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Erratum Low cerebral blood flow velocity and risk of white matter hyperintensities (letter).

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LETTERS
Increased Hair Polyamine Levels in Patients with
Alzheimer’s Disease
Man Ho Choi, MSc,1,2 Kyoung-Rae Kim, PhD,2
In Seong Kim, MD,3 Dong Seok Lho, PhD,1 and
Bong Chul Chung, PhD1
Recently, the neurotoxic amyloid ␤-peptide was shown to
up-regulate polyamine metabolism by increasing ornithine
decarboxylase (ODC) activity and polyamine uptake by initiating free radical damage in Alzheimer’s disease (AD).1 Because of these findings, polyamines have been considered to
play an important role in response to neurodegenerative conditions, including AD.2 According to recent reports, hair fibers may be used to obtain physiologic information.3,4 Hair
specimens, unlike biological fluids, are easy to collect and
require less hygienic handling methods. In this study, we investigated whether hair polyamine concentrations are altered
in AD patients.
We obtained hair fibers from 34 female patients treated at
Baekje Geriatric Hospital from September, 1999, to March,
2000. This group of patients included 1) 16 individuals
(56 – 80 years old, with an average age of 66.8 ⫾ 7.0 years;
mean ⫾ SD) who had been with clinically diagnosed as having dementia of the Alzheimer type (DAT) with histopathologically confirmed AD and 2) 18 healthy females (51–76
years old, with an average age of 64.7 ⫾ 6.8 years) who
underwent the assay for DAT and other neurodegenerative
symptoms. None of the subjects had been treated with chemotherapy before the hair sampling; all of the subjects were
ambulatory, and all of the subjects had similar nutritional
conditions. The hair samples were obtained by collecting the
portions that had been cut off during haircuts.
Hair polyamine levels, measured as described elsewhere,5
were about 3.6 –13.8 times higher for the AD patients compared to the 18 individuals in the control group. Compared
to the healthy subjects (48.03 ng/g, 19.09 –73.59 ng/g;
mean, range), the putrescine levels were significantly higher
in the AD patients (173.01 ng/g, 30.20 – 415.01 ng/g; p ⬍
0.002). The differences in the levels of spermidine between
the AD patients (1,082.71 ng/g, 248.39 –2,532.56 ng/g) and
healthy subjects (233.77 ng/g, 98.85– 476.77 ng/g) were also
significant ( p ⬍ 0.001). In addition, the levels of hair spermine were markedly increased in the AD patients (1,973.22
ng/g, 254.88 –5,941.46 ng/g; p ⬍ 0.001) compared to the
healthy subjects (143.14 ng/g, 57.36 –259.01 ng/g).
The magnitude of increase was similar to that reported
previously for hair polyamines in cancer patients.4 However,
the spermidine to spermine (Spd/Spm) ratios from AD patients were decreased below 1.0 (0.66 ⫾ 0.33; p ⬍ 0.001) in
all but 1 of the patients compared to those for most of the
healthy subjects (1.86 ⫾ 0.95) and cancer patients (1.42 ⫾
0.77) examined (Fig). We suspect that ODC expression is
associated with cell proliferation in hair follicles, where the
up-regulation of the biosynthesis and the metabolism of
polyamines might occur in the AD condition.
This finding suggests that the decrease in the Spd/Spm
ratio below 1.0, combined with the higher levels of spermine
and spermidine, might serve as a potential marker for AD.
This study may be the starting point for additional studies in
the field of polyamine analysis. A study of other neurodegenerative diseases is underway.
128
© 2001 Wiley-Liss, Inc.
Fig. Group difference in the spermidine to spermine (Spd/
Spm) ratio of hair samples between AD patients ( black circles) and healthy subjects (grey circles). The Spd/Spm ratios
of AD patients were significantly lower than unity (about 3–5
times; p ⬍ 0.001) compared to healthy subjects. When each
ratio was plotted in a scatterplot, 78% of the healthy subjects
were located above the unity line, and 22% were distributed
around the line. However, all but 1 of the AD patients
(94%) tested were below the line.
1
Bioanalysis and Biotransformation Research Center, Korea
Institute of Science and Technology, Seoul; 2College of
Pharmacy, Sungkyunkwan University, Suwon; and 3Nonsan
Baekje Geriatric Hospital, Nonsan, Korea
References
1. Butterfild DA. ␤-Amyloid-generated free radical oxidative stress
and neurotoxicity: implications for Alzheimer’s disease. Chem
Res Toxicol 1997;5:495–506.
2. Bernstein HG, Müller M. The cellular localization of the
L-ornithine decarboxylase/polyamine system in normal and diseased central nervous systems. Progr Neurobiol 1999;57:485–
505.
3. Choi MH, Yoo YS, Chung BC. Biochemical roles of testosterone and epitestosterone to 5␣-reductase as indicators of malepattern baldness. J Invest Dermatol 2001;116:57– 61.
4. Choi MH, Kim KR, Kim YT, Chung BC. Elevated polyamine
concentrations in the hair of cancer patients. Clin Chem 2001;
47:145–146.
5. Choi MH, Kim KR, Chung BC. Determination of hair polyamines as N-ethoxycarbonyl-N-pentafluoropropionyl derivatives
by gas chromatography–mass spectrometry. J Chromatogr
2000;897:295–305.
Hiccups Start, Seizures Cease
Akio Ikeda, MD, PhD, Keiko Matsuoka, MD,
Yoshihumi Nakaya, MD, and
Hiroshi Shibasaki, MD, PhD
We had a patient suffering from daily intractable seizures
who developed persistent hiccups for a week, during which
time his seizures stopped. However, once his hiccups disappeared, his daily seizures started again.
The patient was a 31-year-old man diagnosed with
Lennox-Gastaut syndrome and treated by valproic acid
(1,400 mg/day) and ethosuximide (500 mg/day). The patient
had atonic seizures mainly involving the neck, but also the
whole body with knee flexion, occurring at least several series
of four to five seizures, each lasting one to 20 minutes.
Seizure-free intervals of more than one day had not occurred
in the past 10 years. EEG showed slow posterior dominant
rhythm (6 –7 Hz), frequent bifrontal and generalized spikes,
both occurring every 10 to 50 seconds, and frequent irregular generalized slow (3– 4 Hz) activity. On November 15,
2000, the patient began hiccupping continuously and vagal
maneuvers did not stop them. They occurred every one to
three seconds, even during sleep. The hiccups transiently
stopped on the seventh day and completely stopped on the
ninth day. His habitual seizures had not occurred for a total
of eight days immediately after the hiccups started but
started again on the ninth day. EEG on the eighth day during disappearance of seizures showed only several bifrontal
spikes in 40 minutes, but the background activity remained
the same.
Afferent systems for hiccups can course with the vagal and
phrenic nerve, and also dorsal sympathenic fibers,1 and thus
microvascular decompression of the vagal nerve were effective for suppressing hiccups.2 Medulla is regarded as an essential center for the generation of hiccups, and electric stimulation of the medulla in cats can generate hiccups.3 Left
vagal nerve stimulation (VNS) is now widely accepted as the
method to decrease seizure frequency in patients with intractable epilepsy.4 All afferents of the vagal nerve synapse in the
nucleus of the solitary tract, which provides ascending pathways to the parabrachial nucleus, and then into the limbic
system and thalamic nuclei, which have diffuse projections
throughout the cerebral cortex. VNS is effective essentially
for all types of intractable seizures, and high- (30 Hz) rather
than low-frequency (1 Hz) stimulation seems more effective.5
Our case suggests that (1) hiccups may produce inhibitory
effects on epilepsy similar to VNS; (2) in patients with generalized seizures, relatively low-frequency VNS could be effective; and (3) these clinical observations may predict the
effectiveness of VNS.
This study was supported by Grants-in-Aid for Scientific Research
(C) 12210012 2(C2)13670640 from Japan Ministry of Education,
Science, Sports and Culture, and Research for the Future Program
from the Japan Society for the Promotion of Science JSPSRFTF97L00201.
Department of Neurology, Kyoto University Graduate School
of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan
References
1. Kahrilas PJ, Shi G. Why do we hiccup? Gut 1997;41:712–713.
2. Johnson DL. Intractable hiccups: treatment by microvascular
decompression of the vagal nerve. Case report. J Neurosurg
1993;78:813– 816.
3. Arita H, Oshima T, Kita J, Sakamoto M. Generation of hiccup
by electrical stimulation in medulla of cats. Neurosci Lett 1994;
175:67–70.
4. Schachter SC, Saper. Vagus nerve stimulation. Epilepsia 1998;
39:677– 686.
5. Patwardhan RV, Stong B, Bebin EM, et al. Efficacy of vagal
nerve stimulation in children with medically refractory epilepsy.
Neurosurgery 2000;47:1353–1357.
ERRATUM
Mindach M. Low Cerebral Blood Flow Velocity
and Risk of White Matter Hyperintensities
(Letter). 2001;49:819.
Dr. Mindach’s letter was published in the June issue of The
Annals of Neurology. Unfortunately, a Reply to his letter, by
Dr. C. Tzourio, was not published in the issue with Dr.
Mindach’s letter. Dr. Tzourio’s Reply appears below in its
entirety. The publishers regret this oversight and thank Drs.
Mindach and Tzourio for their contributions to the Journal.
Reply
Christophe Tzourio, MD, PhD
We thank Dr. Mindach for his interest in our work and for
giving us the opportunity to clarify some aspects of our findings. The first issue raised by Dr. Mindach is about the potential confounding effect of age on the relationship between
cerebral blood flow velocity (CBF-V) and white matter hyperintensities (WMHs). In our study, the association between
CBF-V and WMHs persisted after adjustment on age, which
excludes the possibility that this association was caused by age
only. We would like to emphasize that adjustment is a widely
used method to take into account the effect of potential confounders. It was our aim to estimate the relationship between
two variables at every level of a third variable (here age) thus
eliminating its confounding effect. It is precisely because age is
a potential confounder that unadjusted results could be misleading. In our sample, the range of age was limited by design
to 63 to 75 years, and it could therefore be anticipated that the
effect of age on the relationship between CBF-V and WMHs is
probably marginal. An indirect confirmation of the lack of effect
of age is the very close values of risk of severe WMHs according to CBF-V without or with adjustment on age. Crude risk
of severe WMHs from highest (referent) to lowest quartile of
mean CBF-V were 1.0, 1.4, 3.1, and 3.9 ( p ⫽ 0.001) and
1.0, 1.4, 3.1, and 3.8 ( p ⫽ 0.001) after adjustment on age.
It is not easy to answer to the second question of Dr. Mindach because it is based on a clinical series for which we have
only limited information. Generally speaking, clinical series,
however large, are exposed to recruitment and indication biases. In this context, extracting a very small subsample of 24
subjects representing 1% of the initial sample, based on an
nonjustified level of 38 cm/s, is questionable from a basic
methodological point of view and any conclusion should be
analyzed with great caution. Furthermore, with very small
samples, it is unlikely that any differences could be shown between “cases” and “controls” with regard to WMHs. In our
study, no participant had a lacunar infarct, which makes the
lacunar hypothesis unlikely to explain our results. Finally, we
think that the limits between silent infarcts, WMHs, and lacunar strokes are less clear than Dr. Mindach indicates and
that this important question, and in particular the prognostic
effect of high grades of WMHs on the risk of future stroke,
would be best approached by further studies on large
population-based samples including transcranial doppler and
cerebral magnetic resonance imaging.
Hôpital de la Salpetriere, Paris, France
E-mail tzourio@chups.jussieu.fr
33 142 16 2541 (fax) 33 142 16 2548 (phone).
Annals of Neurology
Vol 50
No 1
July 2001
129
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