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Central nervous system catecholamine metabolism in Korsakoff's psychosis.

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Central Nervous System Catecholamine
Metabolism in Korsakoffs Psychosis
Peter R. Martin, MD, FRCP(C),*t H e r b e r t Weingartner, PhD,S Edna K. G o r d o n , BS,f R. Stanley Burns, M D , t
Markku Linnoila, MD, PhD,” Irwin J. Kopin, M D , ? and Michael H. Ebert, MD-1
We attempted to replicate previous reports of impaired central noradrenergic activity i n patients with Korsakoff‘s
psychosis. No differences were demonstrated i n lumbar cerebrospinal fluid concentrations of norepinephrine or its
major metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), or i n t h e contribution of plasma to cerebrospinal fluid
free MHPG in 6 patients with clinically well characterized Korsakoff‘s psychosis and 8 age-matched healthy, normal
volunteers. Likewise, cerebrospinal fluid concentrations of the major metabolites of dopamine (homovanillic acid) and
serotonin (5-hydroxyindoleacetic acid) were the same in patients and controls.
Martin PR, Weingartner H , Gordon EK, Burns RS, Linnoila M, Kopin IJ, Ebert MH: Central nervou:;
system catecholamine metabolism in Korsakoff’s psychosis. Ann Neurol 15:184-187, 1984
Cerebrospinal fluid (CSF) concentrations of neurotransmitters and metabolites reflect t h e levels of these
compounds in periventricular brain regions, and their
measurement may provide useful insights into monoamine metabolism in neuropsychiatric disorders 1231.
I n the present study, w e attempted to replicate observations of decreased lumbar CSF levels of 3-methoxy4-hydroxyphenyl glycol ( M H P G ) in patients with alcoholic Korsakoff’s syndrome [ 5 ] . However, in
patients with a well-defined clinical diagnosis of this
disorder, CSF concentrations of norepinephrine and its
major metabolite ( M H P G ) , as well as those of
dopamine (homovanillic acid [HVA]) and serotonin
(5-hydroxyindoleacetic acid [ 5-HIAAJ), were not
significantly different from those in age-matched normal volunteers.
Methods
Six men, aged 53 to 66 years, long-term patients at the
United States Soldiers’ and Airmen’s Home, Washington,
DC, with histories of heavy, chronic alcohol consumption
had a clinically stable amnestic disorder of at least 6 months’
duration. Only 1 patient had consumed alcohol within 6
months prior to admission to the National Institute of Mental
Health, Bethesda, MD. Control subjects (3 men, aged 50 to
62, and S women, aged 60 to 67 years) were healthy, medication free, and without a history of serious medical or psychiatric disease. They were contacted through the Normal Volunteer Program, National Institutes of Health, and received
remuneration for participation in accordance with Human
Research Committee guidelines. All patients fulfilled clinical
From the ‘Laboratory of Clinical Studies, National Institute on Alcoho1 Abuse and Alcoholism, the thboratory of Clinical Sciences,
and the thboratory
Psychology and
Institute of Mental Health, Bethesda, M D 20205.
184
criteria for Korsakoff’s psychosis (KP) {l, 191 and also,
showed characteristic abnormalities on research tests of
learning and memory 1211. N o patient had major cardiovascular, renal, endocrine, or hepatic disease, o r psychiatric illness other than the history of aicohol dependence.
Lumbar punctures were performed, and specimens were
processed in the same manner for patients and normal volunteers. Subjects followed a low-monoamine diet for at least 72
hours prior to collection of specimens. Lumbar puncture was
performed at 8:30 AM with the patient in the lateral decubitus
position after 8 hours’ fast and bedrest. CSF aliquots ( 1 to 2
ml) were collected in polypropylene tubes with ascorbate
preservative, frozen in dry ice at bedside, and stored at
-- 70°C until analysis. Norepinephrine and biogenic amine
metabolite concentrations were determined in the same or
comparable CSF aliquots ( 4 to 10 ml). Within a few minutes
of the lumbar puncture, blood was collected in plastic
heparinized tubes and immediately centrifuged in cold conditions, and the plasma was then stored at - 70°C.
The major CSF metabolites of norepinephrine, dopamine,
and serotonin-MHPG, HVA, and 5-HIAA, respectivelyas well as plasma M H P G were analyzed by gas chromatography-mass spectrometry using deuterated internal standards
[ 3 ] . Free M H P G was measured in direct extractions of CSF
and plasma samples, whereas total MHPG (free plus conjugated) levels were determined after an 18-hour incubation
of samples with a glycuronidase-arylsulfatase preparation.
Plasma and CSF norepinephrine were determined using
high-pressure liquid chromatography (M. Scheinin et al, unpublished observations, 1983). The CNS contribution to
CSF free M H P G was determined from MHPG in simultaneously obtained CSF and plasma (P) samples using the equation (CSF) - 0.9 (P) [4}.
Received May 9, 1983, and in revised form June 27. Accepted for
publication July 2, 1983.
Address reprint requests to Dr Martin, National ltlstitures of Health,
Bldg 10, Rm 3C-218, 9000 Rockville Pike, Berhesda, MD 20209.
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Fig I . Cerebrospinaljuid (CSF) total 3-methoxy-4-hydroxyphenyl glycol (MHPG),homovanillic acid (HVA), and 5 hydroxyindoleacetic acid (5-HIAA) levels in patients with Korsakoff’spsychosis (filled circles) and age-matched n o m l uolunteers (n = 8).Shaded areas indicate 95% conjidence intervals,
and dzshed lines indicate mean values for normal subjects; open
circles and vertical bars indicate mean f SEM for patients with
Korsakoff’spsychosis.
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Results
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In patients with KP, mean CSF levels of total MHPG,
HVA, and 5-HIAA all fell within the 7595 confidence
intervals for these monoamine metabolites derived
from values in age-matched normal volunteers (Fig 1).
Control subjects averaged 10.37 k 0.55 (SEM) ng/ml
of total MHPG, 33.6
5.3 ng/ml of HVA, and 16.5
k 2.42 ng/ml of 5-HIAA, and values for men and
women overlapped for all these metabolites. Mean
CSF metabolite levels for the patients with KP were
11.07 k 1.05 ng/ml for total MHPG, 51.0 i: 15.3 ng/
ml for HVA, and 20.2
4.7 ng/ml for 5-HIAA.
Both central and peripheral noradrenergic function,
as reflected by norepinephrine and MHPG concentrations in CSF and plasma in patients with KP, fell within
the range for normal age-matched volunteers (Fig 2).
For control subjects, average norepinephrine concentrations in plasma and CSF were 456 t 60.0 and
147 2 13.7 pg/ml, respectively (see Fig 2A). In patients
with KP, norepinephrine levels were 499 i: 47.0 and
153 ? 20.3 pg/ml for plasma and CSF, respectively.
For control subjects, average free MHPG concentrations in plasma and CSF were 4.28 2 0.38 and 8.76
0.40 ng/ml, respectively (Fig 2B). These values in patients with KP were 3.96 -+ 0.64 and 9.80 0.40 ng/
ml, respectively. Derived indices of the CNS contribution to CSF free MHPG were 5.11 5 0.37 and 5.75 k
*
Fig 2. Central and peripheral newous system noradrenergicfunction in patients with Korsakoffs psychosis (filled circles) and
age-matched n o m l volunteers (n = 8). Shaded areas indicate
95% conjidence intervals for normal subjects, and open circles
and vertical bars indicate mean f SEM for patients with Korsakoff s psychosis. (A) Plasma and cerebrospinalj u i d (CSF) norepinephrine concentrations;(B)plasma and CSF free 3-methoxy4-hydroxyphenyl glycol (MHPG)concentrations and CNS index
(central nervous system contribution to CSF MHPG).
*
*
*
1.26 ng/ml for normal volunteers and patients with KP,
respectively (see Fig 2B).
McEntee and Mair [5] reported a reduction in the
CSF total MHPG level of approximately 6 ng/ml in
patients with KP compared with their control group.
There is a greater than 79% probability (i.e., power
greater than 0.99) of detecting such a large difference
(type I alpha = 0.05) in a two-tailed t test using our
groups of patients (n = 6) and healthy controls (n = 8)
[2]. The power for detecting a smaller difference (e.g.,
2 ng/ml) between controls and patients with KP in CSF
total MHPG level with a type I alpha set at 0.05 (two
tailed) is about 35% in both our study and that of
McEntee and Mair 151 (control group, n = 34; experimental group, n = 7).
Martin et al: Catecholamines in Korsakoff‘s Psychosis
185
Discussion
Contrary to the findings of McEntee and Mair [5}, we
could demonstrate no difference in central noradrenergic activity between patients with clinically well
characterized KP and age-matched healthy, normal
volunteers. Specifically, neither the lumbar CSF concentration of norepinephrine, which may reflect CNS
release of this neurotransmitter, nor the concentration
of the major norepinephrine metabolite, MHPG,
which may be considered an index of norepinephrine
turnover, was significantly different in patients and controls. The contribution of plasma free M H P G to CSF
MHPG levels was no different in patients than in controls. Finally, n o differences were demonstrable between these groups in the major CSF metabolite
concentrations of dopamine (HVA) and serotonin
(5-HIAA).
From a statistical viewpoint, the probability that a
difference in CSF MHPG of the magnitude reported
by McEntee and Mair [ 5 ] was missed in the present
study is exceedingly low. Furthermore, the statistical
power for detection of smaller differences is approximately the same in our investigation as in the original
study and is consistent with values from other published investigations of CSF neurotransmitter metabolites [ l b ] . Consequently, to explain our discrepant
findings, one must consider the comparability of patients, choice of controls, and methodologies of CSF
collection and monoamine measurements.
We selected abstinent, drug-free patients with stable,
chronic KP who fulfilled accepted clinical criteria for
this disorder; the control group consisted of healthy
volunteers of the same average age as the patients.
Because there are no consistent reports of genderrelated differences in CSF biogenic m i n e metabolism,
we did not match patient and control groups for sex.
Measures of CSF neurotransmitter function had considerably greater variance in our patients than in the
normal controls. It is possible that our patient group
differed from others chosen using very similar diagnostic criteria. However, patients with CSF monom i n e levels above or below the normal range were not
clinically different, and we found no correlation between CSF MHPG concentration and results on various measures of memory.
In our study, preparation of the subjects for lumbar
puncture, and collection, processing, and analysis of
CSF samples, were identical for patients and controls.
Furthermore, our controls were healthy, normal volunteers; the lumbar punctures were not performed for
diagnostic purposes to rule out a serious illness. Hence,
we were able to control for several clinical and
methodological factors that might preferentially alter
biogenic m i n e and metabolite concentrations in one
group: prior physical activity [14, 151, the emotional
stress of the procedure [13], diet El 11, diurnal variation
186 Annals of Neurology
Vol 15
No 2 February 1984
[ 12, 18, 251, CSF concentration gradients, differential
degradation due to storage, and assay variability [24],
among others.
We interpret the neurochemical findings of this
study to indicate that there is no gross abnormality in
any of the major monoaminergic neurotransmitter systems in patients with KP. Such patients are better able
to use such attributes of to-be-remembered material as
organization to enhance recall than are patients with
clinically diagnosed dementia of the Alzheimer type
[21, 221. The severe memory impairment of patients
with KP, therefore, seems t o result predominantly
from deficits in attention, motivation, and reinforcement C213. In these respects, KP may resemble
neuropsychiatric disorders such as depression [20) and,
perhaps, Parkinson's disease [lo}. Treatment strategies
directed toward modifying activation and arousal by
pharmacological modulation of neurotransmitter sys-tems may similarly prove to be efficacious in patients
with KP. Clonidine dosages 161 that reduced blood
pressure and noradrenergic activity in patients with this
disorder [7, 81 did not improve their memory function.,
but there was mild memory enhancement during
clonidine withdrawal when noradrenergic activity was
increased [9]; this finding is consistent with the view
that central noradrenergic mechanisms are relatively
intact in KP. If chronic alcoholics share some of the
cognitive deficits found in KP [17], pharmacothera.peutic approaches developed in small numbers of patients with this disorder may have applicability to it
much larger patient population.
The authors are indebted to the medical staff of the United States
Soldiers' and Airmen's Home, Washington, DC:, for referral of their
patients for these investigations. John J. Bartko, PhD, provided sratistical advice.
References
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Martin et al: Catecholamines in Korsakoff’s Psychosis
187
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