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Effect of folic acid and vitamin B12 deficiencies on 5-hydroxyindoleacetic acid in human cerebrspinal fluid.

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Effect of Folic Acid and Vitamin BE
Deficiencies on 5-Hydroxyindoleacetic Acid
in Human Cerebrospinal Fluid
M. I. Botez, MD,"? Simon N. Young, PhDJ Jocelyne Bachevalier, PhD," and Serge Gauthier, MDZ$
Indoles were measured in cerebrospinal fluid (CISF) from control patients, from patients suffering from folate deficiency, and from patients with vitamin B,, deficiency. The folate-deficient patients were classified according to
whether they exhibited a neuropsychiatric syndrome, consisting of organic mental changes, polyneuropathy, and
depression, which responded to folate administration. CSF 5-hydroxyindoleacetic acid was low in the vitamin B,2deficient patients and in those folate-deficient patients whose neuropsychiatric signs were responsive to folate administration, but was normal in the folate-deficient patients whose symptoms were not related to folate deficiency.
CSF 5-hydroxyindoleacetic acid returned to normal with folate treatment in the patients exhibiting folateresponsive neuropsychiatric signs. The data indicate a close association between folate-responsive neuropsychiatric
symptoms and changes in 5-hydroxytryptamine metabolism in the central nervous system.
Botez MI, Young SN, Bachevalier J, Gauthier S: Effect of folic acid and vitamin B,, deficiencies on
5-hydroxyindoleaceticacid in human cerebrospinal fluid. Ann Neurol 12:479-484, 1982
Several reports indicate an association between folate
deficiency and depressed mood. Some studies have
found that patients with hematological signs of folate
deficiency have a higher than expected incidence of
affective disorders, while others have found a higher
than expected incidence of folate deficiency in patients needing treatment for depression [3, 8, 9,
12, 21, 24, 27, 281. Because of the possible link between depressed mood and brain biogenic amines
[26], and because the regional distribution of 5methyltetrahydrofolate in brain is similar to that of
5-hydroxytryptamine [ 161, several groups have measured cerebrospinal fluid (CSF) amine metabolites in
folate-deficient patients. CSF 5-hydroxyindoleacetic
acid (5HIAA) was found to be normal in folatedeficient subjects comprising psychiatric patients [7],
autistic children [ 171, epileptics [ 191, or patients with
senile dementia [23]. In a preliminary study, patients
who were folate deficient and were selected because
they exhibited a neuropsychiatric syndrome known
to be responsive to folate administration had low CSF
5HIAA [6].This finding could indicate that folate
deficiency only occasionally involves the central
nervous system but that, when it does, it produces
both folate-responsive neuropsychiatric signs and
low CSF 5HIAA.
From the 'Laboratory o f Neuropsychology, Clinical Research Institute of Montreal, tH6tel-Dieu Hospital, and the Departments
Of SPsychiatry and Of 4Neuro10gy
and
Mc(;ill University, Montreal, Que, Canada.
T h e aims of the present study were: (1) to confirm,
if possible, our preliminary observation that CSF
5HIAA is low in patients with folate deficiency and
folate-responsive neuropsychiatric symptoms, (2) to
determine whether CSF 5HIAA is normal in patients
with folate deficiency who d o not show folateresponsive symptoms, (3) to measure CSF 5HIAA in
patients with vitamin BIZdeficiency, and ( 4 ) to determine whether folate treatment increases CSF
5HIAA in those patients who respond to folate.
Materials and Methods
The evaluation of folate status was based on serum and CSF
folate measurements. Serum folate levels below 3 n d m l
were considered low [14].There are few data on normal
CSF folate levels. With the microbiological assay, normal
ranges of 17 to 41 ng/ml [14]and 12.6 to 57 ng/ml [30]
have been reported. Mean values for normal CSF folate
have been reported as 31 ng/ml by microbiological assay
[15, 201 and 27 ng/ml by radioassay [29].On the basis of
these results, which are similar to those from our laboratory, CSF folate was considered low if both the microbiological assay and the radioassay gave values less than
14 nglml or if one assay gave values less than 12 ng/ml.
Serum and CSF folate were determined by a microbiological assay [14] and a radioassay [lo], and plasma B,, levels
were determined by a microbiological assay [2].
Received July 23, 1981, and in revised form Mar 9, 1982. Accepted for publication Mar 2 5 , 1982.
Address reprint requests f O Dr Barez, Laborarory of Neuropsychology, Clinical Research Institute of Montreal, 110 Pine Ave
W, Montreal, Que, Canada H2W 1R7.
0364-5 1341821 110479-06$01.25 @ 1982 by the American Neurological Association
479
Blood and CSF samples were taken on the same day
between 9:OO and 9:30 AM after an overnight fast. Lumbar
puncture was always done by the physician, with the patient
in the sitting position. In some folate-deficient patients a
second lumbar puncture was performed. Approval for the
second lumbar puncture was obtained from the Ethics
Committee of Hotel-Dieu Hospital, and informed consent
was obtained from all patients.
Tryptophan, SHIAA, and indoleacetic acid in CSF were
measured by high-performance liquid chromatography [ 11.
This method involves direct injection of 10 p1 of CSF into
the chromatograph, separation of the various compounds
on a reverse-phase column (a 30 cm x 3.9 m m column of
10 wm particles of pBondapak C18 from Waters Associates Inc., Milford, MA), and measurement of the
fluorescence of the indole ring by means of a modified
Aminco Fluoromonitor (American Instrument Company,
Silver Spring, MD).
Evaluation of the peripheral nervous system included
electrophysiological studies [4, 51 as well as quantitative assessment of the vibration sense with a standardized tuning
fork. Subacute combined degeneration of the spinal cord
was diagnosed from the finding of signs of corticospinal
tract dysfunction together with impairment of vibration
sense, joint position sense, or both, in the legs.
Disturbances of mental state were classified as organic on
the basis of a neuropsychological battery that has been described previously [ 31 and their association with computerized axial tomographic abnormalities, which indicated
both cortical and central atrophy. bfood was assessed using
the Hamilton Rating Scale for Depression [131.
Routine laboratory assessment, hematological assessment, D-xylose absorption test, and roentgenographic
study of the small intestine were carried out in folatedeficient subjects. Jejunal biopsy was performed only in
those patients with abnormally low ~ - x y l o s eabsorption
and with radiological indications of malabsorption.
Selection of Patients
The folate-deficient patients had various neurological disorders or psychological depression and were referred for
various reasons, including mild organic neurological
symptoms, signs of gastrointestinal disease, and a history of
mild or bizarre anemias. The following patients were excluded from the folate-deficient group: (1) those with vitamin B,, deficiency; (2) those taking anticonvulsants or
other drugs that interfere with folate absorption o r
metabolism; and (3) those with medical conditions known
to produce neurological disease, such as diabetes, alcoholism, renal or hepatic failure, and malignant disease.
The study ranged over a three-year period because of the
difficulty of finding suitable folate-deficient patients. There
was definite selection of patients in the folate-responsive
group (classification to be explained), because of our previous recognition of the clinical characteristics of this type of
patient. Most of the patients who did not respond to folate
were found by chance to be folate deficient during clinical
and dietary investigations.
The vitamin B,,-deficient patients had an abnormal
Schilling test that was corrected by the addition of intrinsic
480 Annals of Neurology
factor, had variou:; degrees of pernicious anemia, and had
plasma B,, levels less than 100 p d m l by microbiological
assay [2]. The conitrols were patients who (1) had normal
serum and CSF folate, ( 2 ) did not display any clinical or
biological signs of malabsorption, (3) had a normal dietary
assessment, ( 4 ) were not bedridden, ( 5 ) were not malnourished and had no electrolyte imbalance, ( 6 )were not
taking major tranquilizers, vitamins, anticonvulsants, antibiotics, o r other drugs that interfere with folate absorption or metabolism, ( 7 ) underwent lumbar puncture for
routine neurological purposes, and (8) were neither suffering from any disease nor taking any drug known to affect
CSF indoles.
Classification of Response to Folate
i n Folate-deficient Patients
Patients were considered nonresponsive to folate therapy
when, after 5 months of active treatment (15 mg of folic
acid daily), no improvement was observed on clinical,
neuropsychological, or peripheral nervous system evaluations. Patients were considered partially responsive to folate therapy when improvement was evident only o n
neuropsychological testing procedures and on the Hamilton Scale for Depression after 5 months of active treatment. Patients were considered highly responsive to folate
therapy when active treatment induced a definite improvement on the Hamilton scale, o n neuropsychological
examination, and o n peripheral nervous system assessment
(electrophysiological improvement of polyneuropathy, o r
improvement of the vibration sense as revealed by the
electrical standardized tuning fork ). All testing and
categorization of patients as highly, partially, or unresponsive to folate therapy was done without knowledge of the
biochemical data.
Stlcdies
Initially, we studied 53 patients in whom folate and indole
determinations were made once. There were 19 controls,
28 folate-deficienr patients, and 6 vitamin BIZ-deficient
patients. Subsequently, a second lumbar puncture was carried out in 16 of the 28 folate-deficient patients after 2 to 8
weeks of folate therapy. Thus, the second CSF folate and
indole determinations were made before the final clinical
assessment of the response to folate, which was made after
5 months of vitamin therapy.
Results
Patient Characteristics
Diagnoses of t h e patients are g i v e n i n Table 1. The
patients w h o r e s p o n d e d t o folate exhibited t h e types
of s y m p t o m s described previously [ 3 , 41. M o s t patients who w e r e responsive t o folate had mild organic
mental changes, and about half exhibited each of t h e
o t h e r two s y m p t o m s o f t e n associated with this synd r o m e , i.e., depression a n d mild polyneuropathy.
Some patients, e v e n t h o u g h they m e t t h e DSM ZZZ
criteria for depression, also had e x t r e m e fatigue and
lassitude, s o m e t i m e s associated with mild signs of
p o l y n e u r o p a t h y or neuropsychological evidence of
Vol 12 No 5 November 1982
Table 1 . Contvols und Folute-dejcient Patients with One CSF Folute and indole Determination: Detuils and Diugnosesa
Folate-deficient Group (N = 28)
Controls
(N = 113)
Patient Data
Highly
Responsive
(N = 10)
Partially
Responsive
(N = 7 )
~
=
11)
7 (100)
5 1; 40-82
Vitamin BIZdeficient Group
(N = 6)
3 (50)
3 (50)
66; 42-84
0
0
0
0
0
6 (89)
0
0
0
2 (33)
0
1(14)
0
3 (43)
3 (43)
1(14)
2 (33)
6 (100)
6 (100)
0
0
0
0
0
0
0
~
aDiagnostic methods are described in Materials and Mrthods Values are numbers
bRevealed by electrophysiological studies of muscles and nerves
PAs assessed by the electric tuning fork
organic brain damage, or both. The same symptoms
were seen in patients who were partially responsive
to folate, but less often. Patients who were unresponsive to folate, although folate deficient, exhibited
other symptoms not known to be associated with folate deficiency. All 6 patients with vitamin 13,, deficiency had combined degeneration of the spinal cord,
while only 2 had organic mental changes.
Among folate-deficient patients, the proportion of
women among the responders (16 out of 17) was
higher than among the nonresponders (6 out of 11)
(p = 0.022, Fisher exact probability test [251). Although nonresponsive patients tended to be older
than responsive patients, comparison of the three
folate-deficient groups by one-way analysis of variance showed no significant differences between the
groups (F2.25= 2, 27; NS).
Table 2 gives hematological and other findings in
the folate- and vitamin B,Z-deficient patients. The
incidence of folate-induced anemia was not significantly greater ( p = 0.11, Fisher exact probability test) in folate-responsive patients (10 out of 17)
than in those with folate deficiency unrelated to the
(N
0
Male
Female
Age (mean; range)
Diagnoses
Cervical and lumbar disc
herniation
Vertebrobasilar artery
insufficiency
Transient ischemic attacks
Ophthalmoplegic migraine
Mild organic mental changes
Severe organic mental changes
(Alzheimer's disease)
Depression as major or initial
symptom
Mild polyneuropathyb
Vibration sense impairment"
Combined degeneration of the
spinal cord
Amyotrophic lateral sclerosis
Normal pressure hydrocephalus
Multiple sclerosis
(first attack)
~
Unresponsive
(5%) of patients in each group
actual clinical disorder (nonresponsive patients) (3
out of 11).The folate-deficient groups differed in the
origin of their deficiency. Thus, while there was jejunal atrophy and abnormal absorption in 9 of 17
folate-responsive patients, it was not found in any of
the nonresponsive patients, for whom a dietary origin
was the most common cause of deficiency (p =
0.025, Fisher exact probability test).
Falate, Vitamin B12,and Indoole Levels
Table 3 shows serum and CSF folate and CSF indole
levels in controls, vitamin B,,-deficient patients, and
the three folate-deficient groups. The three groups
(highly responsive, partially responsive, and unresponsive to folate administration) did not differ on
any of the four folate measurements, according to
one-way analysis of variance. Thus, clinical differences between the three groups could not be explained by different degrees of folate deficiency.
The vitamin BIZ-deficient group had higher levels
of folate in serum than did controls as judged by microbiological assay, but not by radioassay. There were
Botez et al: Folic Acid and 5HIAA
481
Table 2. Summary of Gastroenterologicaland Hematological Finding i n Folate-deficient and Vitamin B ,,-deficient Patients”
Folate-deficient GrouD (N = 28)
Finding
Megaloblastic anemia
Macrocytosis and subtle
megaloblastic changes
No hematological abnormalities
Jejunal atrophy and abnormal
D-xylose absorption test
Dietary origin of deficiency
Unknown origin
Schilling test
Vitamin BIZdeficient Group
Partially
Responsive
(N = 7)
Unresponsive
(N = 11)
3 (30)
3 (30)
1(14)
0
4 (40)
6 (60)
3 (43)
3 (43)
0
0
N o t investigated
Normal in all
Normal in all
Abnormal in allb
Highly Responsive
( N = 10)
(N
=
6)
3 (30)
1 (10)
Normal in all
aOne determination for each patient. Values are numbers (%) of patients in each group.
bLow level of elimination corrected by addition of intrinsic factor.
Table 3 . Serum and CSF Folate and CSF lndole Determinations i n Controls and i n Folate-deficieni
and Vitamin B ,,-deficient Patients
Serum Folate ( n g / ~ n l ) ~
Group
Controls (N = 19)
Vitamin BIZ-deficient
(N = 6)
Folate-deficient
Highly responsive
(N = 10)
Partially responsive
(N = 7)
Unresponsive
(N = 11)
CSF Folate (ng/ml)a
L. casei
Method
Radioimmunoassay
L. casei
7.55 ? 1.41
(15)
17.3 t 4.8
(5P
6.65 t 1.61
(15)
11.1 t 3.0
(6)b
2.18 t 0.49
1.91 t 0.33
(10)
2.58 t 0.21
(7)
2.68 t 0.36
(8)
2.93 t 0.57
17)
2.89 t 0.39
(10)
(9)
Radioimmunoassay
Method
CSF Indoles (ng/ml)a
Tryptophan
5HIAA
20.0 2 1.1 18.5 t 1.1
(19)
(16)
24.4 t 1.6 26.2 t 7.4
(6)
(6)
349 2 34
(15)
391 t 56
(6)
20.5 t 2.0 3.58 t 0.92
(17)
(16)
10.1 t 1.9 4.86 t 1.34
(6)
(6)
9.2 +- 2.4 8.1 t 1.1
(9)
(10)
11.5 & 1.7 9.8 t 0.8
(7)
(7)
11.1 t 1.0 10.7 t 1.0
(1 1)
(1 1)
3 0 9 t 43
(10)
271 ? 51
(7)
365 t 52
(10)
8.8 t 1.4
(10)
18.6 t 4.9
17)
22.2 t 3.7
(1 1)
IAA
3.51 t 0.66
(9)
7.53 t 3.04
(6)
4.99 i 1.33
(10)
‘All values are given as mean f SEM (with number of determinations in parentheses)
bSignificance:p < 0.05 against control values using Student f test.
CSF = cerebrospinal fluid; 5HIAA
=
5-hydroxyindoleacetic acid; IAA
=
indoleacetic acid.
no differences in CSF folate between the Bizdeficient group and controls.
CSF indole levels were compared in the five
groups by one-way analysis of variance. There were
no significant differences between the groups for
tryptophan (F4,43= 0.84) or indoleacetic acid (F4,42
= 1.16), but there were significant differences for
SHIAA (F4,46= 4.41, p < 0.01). For SHIAA, all
four vitamin-deficient groups were compared with
the control group using a two-tailed Dunnett t test
[3 11. Both vitamin B12-deficient patients (p < 0.05)
and the highly responsive folate-deficient patients ( p
< 0.01) had levels significantly lower than the control
group.
Effect of Folate Administration on CSF Indoles
Table 4 shows the effect of folate administration on
various biochemical measures in 16 folate-deficient
patients (11 women and 5 men), and also for the subgroups of 9 who were not responsive to folate
therapy and 7 who were. The latter 7 consisted of 4
highly responsive and 3 partially responsive patients.
In all patients, serum and CSF folate rose on treatment with folic acid. However, the increases were
not statistically significant for serum folate as measured by radioassay in the responsive patients,
perhaps because of the variable increase in these patients, or for CSF folate (by both methods) in the
nonresponsive patients. Whereas CSF folate ap-
482 Annals of Neurology Vol 12 No 5 November 1982
Table 4. Effect of Folate Administration on Biochemilal Measures in Folate-dPficient Patientsa
CSF Folate (nglml)
Serum Folate (ng/ml)
Groupb
Whole group
(N = 16)
Before
After
Responsive
patients
(N = 7)
Before
After
Unresponsive
patients
(N = 9 )
Before
CSF Indoles (nglml)
L. casei
Method
Radioactive
Method
L. rasei
Method
Radioactive
Method
Tryptophan
5HIAA
IAA
2.67 rf: 0.35
(14)
27.4 2 2.8
(15)
p < 0.001
2.03 ? 0.17
(15)
30.6 ? 9.4
(12)
p < 0.01
9.7 t 1.1
(16)
18.1 rfr 1.9
(15)
p < 0.005
9.2 t 0.9
(16)
14.4 f 1.1
(16)
p < 0.005
355 f 42
(15)
341 f 38
(14)
NS
19.2 ? 3.5
(16)
24.8 ? 4.3
(16)
NS
5.84 f 1.47
(15)
8.85 ? 1.87
(14)
NS
2.05 c 0.48
(6)
27.1 rf: 4.3
(7)
p < 0.005
1.93 ? 0.33
(7)
37.9 2 15.2
8.26 '. 2.07
(7)
20.7 2 3.3
(6)
p < 0.05
7.77 2 1.26
(7)
13.6 If: 1.8
(7)
p < 0.01
356 rf: 64
(7)
253 f 72
(6)
NS
14.6 ? 5.6
(7)
28.8 2 8.0
(7)
p < 0.05
6.94
(7)
11.0
(6)
NS
10.3 f 1.2
353 2 58
22.9 t 4.2
3.41
(8)
2
0.44
(7)
NS
2.13 2 0.16
(8)
20.3 ? 6.7
(5)
p < 0.05
10.7
?
(9)
1.2
(9)
(9)
(9)
21.6 -t 4.6
395 rf: 41
15.0 ? 1.3
16.4 f 2.3
27.6 rf: 3.9
(8)
(9)
(9)
(8)
(9)
NS
NS
NS
NS
p < 0.001
'All values are given as mean 2 SEM (with number of determinations in parentheses). Comparisons were done using the paired I test.
After
?
2.67
?
3.3
4.87 t 1.56
(8)
7.23
(8)
NS
?
2.20
"Before and After refer to treatment with folate.
CSF
=
cerebrospinal fluid; JHIAA = 5-hydroxyindoleacetic acid; IAA = indoleacetic acid.
proximately doubled in the responsive patients, it
rose only about 50% in the unresponsive group. T h e
only significant change (p < 0.05) seen in CSF indoles was that CSF SHIAA almost doubled in the
group of patients with folate-responsive neuropsychiatric symptoms.
Discussion
This study confirms our preliminary results [6] that
CSF 5HIAA is low in patients who are folate
deficient and exhibit folate-responsive neuropsychiatric symptoms (see Table 3). It also confirms
the conclusion of others that CSF 5HIAA is normal
in folate deficiency when there are no neuropsychiatric symptoms related to the folate deficiency [7, 17,
19, 231 (Table 3). O u r interpretation of the low CSF
SHIAA in the folate-responsive group is in no way
confounded by the greater proportion of women in
this group relative to the nonresponders (see Table
1). CSF 5HIAA tends to be higher in women than in
men [321, which would tend to diminish the difference we found.
The low CSF SHIAA in vitamin BIZdeficiency (see
Table 3) is a new finding. This phenomenon might be
associated with degeneration of the spinal cord, because some of the SHIAA in lumbar CSF is derived
from the spinal cord and not from the brain [l 13. Alternatively, since there is a close association between
vitamin BI2 and folate, the same unknown mechanism may cause the decline of 5HIAA with both vitamins.
O n e interesting result from the present study was
the increase to normal of CSF 5HIAA levels in the
folate-responsive group when the patients were
treated with folate. Previous controlled studies have
established that clinical improvement occurs in this
type of patient when treated with folate [3]. Although the most likely explanation for this increase
in 5HIAA is the folate treatment, we cannot rule out
the possibility that SHIAA would have increased in
response to placebo. For ethical reasons, we did not
perform a second lumbar puncture in placebo-treated
patients. However, in most depressed patients with
low CSF SHIAA, the deficiency persists during
symptom-free and medication-free intervals [ 181.
Thus, it is unlikely that the increase in CSF 5HIAA
Botez et al: Folic Acid and SHIAA
483
in our patients was due to their recovery from depression; it was more likely directly associated with
the folate treatment. The fact that low CSF 5HIAA
persists in depressed patients on recovery [18] and
that we found low CSF 5HIAA in vitamin BIZdeficient patients who were not depressed indicates
that low brain 5-hydroxytryptamine was not the primary cause of the depressed mood in our folatedeficient patients, although it may have been a contributory factor. These results indicate that vitamin
deficiencies, and especially folate deficiency, should
be considered in the evaluation of neuropsychiatric
patients.
Supported by grants from the Medical Research Council of Canada
(S. N. Y.) and the Fonds de la Recherche en Sante du Quebec
(M. I. B.).
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acid, effect, vitamins, folii, b12, cerebrspinal, deficiencies, human, fluid, hydroxyindoleacetic
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