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Cerebrospinal fluid neopterin in human immunodeficiency virus type 1 infection.

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Cerebrospinal Fluid Neopterin in Human
Immunodeficiency Virus Type 1
Bruce J. Brew, MB, FRACP," Ravi B. Bhalla, PhD,? Morris Paul, PhD,* H. Gallardo, MS,*
Justin C. McArthur, MBBS,S Morton K. Schwartz, PhD,t and &chard W. Price, MD"
We evaluated cerebrospinal fluid (CSF) concentrations of neopterin, a putative marker of activated macrophages, in 97
subjects infected with human immunodeficiency virus type 1 who had a spectrum of neurological complications. The
highest CSF neopterin concentrations occurred in those with neurological opportunistic infections, primary central
nervous systems lymphoma, and acquired immunodeficiency syndrome (AIDS)dementia complex. In general, the CSF
concentration of neopterin was independent of CSF cell count and blood-brain barrier disruption to albumin. In the
patients with AIDS dementia complex, CSF neopterin concentrations correlated with severity of disease and decreased
in conjunction with clinical improvement following treatment with zidovudine. These results suggest that CSF neopterin, although not disease-specific, may be useful as a surrogate marker for the presence of AIDS dementia complex
and its response to antiviral therapy.
Brew BJ, Bhalla FLB, Paul M, Gallardo H, McArthur JC, Schwartz MK, Price RW. Cerebrospinal fluid
neopterin in human immunodeficiency virus type 1 infection. Ann Neurol 1990;28.556-560
Elevated serum and urine concentrations of neopterin
(dihydroneopterin), a pteridine compound that has
been considered a marker of cell-mediated immune
reactions 111, have been found to correlate with the
Walter Reed stage of human immunodeficiency virus
type 1 (HIV-1)infection [2-41. We hypothesized that
cerebrospinal fluid (CSF) levels of neopterin might
similarly correlate with central nervous system (CNS)
HIV-1 infection and its clinical counterpart, the acquired immunodeficiency syndrome (AIDS) dementia
complex (ADC) [ S } . Two recent reports 16, 71 documented increases in CSF levels of neopterin in patients
with HIV-1 infection, but included only small numbers of patients with ADC and did not examine CSF
levels of neopterin in patients with other neurological
complications of AIDS or assess what effect therapy
has on these concentrations. Consequently, we assayed
neopterin in the CSF and serum of patients at various
stages of ADC as well as those with other neurological
complications of HIV- 1 infection. We also assessed
the confounding influences of blood-brain barrier impairment and CSF pleocytosis as well as the effects of
treatment with zidovudine (ZDV) (also azidothymidine or AZT) on CSF neopterin levels.
From the Departments of *Neurology and +Clinical Chemistry,
Memorial Sloan-Kettering Cancer Center, New York, NY, and the
$Department of Neurology, The Johns Hopkins University School
of Medicine, Baltimore, MD.
Subjects and Methods
Three groups were studied: (1)HIV-I-infected patients with
various neurological complications; (2) neurologically normal, HIV-1-infected subjects; and ( 3 ) a small group of HIV1 seronegative subjects. The first group (102 samples from
86 patients) will be described in more detail. The HIV1-infected, neurologically normal subjects (16 samples, 11
patients) are participants in a longitudinal study of the
neurological manifestations of HIV-1 infection as part of the
Multicenter AIDS Cohort Study (MACS) for which they
have undergone semiannual neurologcal evaluation, magnetic resonance imaging (MRI) scan, and analysis of the CSF.
None had neurological or neuropsychological abnormalities
at the time of CSF sampling. The HIV-1 seronegative control group included 7 patients: 4 who were studied by myelography, CSF cytology, and CSF tumor markers for suspicion of metastatic cancer, but for whom the findings were
normal; and 3 patients who had syringomyelia, idiopathic
spastic paraparesis, and idiopathic peripheral neuropathy.
patients were part of a larger population of HIV-1-infected
individuals who were being prospectively followed to assess
the neurological complications of HIV-1 infection. Eightynine percent had either AIDS or AlDS-related complex as
Address correspondence to Dr Price, Department of Neurology,
Medical School, University of Minnesota, Box 295 UMHC, Minneapolis, MN 55455.
Received Feb 28, 1990, and in revised form Apr 26. Accepted for
publication Apr 30, 1990.
556 Copyright 0 1990 by the American Neurological Association
defined by systemic disease. All were examined by a neurologist, and additional diagnostic investigations were performed as indicated by the clinical setting. On the basis of
these evaluations, these patients were assigned to one of the
following groups:
Putients with ADC. Patients were included in this group if
they had: (1) characteristic neurological symptoms and signs
181, (2) compatible neuroimaging findings, and (3) exclusion
of other neurological conditions. The severity of the dementia was rated on a functionally based, staging scale ranging
from 0 to 4, such that stage 0 indicates no neurological disease, stage 0.5 indicates only equivocal symptoms of subclinical signs without functional impairment, stage I indicates
mild disturbance but preserved ability to work with minimal
limitation, stage 2 indicates moderate ADC precluding work,
stage 3 indicates severe dementia such that the patient cannot perform even basic activities of daily living, and stage 4
indicates a near vegetative state [2, 93. There were 70 CSF
assessments of 54 patients with ADC: 16 samples from patients with ADC stage 0.5, 27 from patients with stage l, 19
from patients with stage 2, 6 from patients with stage 3, and
2 from patients with stage 4 . As the number of samples from
patients with Stage 3 or 4 was small, these groups were
combined for analysis. Samples of CSF and serum that were
taken from 9 patients with ADC before and after treatment
(mean interval of 8 weeks) with ZDV were also analyzed.
Group without ADC. This consisted of 3 subgroups of
patients, namely: (1)those with primary brain lymphoma, (2)
those with CNS infections, and (3) those with headache of
undetermined cause. The subgroup with primary brain lymphoma comprised 6 patients, 4 of whom had histological
documentation of the diagnosis. In the remaining 2, presumptive diagnosis was based on characteristic clinical and
radiological findings 181; these patients additionally exhibited
no response to a therapeutic trial of antitoxoplasma treatment.
The subgroup with CNS infections included 14 patients
with the following: cerebral toxoplasmosis (1 patient), cryptococcal meningitis (3 patients), progressive multifocal leukoencephalopathy (1 patient), herpes zoster myelitis
(1 patient), cytomegalovirus (CMV) rddiculomyelitis (1 patient), probable CMV encephalitis (CMV retinitis coincident
with seizures, obtundation, and unremarkable neuroimaging
or CSF studies; 2 patients), and HIV-1-related aseptic meningitis (5 patients) [lo}.
The group with headaches comprised 12 patients who presented with severe headaches without an identified infectious, neoplastic, or psychiatric cause and unaccompanied by
CSF pleocytosis. All had equivocal cognitive complaints or
minor neurological abnormalities on examination, qualifying
them in classification as stage 0.5 ADC. All had been HIV-1
seropositive for at least 3 years. The headaches resolved over
several weeks in all patients.
Labmutoy Methods
CSF was analyzed for cell count, protein, and glucose contents, the presence of cryptococcal antigen, cytology, and
VDRL along with bacterial and fungal cultures using routine
methods. Neopterin concentrations in both CSF and serum
were assessed by radioimmunoassay (DRG, Henning, Berlin) with particular attention to minimizing light exposure.
The previously suggested normal values for neopterin levels
in CSF (1.6 +- 0.6 nmol/l) [ll] were compared to that obtained from CSF analysis of the HIV-I negative control
group. The upper normal limit for neopterin levels in serum
was taken to be 8.7 nmolll {127. CSF and serum values for
albumin concentration were determined in order to serve as
an index of the integrity of the blood-brain barrier; a CSF-toserum albumin ratio, multiplied by lo3, of greater than 6.5
was considered abnormal [l 31.
Statistical methods included analyses of variance and Student-Newman-Keuls post hoc tests in comparisons of discrete disease groups and ADC stages. Continuous variables
were compared using Pearson correlations. Alpha (significance) level was established at p I0.05. Changes in neopterin concentration before and after ZDV treatment were
compared using the paired t test. Those neurologically abnormal patients who had more than one CSF analysis were
included in the main data set as independent observations
because the CSF was repeated for assessment of clinical
change. These analyses were carried out using SPSS/PC+
software (SPSS Inc, Chicago, IL).
As shown in the Table, the mean CSF concentration of
neopterin for the HIV-1 seronegative control group
was 3.5 nmol/l, somewhat higher than that found by
Fredrikson and associates El 11. While significantly elevated (more than twice that of seronegatives) neopterin concentrations were noted in the seropositive,
neurologically normal group, markedly higher concentrations (8 to 16 times normal) were found in the
symptomatic patients; the CSF neopterin concentration was highest in those with CNS infections, followed, in turn, by those with ADC, those with lymphoma, and those with headache. The concentrations
in all disease groups were different from those in the
seronegative controls and concentration in the group
with ADC was also different from that in the seropositive control group.
In patients without confounding CNS disorders,
CSF neopterin concentrations correlated with the
ADC stage (Fig 1) (r = 0.54, p < 0.0001). Whereas
there was no difference between those with ADC
stage 0.5 and the neurologically normal seropositives
( p = 0.481), all patients with ADC stages 1 or greater
had CSF neopterin concentrations outside the range of
the HIV-1 seronegative group, and 89% of these patients had concentrations greater than 16.0 nmoV1, the
upper limit of the 95% confidence level of the HIV-1
seropositive, neurologically normal group. In contrast
to CSF levels, serum neopterin concentrations did not
correlate with severity of ADC (r = 0.039).
There was no discernible relationship between neopterin concentration in the CSF and the number of
white blood cells in the CSF. Indeed, only 10 samples
from 5 patients had CSF cell counts greater than 5
Brew et al: CSF Neopterin in HIV-1 557
CSF and Serum Neoptevin Concentrations in Different Patient Groups
Neopterin (nmoV1
Patient Group
No. of Samples
HIV-1-infected, neurologically normal
AIDS dementia complex
CNS infection
3.5 2 0.4
8.2 t 1.0b
26.5 f 5.1b,‘
Not available
13.7 ? 1.8
* ll.?
“Normal range: CSF, < 5.0 nmoul; serum, < 8.7 nmoV1.
bDiffered from seronegative controls ( p < 0.001).
‘Differed from seropositive, neurologically normal controls ( p < 0.0001).
Fig I . CSF neopterin concentration as a function of the stage of
the AIDS dementia complex (ADC).
cells/mm3 and the neopterin values in these did not
differ from those of other patients in the same ADC
stage. Analysis of blood-brain barrier integrity to albumin for the whole data set, including the ADC group,
failed to reveal any association with CSF levels of neopterin ( r = 0.14, p = 0.43). Furthermore, when
the group with ADC was divided into those without
(38 samples) and those with (32 samples) blood-brain
barrier impairment to albumin, analysis revealed that
the samples from patients with an intact blood-brain
barrier evidenced a high correlation between CSF neopterin level and ADC stage (r = 0.64, @ = 0.0001),
whereas those with an impaired blood-brain barrier to
albumin had a less significant correlation ( r = 0.39, p
= 0.01). Lkewise, although there was a correlation
between CSF and serum neopterin levels both for all
patients assessed ( Y = 0.45, @ < 0.0001) and for the
patients with ADC who were considered separately ( r
= 0.49, p < O.OOOl), this correlation was lost when
558 Annals of Neurology Vol 28 No 4 October 1990
Fig 2. CSF neoptwin concentrations before and afer treatment
with zidovudine CZDV).Values have been converted to a log
scale in order to encompass the wide range of values and the
changes with treatment.
those with blood-brain barrier dysfunction were considered separately.
ZDV treatment of patients with ADC resulted in a
reduction of CSF neopterin levels in each of the 9
assessed (Fig 2, p = 0.032), while serum concentrations in these patients did not significantly change
(mean pretreatment level of 28.8 2 5.2 nmol/l only
fell to 20.2 t 4.9 nmol/l after treatment, p = 0.23).
Our results indicate that the CSF concentration of
neopterin is elevated in HIV-1-infected patients who
have a variety of neurological complications. The fact
that the highest CSF levels were observed in patients
with CNS infections and primary CNS lymphoma is
consistent with the concept of neopterin being related
to “activated” cellular immunity [l}and with reports of
elevated serum neopterin concentrations in systemic
infections and malignancies {14, 15}. Elevation of CSF
neopterin, like other recently reported surrogate
markers, such as beta-2 microglobulin 1161 and quinolinic acid C171, is thus not disease-specific. Nonetheless, the finding of greatest interest is the consistent
elevation of CSF neopterin in patients with ADC and
its general correlation with severity of ADC. These
results, which are in keeping with those recently reported in two smaller series 16, 71,are potentially important in relation to both pathogenesis and clinical
management of ADC.
Activated macrophages, and to 3 much lesser extent
T lymphocytes, produce neopterin, and it has been
noted that interferon gamma can induce neopterin
through its effect on guanosine triphosphate (GTP)
cyclohydrolase, the first enzyme in the conversion of
GTP to dihydroneopterin triphosphate, the precursor
of neopterin 1181. Although the source of elevated
CSF concentrations of neopterin in these patients was
not directly studied, it is unlikely that CSF inflammatory cells alone were responsible [l 11since only a very
few patients had discernible pleocytosis. Similarly, several observations suggest that alteration of the bloodbrain barrier likely did not explain the high concentration of CSF neopterin, particularly in the patients with
ADC: (1) There was no correlation between CSF
neopterin concentration and blood-brain-barrier impairment to albumin; (2) CSF neopterin concentration
correlated with severity of ADC, while serum neopterin concentration did not; and (3) in several patients
the CSF concentration of neopterin exceeded the
serum concentration. A similar lack of correlation of
neopterin with CSF cell count and blood-brain barrier
was noted by Fuchs and colleagues [6] and Sonnerborg
and coworkers 17).
The CNS parenchymal cells producing neopterin
are not known, but major candidates are infiltrating
macrophageimononuclear cells and ontogenetically related [191 microglial cells. However, because neuropathological examination of brains from patients with
ADC stage 0.5 or 1 characteristically shows only scant
inflammatory or microglial infiltrates 2201, it is also
possible that intrinsic neural cells, perhaps proliferating astrocytes, may produce neopterin when they are
stimulated by cytokines. Indeed, these findings may
provide insight into the role of “immunopathological”
events in the pathogenesis of ADC. The elevation of
CSF neopterin concentration with increasing severity
of ADC and the decline with antiviral therapy are
compatible with the view that the virus load “drives”
immune-cell activation and putative CNS immunopathology [21). The plateau or possible slight reduction
of neopterin in the patients with the most severe ADC
(stages 3 and 4 ) may indicate a predominant role of
CNS viral infection rather than immunopathology in
such patients [2 11. Whether neopterin itself contributes to CNS dysfunction is highly speculative. Shen
and associates E22) recently found that reduced
pterins, for example neopterin and dihydroneopterin,
can downregulate GTP cyclohydrolase 1 and thereby
reduce the concentration of tetrahydrobiopterin, an essential cofactor in the synthesis of dopamine, serotonin, and noradrenalin. It is conceivable that some of
the basal ganglion dysfunction that is characteristic of
ADC might result from neopterin-induced perturbation of these neurotransmitters.
Elevation of CSF neopterin concentrations in neurologically asymptomatic subjects and the further elevation in patients with headache of unknown cause await
further clarification. The most likely explanation for
elevation in the asymptomatic group relates to subclinical disease activity. This is consistent with other CSF
abnormalities in asymptomatic patients E23-28). It
also is in keeping with the hypothesis that CNS HIV-1
infection is actively “controlled” by effective immune
responses early in the course of infection 1211. Headache is a common, but poorly understood, problem in
HIV- 1 infected patients. Elevated CSF concentrations
of neopterin in such patients may relate in part to the
emergence of neurological dysfunction in this group or
may suggest that headache relates to inflammatory processes not reflected in CSF pleocytosis. Additional
studies are needed to resolve these questions.
Whatever the mechanism of increased levels of CSF
neopterin, our results suggest that assessment of this
“surrogate marker” may at times prove useful in diagnosis and therapeutic monitoring of ADC. Thus, while
increased CSF neopterin is clearly not disease-specific,
once clinical and laboratory evaluations have eliminated other opportunistic CNS infections or tumors,
assessment of this marker may be 3 useful adjunct
to establishing diagnosis of ADC, and particularly its
differentiation from psychiatric ( e g , anxiety and
depression) and degenerative (e.g., Parkinson’s and
Alzheimer’s diseases) disorders in HIV- 1-infected patients. Our present results suggest that a CSF neopterin concentration of 16.0 nmoUl might serve as a
cutoff of “normal” in the HIV-1-infected patient,
although further observations are needed to more
precisely define: the limits of CSF neopterin in HIV-1infected, neurologically normal individuals; the possible effects of systemic infections on CSF concentrations; and the prognostic value of elevated neopterin
concentrations in relation to the development of
With respect to the use of CSF neopterin levels
in monitoring therapy for ADC, further studies are
needed to determine the clinical and pathobiological
significance of the striking decline in CSF neopterin
noted in our patients given ZDV. The time c o m e of
this response and, particularly, its utility as an early
predictor of neurological improvement need to be explored. If this proves to be a reliable surrogate marker
Brew et al: CSF Neopterin in HIV-1 559
for therapeutic efficacy in the CNS, measurement of
CSF neopterin concentration would then represent an
important advance in evaluating new treatments for
Supported by U.S. Public Health Service research grants NS 25701,
NS 26643, A1 72634, and RR 00722, and a grant from the Rudin
We thank William Wolf for help in data management and Howard
Thaler and John Keilp for assistance with statistical analysis.
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