Journal of Neuroimmunology 138 (2003) 156 – 161

www.elsevier.com/locate/jneuroim

Autoimmune markers in HIV-associated dementia

Steven E. Schutzer a,*, Michael Brunner b, Howard M. Fillit c, Joseph R. Berger d
a
Department of Medicine, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA
b
Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
c
Institute for the Study of Aging and the Department of Geriatrics, Medicine and Neurobiology, Mount Sinai School of Medicine, New York, NY 10029, USA
d
Departments of Neurology and Internal Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, USA
Received 10 January 2003; accepted 19 March 2003

Abstract

The etiology of HIV-associated dementia (HAD) is still unknown although direct viral effects have not been supported. Although
evidence supports a role for products of activated macrophages, other evidence suggested the possibility of associated autoimmune
phenomena at least as a marker. In a blinded analysis, non-HIV-infected whole brain material was immunoblotted with samples of serum, and
in certain cases cerebrospinal fluid (CSF), from HAD patients and controls. Distinct antibrain antibodies were detected in 11/12 of HIV+
HAD patients, 7/19 of HIV+ patients without HAD, and 0/11 HIV seronegative controls who were either healthy or had other neurologic
diseases. Reactivity against control tissue was negative. Though the etiopathogenetic relation of these antibrain antibodies remains to be
delineated, the data suggest that they may be a marker of HAD.
D 2003 Published by Elsevier Science B.V.

Keywords: AIDS; HIV dementia; Autoantibodies; Antibrain antibodies

1. Introduction supported. However, indirect effects of the viral infection

The acquired immune deficiency syndrome (AIDS) is
etiologically linked to the human immunodeficiency virus
(HIV). The central nervous system (CNS) is frequently af-
fected (Glass et al., 1993; Price, 1995; Sidtis and Price, 1990).
The most frequent neuropsychiatric disorder is a disabling
subacute encephalitis, termed the AIDS dementia complex
(ADC) or HIV-associated dementia (HAD) which may be, in
some patients, the earliest manifestation of the viral infection
(Glass et al., 1993; Price, 1995; Sidtis and Price, 1990; Navia
et al., 1986a). Although HIV has been documented in the
brain, the precise mechanism by which HIV infection leads to
cognitive dysfunction remains uncertain. On occasion, HIV-
associated dementia may be the heralding manifestation of
AIDS. Additionally, florid dementia may occur with minimal
histopathological abnormalities (Navia et al., 1986a,b) in
some of these patients. Direct viral infection of neural cells
as an important mechanism for the dementia has not been
* Corresponding author. Tel.: +1-973-972-4872; fax: +1-801-383-
8534.
E-mail address: schutzer@umdnj.edu (S.E. Schutzer).
may prove to be important pathogenetically. Some factors
that have been invoked include products of activated macro-
phages as directly cytotoxic for neurons or causing neuronal
dysfunction (Kelder et al., 1998).
Several lines of evidence suggest an autoimmune process
could be associated with HAD: (1) The finding of autoanti-
bodies (autoAbs) in AIDS patients directed against platelets,
sperm, and lymphocyte antigens (Ags) and myelin basic
protein (MBP) (Pruzanski et al., 1983; Daugharty et al.,
1985; Dorsett et al., 1985; Rodman et al., 1985; Rubinstein
et al., 1984; Stricker et al., 1987). (2) The known cross
reactivity between certain lymphocyte Ags and brain com-
ponents (Funke et al., 1987; Gabuzda and Hirsch, 1987;
Klatzmann et al., 1984; Bresnihan et al., 1979; Solinger and
Hess, 1991). (3) The known association between certain
viral infections and subsequent autoimmune disease involv-
ing the CNS (Johnson et al., 1984). (4) The finding of
antineuronal Abs in the cerebrospinal fluid (CSF) in CNS
lupus, and the linkage of lupus psychosis to a specific
autoAb (Bluestein, 1987; Bonfa et al., 1987). (5) The
occurrence of Guillain – Barré Syndrome, a presumed
humorally mediated autoimmune disorder, early in the
course of HIV infections (Navia et al., 1986b). (6) The

0165-5728/03/$ - see front matter D 2003 Published by Elsevier Science B.V.

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 S.E. Schutzer et al. / Journal of Neuroimmunology 138 (2003) 156–161
finding of increased intrathecal IgG synthesis in AIDS
patients of which only 0.2 –2.8% is directed against HIV
(Resnick et al., 1985).
Early studies with different methods produced different
results with respect to antibrain Abs. Although they did not
examine CSF, Kumar et al. (1989) demonstrated antibrain
serum Ab against a 45-kDa protein of human hippocampal
tissue. They found that 14/18 AIDS-dementia sera samples
were positive for the brain reactive Ab as were 4/12 samples
from AIDS patients without the dementia. Mathiesen et al.
(1989) demonstrated CSF autoAb complexed to MBP in
HAD patients. In contrast to this, Lenhardt and Wiley (1989),
investigating the possibility of antibrain immunoglobulin in
AIDS patients, were not able to find a significant association.
Trujillo et al. (1994) did not find any distinct associations.
We decided to investigate the existence of an antibrain
antibody in the setting of HAD more thoroughly as a marker
for the existence of the disorder because it would have great
clinical utility. Furthermore, if autoAbs contributed to the
pathogenesis of the disorder, their effect might be poten-
tially reversible. This reversibility is illustrated by the CNS
lupus psychosis syndrome; the classic humoral autoimmune
disease, myasthenia gravis, caused by autoAbs directed
against the nicotinic acetyl choline receptor; Guillain –Barré
Syndrome responsive to plasmapheresis; and the Lambert –
Eaton myasthenic syndrome with autoAbs directed against
the presynaptic active zone sites.
We investigated the hypothesis that humoral immune
mechanisms could be occurring in HAD by several methods
probing for serum and CSF antibrain Abs.
2. Materials and methods
2.1. Sample collection, patient population, clinical evalua-
tion
Serum and CSF samples were obtained from 31 ran-
domly selected HIV-1 positive subjects from among 185
subjects participating in a longitudinal, prospective study of
the neurological complications of HIV infection performed
at the University of Miami, Miami, FL. Subjects had a
complete clinical evaluation which included a detailed
history, general physical and neurological examination,
and extensive neuropsychological battery. The neurological
examination included assessments of muscle tone, extremity
dexterity, gait, balance and postural stability, and frontal
release signs (snout, glabellar, involuntary grasp). A modi-
fied version of the mini-mental status examination (Folstein
et al., 1983) was administered. This battery was comprised
of tests of orientation, simple calculations, ability to follow
commands, spelling forward and backward, naming and
recent memory and was graded on a 40-point scale. The
detailed neuropsychological battery included tests designed
to evaluate language function, judgment in reasoning, visuo-
spatial constructive abilities, auditory and visual attention,
157
the ability to shift sets, and memory for verbal and figural
material (Levin, 1994).
HIV-1 serological status was determined in each by
enzyme-linked immunoabsorbent assay (ELISA) and con-
firmed by Western blot. Laboratory studies also included
blood for B12 levels, VDRL, and FTA-ABS. Magnetic
resonance image (MR) of the brain was obtained on all
subjects. As part of the study design, lumbar puncture was
performed on all HIV-1 positive subjects. Routine CSF
analysis included cell count and differential, protein, glu-
cose, VDRL, FTA-ABS, immunoelectrophoresis, and viral
cultures on human foreskin fibroblasts, human embryonic
lung fibroblasts, and primary monkey kidney cells. Subjects
with features of encephalopathy also had detailed micro-
biological studies of their CSF including bacterial stain and
cultures, fungal cultures, India ink preparations, and cryp-
tococcal antigens. All subjects provided informed consent.
This study was approved by the institutional review board of
the University of Miami School of Medicine.
AIDS dementia complex (ADC now termed HAD) was
defined as in accordance with the Working Group of the
American Academy of Neurology AIDS Task Force (1991).
Each experienced a ‘‘loss of intellectual abilities of suffi-
cient severity to interview with social or occupational
functioning.’’ The criteria also included: (1) an acquired
abnormality in at least two cognitive and abilities present for
1 or more months; acquired abnormality in order to function
or performance end/or declining in motivation, or emotional
control or change in social behavior; (3) no clouding of
consciousness; and (4) no other identifiable etiology. As
indicated above, all subjects were systemicatically screened
for confounding factors that might contribute to their
dementing illness. HIV-infected subjects with dementia that
may have resulted from a neoplastic, nutritional, metabolic,
or infectious (other than HIV) etiology were excluded from
this study. Also excluded were those with a severe premor-
bid psychiatric disorder, chronic seizure disorder, or head
trauma with residual dysfunction.
2.1.1. Control samples
Control samples came from our bank of paired CSF and
sera on normals and patients with other neurological dis-
eases including neurologic Lyme disease with cognitive
dysfunction, viral and bacterial meningitis, amyotrophic
lateral sclerosis, Guillain – Barré syndrome, herpes encepha-
litis, Creutzfeldt – Jakob disease, multiple sclerosis, syphilis,
sciatica, transverse myelitis, lupus, Alzheimer, and back
pain. The CSF normals derive from patients who had
symptoms such as back pain, had negative workups, and
eventually recovered and remained symptom-free. Many
specimens were obtained before the AIDS epidemic.
2.2. Analysis of autoAbs against brain
We initially used a traditional alkaline phosphatase West-
ern blot technique and then modified the procedure to a
158 S.E. Schutzer et al. / Journal of Neuroimmunology 138 (2003) 156–161
biotin – avidin blot to analyze autoAb in the CSF and serum
samples by blotting normal brain. Control Ags included
HIV negative human liver and neural Ags. Indirect immu-
nofluorescence of brain was used initially and primarily to
screen large numbers of samples.
2.2.1. Alkaline phosphatase Western blots
Target Ags were optimized for protein, run on 10%
SDS-PAGE gels, then transferred to nitrocellulose mem-
branes. The resultant blots were probed with the appro-
priate class-specific alkaline phosphatase-conjugated
antihuman immunoglobulin antisera, then, stained. Molec-
ular weight standards and HIV lysates or the major core
and envelop proteins were run in tandem to these
samples to provide markers and distinguish them from
HIV Ags.
Target Ags included:
1. Normal human brain. This was obtained from a
subject within hours of death, and was snap-frozen
in liquid nitrogen and stored at 70 jC. Samples
were prepared as described by Hall and Choppin
(1981).
2. Structural brain components Ags included galacto-
cerebroside (Sigma C-8752, Type I), and ganglioside
(Sigma G-2250, Type II) as positive controls in
combination with the corresponding monoclonal Ab
probe.
3. HIV lysates and Ags were used to distinguish an Ab
directed against brain from that against the HIV itself.
2.3. Biotin –avidin Western blots
2.3.1. Brain preparation
A piece of brain which had been flash-frozen at autopsy
and kept at 70 jC was sliced with scalpel, and 0.226 g
was placed in a (P35) petri dish on ice with 1 ml of Laemmli
gel sample-reducing buffer consisting of 20% SDS, 10% 60
mM Tris – HCL (pH 6.8), 0.1 M DTT, 0.005% bromphenol
blue, 1 mM PMSF. After mincing with a scalpel, the
solution was forcibly passaged up and down 10 times each
through an 18-G followed by a 21-G needle. A portion was
further diluted in sample buffer, and undiluted aliquots were
frozen at 70 jC for later use. Before electrophoresis, the
diluted sample was boiled for 3 – 5 min, cooled, and applied
to gel.
2.3.2. Gel electrophoresis
Twelve percent SDS-polyacrylamide (7  8 cm) mini-
gels, 0.75 mm thick with stack were run using Hoeffer
apparatus (Mighty small, SE 250). Five microliters of a
0.1% Methyl Green dye solution was added to each well to
serve as a blotted dye front marker (for chamber orienta-
tion). Samples including SDS-PAGE biotinylated low-range
molecular weight standards (Bio-Rad) diluted in sample
buffer containing 5% beta-mercaptoethanol (and in some
lanes, pre-stained SDS-PAGE standards) and diluted brain
were all boiled 3– 5 min, cooled, and applied to wells of the
gel and 125 constant volts applied until samples lined up at
bottom of stacking gel, and then power supply switched to
200 constant volts until dye front marker ran to bottom of
gel.
2.3.3. Electrotransfer
Gels were removed from plates and equilibrated for 15
min in transfer buffer (25 mM Tris, 190 mM Glycine, 20%
Methanol), put in a sandwich containing wetted nitrocellu-
lose (MSI Nitro-Bind 0.2 Am) and transferred for 1 h at 100
V (approximately 0.25 Amps) using Hoeffer apparatus (TE
22). Membrane blots were measured for dye front migra-
tion, appropriately marked if pre-stained markers were not
used, rinsed, dried, and could be stored in the cold or stained
for further use.
2.3.4. Immunoblot stain
Nitrocellulose blots were stained in a 0.2% Ponceau S
solution (Sigma) which served two purposes. Firstly, the
stained bands along with the Methyl Green dye front
marker helped to emboss the blot in proper alignment
with the 28 mini-well immunoblotter (Immunetics). Sec-
ondly, the light red bands confirm that approximately 1
Ag of protein/well, the lower limit of Ponceau S, was
obtained during blotting, corresponding to the 1:64 dilu-
tion, 10-Al sample of brain initially applied to the original
gel well predetermined by a limiting dilution experiment
of brain using secondary reagents in the biotin –avidin
assay.
The membrane was blocked in Tris-buffered saline
(TBS, 50 mM Tris – HCL, 0.2 M NaCl, 3 mM KCl, pH
7.5, 0.02% Azide) containing 1% Non-Fat Dry Milk
(Carnation) and 1% normal goat serum (NGS) for 30 min
in a tray (on a slowly rocking platform (Reliable Scien-
tific). After rinsing in TBS, the membrane was placed in
the-28 lane miniblotter apparatus (MN28, Immunetics), and
lanes aspirated dry with suction. Patient’s serum samples
were diluted 1:100 in Tris-buffered saline –tween 20 (0.1%
v/v) (TBS-T) containing 1% NGS, patient CSF was used
neat or at 1:10 dilution, and positive control mouse mono-
clonal anti-neurofilament 68, NR-4 (Sigma) was diluted
1:500.
Sixty microliters was pipetted into each lane (diluent
alone in secondary reagent controls, and TBS in biotiny-
lated standard wells) and miniblotter was slowly rocked
(setting of 2.8 on rocking platform) for 2 h for the
primary incubation. Wells were aspirated and filled with
TBS-T and miniblotter rocked rapidly for 5 min. This
was repeated with TBS-T three more times and served as
the standard wash procedure between reagent incubations.
Secondary Abs consisted of goat biotinylated antihuman
IgG (gamma chain specific), biotinylated antihuman IgM
(mu chain specific) which were diluted 1:250, and bio-
tinylated horse anti-mouse IgG (H + L) which was diluted
 S.E. Schutzer et al. / Journal of Neuroimmunology 138 (2003) 156–161
1:500 (Vector Laboratories) in TBS-T plus 1% NGS.
After washing, secondary Abs were added and incubated
with slow rocking for 30 min. During this time, the
avidin (reagent A) and biotinylated alkaline phosphatase
(reagent B) complex was formed by adding 10 Al of
reagent A and 10 Al of reagent B to 1 ml of TBS-T and
vortexing. After standing at room temperature (RT) for 30
min, it was further diluted by adding 2 ml of TBS-T. All
wells of the miniblotter, including the biotinylated MW
standards were washed four times, and the diluted avi-
din – biotinylated alkaline phosphatase complex (ABC)
solution was added for a further 30-min incubation. After
standard wash, the membrane was removed from the
miniblotter, rinsed once with TBS and developed in a
tray using Vector Kit II Alkaline phosphatase substrate in
100 mM Tris –HCl pH 9.5 buffer, washed twice with
water and dried.
3. Indirect immunofluorescence
This assay was used as preliminary screen of the
concept of antibrain Abs using a different set of patient
samples. Undiluted CSF and diluted serum (1:5, 1:10,
1:20) were overlaid on sections from normal human brain
which had been obtained within 2 h after death and snap-
frozen in liquid nitrogen and stored at 70 jC until use.
Brain sections were cut to 10-Am thickness by a micro-
tome cryostat, placed on microscope slides, desiccated
overnight at 4 jC, placed in acetone for 1 min, washed in
phosphate-buffered saline (PBS), and then overlaid with
the CSF or serum as above for 1 h at room temperature.
After washing again in PBS, a 1:40 dilution of fluores-
cein-labeled goat antihuman IgG (Sigma) was applied for
30 min. The slides were rewashed in PBS and mounted
in 1% glycerol/PBS. They were read under epifluores-
cence with a Zeiss photomicroscope III (Garvey et al.,
1977).
Liver and spleen served as tissue controls.
3.1. Positive indirect immunofluorescence of HIV+ sera on
normal mouse brain: demonstration of antibrain Abs
Sera from six HIV seronegative patients, eleven HIV+
subjects, including five HAD subjects, two patients with
Alzheimer previously known to be reactive and serum
known to react with neurofilament, were tested by indirect
immunofluorescence for the presence of Ab staining mouse
brain. AIDS patients (10/11) were positive; 5/5 of the AIDS-
dementia patients were positive; 0/6 other disease patients
were positive. Other control samples, i.e., without the first
Ab step, were negative. Mouse liver did not exhibit the same
staining pattern. These findings suggested that IgG directed
against brain tissue was present in the serum of AIDS
patients with dementia and perhaps those with subclinical
disease.
159
3.2. Western blot demonstration of specific antibrain Abs in
serum and CSF
Western blots against non-HIV-infected brain tissue
demonstrated specific IgG antibrain autoAbs in cerebrospi-
nal fluid (CSF) and serum from HAD patients (n = 6).
Reactivity was seen against two antigens between 41 and
48.5 kDa; and a third between 48.5 and 58 kDa. The stained
bands were distinct from those of HIV lysates probed in
parallel by these patients’ sera. As a control, multiple
sclerosis serum and CSF did not stain any of these bands.
This suggested that there are at least some auto-IgG Abs
reactive to brain components in AIDS patients with demen-
tia and that they appear to be distinct from anti-HIV Abs and
are not found in controls. We considered these findings as
preliminary but provocative to perform a blinded study with
HAD patients and controls using a more sensitive biotin –
avidin blot.
3.2.1. Detection of antibrain Abs in serum and CSF from
HAD patients and controls by biotin – avidin Western blots
In a blinded analysis, the brain material was probed
with samples of serum and cerebrospinal fluid from
clinically well-defined groups from the University of
Miami. Distinct antibrain brain Abs were detected in 11/
12 of HIV+ HAD patients, 7/19 of HIV+ patients without
HAD, and 0/11 HIV seronegative controls who were
healthy or had other neurological disorders including
cognitive dysfunction. In one HAD patient, the reactive
antibody was detected only in the CSF. Both IgM and IgG
antibrain Abs were detected. Statistical analysis by Fisher
exact test showed these findings to be significant (see
Table 1). The weight (kDa) of these Ags were: 26, 31, 36,
40, 45, 55, 60, 80 –82. A representative blot is shown in
Fig. 1.
The data suggest that differences between HAD+ and
HAD HIV+ is in the percentage having some antibrain
Abs rather than the total number of bands on the blot.
Stated another way, it may be that HAD HIV patients
who have positive bands are on their way to developing
clinically detectable HAD but are not yet at that thresh-
old.
Table 1
Detection of distinct antibrain antibodies (ABA) in HIV+ patients (also
showing statistical significant association in both groups compared to non-
HIV-infected controls without dementia)
Group Antibrain No antibrain P value (Fisher)
Abs Abs compared to non-HIV
(>four bands) (zero bands) controls as reference
HAD+, HIV + 11 1 8.9  10 6
HAD , HIV + 7 12 2.5  10 2
Non-HIV controls 0 11 reference
Suggests possible marker role for ABA in HAD group and possible
predictive marker of which HIV+ patients might progress to HAD.
160 S.E. Schutzer et al. / Journal of Neuroimmunology 138 (2003) 156–161
Fig. 1. Probe for reactive serum IgG to normal (non-HIV infected) brain. Lanes 1, 9, 10, and 12 show reactivity from HIV+ but not encephalopathy patients
(representing 7 of 19 patients). Lanes 2 – 8, 11 show reactivity from HIV+ HAD patients (representing 11 of 12 patients). Note that the major difference is in the
percentage of each subset reacting to these antigens.
Though the etiopathogenetic relation of these autoAbs
remains to be delineated, the data suggest that they may be a
marker of HAD.
4. Discussion
The results of this set of experiments suggest that anti-
brain Abs may be associated with the HAD. The data, while
supporting a humoral autoimmune process in this syndrome,
do not distinguish between the role of the antibody as a
marker for the disease or a pathogenetically important
molecule.
Our studies began in an open exploratory fashion.
Indirect immunofluorescence as performed on freshly
obtained mouse brain was an exploratory and screening
study. This preceded the use of human brain tissue. Com-
parison to controls including normal individuals when
employing the Western blot is especially important because
even if autoAbs are established as etiologically important in
the brain their origin would still be unknown. Questions that
arise are: (1) does the antibrain autoAb arise de novo after
the disease; is it present in undetectable amounts even in
normals, but produced by activated B cells after HIV has
perturbed the immune system; and (2) is it a cross reactive
Ab directed against epitopes of HIV, altered brain Ag, or
other altered tissue Ags such as those on lymphocytes?
These are unknown, but the preliminary evidence demon-
strating Ab reactivity distinct from reactivity against HIV
Ags suggests this is not a simple cross reaction.
Precedent exists for an infectious agent or its components
triggering an autoimmune process that ultimately results in
neurologic symptoms. Johnson et al. (1984) have provided
evidence that a cell-mediated immunologic reaction trig-
gered by measles is responsible for post-infectious measles
encephalomyelitis. Neuroparalytic accidents following
administration of vaccines based on neural tissue have also
been attributed to immune hyperreactivity. Hemachudha et
al. (1987), in a study of encephalomyelitis and polyneuritis
following rabies vaccination, identified myelin basic protein
(MBP) as an encephalitogen.
Although not of proven pathogenetic significance, in
multiple sclerosis (MS), autoAbs directed against brain
components have been described (Ryberg, 1982) and
anti-MBP in the CSF (even when hidden in the immune
complex form) has been demonstrated by several authors
(Coyle and Procyk-Dougherty, 1984; Coyle, 1985; Warren
and Catz, 1986). Toh et al. (1985) have demonstrated
autoAbs against neurofilamental proteins from patients
with the subacute spongiform encephalopathies of kuru
and Creutzfeldt – Jakob disease. Also noted was similar
staining by some Alzheimer patients and some normal
individuals (Bahmanyar et al., 1983). Gajdusek (1985)
hypothesized that autoAbs interfering with axonal transport
could be a common pathogenetic mechanism in certain
CNS diseases.
Whether these antibrain antibodies play any role in the
pathogenesis of HAD remains to be determined. Conceiv-
ably, HIV could cause brain dysfunction either by cross
reactivity with either normal or altered brain Ags or in fact a
de novo response against an altered Ag. Conversely, the
profound immunosuppression of AIDS, could unleash a
normally suppressed autoAb.
In summary, we believe these results indicate that anti-
brain Abs can be demonstrated in patients with HAD and
may possibly be demonstrated in those who might have
subclinical disease. This information may lead to new
directions in the investigation of the pathogenesis of
HAD. Certainly, the etiopathologic role could only be
determined with future studies. The findings do indicate
that further investigation in these area is warranted because
of the potential to identify a marker of the syndrome at a
point when some reversibility of the manifestations, and
consequently, improvement of quality of life may be
achieved with therapeutic intervention (Cherner et al.,
2002; Ernst et al., 2002).
 S.E. Schutzer et al. / Journal of Neuroimmunology 138 (2003) 156–161
Acknowledgements
This study was supported in part by grants from the NIH-
NINCDS (PO1 NS 25569).
References
Bahmanyar, S., Moreau-Dubois, M.C., Brown, P., Cathala, F., Gajdusek,
D.C., 1983. Serum antibodies to neurofilament antigens in patients
with neurological and other diseases and in healthy controls. J. Neuro-
immunol. 5, 191 – 196.
Bluestein, H.G., 1987. Neuropsychiatric manifestations of systemic lupus
erythematosus. N. Engl. J. Med. 317, 309 – 311.
Bonfa, E., Golombek, S.J., Kaufman, L.D., Skelly, S., Weissbach, H.,
Brot, N., Elkon, K.B., 1987. Association between lupus psychosis
and anti-ribosomal P protein antibodies. N. Engl. J. Med. 317,
265 – 271.
Bresnihan, B., Oliver, M., Williams, B., Hughes, G.R., 1979. An antineuro-
nal antibody cross-reacting with erythrocytes and lymphocytes in sys-
temic lupus erythematosus. Arthritis Rheum. 22, 313 – 320.
Cherner, M., Masliah, E., Ellis, R.J., Marcotte, T.D., Moore, D.J., Grant, I.,
Heaton, R.K., 2002. Neurocognitive dysfunction predicts postmortem
findings of HIV encephalitis. Neurology 59, 1563 – 1567.
Coyle, P.K., 1985. CSF immune complexes in multiple sclerosis. Neurol-
ogy 35, 429 – 432.
Coyle, P.K., Procyk-Dougherty, Z., 1984. Multiple sclerosis immune com-
plexes: an analysis of component antigens and antibodies. Ann. Neurol.
16, 660 – 667.
Daugharty, H., Chorba, T.L., Personette, D.W., Savoca, K.V., MacDonald,
V., 1985. Immunoglobulin bound to platelets as immune complexes or
specific antibody in specimens from acquired immunodeficiency syn-
drome and immune thrombocytopenic purpura. Diagn. Immunol. 3,
205 – 214.
Dorsett, B., Cronin, W., Chuma, V., Ioachim, H.L., 1985. Anti-lymphocyte
antibodies in patients with the acquired immune deficiency syndrome.
Am. J. Med. 78, 621 – 626.
Ernst, T., Chang, L., Jovicich, J., Ames, N., Arnold, S., 2002. Abnormal
brain activation on functional MRI in cognitively asymptomatic HIV
patients. Neurology 59, 1343 – 1349.
Folstein, M.F., Robins, L.N., Helzer, J.E., 1983. The mini-mental state
examination. Arch. Gen. Psychiatry 40, 812.
Funke, I., Hahn, A., Rieber, E.P., Weiss, E., Riethmuller, G., 1987. The
cellular receptor (CD4) of the human immunodeficiency virus is ex-
pressed on neurons and glial cells in human brain. J. Exp. Med. 165,
1230 – 1235.
Gabuzda, D.H., Hirsch, M.S., 1987. Neurologic manifestations of infection
with human immunodeficiency virus. Clinical features and pathoge-
nesis. Ann. Intern. Med. 107, 383 – 391.
Gajdusek, D.C., 1985. Hypothesis: interference with axonal transport of
neurofilament as a common pathogenetic mechanism in certain diseases
of the central nervous system. N. Engl. J. Med. 312, 714 – 719.
Garvey, J.S., Cremer, N.E., Sussdorf, D.H., Campbell, D.H., 1977. Meth-
ods in Immunology: A Laboratory Text for Instruction and Research.
W.A. Benjamin, Reading, MA.
Glass, J.D., Wesselingh, S.L., Selnes, O.A., McArthur, J.C., 1993. Clini-
cal – neuropathologic correlation in HIV-associated dementia. Neurol-
ogy 43, 2230 – 2237.
Hall, W.W., Choppin, P.W., 1981. Measles-virus proteins in the brain tissue
of patients with subacute sclerosing panencephalitis: absence of the M
protein. N. Engl. J. Med. 304, 1152 – 1155.
Hemachudha, T., Griffin, D.E., Giffels, J.J., Johnson, R.T., Moser, A.B.,
Phanuphak, P., 1987. Myelin basic protein as an encephalitogen in ence-
phalomyelitis and polyneuritis following rabies vaccination. N. Engl. J.
Med. 316, 369 – 374.
Johnson, R.T., Griffin, D.E., Hirsch, R.L., Wolinsky, J.S., Roedenbeck, S.,
161
Lindo, d.S.I., Vaisberg, A., 1984. Measles encephalomyelitis—clinical
and immunologic studies. N. Engl. J. Med. 310, 137 – 141.
Kelder, W., McArthur, J.C., Nance-Sproson, T., McClernon, D., Griffin,
D.E., 1998. Beta-chemokines MCP-1 and RANTES are selectively in-
creased in cerebrospinal fluid of patients with human immunodeficiency
virus-associated dementia. Ann. Neurol. 44, 831 – 835.
Klatzmann, D., Champagne, E., Chamaret, S., Gruest, J., Guetard, D.,
Hercend, T., Gluckman, J.C., Montagnier, L., 1984. T-lymphocyte T4
molecule behaves as the receptor for human retrovirus LAV. Nature
312, 767 – 768.
Kumar, M., Resnick, L., Loewenstein, D.A., Berger, J., Eisdorfer, C., 1989.
Brain-reactive antibodies and the AIDS dementia complex. J. Acquir.
Immune Defic. Syndr. 2, 469 – 471.
Lenhardt, T.M., Wiley, C.A., 1989. Absence of humorally mediated dam-
age within the central nervous system of AIDS patients. Neurology 39,
278 – 280.
Levin, H.S., 1994. A guide to clinical neuropsychological testing. Arch.
Neurol. 51, 854 – 859.
Mathiesen, T., Sonnerborg, A., Wahren, B., 1989. Detection of antibodies
against myelin basic protein and increased levels of HIV-IgG antibodies
and HIV antigen after solubilization of immune complexes in sera and
CSF of HIV infected patients. Viral Immunol. 2, 1 – 9.
Navia, B.A., Cho, E.S., Petito, C.K., Price, R.W., 1986a. The AIDS de-
mentia complex: II. Neuropathology. Ann. Neurol. 19, 525 – 535.
Navia, B.A., Jordan, B.D., Price, R.W., 1986b. The AIDS dementia com-
plex: I. Clinical features. Ann. Neurol. 19, 517 – 524.
Price, R.W., 1995. AIDS dementia complex and HIV-1 brain infection: a
pathogenetic framework for treatment and evaluation. Curr. Top. Micro-
biol. Immunol. 202, 33 – 54.
Pruzanski, W., Jacobs, H., Laing, L.P., 1983. Lymphocytotoxic antibodies
against peripheral blood B and T lymphocytes in homosexuals with
AIDS and ARC. AIDS Res. 1, 211 – 220.
Resnick, L., diMarzo-Veronese, F., Schupbach, J., Tourtellotte, W.W., Ho,
D.D., Muller, F., Shapshak, P., Vogt, M., Groopman, J.E., Markham,
P.D., 1985. Intra-blood – brain-barrier synthesis of HTLV-III-specific
IgG in patients with neurologic symptoms associated with AIDS or
AIDS-related complex. N. Engl. J. Med. 313, 1498 – 1504.
Rodman, T.C., Laurence, J., Pruslin, F.H., Chiorazzi, N., Winston, R.,
1985. Naturally occurring antibodies reactive with sperm proteins: ap-
parent deficiency in AIDS sera. Science 228, 1211 – 1215.
Rubinstein, A., Small, C.B., Bernstein, L.J., 1984. Autoantibodies to T cells
in adult and pediatric AIDS. Ann. N.Y. Acad. Sci. 437, 508 – 512.
Ryberg, B., 1982. Antibrain antibodies in multiple sclerosis. Relation to
clinical variables. J. Neurol. Sci. 54, 239 – 261.
Sidtis, J.J., Price, R.W., 1990. Early HIV-1 infection and the AIDS demen-
tia complex. Neurology 40, 323 – 326.
Solinger, A.M., Hess, E.V., 1991. Induction of autoantibodies by human
immunodeficiency virus infection and their significance. Rheum. Dis.
Clin. North Am. 17, 157 – 176.
Stricker, R.B., McHugh, T.M., Moody, D.J., Morrow, W.J., Stites, D.P.,
Shuman, M.A., Levy, J.A., 1987. An AIDS-related cytotoxic auto-
antibody reacts with a specific antigen on stimulated CD4+ T cells.
Nature 327, 710 – 713.
Toh, B.H., Gibbs Jr., C.J., Gajdusek, D.C., Goudsmit, J., Dahl, D., 1985.
The 200- and 150-kDa neurofilament proteins react with IgG autoanti-
bodies from patients with kuru, Creutzfeldt – Jakob disease, and other
neurologic diseases. Proc. Natl. Acad. Sci. U. S. A 82, 3485 – 3489.
Trujillo, J.R., Navia, B., McLane, M.F., Worth, J.L., Lee, T.H., Essex, M.,
1994. Evaluation of autoantibodies to brain proteins in patients with
AIDS dementia complex. J. Acquir. Immune Defic. Syndr. 7, 103 – 108.
Warren, K.G., Catz, I., 1986. Diagnostic value of cerebrospinal fluid anti-
myelin basic protein in patients with multiple sclerosis. Ann. Neurol.
20, 20 – 25.
Working Group of the American Academy of Neurology AIDS Task Force,
1991. Nomenclature and research case definitions for neurologic man-
ifestations of human immunodeficiency virus-type 1 (HIV-1) infection.
Neurology 41, 778 – 785.