Neurobiology of Aging, Vol. 19, No. 5, pp. 379 –384, 1998
Copyright © 1998 Elsevier Science Inc.
Printed in the USA. All rights reserved
0197-4580/98 $19.00 ϩ .00

PII:S0197-4580(98)00086-4

Decreased Monoamine Metabolites in
Frontotemporal Dementia and
Alzheimer’s Disease
¨
MAGNUS SJOGREN,*1 LENNART MINTHON,† ULLA PASSANT,‡ KAJ BLENNOW,* AND
ANDERS WALLIN*
*Goteborg University, Institute of Clinical Neuroscience, Department of Psychiatry and Neurochemistry, Sahlgrenska
¨
University Hospital, Molndal; †Department of Psychogeriatrics, University of Lund, University Hospital MAS, Malmo;
¨
¨
and ‡Department of Psychogeriatrics, University of Lund, University Hospital, Lund, Sweden
Received 11 December 1997; Revised 20 August 1998; Accepted 3 September 1998
¨
SJOGREN, M., L. MINTHON, U. PASSANT, K. BLENNOW AND A. WALLIN. Decreased monoamine metabolites in
frontotemporal dementia and Alzheimer’s disease. NEUROBIOL AGING 19(5) 379 –384, 1998.—The concentrations of the
monoamine metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol
(HMPG) in the cerebrospinal fluid (CSF) of patients with clinical frontotemporal dementia (FTD; n ϭ 30), early onset Alzheimer’s
disease (EAD; n ϭ 33), late onset Alzheimer’s disease (LAD, n ϭ 27) and normal controls (n ϭ 31) were determined using HPLC.
ANCOVA showed no significant effect of neuroleptic medication, extrapyramidal signs, myoclonia or gender on the CSF levels of the
monoamine metabolites. Homovanillic acid was significantly reduced in all diagnostic groups (FTD, p ϭ 0.0002; EAD, p ϭ 0.016;
LAD, p ϭ 0.013). 5-hydroxyindoleacetic acid was significantly reduced in EAD (p ϭ 0.013) and in LAD (p ϭ 0.0014), and HMPG
was reduced in LAD only (p ϭ 0.020). HMPG was significantly higher in FTD compared to EAD (p ϭ 0.0005) and LAD (p ϭ 0.0003).
CSF-5-HIAA was significantly reduced in patients with antidepressant medication (p ϭ 0.006). ANCOVA within the FTD group
showed no significant effect of neuroleptic or antidepressant medication, extrapyramidal signs, myoclonia, gender or FTD subtype on
the CSF levels of the monoamine metabolites. The results suggest that CSF-HMPG might differentiate FTD from EAD and LAD, but
not from normals. © 1998 Elsevier Science Inc.
Dementia
Diagnosis
Frontotemporal dementia
High-performance liquid chromatography (HPLC)

Alzheimer’s disease

Monoamine metabolites

olite 5-hydroxyindoleacetic acid (5-HIAA; 4,13,17,19) and the
dopaminergic metabolite homovanillic acid (HVA; 4,8,13,17,19,
23,31). The noradrenergic metabolite 4-hydroxy-3-methoxy-phenylglycol (HMPG) has mostly been found to be normal in the CSF,
but there are some studies showing decreased levels (17). This
discrepancy between the results obtained in investigations of brain
tissue and CSF regarding the noradrenergic system might be
explained by the influence on the CSF of serum levels of HMPG,
resulting in overstated levels of CSF-HMPG (22). Although it is
possible that psychopharmacological medication (37) and neurological signs influence the CSF levels of the monoamine metabolites (20,21), these factors have not always been taken into
account.
There have been few investigations of neurochemical changes
in frontotemporal dementia (FTD). These have suggested no or
limited disturbances of the noradrenergic and dopaminergic systems (11) and loss of serotonergic postsynaptic sites (11,35), i.e.,
almost the reverse of what is found in AD (13,17,29). One study

THE STUDY of the monoamine systems is one of the cornerstones of biological psychiatry. For some years it has been
established that disturbances in these systems are present in
psychiatric disorders, such as schizophrenia and affective disorders, and in degenerative disorders, such as dementia (13,17,29,
32,41). The majority of the therapeutic compounds developed
today are aimed mainly at correcting imbalances in these systems,
thereby alleviating the psychiatric symptoms. One example is the
emotionally stabilizing effect of the selective serotonin reuptake
inhibitors on demented patients with depressive symptoms (14,28).
A large number of studies on the monoamine systems in
Alzheimer’s disease (AD) have revealed disturbances of the
noradrenergic and serotonergic systems in the brain (13,17,29).
The results concerning the dopaminergic system are conflicting.
Some studies have found disturbances of dopaminergic neurons in
AD, whereas other studies have not (17,29). Investigations of the
cerebrospinal fluid (CSF) levels of the monoamine metabolites
have mostly revealed decreased levels of the serotonergic metab-

1
Address correspondence to: Dr. Magnus Sjogren, Department of Psychiatry and Neurochemistry, Sahlgrenska University Hospital/Molndal, S-431 80
¨
¨
Molndal, Sweden.
¨

379

380

SJOGREN ET AL.
TABLE 1
CLINICAL CHARACTERISTICS

Diagnosis

FTD
EAD
LAD
Controls

Age (y)

Age at
onset (y)

Duration
(y)

63.6 Ϯ 9.3
59.0 Ϯ 9.8 4.4 Ϯ 2.4
63.2 Ϯ 4.7
58.4 Ϯ 5.0 4.6 Ϯ 2.9
74.7 Ϯ 2.7*** 72.0 Ϯ 4.5 3.2 Ϯ 1.9
65.0 Ϯ 6.6

Body length
(cm)

Albumin
ratio

169 Ϯ 10
170 Ϯ 9
164 Ϯ 8
172 Ϯ 8

6.4 Ϯ 1.9
6.0 Ϯ 2.2
6.5 Ϯ 1.8
5.6 Ϯ 2.1

All values are expressed as means Ϯ SD. The following abbreviations
are used: y ϭ years, FTD ϭ frontotemporal dementia, EAD ϭ early onset
Alzheimer’s disease, LAD ϭ late onset Alzheimer’s disease.
*** p Ͻ 0.001 (statistical difference is between the LAD group and the
other diagnostic groups and controls).

thorough clinical investigation, including medical history, physical, neurological and psychiatric examinations, screening laboratory tests of blood, routine analysis of the CSF, electrocardiography, x-ray of the chest, electroencephalography, computerized
tomography (CT) or magnetic resonance imaging (MRI) of the
brain and single photon emission computerized tomography
(SPECT) of the brain. Excluded were patients with a history of
severe psychiatric disease (e.g., schizophrenia, manic-depressive
disorder), chronic alcoholism, distinct nondegenerative neurological disease (e.g., normotensive hydrocephalus, cerebral tumor,
multiple sclerosis), history of severe head injury, severe infections
in the CNS, systemic diseases (e.g., malignant tumors, liver
diseases), and secondary (e.g., hypothyreosis, Borrelia encephalitis) causes for dementia.
Diagnoses of Clinical FTD and AD

of the CSF levels of the monoamine metabolites in FTD showed
normal levels (11), but the number of patients in this study was
limited (n ϭ 3). If these findings could be replicated and
recognized as reliable, the monoamine metabolites might be used
as diagnostic markers to separate FTD from AD.
Most studies on the monoamine systems in dementia have
examined postmortem material. This implies that the samples have
been drawn from terminal cases. To study possible neurotransmitter disturbances in AD and FTD at stages of the disease which may
be clinically relevant, investigations of CSF is one way to obtain
information about biochemical changes in the brain (4).
The need for further studies on brain neurotransmitter metabolism in FTD induced us to investigate as follows:
1) CSF monoamine metabolites in a large sample of FTD
patients, healthy controls and AD patients;
2) the effects of neuroleptic and antidepressant medication,
extrapyramidal signs, myoclonia, and sex on the CSF levels of the
monoamine metabolites in patients with EAD, LAD, and FTD;
3) the effects of neuroleptic and antidepressant medication,
extrapyramidal signs, myoclonia and FTD subtype (disinhibited or
apathetic) within the FTD group on the CSF levels of the
monoamine metabolites.
In addition, the degree of association between some clinical
symptoms and the CSF levels of the monoamine metabolites
within the FTD group were investigated.
MATERIALS AND METHODS

Patients
Included in the study were 30 patients with FTD (12 men and
18 women, mean age 63.6 Ϯ 9.3 years, range 40 –77 years), 33
patients with early onset AD, defined as onset of dementia before
the age of 65 years (EAD; 16 men, 17 women, mean age 63.2 Ϯ
4.7 years, range 51–74 years), 27 patients with late onset AD,
defined as onset of dementia at the age of 65 years or later (LAD;
10 men, 17 women, mean age 74.7 Ϯ 2.7 years, range 68 –79
years) and 31 controls (21 men, 10 women, mean age 65.0 Ϯ 6.6
years, range 51–77 years). The characteristics are summarized in
Table 1.
The patients who entered the study were admitted for clinical
evaluation of dementia at the neuropsychiatric diagnostic ward at
the Department of Psychiatry and Neurochemistry at Sahlgrenska
University Hospital, Molndal, Sweden, or the Department of
¨
Psychogeriatrics, University Hospital, Lund, Sweden, in the period
1987–1991. Preferably patients under 80 years of age with mild or
moderate dementia, as assessed according to the DSM-III-R
criteria (1), were included in the study. All patients underwent a

FTD was diagnosed in patients who presented with a predominant frontal lobe syndrome, i.e., personality change, lack of
personal and social awareness, disinhibition, apathy and lack of
initiative, emotional disturbances, eating disturbances, hypermetamorphosis, hyperorality, insignificant other clinical signs of dementia early in the course of disease, such as memory and
visuospatial disturbances, and absence of signs of vascular dementia, neurological disorders (e.g., multiple sclerosis, Huntington’s
chorea) and other systemic diseases. CT or MRI of the brain was
performed on all patients, and rCBF (regional cerebral blood flow;
SPECT) was performed on almost all patients. The results support
the clinical diagnosis of FTD according to the Lund/Manchester
criteria (9,33), although some patients were too severely behaviorally disturbed to undergo SPECT.
The diagnostic criteria for AD were those of “probable Alzheimer’s disease” outlined by the NINCDS-ADRDA work group
(25). The severity of dementia was evaluated according to DSMIII-R (1).
For all patients, medication with neuroleptics (n ϭ 10) and
antidepressant medication (n ϭ 11) was recorded, as were extrapyramidal (n ϭ 11) signs and signs of myoclonia (n ϭ 1). The
frequency within the FTD group was 3 for neuroleptics, 1 for
antidepressant medication, 3 for extrapyramidal signs, and 0 for
myoclonia.
For the FTD patients, individual clinical symptoms were
recorded and rated. In Molndal, we used a predecessor of the
¨
Stepwise Comparative Status Analysis [preSTEP; (40)] and the
GBS (15) scale to identify the symptoms. In Lund, the Organic
Brain syndrome Scale [OBS; (16)] was used to identify the
symptoms in FTD. Since these scales differ regarding how the
symptoms are rated, we translated the rating-points for each
symptom into a two-point scale assigned as follows: zero ϭ
symptom not observed, 1 ϭ symptom present. For each symptom,
the CSF levels of the monoamine metabolites (HVA, 5-HIAA,
HMPG) and the HVA/5-HIAA, HVA/HMPG and 5-HIAA/HMPG
ratios in the FTD patients expressing the symptom were compared
with the same variables in the FTD patients lacking the symptom.
The following clinical variables were recorded during the clinical
examination of the patients and/or observed on the ward:
Disturbance of memory, emotional reduction, emotional lability, aggressiveness, lowered mood, and apathy using GBS or OBS.
Lack of judgment using preSTEP or OBS.
Based on the clinical rating of individual symptoms, the FTD
patients were subdivided, as suggested by Neary (27), into one
group with predominating apathetic symptomatology (n ϭ 14),
and one group with predominating disinhibitory symptomatology
(e.g., aggressiveness, lack of judgement, restlessness, and social
disinhibition) (n ϭ 16).

MONOAMINE METABOLITES IN FTD AND AD
Neuropathological confirmation or refutation of these diagnoses will be carried out postmortem.
Controls
The control group included 21 men and 10 women admitted to
Sahlgrenska University Hospital, Molndal, for minor surgery (e.g.,
¨
coxarthrosis or prostate hyperplasia) under spinal anesthesia. Their
mean age was 65.0 Ϯ 6.6 years. No controls had histories,
symptoms or signs of psychiatric or neurological disease, malignant disease or systemic disorders (e.g., rheumatoid arthritis,
infectious disease). No controls were subject to psychopharmacological medication, e.g., neuroleptic or antidepressant medication.
Their cognitive status was examined using the Mini Mental State
Examination (10). Individuals with scores below 28 were not included.
CSF Analysis
Lumbar punctures, at the L3/L4 or L4/L5 interspace, were
performed in the morning with the patient remaining in bed. The
first 12 mL portion of CSF was collected in a tube and gently
mixed to avoid gradient effects (4). A blood sample was taken at
the same time. All CSF samples with more than 1000 erythrocytes
per ␮L were excluded. The CSF samples were centrifuged at
2000 ϫ g for 10 min. to remove cells and other insoluble material,
and then stored at Ϫ70°C pending biochemical analysis.
Quantitative determination of albumin in serum and CSF was
performed by nephelometry using the Behringwerke Nephelometer Analyzer (BNA; Behringwerke, Marburg, Germany). The
albumin ratio, defined as CSF albumin (mg/mL)/serum albumin
(g/L), was used as a measure for blood-brain barrier function (6).
Determination of the absolute levels of the monoamine metabolites HVA, 5-HIAA, and HMPG was performed using HPLC
with electrochemical detection, as previously described (30). Since
the monoamine metabolites in CSF are known to be highly
intercorrelated, we also calculated the ratio between the metabolites (i.e., HVA/5-HIAA, HVA/HMPG, 5-HIAA/HMPG), which
may give information about the relative disturbances between the
different transmitter systems (7).
Statistical Analysis
Before the statistical analysis, the groups were matched for age
(except the LAD group), and albumin ratio. A complete match for
sex could not be obtained before the statistical analysis.
For each of the monoamine metabolites and their ratios, a fully
factorial ANCOVA was performed with diagnostic category,
neuroleptic medication, antidepressant medication, extrapyramidal
signs and sex as factors, and the albumin ratio, body length and age
as covariates. Since only one patient had any signs of myoclonia,
this factor was excluded from the statistical analysis. Before
calculating, the continuous variables were log-transformed to meet
the demand of normal distribution. Post hoc comparisons between
individual groups were performed using Tukey’s post hoc test for
unequal n values. Kruskal–Wallis’ ANOVA was used to compare
the diagnostic groups regarding degree of dementia. According to
the Bonferroni method, the significance level was set to 0.025.
Pearson’s correlation was used for quantitative variables and
Spearman’s Rank correlation was used for qualitative variables.
Within the FTD group, a five-way ANCOVA was performed
for each of the monoamine metabolites and their ratios, with
neuroleptic medication, antidepressant medication, sex, FTD subtype, and extrapyramidal signs as factors, and age, body length and
albumin ratio as covariates. Post hoc comparisons were performed
using Tukey’s post hoc test for unequal n values. Because no

381
patient with FTD had any signs of myoclonia, this factor was not
included in the statistical analysis.
In addition, t-test was used to investigate the association
between symptoms and CSF levels of the monoamine metabolites
in the FTD group. Each symptom was calculated separately; the
t-value was used as a measure of association.
This study was approved by the Ethics Committees of Gote¨
borg University and Lund University.
RESULTS

The diagnostic groups and controls did not differ significantly
with respect to duration of disease or albumin ratio (Table 1).
There were no significant differences in degree of dementia
between the different patient groups (mild [FTD 27%, EAD 39%,
LAD 48%], moderate [FTD 63%, EAD 57%, LAD 52%], severe
[FTD 10%, EAD 4%, LAD 0%]).
The results from the five-way ANCOVA for all patients and
controls included in the study are presented in Table 2. Significant
effects were found for diagnostic groups and antidepressant
medication.
Using Tukey’s post hoc test for unequal n values, calculating
each monoamine metabolite and monoamine metabolite ratio
separately, the following significant decreases were found between
the diagnostic groups and controls: for HVA (FTD p ϭ 0.0003,
EAD p ϭ 0.016, LAD p ϭ 0.013); for 5-HIAA (EAD p ϭ 0.013,
LAD p ϭ 0.001); and for HMPG (LAD p ϭ 0.02) (Table 3). The
HVA/HMPG ratio was significantly decreased in FTD only (FTD
4.1 Ϯ 2.5 (p ϭ 0.0003), EAD 5.3 Ϯ 2.4, LAD 5.5 Ϯ 2.5, controls
6.0 Ϯ 2.4) as was the HIAA/HMPG ratio [FTD 2.5 Ϯ 0.9 (p ϭ
0.0048), EAD 3.0 Ϯ 0.8, LAD 3.2 Ϯ 1.4, controls 3.0 Ϯ 1.0]. No
difference was found in the HVA/5-HIAA ratio (FTD 1.9 Ϯ 0.6,
EAD 1.8 Ϯ 0.6, LAD 1.8 Ϯ 0.6, controls 2.0 Ϯ 0.5) between the
different diagnostic groups and controls.
When comparing the diagnostic groups, significant differences
were found for HMPG between FTD and EAD (p ϭ 0.00046) and
FTD and LAD (p ϭ 0.00032), and for HVA/5-HIAA between the
FTD and the LAD group (p ϭ 0.016).
For all patients, those with antidepressant medication had
significantly lower levels of CSF-5-HIAA (p ϭ 0.006) (Table 2).
Correlations were found between age at onset and CSF-HVA
(r ϭ 0.46) in the LAD group; and between age and the 5-HIAA/
HMPG ratio (r ϭ 0.36) in the control group. Thus, the higher the
age at onset in the LAD group, the higher was the CSF-HVA level.
The results from the five-way ANCOVA for the FTD patients
are presented in Table 4. No significant effects of neuroleptic
medication, antidepressant medication, sex, FTD subtype, or
extrapyramidal signs emerged.
When comparing the CSF monoamine metabolite levels in
FTD patients expressing a particular clinical symptom with the
levels in FTD patients lacking this symptom, analyzing each
symptom separately, the four most extreme t-values were found for
emotional lability and CSF-HMPG (t ϭ Ϫ2.3), depressed mood
and CSF-5-HIAA (t ϭ 2.3), apathy and CSF-HVA (t ϭ Ϫ2.8), and
apathy and CSF-5-HIAA (t ϭ Ϫ2.1).
DISCUSSION

The main findings of the present study are normal CSF levels
of HMPG in the FTD group, decreased CSF levels of HVA in all
patient groups, and decreased CSF levels of 5-HIAA in the EAD
and the LAD groups. A comparison of the ratios suggests that the
monoaminergic disturbances were uneven in the FTD group, with
more pronounced changes in the dopaminergic and serotonergic
systems. However, as mentioned in the introduction, the CSFHMPG levels might have been influenced by serum HMPG levels

382

SJOGREN ET AL.
TABLE 2
MAIN EFFECTS OF 5-WAY ANCOVA, ALL GROUPS INCLUDED
Variables
HVA

5-HIAA

HMPG

HVA/5-HIAA

HVA/HMPG

5-HIAA/HMPG

Factors

df†

F

p

F

P

F

p

F

p

F

p

F

p

Neuroleptics
Antidepres.
Extrapyram.
Sex
Diagnosis
Length
Alb. Ratio
Age

1,10
1,10
1,10
1,10
3,10
1,10
1,10
1,10

0.6
1.56
0.51
0.03
4.81
7.65
4.12
0.08

0.44
0.21
0.48
0.86
0.004**
0.007*
0.04
0.78

0.13
7.83
0.03
1.78
4.0
1.52
0.02
0.34

0.72
0.006*
0.86
0.18
0.009*
0.22
0.89
0.56

2.53
2.23
0.00
0.23
7.2
0.96
0.45
0.01

0.11
0.14
0.95
0.63
0.00002***
0.33
0.50
0.94

2.11
1.15
0.87
1.92
1.07
4.29
4.55
0.19

0.15
0.22
0.35
0.17
0.36
0.04
0.04
0.66

0.01
3.18
0.48
0.16
3.20
5.00
2.83
0.01

0.91
0.08
0.49
0.69
0.03
0.03
0.09
0.91

2.24
12.71
0.01
4.27
3.31
0.51
0.87
0.91

0.13
0.0005***
0.92
0.04
0.02*
0.47
0.35
0.34

* p Ͻ 0.025, ** p Ͻ 0.005, *** p Ͻ 0.0005 (adjusted according to the Bonferroni method).
† df (degrees of freedom) for each factor, respectively, and their error. df for one factor applies to all variables included. The following abbreviations
are used: Antidepres. ϭ antidepressant medication, Extrapyram. ϭ extrapyramidal signs, Alb. ratio ϭ albumin ratio, F ϭ F-value, p ϭ p-value.

and should therefore be interpreted with caution (22). As CSFHVA and CSF-5-HIAA are considered to reflect central monoaminergic metabolism (4,34), decreases most likely reflect disturbances of the central dopaminergic and serotonergic systems (4).
Degenerative changes of the monoaminergic systems in AD
have been reported, and the results of the present investigation
support this finding (13,17,29). In the present study, the disturbances of the monoamine systems seemed to be more advanced in
LAD than in EAD. This might be attributable to differences in the
distribution of the degenerative changes in EAD and LAD. Some
studies have suggested that EAD and LAD may be separate
diseases, pointing out that there are clinical (3,5), biochemical (42)
and genetic (36) findings to support this hypothesis. The differences between the EAD and LAD groups in the present study are
too small to support or refute the same notion.
The results also suggest that, in the LAD group, the earlier the
onset of dementia, the more disturbed the CSF-HVA, a finding
which might be of pathophysiological importance.
The results also suggest that antidepressant medication is
associated with decreased CSF levels of 5-HIAA in patients with
dementia. However, in the present study it is not possible to
elucidate whether CSF-5-HIAA was decreased due to antidepressant medication or due to biochemical changes accompanying
depressive symptomatology. This finding has to be considered in
future studies on the monoamine metabolites.

TABLE 3
MEAN VALUES OF THE MONOAMINE METABOLITES IN FTD, EAD AND
LAD COMPARED TO CONTROLS. RESULTS FROM POST HOC ANALYSIS
USING TUKEY’S TEST FOR UNEQUAL N’S

Diagnosis

HVA
(nmol/L)

5-HIAA
(nmol/L)

HMPG
(nmol/L)

FTD
EAD
LAD
Controls

208 Ϯ 101***
223 Ϯ 101*
200 Ϯ 76*
293 Ϯ 121

114 Ϯ 37
128 Ϯ 45*
117 Ϯ 39**
146 Ϯ 50

50 Ϯ 14
42 Ϯ 8
40 Ϯ 13*
49 Ϯ 10

All values are expressed as means Ϯ SD. The following abbreviations
are used: FTD ϭ frontotemporal dementia, EAD ϭ early onset Alzheimer’s disease, LAD ϭ late onset Alzheimer’s disease.
* p Ͻ 0.025, ** p Ͻ 0.005.

Because of lack of comparable investigations regarding sample
size and method of investigation, the results with regard to FTD
cannot be uncritically compared with those in earlier reports. The
results of the present study suggest that there is an undisturbed
noradrenergic system but marked disturbances of the dopamine
system in FTD. Regarding the noradrenergic system, the results
confirm the findings by Francis et al. (11). The dopaminergic
disturbances seem to be more advanced in FTD than in EAD and
LAD. This might reflect the location of the cortical lesion in the
dementing disorder. It is frontal (and temporal) in FTD, i.e., has a
location where dopaminergic neurons are abundant (2), and more
posterior in EAD and LAD, i.e., has a location where dopaminergic neurons are sparse. Other studies have found disturbances of
the serotonergic system in FTD (18,35). One study suggested a
correlation between disturbances of the serotonergic system and
the disordered behavior and eating disturbances often found in
FTD (26). In the present study, the lowest (most negative) t-values
were found in FTD patients with apathy (for CSF-HVA and
CSF-5-HIAA) and emotional lability (for CSF-HMPG), which
might be interpreted as an association between these symptoms
and low levels of the corresponding monoamine metabolites.
Interestingly, the highest t-values were found in FTD patients with
depressed mood (for CSF-5-HIAA), which similarly might be
interpreted as an association between depressed mood and high
levels of CSF-5-HIAA in FTD patients. No difference was found
between the FTD patients with or without apathy regarding sex or
degree of dementia (data not shown). The same applies for the
FTD patients with or without depressed mood (data not shown).
This might indicate that FTD patients with depressive traits have a
better preserved serotonergic system than the non-depressed FTD
patients.
The results of the ANCOVA within the FTD group suggest that
neither psychopharmacological medication nor FTD subtype, extrapyramidal signs or sex influences the CSF levels of the
monoamine metabolites in these patients.
The finding that CSF-HMPG is significantly higher in FTD
compared to both EAD and LAD suggests that this marker might
be useful to differentiate FTD from EAD and LAD. But it cannot
be used to differentiate FTD patients from controls. Thus, CSFHMPG cannot be used as a single marker to differentiate FTD
patients from other patients who are investigated for possible
dementia, but must be used in conjunction with other diagnostic
tools such as clinical evaluation of symptoms and signs and brain

MONOAMINE METABOLITES IN FTD AND AD

383
TABLE 4

MAIN EFFECTS OF 5-WAY ANCOVA WITHIN THE FTD GROUP
Variables
HVA

5-HIAA

HMPG

HVA/5-HIAA

HVA/HMPG

5-HIAA/HMPG

Factors

df†

F

p

F

P

F

p

F

p

F

p

F

p

Neuroleptics
Antidepres.
Extrapyram.
Sex
FTD-subtyp.
Length
Alb. Ratio
Age

1,8
1,8
1,8
1,8
1,8
1,8
1,8
1,8

0.19
1.51
0.31
0.47
2.27
0.25
0.07
0.19

0.67
0.23
0.58
0.49
0.14
0.61
0.78
0.67

0.76
0.42
2.41
0.33
1.04
0.57
0.16
1.24

0.39
0.52
0.14
0.57
0.32
0.46
0.69
0.28

3.49
0.00
1.71
1.07
0.14
0.37
1.30
3.59

0.08
0.95
0.20
0.31
0.71
0.55
0.27
0.07

0.40
0.75
4.96
0.00
1.18
0.19
0.00
0.58

0.53
0.39
0.04
0.99
0.29
0.67
0.96
0.45

0.00
0.57
0.65
0.00
0.48
0.01
0.29
0.38

0.95
0.46
0.43
0.99
0.49
0.94
0.59
0.55

0.37
0.26
0.13
0.03
1.59
0.02
1.97
0.13

0.55
0.62
0.73
0.87
0.22
0.88
0.17
0.72

† df (degrees of freedom) for each factor respectively, and their error. df for one factor applies to all variables included. The following abbreviations are
used: Antidepres. ϭ antidepressant medication, Extrapyram. ϭ extrapyramidal signs, Alb. ratio ϭ albumin ratio, FTD-subtyp. ϭ FTD subtype (disinhibited
type or apathetic type), F ϭ F-value, p ϭ p-value.

imaging. As mentioned above, the CSF levels of HMPG must be
interpreted with caution.
Because the levels of monoamine metabolites in body fluids
might be related to individual factors, such as premorbid personality traits (e.g., impulsiveness and aggressiveness) (12,24), and
because such factors were not taken into account in the present
study, we cannot rule out the possibility that they have affected the
results. This applies to the comparisons of the CSF monoamine
metabolite levels both between the different diagnostic groups and
between FTD patients with a certain symptom and those without
the same symptom.
A more differentiated grading of the symptoms in the FTD
group would perhaps have revealed greater differences. The
grading was done according to the DSM-III-R criteria (1). These
criteria are applicable to AD, but there is the possibility that they
may not be applicable to FTD. The staging of FTD is often
complicated, because cognitive symptoms may vary between FTD
patients who seem to have the same degree of functional handicap.
To our knowledge, no reliable study on the staging of FTD has
been performed to date, so we were obliged to use the DSM-III-R
criteria, which were those in common use in the years when the
patients in the present study were diagnostically evaluated.
The normal albumin ratio values for all patients and controls,
along with the absence of significant differences in albumin ratio
between the patient groups and controls, suggest that the patients
in this study had undamaged blood-brain barriers. Any differences
in this respect, however small, between the patient groups and
controls were taken into account, as the albumin ratio was included
in the statistical analysis.
Studies on the monoamine metabolite levels in the CSF of

patients with vascular dementia (38,39) have found the levels to be
decreased to the same extent as in EAD and LAD in the present
study. Whether or not FTD can be separated from vascular
dementia by means of the monoamine metabolites has still to be
elucidated.
CONCLUSIONS

The results of the present study show that the monoamine
metabolite levels in the CSF are decreased in FTD as well as in
EAD and LAD. CSF-HMPG might be used to differentiate FTD
from EAD and LAD. The results also suggest that CSF-5-HIAA is
decreased in demented patients with antidepressant medication.
Apathy might be correlated with decreased CSF levels of HVA
and 5-HIAA in FTD patients. With regard to EAD and LAD, the
results are consistent with previous reports. To our knowledge, the
present study is the first large study of the CSF levels of
monoamine metabolites in FTD.
ACKNOWLEDGEMENTS

This work was supported by grants from the Swedish Medical Research
Council (#12103 and 09946); Alma och Anna Yhlens Stiftelse; Alzheimerfonden, Lund Sweden; Handlanden Hjalmar Svenssons Forskningsfond; Konung Gustaf V:s och Drottning Victorias Stiftelse; Stiftelsen for
¨
Gamla Tjanarinnor, Stockholm, Sweden; Stiftelsen Professor Bror Gade¨
lius Minnesfond; Pfannenstills forskningsstiftelse; Stiftelsen Soderstrom¨
¨
Konigska Sjukhemmet; The Swedish Society of Medicine; Tore Nilssons
¨
Fond for Medicinsk Forskning, Stockholm, Sweden; Werner och Martina
¨
Lundgrens stiftelse; and Åke Wibergs Stiftelse, Stockholm, Sweden. We
are grateful to B. Holmberg, E. Styrud and I. Wrimell for technical assistance.

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