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Disease penetrance in amyotrophic lateral sclerosis associated with mutations in the SOD1 gene.

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LETTERS
Multiple Sclerosis: Should MR Criteria for
Dissemination in Time be Less Stringent
1
References
2
Chris H. Polman, MD, Jerry S. Wolinsky, MD,
and Stephen C. Reingold, PhD3
The International Panel on Diagnosis of Multiple Sclerosis is
pleased to see that many research groups have taken steps to
validate and refine the recommended “McDonald criteria”
for diagnosis of MS.1 Among those, Dalton and colleagues2
have suggested an addition to the Panel’s recommendation
for imaging to determine “dissemination in time” when the
initial presentation is a monosymptomatic, clinically isolated
syndrome consistent with demyelinating disease and a first
image is done within 3 months of presentation. From a retrospective analysis of 56 patients in whom optic neuritis was
the most common presentation, the appearance of a new T2weighted lesion at a 3-month follow-up scan is more sensitive and just as specific for predicting a clinical diagnosis of
multiple sclerosis as a new gadolinium-enhancing lesion (the
recommended criterion.) The authors suggest expanding the
International Panel magnetic resonance imaging criteria to
include T2 lesions at the 3-month follow-up in these patients.
The International Panel originally considered, but rejected, the inclusion of new T2 lesions at a 3-month imaging follow-up. The point of this criterion was to identify
lesions that clearly represent new pathology. T2 lesions, as
Dalton and colleagues note, can arise at any time and thus
do not necessarily represent new disease activity since presentation.
At this moment, the generalizability of these new results is
not clear. The Queen Square MS Research Center is among
the world’s most experienced at comparing scans from different time points, using highly standardized protocols with a
minimum of repositioning error. They have great expertise,
which may not be in place at all centers, at defining what is,
and what is not, a new T2 lesion. Their baseline scans were
performed a median of 5 (range, 1–12) weeks after onset of
visual symptoms. This delay will vary in different practices
and countries and has considerable bearing on whether an
increase in T2 lesion load at 3 months reflects lesions that
developed around the time of initial symptoms or truly occurred separated in time from the clinical finding. This problem may be greater still for initial isolated clinical presentations other than optic neuritis.
Despite the demonstrated sensitivity and specificity of including T2 lesions at a 3-month follow-up scan at Queen
Square, for most diagnosticians gadolinium-enhancing lesions at that point likely still provide the most unequivocal
demonstration of new pathology.
The “McDonald criteria” were intended to be revised as
additional data became available. We are grateful for the
contribution of Dalton and colleagues and look forward to
guidance to ensure that, if incorporated, their suggestion can
enhance multiple sclerosis diagnosis in everyday clinical practice.
1
VU Medical Centre, Amsterdam, The Netherlands;
University of Texas Health Sciences Center, Houston, TX;
and 3National Multiple Sclerosis Society, New York, NY
2
1. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol
2001;50:121–127.
2. Dalton CM, Brex PA, Miszkier KA, et al. New T2 lesions enable
an earlier diagnosis of multiple sclerosis in clinically isolated syndromes. Ann Neurol 2003;53:673– 676.
DOI: 10.1002/ana.10856
More Transgenic Mouse Models of
Dopamine Deficiency
Beat Thöny, PhD,1 and Nenad Blau, PhD1
Recently, Chen and Zhuang1 reviewed genetic mutations
and variations of transgenic mouse models affecting dopamine functions. In their overview, they discussed that transgenic mouse models with genes involved in dopamine synthesis, release, clearance, and receptor signaling present with
variable phenotypes. Furthermore, they stressed that the only
available mouse model for tetrahydrobiopterin (BH4) deficiency is the “hph-1 mouse,” which is not a good model for
dopamine deficiency. It was generated by chemical mutagenesis and is still undefined regarding the genetic alterations.
These mice present with low GTP cyclohydrolase I activity
in the first weeks of life, no significant behavior abnormality,
and with transient neurochemical deficiency.2 Chen and
Zhuang emphasized the necessity for a more defined transgenic mouse for GTP cyclohydrolase I (or BH4 deficiency) as
a model for L-dopa–responsive dystonia and other dopamine
deficiencies.
We and others described independently a knockout mouse
model for neurotransmitter deficiency generated by targeting
the 6-pyruvoyl-tetrahydropterin synthase (Pts) gene.3,4 The
6-pyruvoyl-tetrahydropterin synthase is catalyzing the second
step in the de novo BH4 biosynthesis.5 These mice die perinatally with hyperphenylalaninemia and deficiency of BH4,
dopamine, and serotonin (Table). The Pts mutant mice can
be rescued only if treated with BH4 and the neurotransmitter
precursors L-dopa and 5-hydroxytryptophan. Treated mice
present with severe dwarfism and low levels of insulin-like
growth factor–1 (IGF-1).3 Treatment resulted in normal
blood phenylalanine and almost normal brain serotonin and
BH4 levels, but brain dopamine was still 3% of age-matched
controls. Similar to human patients,5 the Pts knockout
mouse also presented with hypotonia, hypersalivation, and
temperature instability. Obviously, catecholaminergic, serotonergic, and nitric oxide systems are affected differently by
BH4 depletion.4 Despite lethality during the first days of life,
which is not typical for BH4 deficiency due to mutations in
the PTS gene in humans, we think that the complete Pts
knockout mouse is a suitable animal model to study the
pathophysiology of BH4 and monoamine neurotransmitter
deficiencies. Also, it is another transgenic mouse model of
dopamine deficiency.
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
297
Table. Levels of Neurotransmitters and Their Metabolites in Mouse Brain
Genotype
Age (days)
DA (pmol/mg)
HVA (pmol/mg)
5-HT (pmol/mg)
5HIAA (pmol/mg)
Pts⫺/⫺
Wild type
1
35
⬍0.2
13.0–24.7
0.6–1.0
21.7–25.9
0.2–0.4
6.3–6.6
2.9–3.0
66.2–95.0
DA ⫽ dopamine; HVA ⫽ homovanillic acid; 5-HT ⫽ 5-hydroxytryptamin; 5HIAA ⫽ 5-hydroxyindoleacetic acid.
1
Division of Clinical Chemistry and Biochemistry, University
Children’s Hospital, Zurich, Switzerland
References
1. Chen L, Zhuang X. Transgenic mouse models of dopamine deficiency. Ann Neurol 2003;54:S91–S102.
2. Hyland K, Gunasekera RS, Engle T, Arnold LA. Tetrahydrobiopterin and biogenic amine metabolism in the hph-1 mouse.
J Neurochem 1996;67:752–759.
3. Elzaouk L, Leimbacher W, Turri M, et al. Dwarfism and low
IGF-1 due to dopamine depletion in Pts⫺/⫺ mice rescued by
feeding neurotransmitter precursors and H4-biopterin. J Biol
Chem 2003;278:28303–28311.
4. Sumi-Ichinose C, Urano F, Kuroda R, et al. Catecholamines and
serotonin are differently regulated by tetrahydrobiopterin. A
study from 6-pyruvoyltetrahydropterin synthase knockout mice.
J Biol Chem 2001;276:41150 – 41160.
5. Blau N, Thöny B, Cotton RGH, Hyland K. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR,
Beaudet AL, Sly WS, et al., eds. The metabolic and molecular
bases of inherited disease. 8th ed. New York: McGraw-Hill,
2001:1725–1776.
DOI: 10.1002/ana.10847
Disease Penetrance in Amyotrophic Lateral
Sclerosis Associated with Mutations in the
SOD1 Gene
Peter M. Andersen, MD, DMSc,1
Gabriella Restagno, PhD,2 Heather G. Stewart, PhD,1,3
and Adriano Chiò, MD, PhD4
We welcome the publication by Mayeux and colleagues reporting a novel mutation N19S in the SOD1 gene in an
apparently sporadic case of ALS (SALS).1 We have recently
published a clinical study of 16 novel American SOD1 mutations,2 bringing the total number of SOD1 mutations
worldwide to 109. Five modes of inheritance were identified
in ALS associated with SOD1 mutations: (1) dominant inheritance with complete penetrance, (2) dominant inheritance with reduced penetrance, (3) recessive inheritance, (4)
recessive inheritance with compound heterozygosity, and (5)
de novo mutation.
The first group is easily identified clinically and the patient will be given the diagnosis of familial ALS (FALS) and
will be among the 5 to 10% of ALS having genetically determined ALS as listed in the textbooks. However, the other
four groups may be given diagnoses of apparent SALS. Epidemiological studies have shown 14 to 23% of recognized
FALS and 4 to 7% of apparent SALS cases to carry a SOD1
mutation. Of the 109 SOD1 mutations, 17 (V14G, G16S,
N19S, E21K, N65S, D76Y, H80R, N86S, D90A, A95T,
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February 2004
D101N, I113T, V118L, V118KTGPX, E133⌬E, V97L,
L144F) have been reported in SALS.
This is best documented for the D90A, the most frequent
SOD1 mutation worldwide. The D90A can be inherited
both as a recessive trait with slowly progressing ALS with an
uniform phenotype or as a dominantl trait with greatly reduced penetrance and variable phenotype and survival time.
In Finland (population 5.1 million) alone, there are an estimated 99,000 unaffected carriers of the D90A SOD1 allele.
A recent global haplotype study has shown that all reported
ALS cases with the D90A had a single common founder approximately 18,000 years ago.3 The third most common
SOD1 mutation is the I113T, which has been found both in
families with complete penetrance as well as in apparently
SALS cases in the United States. A haplotype study of Scottish SALS and recognized FALS cases with I113T showed
them all to have a common ancestor.4 It is our experience
that in ALS-SOD1 families with diminished penetrance the
unaffected transmitting individual is often an elderly woman
with affected sons. This is being further studied in ongoing
epidemiological studies in Canada and Scandinavia.
We have found an apparent SALS case with N19S: a 77year-old childless Italian woman developed sudden paresis in
the hands with fast dissemination to the rest of the body.
The patient died 15 months after onset. Her father had died
at age 85 years of a heart disease, her mother at age 78 years
of cancer, and a sibling at age 65 years of cancer. The sister
had three children 60, 55, and 52 years old without ALS and
none of them carried the mutation. The N19S were not
found among 120 unrelated Italian controls.
The collective results suggest the existence of a trigger factor in ALS associated with SOD1 gene mutations. Elucidating this factor would have immense importance, in particular, to the unaffected carriers of SOD1 gene mutations. It
would be interesting to learn what genetic counseling the
authors1 have provided to the seven asymptomatic N19S carriers of their index N19S case.
In this context, it should be recognized that in 1848 F. A.
Aran depicted the existence of familial motor neuron disease
with reduced disease penetrance.5
1
Department of Clinical Neuroscience, Umeå University,
Umeå, Sweden; 2Laboratory of Molecular Genetics, OIRMSant’Anna, Turin, Italy; 3The Neuromuscular Diseases Unit,
Vancouver Hospital, Vancouver, British Columbia, Canada;
and 4Department of Neuroscience, University of Turin, Italy
References
1. Mayeux V, Corcia P, Besson G, et al. N19S, a new SOD1 mutation in sporadic ALS: no evidence for disease causation. Ann
Neurol 2003;53:815– 818.
2. Andersen PM, Sims KB, Xin WW, et al. Sixteen novel mutations in the gene encoding CuZn-superoxide dismutase in ALS.
Amyotroph Lateral Scler Other Motor Neuron Disord 2003;2:
62–73.
3. Parton MJ, Broom W, Andersen PM, et al. D90A-SOD1 mediated amyotrophic lateral l sclerosis: a single founder for all cases
with evidence for a Cis-acting disease modifer in the recessive
haplotype. Hum Mutat 2002;20:473.
4. Hayward C, Swingler RJ, Simpson SA, Brock DJ. A specific superoxide dismutase mutation is on the same genetic background
in sporadic and familial cases of amyotrophic lateral sclerosis.
Am J Hum Genet 1996;59:1165–1167.
5. Aran FA. Researches sur une maladie non encore décrite du
système musculaire (atrophie musculaire progressive). Arch Gén
Méd 1850;24:172–214.
DOI: 10.1002/ana.10850
Reply
Philippe Corcia, MD, PhD,1
Helene-F. Jafari-Schluep, MD,2
and William Camu, MD, PhD2
We read with great interest the letter from Dr Andersen and
colleagues.1 The authors indeed underline several points that
are key issues of our article.
First, from a scientific and genetic point of view, how do
we consider apparently sporadic amyotropic lateral sclerosis
cases (ASAC) associated with SOD1 mutations? We are
aware that the example of N19S is only one example among
a large series of SOD1 mutations found in ASAC. Are these
cases potentially hereditarily transmissible or not? How do
we go forward?
It appears that Andersen and colleagues agree that SOD1
mutations in ASAC do, in fact, play a role in disease onset.
At the same time, they also write “the collective results suggest the existence of a trigger factor in ALS associated with
SOD1 gene mutations.” We completely agree with the latter
sentence, but it is difficult to agree with the former. Which
role are we potentially prepared to accept for this so-called
“trigger factor”? In a family with very low penetrance, in
which SOD1 mutations poorly segregate with ALS, it is
most likely that the trigger factor will closer segregate with
the disease than SOD1 mutations would. Subsequently, the
SOD1 mutations in this context could go from being “a trigger factor” to “a causal factor.” The D90A experience seems
to be fairly demonstrative about this last point. Andersen has
well demonstrated since 1995 that D90A, in Scandinavian
pedigrees, is the cause for recessive ALS.1,2 A common
founder effect was found to exist almost 1,000 years ago for
recessive cases but not for heterozygous D90A (het-D90A)
ALS cases.3 A more complete work suggested the existence of
a common ancestor for every D90A (het- and homozygotes)
cases almost 18,000 years ago, but this last result does not
prove per se that het-D90A is responsible for autosomal
dominant ALS.4 The problem with het-D90A is that we lack
scientific proof for ascertaining that D90A has another role
than that of a recessive mutation. One D90A allele alone is
likely to play a role only of susceptibility factor, just like
N19S in our population.
Second, Andersen and colleagues ask what genetic counseling has been provided to the family members with N19S.
We believe the answer lies in the title of Dr Andersen’s letter. One can consider that N19S is either responsible for
ALS with very low penetrance or only plays a secondary role
regarding disease onset, and at least plays a role of susceptibility factor. In both cases, the risk of developing ALS for
other family members carrying N19S is weak but cannot be
determined precisely. This was the information given to this
family, because we still have no means to determine this risk,
whether N19S is a susceptibility factor or a causal factor.
Is the putative trigger factor also a susceptibility factor?
Where is the exact frontier between being a susceptibility factor and a causal factor? What should we do then with SOD1
mutations in ASAC? Andersen and colleagues gave a very
interesting perspective about this major question. We are
confident that their epidemiological and genetic studies in
Canada and Scandinavia will give important clues, and we
will be very keen to read their results. We have very recently
identified a new family in France with het-D90A that seems
to have a dominant inheritance. Family collection is under
way to analyze the segregation of the D90A allele with ALS.
It will be very useful to continue to compare and to pool
data about those cases worldwide as it originally was done in
the first international collaborative work with D90A.3
1
Department of Neurology, University Hospital of Tours,
Tours; and 2ALS Center of Montpellier, Department of
Clinical Neurophysiology, University Hospital of Montpellier,
Montpellier, France
References
1. Andersen PM, Nilsson P, Ala-Hurula V, et al. Amyotrophic lateral sclerosis associated with homozygozity for an Asp90Ala mutation in Cu-Zn-superoxide dismutase. Nat Genet 1995;10:
61– 66.
2. Andersen PM, Forsgren L, Binzer M, et al. Autosomal recessive
adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala Cu-Zn-superoxide dismutase mutation. A
clinical and genealogical study of 36 patients. Brain 1995;119:
1153–1172.
3. Al-Chalabi A, Andersen PM, Chioza B, et al. Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation
share a common founder: evidence for a linked protective factor.
Hum Mol Genet 1998;7:2045–2050.
4. Parton MJ, Broom W, Andersen PM, et al. D90A-SOD1 mediated amyotrophic lateral sclerosis: a single founder for all cases
with evidence for a Cis-acting disease modifier in the recessive
haplotype. Hum Mutat 2002;20:473.
DOI: 10.1002/ana.10851
Herpes Simplex Virus Type 1 and
Alzheimer’s Disease
Ruth F. Itzhaki, PhD, Curtis B. Dobson, PhD,
and Matthew A. Wozniak, PhD
Hemling and colleagues1 conclude that there is no association between herpes simplex virus type 1 (HSV1) in the
brain and the type 4 allele of the apolipoprotein E gene
(APOE-ε4) in Alzheimer’s disease (AD) patients based on a
sample size of one. Their detection of HSV1 DNA in the
brain of only a single patient out of 34 contrasts greatly with
four previous publications (reviewed in Dobson and col-
Annals of Neurology
Vol 55
No 2
February 2004
299
leagues2), following the study from this laboratory, all of
which found HSV1 DNA in brain of many people, values
ranging from 30 to 75% for AD patients and 22 to 72% in
controls, comparable to our values of 64 and 73%, respectively. (Our finding that only very few brains of younger
people contain HSV1 DNA would account for some of the
lower values above, obtained in studies that did not take account of age (see Dobson and colleagues2); the others were
for Japanese patients, probably reflecting the lower HSV1 infection level in that population.) Our polymerase chain reaction (PCR) values are substantiated by our recent detection
of intrathecal antibodies in a high proportion of AD patients
and elderly normal subjects (not attributable to leakage from
serum across the blood–cerebrospinal fluid barrier) (M.A.
Wozniak M. Combrinck, G.K. Wilcock, R.F. Itzhaki, unpublished data).
Because of the proneness of PCR to artefacts, it is essential
to make relevant checks; the apparent absence of such checks
by Hemling and colleagues,1 for example, seeking a host
gene or conducting recovery experiments (again in contrast
with previous studies), suggests that their very low proportion reflects negative interference by contaminants. Furthermore, their assessment of sensitivity is based on pfu of
HSV1; because HSV1 suspensions probably contain noninfectious, but still amplifiable, virions, their value was doubtless an overestimate of sensitivity. Also, whether they used
the same kit for preparation of brain DNA and positive control DNA is not stated.
Deatly and colleagues,3 who are cited for further evidence
against latent HSV1 infection of brain, used the far less sensitive method of in situ hybridization, and simple calculation
shows that viral transcripts would have been detected only if
present at one copy or more per cell. Also, LAT RNA has
been detected in brains of elderly people. A correlation between HSV1 DNA in brain and carriage of an APOE-ε4
allele in AD was shown by Itabashi and colleagues5 and in
our laboratory; furthermore in the cited study by Beffert and
colleagues6 (see also Corcler and colleagues7) although
HSV1–APOE-ε4 association in AD did not reach statistical
significance, it showed a definite trend. Finally, the concept
that HSV1 in brain and APOE-ε4 together confer a major
risk of AD is strongly even if indirectly supported by the
discovery that in several diverse diseases of known infectious
cause, namely, herpes labialis, Herpes simplex encephalitis
(HSE), Hepatitis C virus (HCV)-induced damage in liver,
HIV damage in central nervous system and peripheral nervous system in pre–acquired immune deficiency syndrome,
patients the severity of the symptoms (and in the case of the
malaria protozoon, susceptibility to infection) are determined
by APOE genotype (reviewed in Dobson and colleagues2).
Molecular Neurobiology Laboratory, Department of Optometry
and Neuroscience, University of Manchester Institute of
Science and Technology, Manchester, United Kingdom
References
1. Hemling N, Röyttä M, Rinne J, et al. Herpesviruses in brains in
Alzheimer’s and Parkinson’s diseases. Ann Neurol 2003;54:
267–271.
2. Dobson CB, Wozniak MA, Itzhaki RF. Do infectious agents
play a role in dementia? Trends Microbiol 2003;11:312–317.
300
Annals of Neurology
Vol 55
No 2
February 2004
3. Deatly AM, Haase AT, Fewster PH, et al. Human herpes virus
infections and Alzheimer’s disease. Neuropathol Appl Neurobiol
1990;16:213–223.
4. Itzhaki RF, Maitland NJ, Wilcock GK, Yates CM, Jamieson GA.
Detection by polymerase chain reaction of herpes simplex virus
type 1 (HSV1) DNA in brain of aged normals and Alzheimer’s
disease patients. In: B Corain, K Iqbal, M Nicolini, B Winblad,
H Wisniewski and P Zatta, eds. Alzheimer’s Disease: Advances
in Clinical and Basic Research. John Wiley and Sons Ltd. 1993:
97–102.
5. Itabashi S, Arai H, Matsui T, et al. Herpes simplex virus and risk
of Alzheimer’s disease. Lancet 1997;349:1102.
6. Beffert U, Bertrand P, Champagne D, et al. HSV-1 in brain and
risk of Alzheimer’s disease. Lancet 1998;351:1330 –1331.
7. Corder E, LannFelt L, Mulder M. Apolipoprotein E and herpes
simplex virus in Alzheimer’s disease. Lancet 1998;352:
1312–1313.
DOI: 10.1002/ana.10852
Reply
Niina Hemling, BM, BSc,1,2 Matias Röyttä, MD, PhD,3
Juha Rinne, MD, PhD,4,5 Paju Pöllänen, MD,1,2
Eeva Broberg, MSc,1,2 Virpi Tapio, BSc,1,3
Tero Vahlberg, MSc,6 and Veijo Hukkanen, MD, PhD1,2
We thank Drs Itzhaki, Dobson, and Wozniak for interest in
our study. The polymerase chain reaction (PCR) controls,
which they assumed to be absent, had been included in our
study, but could not be reported in our article, due to the
limits of a Brief Communication.
In our report,1 the sample size was 34 cases of Alzheimer’s
Disease (AD) and 40 cases of Parkinson’s disease (PD) as
well as 40 controls. By careful statistical analysis, we found
no evidence for association of brain HSV-1 DNA together
with ApoE-ε4 allele in AD or PD (multivariate analysis).
The fact that we found HSV-1 DNA in 17.5% of PD patients and in 25% of controls proves that our PCR analysis
does not lack the sensitivity in study of the brain sample
material. At the initial phases of our PCR project, we tested
approximately 80 consecutive brain samples of our material,
including 36 AD samples representing the different brain areas, also for the housekeeping gene GAPDH, which yielded
in every case a clear-cut positive result, suggesting that our
sample preparation removed the inhibitory factors. We also
conducted spike-back experiments in which a low amount of
HSV-1 DNA was added to HSV-negative brain sample material and then purified and subjected to PCR analysis. The
DNA purification method was selected among several tested
methods based on the spike-back experiments. The DNA
concentration of the specimens was determined with a kit
(DNA Dipstick; Invitrogen, La Jolla, CA) to equalize the
DNA amount tested. Our laboratory is also a qualified clinical virology laboratory, testing cerebrospinal fluid samples
for herpesviral DNA for diagnostics of viral meningitis and
encephalitis, using advanced PCR technologies2,3 under regular international quality control. Thus, we are particularly
aware of the precautions in PCR testing, such as PCR inhibition and avoidance of contamination. One aspect to be
considered in clinical virology is the need to prevent contamination from positive PCR products and from positive specimens and controls. In this respect, our laboratory is very
careful, and because we regularly conduct a large number of
tests for HSV-1 DNA, we see that the use of a secondary
PCR test for HSV-1 DNA is warranted. In our laboratory, it
is done by testing first for HSV-1 gD sequences and then for
gB sequences for confirmation of a positive result. The sensitivities of the tests have been determined on a copy number
basis and also mentioned in the article (10 –50 DNA copies
of HSV-1).1
The pioneer work and reports by Itzhaki and colleagues,
on the association of HSV-1 with ApoE-ε4 allele and AD,
foster necessary and interesting discussion on the roles of
herpesviruses in chronic diseases of the central nervous system. We appreciate and look forward to learning the intrathecal HSV antibody results mentioned in their letter. The
issue of sensitivity of LAT RNA in situ hybridizations,
brought up in the letter, is relevant. We also have long-term
experience in developing HSV-1 LAT in situ hybridization
methods,4 and we do agree with Itzhaki and colleagues regarding the question of sensitivity. Our study1 could not
confirm the association of HSV-1 with AD in the Finnish
population, although the observed association of AD with
the APOE-ε4 allele was evident. As Itzhaki and colleagues do
state, there may be differences in different populations.
1
Department of Virology, 2MediCity Research Laboratory,
Department of Pathology, 4Department of Neurology, 5Turku
PET Centre, and the 6Department of Biostatistics, University
of Turku, Turku, Finland
3
References
1. Hemling N, Röyttä M, Rinne J, et al. Herpesviruses in brains in
Alzheimer’s and Parkinson’s diseases. Ann Neurol 2003;54:
267–271.
2. Hukkanen V, Rehn T, Kajander R, et al. Time-resolved
fluorometry PCR assay for rapid detection of herpes simplex
virus in cerebrospinal fluid. J Clin Microbiol 2000;38:
3214 –3218.
3. Hukkanen V, Vuorinen T. Herpesviruses and enteroviruses in
infections of the central nervous system: a study using timeresolved fluorometry PCR. J Clin Virol 2002;25:S87–S94.
4. Hukkanen V, Heino P, Sears A, Roizman B. Detection of Herpes simplex virus latency-associated RNA in mouse trigeminal
ganglia by in situ hybridization using nonradioactive
digoxigenin-labeled DNA and RNA probes. Methods Mol Cell
Biol 1990;2:70 – 81.
DOI: 10.1002/ana.10855
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