close

Вход

Забыли?

вход по аккаунту

?

Chemokines in serum and cerebrospinal fluid of Alzheimer's disease patients.

код для вставкиСкачать
LETTERS
Coffee Drinking, Cigarette Smoking, and
Parkinson’s Disease
William H. James
Hernán and colleagues1 used meta-analytic methods to show
that there is strong epidemiological evidence that smokers
and coffee drinkers have a lower risk of Parkinson’s disease
(PD) than controls. Marder and Logroscino2 commented on
this study, writing “Reverse causation (individuals prone to
the development of PD are either less likely to initiate the
behavior or more likely to quit) is hard to prove. Individuals
who are destined to develop PD might have a genetic predisposition or a metabolic factor associated with reduced
novelty seeking.” I suggest that this is correct and that the
factor is estrogen (as well, possibly, as testosterone). Zuckermann3 noted that people who score highly on psychological
scales of sensation seeking (which is associated positively with
both smoking and coffee drinking) have higher levels of the
gonadal hormones estrogen and testosterone than controls.
Thus, gonadal hormones may be expected to act as confounders between sensation-seeking behaviors (treated as risk
factors) and disease conditions that are caused by low (or
high) levels of these hormones. And there can be little doubt
that estrogens provide neuroprotection of central nervous
system cells implicated in PD.4 I have given additional reasons to support the hypothesis that estrogen acts as a confounder between sensation-seeking behavior and PD.5 It is
not clear whether this form of confounding is the sole cause
of the associations between PD and various behaviors, but it
is highly likely that it is a cause.
The Galton Laboratory, University College London, London,
United Kingdom
References
1. Hernán MA, Takkouche B, Caamaño-Isorna F, et al. A metaanalysis of coffee drinking, cigarette smoking, and the risk of
Parkinson’s disease. Ann Neurol 2002;52:276 –284.
2. Marder K, Logroscino G. The ever stimulating association of
smoking and coffee and Parkinson’s disease. Ann Neurol 2002;
52:261–262.
3. Zuckermann M. Behavioral expressions and biosocial bases of
sensation seeking. Cambridge, UK: Cambridge University Press,
1994.
4. Cyr M, Calon F, Morissette M, et al. Drugs with estrogen-like
potency and brain activity: potential therapeutic application for
the central nervous system. Curr Pharm Des 2000;6:1287–1312.
5. James WH. The curious negative (protective?) associations between Parkinson’s disease and certain behavioral risk factors.
Neuroepidemiology 2002;21:305–306.
DOI: 10.1002/ana.10510
Reply
Miguel A. Hernán, MD, DrPH,1
Bahi Takkouche, MD, PhD,2
Francisco Caamaño-Isorna, PharmD,2
and Juan-Jesús Gestal-Otero, MD, PhD2
According to James’ hypothesis, higher levels of estrogens,
and, possibly, testosterone, partially explain the lower risk of
Parkinson’s disease (PD) among smokers and coffee drinkers
546
© 2003 Wiley-Liss, Inc.
compared with those who do not smoke or drink coffee. A
potentially protective effect of estrogens is supported by the
lower risk of PD in women compared with men,1 and by in
vitro studies and animal experiments. James’ hypothesis
would be strengthened if prospective studies found that
young individuals with high levels of estrogens have a higher
risk of becoming smokers and coffee drinkers than those
with low estrogen levels. A recent study suggests that caffeine
reduces the risk of PD among women who do not use postmenopausal hormones but increases the risk among hormone
users.2 Thus, another plausible hypothesis is that estrogens
may modify the effect of cigarette smoke and caffeine.
1
Department of Epidemiology, Harvard School of Public
Health, Boston, MA; and 2Department of Preventive
Medicine, Faculty of Medicine, University of Santiago de
Compostela, Santiago de Compostela, Spain
References
1. Hernán MA, Zhang SM, Rueda-deCastro AM, et al. Cigarette
smoking and the incidence of Parkinson’s disease in two prospective studies. Ann Neurol 2001;50:780 –786.
2. Ascherio A, Chen H, Schwarzschild MA, et al. Caffeine, postmenopausal estrogen, and risk of Parkinson’s disease. Neurology
(in press).
DOI: 10.1002/ana.10511
Quinacrine-Induced Cytolytic Hepatitis in
Sporadic Creutzfeldt–Jakob Disease
Jean-Yves Scoazec, MD, PhD,1
Pierre Krolak-Salmon, MD,2 Olivier Casez, MD,3
Gérard Besson, MD, PhD,3 Stéphane Thobois, MD,4
Nicolas Kopp, MD, PhD,2 Armand Perret-Liaudet, MD,2
and Nathalie Streichenberger, MD2
Quinacrine has been proposed as a treatment for patients
with Creutzfeldt–Jakob disease (CJD).1,2 Whereas quinacrine
hematological and liver toxicity have been reported, its incidence remains to be evaluated in patients with CJD.
Three patients with World Health Organization criteria of
probable CJD were given quinacrine according to the procedure recommended by the French National Surveillance Network of Prion Diseases: 1,000mg the first day, then 300mg
each day. Alterations in liver function tests were detected 25,
7, and 42 days, respectively, after initiation of quinacrine
treatment. Relative to pretreatment values, increase of the serum level of alanine aminotransferase (3–30-fold), aspartate
aminotransferase (2–11-fold), ␥GT (2– 4-fold), and alkaline
phosphatase (2– 8-fold) was observed. Quinacrine was discontinued after 25, 7, and 80 days, respectively, as no significant clinical improvement was noted. Liver function tests
progressively returned to normal values 21 and 30 days after
quinacrine discontinuation in two patients (Fig). The patients died 3, 22, and 45 days, respectively, after quinacrine
discontinuation from respiratory failure, and not from hepatocellular insufficiency. One patient developed progressive
bone marrow aplasia several days after quinacrine discontinuation, which was confirmed by bone marrow postmortem
examination. In all cases, diagnosis of CJD was confirmed by
postmortem histological brain examination and detection of
cause of hepatitis, (4) association with severe hematological
toxicity in one patient, and (5) combination of hepatocellular and biliary alterations suggestive of drug-induced liver
disease.4
Liver toxicity of quinacrine in CJD treatment may be related to the comparatively high dose recommended for CJD.
Whereas quinacrine clinical effect in transmissible spongiform encephalopathy diseases is still under assessment,5 the
evaluation of the respective risks and benefits appears to be
crucial.
We thank Dr B. Chesebro for his critical review and valuable suggestions and E. Gros for his technical help.
1
Service d‘Anatomie Pathologique, Hôpital Edouard Herriot;
Centre de Diagnostic, de Traitement et de Prévention des
Maladies à Prions; Services de Neuropathologie et de
Biochimie, Hôpital Neurologique et Neurochirurgical, Lyon;
and 3Service de Neurologie, CHU de Grenoble, Grenoble;
and 4Service de Neurologie D Hôpital Neurologique et
Neurochirurgical, Lyon, France
2
References
1. Doh-Ura K, Iwaki T, Caughey B. Lysosomotropic agents and
cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation. J Virol 2000;74:4894 – 4897.
2. Korth C, May BC, Cohen FE, et al. Acridine and phenothiazine
derivatives as pharmacotherapeutics for prion disease. Proc Natl
Acad Sci USA 2001;98:9836 –9841.
3. Danan G. Causality assessment of drug-induced liver injury.
Hepatology Working Group. J Hepatol 1988;7:132–136.
4. Zimmerman HJ. Drug-induced liver disease. Clin Liver Dis
2000;4:73–96.
5. Collins SJ, Lewis V, Brazier M, et al. Quinacrine does not prolong survival in a murine Creutzfeldt-Jakob disease model. Ann
Neurol 2002;52:503–506.
DOI: 10.1002/ana.10530
Fig. Time course of plasma alanine aminotransferase level
(IU/L) after initiation (J0) and discontinuation of quinacrine
treatment, in the three patients (1, 2, 3). Aspartate aminotransferase, ␥GT, and alkaline phosphatase levels followed a
similar kinetic pattern. ALAT ⫽ alanine aminotransferase.
pathological prion protein. Histological examination of liver
samples showed mild to moderate portal inflammatory infiltrates containing lymphocytes, plasma cells, and eosinophils.
Mild cytolysis was present in the hepatic lobules. Lesions of
cholangitis were observed, characterized by marked duct wall
fibrosis mimicking primary sclerosing cholangitis, and neoductular proliferation. In five CJD controls with no quinacrine, neither alteration of liver function tests nor significant
liver lesions at autopsy.
The role of quinacrine in the induction of cytolytic hepatitis in these three cases is strongly supported by the following arguments3,4: (1) chronological relationship between
quinacrine administration and alterations in liver function
tests, (2) return of liver enzymes to normal serum values after
discontinuation of the drug, (3) absence of other detectable
Chemokines in Serum and Cerebrospinal Fluid of
Alzheimer’s Disease Patients
Daniela Galimberti, PhD,1 Niki Schoonenboom, MD,2,3
Elio Scarpini, MD,1 Philip Scheltens, MD,2,3
on behalf of the Dutch-Italian Alzheimer Research Group
Immunoreactivity for some chemokines has been demonstrated in resident cells of the central nervous system, and
upregulation of some of them is associated with the pathological changes found in Alzheimer’s disease (AD).1 Gene array technology confirmed that 104 genes were either upregulated or downregulated in A␤-stimulated microglia, in which
interleukin (IL)– 8 and MCP-1 were among the highest induced.2 We evaluated the levels of interferon-␥–inducible
protein-10 (IP-10), monocyte chemotactic protein–1 (MCP1), and IL-8 in cerebrospinal fluid (CSF) and serum samples
of patients with probable AD3 compared with age-matched
healthy controls.
In 9 of 21 AD patients, IP-10 levels in CSF were increased, compared with controls. MCP-1 and IL-8 levels
were increased in CSF from almost all AD patients. No differences were found in mean chemokine serum levels be-
Annals of Neurology
Vol 53
No 4
April 2003
547
IP-10. In the promoter region of IP-10 coding gene, there
are critical regulatory sequences responding to IFN-␥ and
TNF-␣–activated factors, which lead to the transcriptional
activation of the gene.4 The positive correlation between
IP-10 and MMSE scores suggests that IP-10 increase is
linked to an early stage of the disease, when inflammatory
events are probably more pronounced. Microglial cells demonstrated an increased migratory response to MCP-1.5 However, despite its chemotactic effect, MCP-1 alone does not
cause inflammatory activation of cells but leads to an enhanced inflammatory response upon treatment with other
stimuli.6 MCP-1 may exert a role in the recruitment of
phagocytic cells within the brain during the course of AD,
although activation of these cells may depend by the presence of other molecules, such as IP-10.
The increase of IL-8 in AD suggests a possible involvement in compensative and reparative mechanisms, through
its capability to promote neuronal survival.7 Thus, the inverse correlation shown between IL-8 levels and MMSE
scores may be considered as an attempt to limit neuronal
damage in subjects who already have progressed markedly.
The study of chemokine profile in AD may lead to a better
understanding of its pathological mechanisms and serve as a
very useful marker for the early diagnosis, for monitoring
disease progression and therapeutic efficacy. However, to
confirm these preliminary data, analysis of a larger group of
patients is needed in different stages of the diseases and preferably in a longitudinal fashion.
1
Fig. Scattergrams of chemokine levels in cerebrospinal fluid
(CSF) of Alzheimer’s disease (AD) patients compared with
controls (con). (A) ␣ chemokines. (B) ␤ chemokines. The
black line in each column indicates the mean value. CSF cell
number and albumin were measured. To evaluate the integrity of the brain blood barrier and the intrathecal IgG production, we calculated the albumin quotient and the IgG index. IP-10, MCP-1, and IL-8 levels were measured with
human specific enzyme-linked immunosorbent assay kits, based
on the quantitative sandwich enzyme immunoassay technique.
The sensitivity of these assays was 15.6, 10, and 5pg/ml, respectively. Nonparametric Mann–Whitney U test was used for
the comparison of the mean data between AD patients and
controls. Statistical significance was set at p ⬍ 0.05. IP-10:
p ⬎ 0.05; MCP-1: p ⬍ 0.005; IL-8: p ⬍ 0.001.
tween the groups. CSF concentrations of chemokines did not
significantly correlate with Mini-Mental State Examination
(MMSE) scores, disease duration, age, ApoE genotype, or
CSF cell number or proteins, with the exception of a positive
correlation between IP-10 levels and MMSE scores (␳ ⫽
0.37; p ⫽ 0.158) and a negative correlation between IL-8
levels and MMSE scores (␳ ⫽ ⫺0.48; p ⫽ 0.06).
At time of sampling, none of the patients received any
nonsteroidal antiinflammatory medication, and three patients
were treated with donepezil, one with galantamine and one
with rivastigmine. Various treatments were not linked to a
specific chemokine profile.
Amyloid-activated microglia produces proinflammatory
cytokines, which may be responsible for the accumulation of
548
Annals of Neurology
Vol 53
No 4
April 2003
Department of Neurological Sciences, “Dino Ferrari” Center,
University of Milan, IRCCS Ospedale Maggiore Policlinico,
Milan, Italy; and 2Department of Neurology and Alzheimer
Center, and 3Department of Clinical Chemistry, VU
University Medical Center, Amsterdam, The Netherlands
References
1. Xia MQ, Hyman BT. Chemokines/chemokine receptors in the
central nervous system and Alzheimer’s disease. J Neurovirol
1999;5:32– 41.
2. Walker DG, Lue LF, Beach TG. Gene expression profiling of
amyloid beta peptide-stimulated human post-mortem brain microglia. Neurobiol Aging 2001;22:957–966.
3. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis
of Alzheimer’s disease: report of the NINCDS-ADRDA Work
Group under the auspices of Department of Health and Human
Services Task Force on Alzheimer’s Disease. Neurology 1984;34:
939 –944.
4. Ohmori Y, Hamilton TA. The interferon-stimulated response element and a kappa B site mediate synergistic induction of murine IP-10 gene transcription by IFN-gamma and TNF-alpha.
J Immunol 1995;154:5235–5244.
5. Peterson PK, Hu S, Salak-Johnson J, et al. Differential production of and migratory response to beta chemokines by human
microglia and astrocytes. J Infect Dis 1997;175:478 – 481.
6. Gunn MD, Nelken NA, Liao X, Williams LT. Monocyte chemoattractant protein-1 is sufficient for the chemotaxis of monocytes in transgenic mice but requires an additional stimulus for
inflammatory activation. J Immunol 1997;158:376 –383.
7. Araujo DM, Cotman CW. Trophic effects of interleukin-4, -7
and -8 on hippocampal neuronal cultures: potential involvement
of glial-derived factors. Brain Res 1993;600:49 –55.
DOI: 10.1002/ana.10531
Документ
Категория
Без категории
Просмотров
2
Размер файла
69 Кб
Теги
chemokine, patients, serum, disease, alzheimers, fluid, cerebrospinal
1/--страниц
Пожаловаться на содержимое документа