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Cerebrospinal fluid choline levels are decreased in Parkinson's disease.

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Cerebrospinal Fluid
Choline Levels Are
Decreased in Parkmson’s
in untreated Parkinson’s disease patients and in those
who were treated with carbidopa-levodopa and carbidopa-levodopa plus amantadine, which is known to
have anticholinergic activity.
Bala V. Manyam, MD,+ Ezio Giacobini, MD, PhDJ
and Jerry A. Colliver, PhD$
We examined acetylcholinesterase (AChE) activity and
choline levels in cerebrospinal fluid (CSF) in 16 patients
with idiopathic Parkinson’s disease and 9 control subjects of corresponding age: 8 were untreated Parkinson’s
patients; 4 were treated with carbidopa-levodopa (1001
1,000 mg/day) for 20
3 months; and 4 were treated
with carbidopa-levodopa (110/1,100 mg/day) for 28 &
18 months plus amantadine (200 mg/day) for 16
months. CSF choline levels (nmoUml) were 2.97 & 0.79
(control subjects); 1.31 0.29 (untreated patients); 1.00
0.29 (carbidopa-levodopa treated); and 1.26
(carbidopa-levodopdamantadinetreated). Choline levels
were significantly lower in untreated and treated patients compared to control subjects (p = 0.0001).AChE
activity did not differ in Parkinson’s disease patients as
compared to control subjects. The reduced level of
choline in CSF may reflect a deficit in choline transport
into the brain or a decrease of choline-phospholipid output from the brain.
Manyam BV, Giacobini E, Colliver JA.
Cerebrospinal fluid choline levels
are decreased in Parkinson’s disease.
Ann Neurol 1990;27:683-685
Patients and Methods
Sixteen men with idiopathic Parkinson’s disease were included in the study after informed consent was obtained.
The clinical profile of patients is presented in Table 1. Objective recording of mental status was not undertaken, hence,
cognitive state was not compared. The control group consisted of 9 men with a mean ( * SD) age of 64 & 9 years
who had no known neurological or mental disease.
Lumbar Puncture
CSF was collected via lumbar puncture in all patients following overnight bed rest and fasting for 12 hours. In patients
who were treated for Parkinson’s disease, the interval between the last dose of medication and CSF collection was at
least 12 hours. The details of CSF collection, preparation,
and storage conditions are described elsewhere fbf. CSF
used for measurement of choline and AChE activity from
both control subjects and the experimental group was taken
from the first 10 ml of CSF drawn.
For study of gradient effect on AChE activity and choline,
CSF was collected in 4-ml sequential aliquots in 6 patients
with Parkinson’s disease. Choline levels and AChE activity
were measured in the first, third, and fifth 4-ml samples.
Assay of Acetylcholinesterase Activity
The radiometric method of Johnson and Russell 171was used
to determine AChE activity with 3H-acetylcholineiodide as a
substrate (90 mCdmmo1, sp. act.). The details are described
elsewhere f4}.
Choline Assay
There is both biochemical and pharmacological evidence for the role of cholinergic function in Parkinson’s disease [l]. Choline is a precursor in the synthesis of acetylcholine (ACh) and neuronal membrane
phospholipids. Acetylcholinesterase (AChE), the enzyme that inactivates ACh, is neuronal in origin and is
secreted into cerebrospinal fluid (CSF) following electrical stimulation of the brain 121 or treatment with
drugs 131. CSF choline levels and AChE activity may
be important biochemical markers of cholinergic dysfunction and neuronal damage in Alzheimer’s disease
14, 51. We measured CSF choline and AChE activity
From the *Division of Neurology, Department of Medicine; tDepartment of Pharmacology; and the $Division of Statistics and Research Consulting, Southern Illinois University School of Medicine,
Springfield, IL.
Received Jun 23, 1989, and in revised form Oct 5 and Nov 27.
Accepted for publication Nov 27, 1989.
Address correspondence to Dr Manyam, Division of Neurology,
D411, SIU School of Medicine, PO Box 19230, Springfield, IL
For the assay of CSF choline, 1 ml of CSF was mixed with 10
ml 1 N formic acid-acetone (15535) and centrifuged at
3,OOOg for 20 minutes to remove protein. The levels of
choline were measured in 15-(*.1aliquots of CSF by the
radiometric enzymatic assay [ S ] .
Statistical Analysis of Results
Computations were done on an IBM 4341 computer. The
Statistical Analysis System (SAS) procedure was used to estimate means, standard deviations, and significance. The mean
choline levels and AChE activity for the four groups (normal
control subjects, untreated, carbidopallevodopatreated, and
carbidopallevodopaplus amantadine treated) were compared
with analysis of covariance, using age as the covariate to
adjust for difference among the four groups due to age.
Follow-up tests were used for pairwise comparison of the
four groups. All group means were reported as the mean 2
1 standard deviation and significance expressed as a p value.
The mean ( * SD) CSF choline levels adjusted for age
were significantly lower (p = 0.0001) in patients with
untreated Parkinson’s disease than in control subjects
Table 1. Clinical Summary of Patients with Parkinson's Disease"
No. of patients
Age (yr)
Duration of illness (mo)
Carbidopa-levodopa (mg/day)
Duration of treatment (mo)
Amantadine (mglday)
Duration of treatment (mo)
"All values are expressed as mean
65 t 7
123 2 57
110/1, 100
28 t 18
+ Amantadine
53 ? 12
20 t 3
57 ? 15
22 c 16
Table 2. Parkinson's Disease: CSF AChE Activity and Choline Levels"
Age (yr)
Choline (nmoyml)
AChE (dmVhr)
Normal controls
Parkinson's disease
N o treatment
and amantadine
64 c 9
1.31 ? 0.2gb
0.83 t 0.19'
53 t 12
1.00 ? 0.29b
0.90 t 0.43'
* 0.28
"All values are expressed as mean f SD.
bSignificant compared to controls (p = 0.0001) by analysis of covariance with age as covariate.
'Not significant when compared to controls.
CSF = cerebrospinal fluid; AChE = acetylcholinesterase.
Table 3. Efect of Gradient on CSF Choline Leveh and AChE Activity (n
Order of CSF Aliquots (4 ml) Withdrawn
Choline (nmoVml)
AchE (pmoVmVhr)
Protein (mg/dl)
Albumin (mg/dl)
* 0.03
* 0.06
52 ?
1.07 +.
1.15 t
47 +23 -t
1.29 ? O.OSb
1.11 f O.Obb
44 c
22 c 3d
"All values are expressed as mean 2 SEM.
bNot significant.
'Significant at p < 0.01 by paired Student's t test.
dSignificant at p < 0.005 by paired Student's t test.
cerebrospinal ffuid; AChE = acetylcholinesterase.
(Table 2). No difference in the mean CSF AChE activity adjusted for age was seen between control subjects
and untreated Parlunson's disease patients. No significant difference was seen between untreated Parkinson's disease patients, carbidopa-levodopa treated patients, and carbidopa-levodopa plus amantadine
treated patients for mean choline levels and CSF
AChE activity adjusted for age, showing that the treatment did not have any effect.
The correlation coefficient between CSF AChE activity and choline levels and duration of illness, sever684 Annals of Neurology Vol 27 N o 6 June 1990
ity of the disease, and effect of treatment did not show
any significant relationships. CSF choline levels and
AChE activity in sequential aliquots of CSF are shown
in Table 3. Whereas CSF protein and albumin levels
decreased significantly in serial aliquots, choline levels
and AChE activity showed no significant change.
The relationship between age and CSF choline has previously been investigated; two studies have found no
variation of CSF choline levels with advancing age { S ,
97, whereas others [lo, 111 reported a modest agedependent increase in CSF choline levels. In our study,
the mean age of control subjects and that of Parkinson’s disease patients treated with carbidopdlevodopa
plus amantadine was identical, whereas the untreated
group and the patients treated with carbidopdlevodopa had a slightly lower mean age. The values in CSF
choline levels adjusted for age showed a significant
difference between the control subjects and the Parkinson’s disease patients. Aquilonius and colleagues
[9], Welch and colleagues 1127, and Flentge and colleagues [lo} measured choline levels in CSF of Parkinson’s disease patients using radioenzymatic or gas
chromatographidmass spectrometric methods. These
authors did not find significant changes in CSF choline
levels. The significantly lower mean age of the control
subjects used in those three studies could explain the
difference with our results.
We found no evidence of caudocranial gradient for
CSF choline levels or for AChE activity, although CSF
protein and albumin values measured from the same
aliquots fell significantly (see Table 3). Welch and associates 1127, taking an “early” and a “late” aliquot of
CSF when a pneumonoencephalogram or myelogram
was done, reported a ventricular-lumbar gradient for
CSF choline, with ventricular fluid levels being higher
than lumbar CSF levels. A similar finding was also
reported by Bowers C131, but our data (see Table 3 )
with sequential CSF collection during lumbar puncture, with measurement of CSF protein and albumin as
controls, failed to show a gradient for choline,
Dietary intake is not a factor to be considered, as
none of our patients were on any dietary restriction.
Although we did not measure plasma choline levels,
we performed lumbar puncture at the same time of
the day (between 8:OO AM and 9:OO AM) in both the
control group and the experimental group. We postulate that low plasma choline levels do not explain the
low CSF choline levels in Parkinson’s disease patients
reported here. We propose that a decline in CSF choline may be due to a defect in choline transport into
the brain or a decrease of choline-phospholipid output
from the brain. The origin of CSF choline is twofold;
plasma choline and choline from brain extracellular
fluid. Thus, a reduced level of CSF choline may be due
primarily to a lower uptake into the brain or secondarily to a lower release from the membrane cholinephospholipid pool. Alternatively, increased active
transport of choline out of CSF into the blood could
explain the decreased levels of this substance in CSF.
Our finding of lower lumbar CSF choline in Parkinson’s disease is of interest in view of the reported loss
of cholinergic neurons in the basal forebrain and
deficiencies in cortical cholinergic enzymes seen in
these patients 114, 151. However, the contribution of
altered ACh metabolism to choline changes in CSF
may be small. Further investigation into the specificity
and mechanism of our finding may provide insight into
choline metabolism and transport in Parkinson’s disease.
This work was supported in part by National Institute of Aging grant
We wish to thank D. Linville, MS, and E. Williams, BS, for their
technical assistance.
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Brief Communication: Manyam et al: CSF Choline Levels in PD 685
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decrease, level, disease, parkinson, choline, fluid, cerebrospinal
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