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Cerebrospinal fluid monoaminergic metabolites are elevated in adults with Down's syndrome.

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Cerebrospinal Fluid
M0no-ner-c Metabolites
Are Elevated in Adults
with Down’s Syndrome
Arthur D. Kay, MD, Mark B. Schapiro, MD,
Amy K. Riker, BS, James V. Haxby, WD,
Stanley I. Rapoport, MD, and Neal R. Cutler, MD
~~~~
~
~~
Under conditions of rest and a low monoamine diet,
brain monoamine activity was examined in young (<35
years) and old (>35 years) adults with Down’s syndrome
and in control subjects by measuring the cerebrospinal
fluid (CSF) and plasma concentrations of the neurotransmitter norepinephrine, and of 5-hydroxyindoleacetic
acid (5-HIAA), homovanillic acid (HVA), and 3methoxy 4-hydroxyphenylglyco1 (MHPG), the respective metabolites of the neurotransmitters serotonin,
dopamine, and norepinephrine. There were no agerelated differences in metabolite concentrations in
either the Down’s syndrome or control subjects. CSF
concentrations of 5-HIAA, HVA, and norepinephrine
were significantly higher in young subjects with Down’s
syndrome as compared with young controls, and CSF
concentrations of 5-HIAA and norepinephrine were
significantly higher, by twofold or more, in old subjects
with Down’s syndrome as compared with older controls.
The results suggest that monoamine turnover and brain
functional activity involving monoamines is elevated in
Down’s syndrome, and that the early neuropathological
changes in the disorder are not associated with a monoamine deficit.
Kay AD, Schapiro MB, Riker AK, Haxby JV,
Rapoport SI, Cutler N R Cerebrospinal fluid
monoaminergic metabolites are elevated
in adults with Down’s syndrome.
Ann Neurol21:408-411, 1987
Older adults (>35 years) with Down’s syndrome (DS)
develop neuropathological findings similar to those
seen in Alzheimer’s disease 1121. Some develop neuropsychological changes consistent with dementia
{12}. As an index of brain function, postmortem studies on DS subjects have revealed reduced brain concentrations of neurotransmitters and their metabolites
From the Section on Brain Aging and Dementia, Laboratory of
Neurosciences, National Institute on Aging, National Institutes of
Health, Bethesda, MD 20205.
ReceivedJune 9, 1986, and in revised form Sept and 3’. Accepted
for publication Oct 4, 1986.
Address correspondence to Dr Kay, Department of Geriatrics and
Adult Development, Mount Sinai Medical Center, One Gustave L.
Levy Place, New York, NY 10029.
408
ElGI. There are multiple limitations to such measurements, however, relating to cognition
and behavior
during life {6].The meiwements are subject to postmortem artifacts and may reflect the immediate premorbid status of the subjects, rather than the fundamental aging or disease process. Furthermore, they
cannot provide information about disease progression
in its early stages.
As an index of brain functional activity during life,
we measured cerebrospinal fluid (CSF) concentrations
of the neurotransmitter norepinephrine (NE), and of
5-hydroxyindoleacetic acid (5-HIAA), homovanillic
acid (HVA), and 3-methoxy 4-hydroxyphenylglycol
(MHPG), the respective metabolites of the neurotransmitters serotonin (5-HT), dopamine (DA), and
NE, in healthy adults with DS and in healthy agematched controls. 5-HIAA, HVA, and NE do not
readily cross from plasma to brain or CSF, and CSF
concentrations of these substances provide at least relative estimates of brain serotoninergic, dopaminergic,
and noradrenergic activity 1261. Conversely, MHPG
crosses from plasma to brain and CSF, so that a correction factor is used to calculate the true brain contribution to CSF MHPG (corrected CSF MHPG =
MHPGcsf - E0.9 X MHPGplasma}) {lo}. A previous study has reported significantly elevated levels of
CSF 5-HIAA in D S as compared to mentally retarded
controls 1231, whereas others have found no alterations in levels of 5-HIAA or HVA {I, 8, 13, 241.
Subjects and Methods
Thirteen noninstitutionalizedadults with trisomy 2 1 DS-10
young (6 males, 4 females; mean age, 27 year; range, 21 to
34 years) and 3 old (2 males, 1 female; mean age, 55 year;
range, 47 to 63 years)-and 19 healthy controls-5 young
males (mean age, 27 year; range, 20 to 35 years) and 14 older
subjects (10 males, 4 females; mean age, 65 year; range, 43
to 85 years)-were screened for absence of secondary brain
disease or medical and psychiatric illnesses. The controls
were also screened for absence of primary brain disease. DS
and control subjects underwent computed tomographic head
scans that were within normal limits for the subjects’ ages.
The 3 older DS subjects performed significantly worse on
neuropsychological tests* than did the 10 younger ones, and
2 of the 3 older DS subjects were judged clinically demented
based on histories of failing memory and recent behavioral
changes. All subjects were medication-free for at least two
weeks, and none had been taking long-term medication.
Subjects were kept on a diet low in monoaminergic pre-
*Because of pervasive floor effects, three standard neuropsychological tests (Peabody Picture Vocabulary test, Dunn and Dunn, 1981;
Block Pamerns Subtest in Hiskey-NebrSka Tests, Hiskey, 1955;
and CORSI Block Span, Milner, 1971) were administered in
modified form. Three additional unpublished tasks to test memory
and visuospatial skills were designed by one of the authors 0. V. H.)
and also administered.
cursors for 72 hours prior to lumbar puncture f7). Following
nine hours of fasting and restricted bed rest, a lumbar puncture was performed between 08:30 and 10:30 with the subject in a lateral decubitus position. Following the subcutaneous administration of local anesthesia with 1% lidocaine, the
L3-4 interspace was penetrated with a 20-gauge spinal needle. Only clear cell-free CSF specimens with normal protein
and glucose levels were used. The first 12 ml of CSF was
pooled immediately on wet ice, then I-ml aliquots were frozen at - 70°C until assayed. Twenty microliters of acetic acid
(an antioxidant) were added prior to freezing to the aliquot
to be assayed for NE. Immediately before the lumbar puncture, venous blood was withdrawn into a plastic syringe from
an indwelling intravenous catheter which had been placed 10
hours earlier (to prevent acute perturbation of blood and
CSF neurotransmitters) 171. Three or more successive stable
blood pressures and heart rates were recorded at ten-n$nute
intervals prior to venous sampling.
The blood was placed in heparinized polypropylene tubes,
immediately centrifuged at 5000 rpm at 4°C for 20 minutes,
and 1-ml aliquots of the resultant plasma were frozen at
- 70°C until assayed. All assays were performed with highperformance liquid chromatography (HPLC) using electrochemical detection [ 5 , 19, 20, 221. Limits of reliable detection using a 1oo-pl injection vohme were 8 nM for
MHPG, 10 nM for 5-HIAA, and 20 nM for HVA. Betweenrun reproducibility, determined by measuring a single sample for each of the CSF metabolites on each of 25 consecutive working days, yielded a coefficient of variation of 9.0%
for MHPG, 3.6% for 5-HIAA, and 4.2% for HVA E207.
The between-day reproducibility for CSF NE, expressed as
the coefficient of variation of 30 assays during a 90-day period, was 12.3% f22). Statistical analyses of differences in
mean values among the four groups (young DS, old DS,
young controls, old controls) were made with an analysis of
variance procedure (ANOVA). Where statistically significant F values were obtained (p < 0.05), Bonferroni t tests
were done on each of four comparisons; young DS versus
young controls; old DS versus old controls; young DS versus
old DS;and young controls versus old controls. Pearson
product moment correlations were used to relate CSF and
plasma metabolite concentrations tp each other and to age,
height, and weight. The level of significance was taken asp <
0.05.
Results
CSF concentrations of NE, 5-HIAA, HVA, and
MHPG did not correlate significantly with respective
plasma concentrations either in the DS (young and old
groups combined) or in control subjects (young and
old groups combined) (p > 0.05), indicating a lack of
appreciable plasma contribution to CSF concentrations. In the control group (young and old combined),
age, height, and weight were not correlated with neurotransmitter or metabolite concentrations, except
for a significant negative correlation between plasma
HVA levels and age (r = 0 . 4 7 ; p < 0.05).
The Table presents characteristics of the DS and
control subjects, as well as mean plasma and CSF concentrations of NE, 5-HIAA, HVA, and MHPG. Old
Various Measurements in DS and Age-Matched Control Subjectsa
~
~
Variables
Young DS
Young
Controls
Old DS
Old
Controls
Number of subjects
Age (yr)
MABP (mm Hg)
Heart rare (beatshin)
5-HIAA (ng/ml)
CSF
Plasma
HVA (ng/ml)
CSF
Plasma
NE W m l )
10
26.9
87.2
71.4
*
2.7
5
26.6 -c 2.4
92.8 2.2
67.2 t 3.9
3
55.0 2 4.6
80.9 f 5.5
62.7 2 2.7
14
64.7 -t 3.1
89.0 t 2.9
61.9 2 2.2
24.4 2 l.Gb
7.4 -c 0.7
13.3 2 3.1
6.1 2 0.7
24.5 2 5.5d
8.5 2 1.0
12.7 2 1.6
8.2 2 1.3
46.2 5 4.5‘
15.0 f 1.1
28.3 2 4.2
12.1 1.4
*
35.6 f 5.1
12.1 5 1.1
28.7
3.2
10.0 t 0.7
28.8
108.3 t 14.3
167.3 2 29.2
235.8 It 19.3d
311.0 f 44.9
0.5
0.4
0.4
6.9 t 0.3
2.2 2 0.5
4.9 ? 0.4
9.8 f 0.5
3.1 f 0.6
7.0 2 0.8
CSF
Plasma
MHPG (ng/ml)
CSF
Plasma
Corrected (CSF)
~~
~~
* 1.3
* 2.4
&
249.0
272.2
&
‘-c
8.2
3.0
5.5
2
2
31.’jb
*
80.1
207.3
2
2
9.0
16.4
7.6
2.2
5.6
?
rfi:
0.6
0.2
0.G
*
~~
‘Values are mean f standard error of the mean.
bMean of young DS group sign&cantly higher tha.p mean of young control subjects at <0.01 level, by Bonferroni t statistical analysis.
cMean of young DS group significantly higher than mean of young coptrol subjects at 4 . 0 5 level, by Bonferroni t Statistical anaysis.
d&fean of old DS group significantly higher than mean of old control subjects at <0.05 level, by Bonferroni t statistical analysis.
DS = Down’s syndrome; MABP = mean arterial blood pressure; 5-HIAA = 5 hydroxyindoleacetic acid; HVA
norepinephrine; MHPG = 3-methoxy-4-hydroxyphenylglycol.
=
homovanillic acid; NE =
Brief Communication; Kay et al: Down’s Syndrome and CSF Metabolites 4051
controls did not differ from young controls with respect to any of the metabolite or neurotransmitter
levels measured. Age-related changes in these measurements were also not seen for the DS subjects.
Conversely, young DS subjects had significantly higher
CSF concentrations of NE, 5-HIAA (p < O.Ol), and
HVA (p < 0.05) than did young controls, while older
DS subjects had significantly higher CSF concentrations of 5-WAA and NE (p < 0.05) than did older
controls. These significant differences were of the order of twofold or higher.
Other measured variables, such as plasma concentrations, mean arterial blood pressure, and heart rate, did
not differ between DS and control subjects.
Discussion
This study demonstrates statistically significant, twofold or greater elevations in the CSF concentrations of NE, 5-HIAA, and HVA in young adult subjects with DS as compared to young controls, and in
the CSF concentrations of NE and 5-HIAA of older
subjects with DS as compared to older controls. No
biologically significant age difference was found in the
CSF and plasma concentrations of 5-HIAA, HVA,
NE, and MHPG for DS or control subjects. As
neuropathological changes and a central cholinergic
deficit are reported to characterize the postmortem
brain tissue of older DS subjects [17], and as the older
DS subjects in our study showed distinct neuropsychological deficits as compared to the younger DS
subjects, the lack of an age difference in DS, with
respect to the measured CSF concentrations, suggests
that central monoamine dysfunction does not play a
major role in the dementia of DS.
Increased CSF neurotransmitter and metabolite concentrations have been described in schizophrenia [ 111
and mania [25}, but increased concentrations in a congenital brain dysfunction such as DS have not been
described routinely. One previous study [23] found
increased concentrations of 5-HIAA in the CSF of DS
subjects, but all other reports [I, 8, 13, 241 have failed
to demonstrate statistically significant differences in
CSF concentrations of 5-hydroxyindoles or HVA between DS and control subjects. Ours is the first study,
as far as we know, that assessed DS and control subjects who were rigorously screened for health status.
Furthermore, we believe ours is the first study in
which three neurotransmitter systems were examined
for both CSF and plasma.
The fact that our findings differ from those of previous reports could reflect differences in methodology,
such as proper selection of controls, age and health
status of subjects, diet restriction, medication-free
periods, controlled activity, and collection methods
410 Annals of Neurology Vol 21 No 4 April 1987
which took into consideration the time of collection
and CSF gradients, factors known to affect CSF concentrations of neurotransmitters or their metabolites
v73.
Although CSF gradients along the neuraxis have
been described for 5-HIAA, HVA, and NE [26], the
lack of correlation between metabolite concentrations
and height in the control group (whose height varied
from 167 to 197 cm) makes it unlikely that the shorter
stature of the DS subjects produced a significant concentrating effect on metabolite levels. Brain metabolism and CSF neurotransmitter concentrations can be
affected by anxiety [7], but differences in global anxiety between DS subjects and controls were not observed in our study. In addition, objective measures of
stress, such as blood pressure and heart rate, were
assessed before lumbar puncture and were not found
to be significantly different between DS and control
subjects.
We have no simple explanation for our findings of
increased CSF neurotransmitter and metabolite concentrations of monoamines in DS. As elevated levels
have been reported in schizophrenia and mania, and
during anxiety, it may be that the increases reflect increased synthesis and turnover of the monoamines,
and a general increase in brain functional activity.
Reivich and Alavi {I83 reported that acute anxiety can
increase the cerebral metabolic rate for glucose as a
factor in increased cerebral functional activity. In this
regard, Schwartz and associates [21] reported a global
elevation of the cerebral metabolic rate for glucose in
young subjects with DS, consistent with our evidence
of increased monoamine turnover.
Increased monoamine turnover may be the result of:
(i) impaired neurotransmitter binding {2], resulting in
increased turnover demand or lack of feedback inhibition; (ii) a gene dosage effect, with increased activity of
synthetic enzymes [ 151; (iii) hormonal immaturity in
DS 141, which is known to be associated with an elevated metabolism in humans {9]; (iv) or a deficiency in
the primary inhibitory pathways (such as gamma-aminobutyric acid pathways) I17). Electrophysiological evidence exists to support this latter theory. Studies on
the visual, auditory, and somatosensory evoked responses [ 3 ] have shown that the evoked responses are
of higher amplitude in DS subjects than in controls,
with loss of the characteristic age-related decrement in
amplitude seen in controls, suggesting a failure of cerebral inhibitory pathways in DS.
It is also possible that our finding of elevated CSF
neurotransmitter and metabolite concentrations for
monoamines in DS does not reflect increased turnover, but rather impaired neurotransmitter uptake
1141, with a consequential increase in the synaptic degradative metabolites.
We wish to thank Dr Karen Pettigrew for her help with the statistical analysis, and Mr John Schreiber for his technical assistance.
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411
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