽ 1005mm3, p ⬍ 0.0005). Neither
left hippocampal volumes (multiple correlation coefficient ⫽ 0.17, p ⫽ 0.39) nor hippocampal asymmetry
values (r ⫽ 0.16, p ⫽ 0.43) predicted performance on
arbitrary word pairs. Similarly, memory for semantically related word pairs was not predicted by left hippocampal volume (r ⫽ 0.15, p ⫽ 0.46) and was not
associated with hippocampal asymmetry values (r ⫽
0.04, p ⫽ 0.85).
Annals of Neurology
Vol 51
No 6
June 2002
799
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associations, polymorphism, interleukin, disease, alzheimers, australia
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