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Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease Evidence of impaired glutamatergic neurotransmission.

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LETTERS
Lack of Association between the BDNF Val66Met
Polymorphism and Parkinson’s Disease in a
Swedish Population
Anna Håkansson, MS,1 Jonas Melke, MS,1
Lars Westberg, BS,1 Haydeh Niazi Shahabi, MS,1
Silva Buervenich, PhD,2 Andrea Carmine, MS,2
Kjell Klingborg, MD,3 Maj-Britt Grundell, MD,3
Barbara Schulhof, MD,3 Björn Holmberg, MD, PhD,4
Jarl Ahlberg, MD,4 Elias Eriksson, PhD,1
Olof Sydow, MD, PhD,5 Lars Olson, PhD,2
Bo Johnels, MD, PhD,4 and Hans Nissbrandt, MD, PhD1
Several findings indicate a role for brain-derived neurotrophic factor (BDNF) in the pathogenesis of Parkinson’s disease (PD). For example, BDNF has been found to promote
survival of nigral dopaminergic neurons,1 and a reduced expression of BDNF protein in the substantia nigra of individuals with PD has been demonstrated.2 Furthermore, in a recent study by Momose and colleagues,3 the
Val66Met(G196A) polymorphism of the BDNF gene was
found to be associated with PD in Japanese subjects. The
aim of this study was to investigate this polymorphism in
white PD patients and controls.
All subjects (257 patients and 307 controls) had provided
informed consent, and the study was approved by the ethical
committees at Göteborg University and Karolinska Institutet.
The patients fulfilled the PDS Brain Bank criteria for PD,4
except that eight cases had more than one affected relative.
The mean age of onset was 60 years. DNA was amplified by
polymerase chain reaction, and genotyping of the
Val66Met(G196A) polymorphism of the BDNF gene was
performed by pyrosequencing5 on a PSQ 96 MA instrument
(Pyrosequencing AB, Uppsala, Sweden).
No significant difference in genotype or allele frequency
between patients with PD and control subjects was observed (Table), and this was the case also if men and
woman were analyzed separately (data not shown). Moreover, analyzing patients with an early age of onset (ⱕ50
years) versus a late age of onset (⬎50 years) of the disease
Table. Genotype and Allele Frequencies for the
Val66Met(G196A) Polymorphism in the BDNF Gene
Genotype or Allele
PD Patients
(n ⫽ 257) (%)
BDNF genotype
G/G
171 (66.5)
G/A
79 (30.7)
A/A
7 (2.7)
␹2 ⫽ 1.08; p ⫽ 0.58; df ⫽ 2
BDNF allele
G
421 (81.9)
A
93 (18.1)
␹2 ⫽ 0.02; p ⫽ 0.90; df ⫽ 1
Controls
(n ⫽ 306) (%)
209 (68.3)
85 (27.8)
12 (3.9)
503 (82.2)
109 (17.8)
PD ⫽ Parkinson’s disease; BDNF ⫽ brain-derived neurotrophic
factor.
did not show any association between the polymorphism
and age of onset (data not shown). In the study investigating the Val66 Met(G196A) polymorphism in a Japanese
population,3 the A allele and the A/A genotype were more
frequent, both among patients and controls than in our
Swedish population, indicating that the genotype and allele
frequencies of this polymorphism differs between Asians
and whites. The power of this study to identify an association with an odds ratio of at least 2.0 was greater than
99% (␣ ⫽ 0.05). In the Japanese study, the association
between the Val66Met(G196A) polymorphism and PD was
observed when subjects homozygous for the A allele (being
more frequent in PD) were compared with G allele carriers.
Because of the low frequency of the A/A genotype observed
in our sample, we had a power of only 47% (␣ ⫽ 0.05) to
detect a similar association.
In conclusion, our results do not support a major role for
the BDNF Val66Met(G196A) polymorphism in the cause or
pathogenesis of PD in whites.
The study was supported by the Swedish Research Council and
Åhlén’s, Golje’s Bergvall’s, and Hedblom’s Foundations.
The skilful technical assistance of B. Eriksson, A. Larsson, and G.
Nordlund is gratefully acknowledged.
1
Department of Pharmacology, Göteborg University, Göteborg;
Department of Neuroscience, Karolinska Institutet,
Stockholm; 3Slottskogens Care Centre; 4Institute of Clinical
Neurosciences, Göteborg University, Göteborg; and
5
Department of Clinical Neuroscience, Karolinska Institutet,
Stockholm, Sweden
2
References
1. Murer MG, Yan Q, Raisman-Vozari R. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s
disease and Parkinson’s disease. Prog Neurobiol 2001;63:
71–124.
2. Parain K, Murer MG, Yan Q, et al. Reduced expression of
BDNF protein in Parkinson’s disease substantia nigra. Neuroreport 1999;10:557–561.
3. Momose Y, Murata M, Kobayashi K, et al. Association studies
of multiple candidate genes for Parkinson’s disease using
single nucleotide polymorphisms. Ann Neurol 2002;51:
133–136.
4. Daniel SE, Lees AJ. Parkinson’s Disease Brain Bank, London:
overview and research. J Neural Transm Suppl 1993;39:
165–172.
5. Nordfors L, Jansson M, Sandberg G, et al. Large-scale genotyping of single nucleotide polymorphisms by Pyrosequencing™
and validation against the 5⬘nuclease (Taqman威) assay. Hum
Mutat 2002;19:395– 401.
DOI: 10.1002/ana.10585
© 2003 Wiley-Liss, Inc.
823
Motor Cortex Hyperexcitability to
Transcranial Magnetic Stimulation in Alzheimer’s
Disease: Evidence of Impaired
Glutamatergic Neurotransmission?
Vincenzo Di Lazzaro, MD, Antonio Oliviero, MD,
Fabio Pilato, MD, Eleonora Saturno, MD,
Michele Dileone, MD, and Pietro A. Tonali, MD
Ferreri and colleagues1 recently demonstrated a global increase in motor cortex excitability to transcranial magnetic
stimulation (TMS) in patients with Alzheimer’s disease
(AD). Because neither biochemical nor neurophysiological
investigations in patients with AD have shown any significant dysfunction of GABAergic intracortical inhibitory circuits, the authors conclude that the motor cortex hyperexcitability of AD is not caused by the dysfunction of
inhibitory circuits and suggest a different possible explanation represented by a selective alteration of excitatory glutamatergic neurotransmission. Currently, the involvement
of glutamatergic neurotransmission in the pathophysiology
of AD is still controversial. Can the evidence of an increased motor cortex excitability to TMS contribute to improve our understanding of the functional involvement of
glutamatergic system in AD? Considering that glutamate is
the main excitatory neurotransmitter in the brain, could it
be argued that the hyperexcitability of the motor cortex to
TMS represents the hallmark of an increased glutamatergic
transmission? A possible answer to this question is provided
by a recent study,2 that suggests a more complex interpretation of hyperexcitability. Hyperexcitability of the motor
cortex to TMS can be determined in normal subjects by
administration of ketamine, a drug that modulates glutamatergic neurotransmission.2 Ketamine determines a dual
modulating effect on glutamatergic transmission, blocking
N-methyl-D-aspartate (NMDA) receptor activity and enhancing non-NMDA transmission through an increase in
the release of endogenous glutamate. Because of the different kinetics of ionotropic glutamatergic receptors, NMDA
channels participate selectively in low-frequency transmission and may act as low-pass filter for high frequencies,
whereas non-NMDA channels are more involved in highfrequency transmission. Therefore, the net effect of ketamine is an increase in high-frequency glutamatergic neurotransmission that determines an increase in motor cortex
excitability to TMS, a technique producing a very high frequency repetitive discharge of pyramidal neurones.2
Analogous with findings in normal subjects after
ketamine, the motor cortex hyperexcitability in AD patients
can be interpreted as the consequence of an imbalance
between non-NMDA and NMDA neurotransmission in favor of the non-NMDA transmission. Therefore, the effects
of ketamine support the hypothesis of Ferreri and colleagues1 that the motor cortex hyperexcitability in AD
could be caused by an alteration of glutamatergic neurotransmission.
A further question is whether this is the expression of a
direct involvement of glutamatergic system in AD or
whether the glutamatergic imbalance can be explained by the
most consistently demonstrated deficit in AD that involves
reduced cholinergic activity.
824
Annals of Neurology
Vol 53
No 6
June 2003
A recent study3 that has demonstrated that activation of
cholinergic muscarinic receptors selectively inhibits the
non-NMDA neurotransmission favoring at the same time
the NMDA component gives support to the latter hypothesis. Interestingly, an increase in cortical excitability to
TMS also has been demonstrated in normal subjects after
blockade of cholinergic muscarinic neurotransmission with
scopolamine.4
In conclusion, the study by Ferreri and colleagues1 together with a recent study that used TMS paired with peripheral nerve stimulation to investigate some cholinergic
connections of cerebral cortex in AD patients5 suggests that
TMS techniques may contribute to in vivo demonstration of
AD-related cholinergic and glutamatergic neurotransmission
dysfunction.
Institute of Neurology, Università Cattolica, Rome, Italy
References
1. Ferreri F, Pauri F, Pasqualetti P, et al. Motor cortex excitability
in Alzheimer’s disease: a transcranial magnetic stimulation study.
Ann Neurol 2003;53:102–108.
2. Di Lazzaro V, Oliviero A, Profice P, et al. Ketamine increases
motor cortex excitability to transcranial magnetic stimulation.
J Physiol 2003;547:485– 496.
3. De Sevilla DF, Cabezas C, De Prada AN, et al. Selective muscarinic regulation of functional glutamatergic Schaffer collateral
synapses in rat CA1 pyramidal neurons. J Physiol. 2002;545:
51– 63.
4. Di Lazzaro V, Oliviero A, Profice P, et al. Muscarinic receptor
blockade has differential effects on the excitability of intracortical
circuits in the human motor cortex. Exp Brain Res 2000;135:
455– 461.
5. Di Lazzaro V, Oliviero A, Tonali PA, et al. Noninvasive in vivo
assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation. Neurology 2002;59:392–397.
DOI: 10.1002/ana.10600
Reply
Paolo Maria Rossini, MD
The letter by Di Lazzaro supports the possible role of an
altered glutamatergic neurotransmission in determining motor cortex hyperexcitability in Alzheimer disease.1
N-methyl-d-aspartate (NMDA) receptor is a subtype of
ionotropic glutamate receptor that is involved in synaptic
mechanisms of learning and memory. The three types of
glutamate binding sites on neuronal elements are differently
susceptible to degenerative processes in AD. A positive correlation has been noted between kainate receptor binding
and amyloid plaques in deep cortical layers of AD patients.2 Glutamatergic transmission is severely altered by
the early degeneration of corticocortical connections and
hippocampal projections in AD.3 Glutamate can reach
toxic extracellular levels in AD by malfunction in cellular
transporters, together with the continuous release of glutamate from presynaptic neurons and supersensitive postsynaptic receptors. In fact, AD-related degeneration is associ-
ated with the expression of glutamate transporters in altered
neurons as astrocytes. Long-term potentiation of synaptic
transmission is significantly impaired by pretreatment with
A 〉 1-42 and glutamate.4
The same group has shown in normal controls that transient increase of glutamatergic transmission as at nonNMDA receptors as produced by ketamine enhances motor
cortex excitability to transcranial magnetic stimulation5 and
the indications about the possible imbalance between nonNMDA and NMDA glutamatergic transmission nicely fits
with recent molecular acquisition in Alzheimer disease.
The authors also provide a robust theoretical background
about the possible interactions between glutamatergic and
cholinergic neurotransmission; moreover, their observation
are compatible with recent and unpublished observations on
Alzheimer patients motor cortex excitability after 1 year of
Acetyl CholinEstherasi therapy.
As a general comment, an indirect mechanisms might be
hypothesized whereby blockade of NMDA receptors on inhibitory neurons disinhibits glutamatergic projections to the
cortex, which combined with excitotoxic stimulation of muscarinic and glutamate receptors (alpha-amino-isorazolepropionic/kainate) appears to be the mechanism for neurotoxic
effects.
Department of Neuroscience, Hospital Fatebenefratelli,
Rome, Italy
References
1. Ferreri F, Pauri F, Pasqualetti P, et al. motor cortex excitability
in Alzheimer’s disease: a transcranial magnetic stimulation study.
Ann Neurol 2003;53:102–108.
2. Blanchard BJ, Konopka G, Russell M, Ingram VM. Mechanism
and prevention of neurotoxicity caused by beta-amyloid peptides:
relation to Alzheimer’s disease. Brain Res 1997;776:40 –50.
3. Lee HG, Zhu X, Ghanbari HA, et al. Differential regulation of
glutamate receptors in Alzheimer’s disease. Neurosignals 2002;
11:282–292.
4. Nakagami Y, Oda T. Glutamate exacerbates amyloid beta1– 42induced impairment of long-term potentiation in rat hippocampal slices. Jpn J Pharmacol. 2002;88:223–226.
5. Di Lazzaro V, Oliviero A, Profice P, et al. Ketamine increases
motor cortex excitability to transcranial magnetic stimulations.
J Physiol 2003;547:485– 496.
DOI: 10.1002/ana.10604
Influence of Red Wine on Visual Function and
Endothelin-1 Plasma Level in a Patient with
Optic Neuritis
Timo Haufschild, MD, Hedwig J. Kaiser, MD,
Thomas Preisig, Christian Pruente, MD,
and Josef Flammer, MD
A 34-year-old man with a 13-year history of chronic relapsing multiple sclerosis presented with typical symptoms of an
acute optic neuritis on both eyes (acute decrease of visual
acuity, new visual field defects in both eyes, and pain during
eye movements). The symptoms aggravated during physical
activity (Uhthoff phenomenon).
Since the first episode in 1988, 11 phases of optic neuritis
(six times on the left side and five times bilateral) occurred;
all were treated with high doses of steroids. Visual acuity and
visual field had recovered completely each time.
During an earlier episode, the patient described reproducible temporary improvements of visual function after consumption of red wine, but not white wine or other alcoholic
beverages, lasting for 3 to 4 hours with a maximal effect
about 30 minutes after consumption.
To verify this effect, we performed examinations before
(“baseline”) and 30 minutes after consumption of 0.3dl of
red wine (Beaujolais-Villages Moulin-a-Vent Duboeuf AC,
France, 1995) during the acute phase of the optic neuritis,
while the patient was not taking medication.
Before wine consumption, visual acuity was reduced profoundly, and visual fields (measured with the Octopus program
G 2 Interzeag; Berne, Switzerland) demonstrated extensive and
deep defects on both sides. Visual-evoked potentials showed decreased amplitudes and prolonged latencies. Furthermore, nailfold capillaroscopy1 demonstrated a vascular dysregulation: in
10 of 10 capillaries, blood flow completely stopped for 80 seconds after cold exposure.
After red wine, visual acuity improved markedly and visual fields recovered completely on both sides. Visual-evoked
potentials improved in both eyes (Table). In nailfold capil-
Table. Measured Visual and Vascular Parameters before and 30 Minutes after Red Wine Consumption
Right Eye
Visual acuity
Visual field (mean defect)
Resistivity index central retinal artery (color
doppler imaging) (normal, 0.7–0.85)
Visual-evoked potentials amplitudes (40⬘
pattern, normal, 6.1–15.5␮v)
Visual-evoked potentials latencies (40⬘ pattern, normal, 96.1–107.1msec)
Left Eye
Before
Red Wine
30 Minutes after
Red Wine
Before
Red Wine
30 Minutes after
Red Wine
20/50
4.6
0.74
20/25
⫺1.0
0.67
20/200
5.6
0.70
20/25
0.6
0.67
2.08
2.14
4.75
133
5.2
109
Annals of Neurology
155
Vol 53
145
No 6
June 2003
825
laroscopy, no blood flow standstill could be detected anymore. The endothelin-1 (ET-1) plasma level decreased to
2.63pg/ml from 3.08pg/ml at baseline (reference value for
men, 1.67pg/ml; standard deviation, 0.34).
All measurements were repeated after 4 days of red wine
restriction, and no improvement compared with baseline values could be found.
The relatively fast but only temporarily improved visual
function in association with the improvement of the peripheral blood flow and the decrease of the ET-1 plasma level after
red wine consumption suggests a participation of this peptide.
The role for ET-1 in the ocular circulation has been well
documented.1 ET-1 has been shown to be increased in the
plasma as well as in the cerebrospinal fluid of multiple sclerosis patients.2,3 Recently, it has been shown that red wine,
but not white or rosé wine, reduces ET-1 synthesis.4 We
therefore hypothesize that the temporary improvement of visual function and peripheral blood flow in our patient with
optic neuritis could be, at least in part, caused by a ET-1
synthesis modulating effect of red wine.
University Eye Clinic, Basel, Switzerland
References
1. Flammer J, Pache M, Resink T. Vasospasm, it’s role in the
pathogenesis of diseases with particular reference to the eye. Prog
Retin Eye Res 2001;20:319 –349.
826
Annals of Neurology
Vol 53
No 6
June 2003
2. Haufschild T, Shaw SG, Kesslering J, Flammer J. Increased
endothelin-1 plasma levels in patients with multiple sclerosis.
J Neuroophthalmol 2001;21:37–38.
3. Speciale L, Sarasella M, Ruzzante S, et al. Endothelin and nitric
oxide levels in cerebrospinal fluid of patients with multiple sclerosis. J Neurovirol 2000;6(suppl):S62–S66.
4. Corder R, Douthwaite JA, Lees DM, Khan NQ. Endothelin-1
synthesis reduced by red wine. Nature 2001;414:863– 864.
DOI: 10.1002/ana.10602
Corrections
In the January 2003 issue of the Annals, the title of the
Letter to the Editor by Drs Anne McCune and Mark
Worwood on page 145 was published incorrectly. The
correct title of the Letter is:
Headache as a presenting symptom in hereditary hemachromatosis
In the May 2003 issue of the Annals, the title of the
Letter to the Editor by Drs Josemir W. Sander and
John S. Duncan was published incorrectly. The correct
title of the Letter is:
Valproic acid and prion proteins
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glutamatergic, transcranial, motor, impaired, evidence, hyperexcitability, magnetic, neurotransmission, disease, corte, alzheimers, stimulating
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