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Cerebrospinal fluid neurochemistry in the myoclonic subtype of Alzheimer's disease.

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Cerebrospinal Fluid Neurochemistry in the
Myoclonk Subtype of Alzheimer's Disease
Jeffrey A. Kaye, MD," Conrad May, MD," John R. Atack, PhD," Eileen Daly, BA," Daniel L. Sweeney, MA,"
M. Flint Bed, MD,S Seymour Kaufman, PhD,? Sheldon Milstien, PhD,? Robert P. Friedland, MD,"
and Stanley I. Rapoport, MD"
Monoamine metabolites, biopterin, acetylcholinesterase (AChE) activity, and somatostatin-like immunoreactivity (SLI)
were determined in the lumbar cerebrospinal fluid (CSF) of 24 patients with dementia of the Alzheimer type (DAT)
without myoclonus or extrapyramidal signs, in 8 patients with DAT and myoclonus, and in 14 age-matched healthy
control subjects. In patients with DAT with myoclonus as compared with both DAT patients without myoclonus and
control subjects, the concentrations of homovanillic acid and biopterin were significantly decreased. 5-Hydroxyindoleacetic acid was significantly lower in patients with myoclonic DAT as compared to patients with nonmyoclonic DAT,
but not significantly lower than in control subjects. CSF AChE and SLI were significantly reduced in patients with
DAT with or without myoclonus, as compared with control subjects, but AChE and SLI were not significantly
different between dementia groups. These results suggest that DAT patients with myoclonus represent a distinct
clinical and neurochemical DAT subtype.
Kaye JA, May C, Atack JR, Daly E, Sweeney DL, Beal MF, Kaufman S, Milstien S, Friedland RP,
Rapoport SI. Cerebrospinal fluid neurochemistry in the myoclonic subtype
of Alzheimer's disease. Ann Neurol 1988;24:647-650
Dementia of the Alzheimer type (DAT) is a heterogeneous syndrome comprised of several clinical subtypes
{l, 2). Two of these subtypes are distinguished by an
association of the dementia with movement disorders:
myoclonus and a parkinsonian or extrapyramidal syndrome. We recently showed C3] that the subtype of
DAT with extrapyramidal signs is not only clinically
distinct but is associated with an underlying deficit of
the cerebrospinal fluid (CSF) dopamine metabolite
homovanillic acid (HVA) and of the hydroxylase
cofactor biopterin. We now report on the clinical and
CSF neurochemical characteristics of the myoclonic
subtype of DAT. An abstract of part of this work has
been published C4).
had been free of medication for at least 2 weeks prior to the
study. Probable Alzheimer's disease (DAT) was diagnosed
by the NINCDS-ADRDA Work Group guidelines [6]. Dementia severity was graded with the Mini-Mental State Examination [ 7 ] as mild (> 21), moderate (11-20) or severe
(10-0). Myoclonus was determined on clinical examination
by at least two neurologists. Twenty extrapyramidal signs
such as rigidity, bradykinesia, or flexion posture were rated
as absent (O), mild to moderate (l), or severe ( 2 ) , and those
patients with a score of 5 or more on this scale were designated as having the extrapyramidal subtype of DAT. Four of
the 8 myoclonic patients were classified as also having the
extrapyramidal subtype of DAT. Nonmyoclonic patients did
not have extrapyramidal signs. Informed consent was obtained from all subjects or from the patient's family or legal
guardian when necessary.
Methods
Quantitative Computed Tomography
Quantitative computed tomography (CT) of the brain was
performed as previously described [ S ] . All scans were obtained without contrast material on an 8800 CT scanner
(General Electric, Milwaukee, WI). Ten-mm-thick CT slices
were oriented parallel to the externally defined inferior orbitomeatal line. Interslice separation was 7 mm. CSF volume
was calculated with a semiautomated procedure [8]. The volumes of the lateral and third ventricles were used to estimate
brain atrophy.
Patients and Control Subjects
Twenty-four DAT patients without myoclonus (mean age t
standard error [SE] = 69.4 ? 3.0 years, 12 women and 12
men), 8 DAT patients with myoclonus (60.0 t 2.6 years, 3
women and 5 men), and 14 control subjects (68.0 +. 2.9
years, 3 women and 11 men) were selected from our clinic
on healthy brain aging and dementia. Using health screening
criteria described previously [ 5 } , all patients and control subjects were free of major medical or psychiatric disease and
From the 'Laboratory of Neurosciences, Section on Brain Aging
and Dementia, National Institute on Aging, and the thboratory of
Neurochemistry, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, and the SDepartment of Neuralogy, Massachusetts General Hospital, and Harvard Medical School,
Boston, MA.
Received for publication Nov 30, 1987, and in revised form Mar 4
and May 3, 1988. Accepted for publication May 7, 1988.
Address correspondence
Dr
Department of Neurology,
2226, oregon
Health sciences university, 3 181
sam jackson
OR 97201,
park Road,
sw
647
Lumbur Puncture
Statistics
All subjects followed a low monoamine diet for 7 2 hours
prior to lumbar puncture and blood sampling. Lumbar puncture was performed between 8:30 and 1030 A.M., after 9
hours of bedrest and fasting. The first 12 ml of CSF was
pooled and immediately placed on wet ice. Aliquots of 0.5
ml were frozen at - 70°C until assayed. Only acellular CSF
with normal glucose and protein concentrations was used.
Just prior to lumbar puncture, a blood sample was obtained
through an indwelling intravenous catheter that had been
placed 10 hours earlier. Stable pulse and blood pressure
were required before venous sampling to obtain relatively
stress-free catecholamine concentrations. Blood was placed
in heparinized polypropylene tubes, centrifuged at 3,000 g at
4°C for 20 minutes, and I-ml aliquots of resultant plasma
were stored at - 70°C until assayed.
Comparisons between groups were made using two-sample t
tests. Differences in mean values among control, DAT without myoclonus, and D A T with myoclonus groups were analyzed with an analysis of variance procedure. Where statistically significant F values were found, Bonferroni t tests were
performed. The level of statistical significance was p < 0.05.
Assays
CSF somatostatin-like immunoreactivity (SLI) was measured
by radioimmunoassay "9- 101. Acetylcholinesterase (AChE)
activity was measured using 0.5 mM acetyl-P-methylthiocholine as a specific substrate, by the colorimetric method of
Ellman and colleagues [ 111. The specificity of the reaction
was further established by performing the AChE assay in the
presence and absence of a specific AChE inhibitor [12}. CSF
3-methoxy-4-hydroxy-phenethyleneglycol(MHPG), HVA,
and HIAA were determined simultaneously using high-performance liquid chromatography with electrochemical detection 1133. Plasma MHPG was assayed by the method of
Scheinin and coworkers 1141. Because MHPG crosses from
plasma to brain and CSF, a correction factor was used to
calculate the central nervous system contribution to CSF
MHPG (corrected CSF MHPG = CSF M H P G - 10.9 x
plasma MHPG]) [15]. Total biopterin (tetrahydro- and
dihydro-forms) was measured by a modification of a previously published high-performance liquid chromatography
method 1161.
Results
DAT patients with myoclonus were first compared to
24 nonmyoclonic DAT patients and 14 control subjects (Table 1). The mean age of patients with myoclonus was significantly younger than both patients
without myoclonus and control subjects. The mean
age at dementia onset was significantly lower ( p <
0.05) i n patients with myoclonus than in nonrnyoclonic
patients. The m e a n duration of dementia did not
significantly differ between patient groups. Myoclonic
patients were more severely demented than nonmyoclonic patients as shown by significantly lower MiniMental State Examination scores (see Table 1). Myoclonic patients had greater cerebral atrophy as
indicated by larger lateral and third ventricle volumes
w h e n compared with both control and nonmyoclonic
patients (see Table 1).
A n analysis of variance for t h e patient groups and
t h e age-matched control subjects (see Table 1) showed
a significant difference ( p < 0.05) in CSF AChE concentration between groups. AChE concentrations in
both myoclonic and nonmyoclonic DAT groups were
decreased by 2 1 relative to control subjects. CSF
SLI was also significantly different ( p < 0.05) between
groups (see Table l), with nonmyoclonic patients having lower concentrations than control subjects.
Table 1 . Clinical Characterirticr and Biochemical Measurements in Myoclonic and Nonmyoclonii
DAT Patients and in Control subjects
Control Subjects
Age (yr)
Age at dementia onset (yr)
Duration of dementia (yr)
Mini-Mental State score
CSF HVA (nmoliL)
CSF biopterin (nmol/L)
CSF HIAA (nmoliL)
Corrected MHPG (nmol/L)/day
CSF AChE (nmolimidml)
CSF somatostatin (pdml)
Lateral ventricle volume (ml)
Third ventricle volume (ml)
68.0 2 2.9 (14)"
30.0
201.9
17.9
90.6
24.5
21.7
23.7
33.6
2.0
2
5
0.0 (14)
26.9 (14)
2 1.7 (11)
13.7 (14)
k 2.2 ( 1 3 )
2 1.7 ( 1 2 )
2 2.5 ( 1 2 )
? 6.5 ( 1 2 )
2 0.3 (12)
5
DAT Without Myoclonus
70.4
63.4
6.0
14.8
168.1
16.1
115.6
21.2
17.2
17.0
57.5
3.3
"Values given are the means -t SEM; number of subjects are in parentheses.
bDiffers from mean in control subjects by Bonferroni I test ( p < 0.05).
'Differs from mean in DAT patients without myoclonus by Bonferroni t test
'Corrected MHPG = CSF MHPG - 0.9 X (plasma MHPG).
t 3.0 (24)
1.3 (24)
i 0.6 (24)
5 1.6 (24)b
5 26.9 (24)b
2 1.0 (22)
2 9.6 (24)
2 1.6 (24)
5 0.7 (24)b
2 0.7 ( 2 3 P
2 4.9 (24)b
+- 0.4 (24)
5
Vol 24
No 5
November 1988
f 2.6 (8)b,'
60.0
54.0
6.0
4.3
60.0
9.4
63.6
20.8
17.1
20.3
65.6
k
4.5
2
-t
_f
t
-t
t
k
-e
-c
2
2.5 (8)'
1.0 ( 8 )
1.9 (8P'
16 1 (8)"'
1.7 (7)",'
8.3 (8)'
7.7 (6)
1.2 ( 7 )
3 3 (6)
7.2 (6)'
0.5 (6)''
( p < 0.05).
D A T = dementia of the Alzheimer type; CSF = cerebrospinal fluid; HVA = homovanillic acid; HIAA
= 3-merhoxy-4-hydroxy-phenethyleneglycol;
AChE = acetylcholinesterase.
648 Annals of Neurology
DAT With Myoclonus
=
5-hydroxyindoleacetic acid; MHPG
L, HIAA = 67.5 i- 17.6 nmol/L, biopterin = 11.6 +2.7 nmoVL; myoclonus alone: HVA = 36.3 rr, 8.2
Table 2. Clinical Characteristics and Biochemical
Measurements in Severity-Matched Myoclonic and
Nonmyoclonic DAT Patients
DAT Without DAT With
Myoclonus
Myoclonus
(n = 7)”
(n = 7)
Age (yr)
Age at dementia onset (yr)
Duration of dementia (yr)
Mini-Mental State score
67.5 r 2.8
60.7 t 2.8
6.8 r 0.9
5.4 2 1.8
CSF HVA (nmoUL)
176.6 t 43.7
CSF biopterin (nmoUL)
15.3 l?r 1.2
CSF HIAA (nmoUL)
131.6 t 21.2
Lateral ventricle volume (ml) 70.4 t 6.5
61.1 r 2.4
55.4 t 2.4
5.7
3.1
62.5
9.5
66.9
60.8
2 1.1
5 1.7
r 18.3b
r 2.0b
r 8.9b
2 10.0
”Values given are the means 5 SEM.
bDiffers from mean in DAT patients wirhout myoclonus by Bonferroni f rest ( p < 0.05).
DAT
= dementia of the Alzheimer type; CSF = cerebrospinal
fluid; HVA = homovanillic acid; HIAA = 5-hydroxyindoleacetic
acid.
CSF HVA and biopterin concentrations in myoclonic patients were significantly lower ( p < 0.05) than
in both nonmyoclonic patients and control subjects
(see Table 1). CSF HIAA concentration was significantly greater ( p < 0.05) in nonmyoclonic patients as
compared with myoclonic patients. The difference in
CSF HIAA between control subjects and both DAT
groups was not significant. CSF MHPG corrected for
plasma MHPG concentration was not significantly different between groups.
Because the myoclonic patients were more severely
demented as measured by Mini-Mental State Examination and degree of ventricular enlargement, the significant HVA, HIAA, and biopterin concentration differences could have been related to dementia severity.
Thus, a comparison was made between 7 myoclonic
and 7 nonmyoclonic DAT patients with Mini-Mental
state scores of 12 or less who did not significantly
differ in age, age at dementia onset, duration of dementia, or total lateral ventricle volume (Table 2). This
analysis showed that CSF HVA, HIAA, and biopterin
remained significantly less in the myoclonic subtype as
compared with the severity-matched nonmyoclonic
group.
Finally, in view of the fact that we recently reported
chat HVA, HIAA, and biopterin are decreased in
DAT patients with extrapyramidal signs [3], the decrements in these neurochemicals may be related to the
coexistence of extrapyramidal signs in 4 of the 8 myoclonic patients. However, when the 4 DAT patients
with both myoclonus and extrapyramidal signs were
compared to the 4 DAT patients with myoclonus
alone, the mean HVA, HIAA, and biopterin concentrations were not significantly different (myoclonus
and extrapyramidal signs: HVA = 82.9 ? 28.0 nmoll
nmoYL, HIAA = 59.8 i- 2.1 nmoUL, biopterin = 7.2
t 1.2 nmoVL). For comparison, the CSF concentrations of HVA, HIAA, and biopterin were 88.6 2
18.4 nmollL, 81.6 2 12.2 nmollL, and 8.3 2 0.3
nmol/L, respectively, in 6 age- and severity-matched
DAT patients with only extrapyramidal signs (from
reference 131). These CSF neurochemical concentrations were not significantly different from those in the
purely myoclonic DAT patients.
Discussion
Compared to nonmyoclonic DAT patients with a similar dementia duration, myoclonic DAT patients experienced dementia onset at a younger age and were
more severely demented, as measured by both the
Mini-Mental State Examination and the amount of
ventricular enlargement assessed with CT volumetrics.
We also found that extrapyramidal signs coexisted in 4 of
8 myoclonic patients in the absence of medication. This
clinical profile of the myoclonic D A T subtype agrees
with other clinical surveys of DAT populations 11, 2 ) .
We recently reported 131 that the extrapyramidal
subtype of DAT differs significantly from DAT in
which patients are free of extrapyramidal signs. DAT
patients who develop significant extrapyramidal signs
had a younger age at dementia onset and a more severe
dementia. The DAT patients with extrapyramidal signs
also had significantly lower CSF HVA and biopterin
when compared to nonextrapyramidal patients of similar dementia severity without extrapyramidal signs.
Thus, the clinical and neurochemical profiles of the
extrapyramidal DAT subtype are very similar to those
of the myoclonic subtype. This is not unexpected, because the two motor disorders frequently coexist in
DAT. Whether the clinical and neurochemical characteristics of the two motor subtypes result from a
unique, or more widespread, degeneration of critical
neuron populations will require careful neuropathological studies in patients who have been well characterized according to motor signs during life.
Previous studies of the neurochemistry of myoclonus in disorders other than Alzheimer’s disease
have called attention to a cerebral deficiency of serotonin and, to a lesser extent, dopamine {17}. For example, in patients with postanoxic action myoclonus,
CSF HIAA is decreased and the myoclonus improves
with administration of the serotonin precursor 5-hydroxytryptophan 118, 173.Although it has been less
extensively studied, CSF HVA has been demonstrated
to be decreased in postanoxic action myoclonus [18),
with a dose-dependent response of the myoclonus to
dopaminergic drugs 1171.
A recent detailed postmortem study of the distribution of monoamines in the brain of a familial Alzheimer’s disease patient with myoclonus has called at%ye
et al: CSF in DAT with Myoclonus
649
tention to an association of the myoclonus with a
severe central nervous system serotonin deficiency
120). The decrease in serotonin was accompanied by
neuronal loss and prominent neurofibrillary tangles in
the raphe nuclei. These brainstem neurons are the major sites of origin for ascending serotonergic fiber systems. Previous neurochemical studies of CSF 1211 and
brain [21, 22) from patients with Alzheimer’s disease
have shown decrements in serotonin and HIAA. In
addition, binding of synaptic markers for serotonin uptake sites has also been shown to be decreased in the
brains of those with Alzheimer’s disease E22). The relation between these neurochemical results and clinical
signs cannot be determined from these studies, since
the number of patients with myoclonus or other involuntary movements was not specifically noted. Furthermore, the age at onset and estimated severity of
illness are generally lacking in these reports.
Other neurochemical systems such as the cholinergic system have been implicated in the pathogenesis of
myoclonus in Alzheimer’s disease. Bird and coworkers
[ 2 3 } , in a study of postmortem brain, noted that 4
Alzheimer’s disease patients with myoclonus had significantly lower cortical choline acetyltransferase activity than did patients without myoclonus. However, it is
not clear that the myoclonic patients were compared to
nonmyoclonic patients of equivalent pathological severity. Brain monoamines were not assayed in this
study.
Ultimately, myoclonus in Alzheimer’s disease may
be the result of a change in the balance between the
cholinergic and monoaminergic neurotransmitter systems 124, 257. Our data suggest that in the clinically
defined subgroup of DAT patients with myoclonus,
monoaminergic as well as cholinergic deficiencies are
present. Whether this neurochemical profile reflects
specific neuropathological changes unique to this clinical subtype will require future clinicopathological studies.
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November 1988
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