Journal of Neuroscience Research 28:406-409 (1991)
Cerebrospinal Fluid Catecholamine Metabolites in HIV-Infected Patients M. Lacsson, L. Hagberg, A. Forsman, and G. Norkrans Department of Psychiatry, Lillhagen Hospital (M.L., A.F.) and Department of Infectious Diseases, East Hospital (L.H., G.N.), University of Goteborg, Goteborg, Sweden Twenty-eight HIV-seropositive individuals-11 asymptomatic cases, 8 with lymphadenopathy syndrome (LAS), and 9 with A I D S w e r e investigated. Clinical staging of the AIDS dementia complex was done in the 9 AIDS patients. The catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol(MHPG) and homovanillic acid (HVA) in CSF were determined in all the HIV patients and in 20 healthy volunteers. The CSF MHPG levels did not differ significantly between healthy subjects and HIV-infected patients at any stage of the infection. The CSF concentrations of HVA differed between the groups only during the AIDS stage. The mean CSF HVA value in the AIDS patients was 42% lower than in the healthy subjects and significantly lower than in any other stage of HIV infection (I' < .01). Patients with signs of the AIDS dementia complex had reduced CSF HVA levels, but there was no clear relationship between HVA concentration and stage of the AIDS dementia complex.
stages of the disease (Navia et al., 1986). We have recently reported deficiencies in the CSF and serum indole amine system in HIV-infected patients (Larsson et al., 1989). Deficient catecholaminergic neurons are often observed in non-HIV-related psychiatric and neurological diseases (Adolfsson et al., 1978; Winblad et al., 1985; Hornykiewicz, 1983). Aiming to gain further insight into the implications of these facts and theories, we have investigated the dopamine and noradrenaline metabolites homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) in HIV-seropositive individuals with and without clinical manifestations of the AIDS dementia complex.
SUBJECTS AND METHODS Subjects Twenty-eight HIV-seropositive individuals, 25 men and 3 women, aged 24-68 years (mean age 40), were included in the study. Classification according to the Center for Disease Control (CDC) criteria showed Key words: AIDS dementia complex, neurotransCDC stage I1 (asymptomatic) in 11 of the patients, CDC mitters, HVA, MHPG stage I11 (LAS) in 8, and CDC stage IV-Cl (AIDS) in 9. All 9 AIDS patients had pneumocystis carinii pneumoINTRODUCTION nia, in one case with concomitant Kaposi's sarcoma and in another with CNS lymphoma. Two of the patients Human immunodeficiency virus type 1 (HIV-1) inwere blood transfusion recipients, 6 were heterosexual, duces a slow degeneration of the immune system, and and 20 were homosexual. No clinical or laboratory findthe late stages of HIV infection are often associated with ings indicated opportunistic CNS infections such as toxneuropsychiatric disorders (Navia et al., 1986). A cur, cryptococcal meningitis, cytomegalovirus , oplasmosis rent hypothesis suggests that infected macrophages, or progressive multifocal leukoencephalopathy . No pawhich are able to penetrate the blood-brain barrier, carry tient was treated with antiviral or CNS-active drugs durthe virus into the brain where it may cause subsequent ing the month preceding the investigation. A group of 20 dysfunction (Wiley et al., 1986; Popovic et al., 1988). healthy and drug-free volunteers, aged 20-60 years The detection of HIV-positive isolates from the cerebrospinal fluid (CSF) in asymptomatic HIV-seropositive (mean age 38), was used for comparative analyses of the individuals indicates that the virus replication may start a CSF samples. latent and slowly progressing infection in the central nervous system (CNS) long before other manifestations of disease appear (Chiodi et al., 1988). Abnormalities in Received April 17, 1990; accepted July 16, 1990. cognitive, behavioural , and motor functions are fre- Address reprint requests to Margareta Larsson, M.D., Department of quently reported in patients with AIDS (Goethe et al., Psychiatry, Lillhagen Hospital, Box 3005, 422 03 Hisings Backa, 1989), and dementia is commonly seen during the late Sweden. 0 1991 Wiley-Liss, Inc.
CSF Catecholamine Metabolites in HIV Patients
407
TABLE I. CSF Catecholamine Metabolites in Healthy Subjects and Patients at Various Stages of HIV Infection CSF concentrations of
No. of aubiects Healthy subjects CDC I1 stage (asymptomatic) CDC I11 stage (LAS) CDC IV C1 stage (AIDS)
HVA (ngiml) Mean
20 11
8 9
+ SD
38 t 12 42 t 17 36 2 10 22 2 8*
Range 25-13 30-84 25-52 1-34
MHPG (ngiml) Mean
2
SD
*4
10 8 + 1 + 8 2
2 2 4
Range
6-16 5-12 5-10 5-14
*Significance of difference in HVA value between AIDS patients and any other group of subjects: P < .01.
AIDS Dementia Complex Clinical staging of the AIDS dementia complex on a scale of 0-4 (Aronow et al., 1988) was done in the 9 patients with AIDS. Stage 0 = normal mental and motor functions, stage 1 = mild symptoms of impairment, stage 2 = moderate symptoms, stage 3 = severe symptoms, and stage 4 = the final stage.
RESULTS The AIDS Dementia Complex The clinical staging of AIDS dementia complex in our 9 AIDS patients showed 3 cases at stage 0, 3 cases at stage 1, 1 case at stage 2, and 2 cases at stage 3 .
CSF Values of HVA and MHPG CSF concentrations of HVA and MHPG in the HIV patients and in the healthy volunteers are given in Table CSF Samples 1. The mean HVA concentration in the group of AIDS CSF samples were collected from patients and volpatients was 42% lower than in the healthy subjects and unteers in the morning before breakfast, and 22 ml CSF significantly lower than in any other category ( P < .01) was obtained from each subject, The CSF flow was di(Fig. 1). There were no other significant differences bevided into fractions for use in various analyses; the contween the groups in HVA or MHPG concentrations. centrations of HVA and MHPG were determined in the HVA levels within normal limits were seen in 3/9 first 12 ml fraction. Samples were frozen at -70°C imAIDS patients, 2 of whom were at the AIDS dementia mediately after collection and stored until analysed. stage 0 and 1 who was at stage 1. One of the 6 AIDS patients with HVA levels below normal was at the AIDS dementia stage 0 , 2 were at stage 1, 1 was at stage 2, and Analytical Techniques The analyses of catecholamine metabolites in CSF 2 were at stage 3. The severity of AIDS dementia comwere performed by means of high-performance liquid plex was not significantly correlated to CSF concentrachromatography (HPLC) technique with electrochemical tions of HVA, but each of the 3 patients at the most severe stages in our study had decreased HVA levels. detection, based upon Scheinin (1987) and with some Three subjects-I asymptomatic case, 1 with modifications. The Waters Associates M460 detector LAS, and 1 with AIDS-had subnormal CSF concentrawas set to 0.75 V. The column was a 10 p m tions of MHPG. pBondapack C,, (3.9 mm X 30 cm) at a flow rate of 2.0 ml/min. The mobile phase consisted of a 0.01 M citric acid monohydrateitri-sodium citrate 2-hydrate buffer at DISCUSSION pH = 4.1, and CH,OH (90: 10). Immediately after thawDisturbed monoamine metabolism has been found ing, 0.5 ml CSF was extracted with 1 ml ethylacetate in the presence of 100 pl 1 M sodium-acetate at pH = 4.1. in patients with dementia and motor dysfunction. Low A sample of 200 p l organic layer was evaporated to CSF levels of monoamine metabolites are thus common dryness, resolved in mobile phase, and injected into the in, for instance, Parkinson’s and Alzheimer’s diseases (Adolfsson et al., 1978; Winblad et al., 1985; Hordescribed HPLC system. nykiewicz, 1983). Progressive dementia, a frequent manifestation of HIV- 1 infection, has been associated Statistical Analyses with the presence of HIV in the brain (Price et al., 1988), Statistical evaluations of differences between where the virus may affect neuronal functions and transmitter substances. We found significantly lower CSF groups of values were performed by means of a t-test.
408
Larsson et al.
.
.
.
....
.
..
*.
u
.
**
.*
0 ‘
I
1
HEALTIIY SUBJECTS ln=201
1
I
1
ASYMPTOMATIC PATIENTS i n = l l i
1
LAS PATIENTS in%
. . .
0 .
CI
1
1
AIDS PATIENTS in=9)
Fig. 1. CSF concentrationsof HVA in healthy subjects and in patients at various stages of HIV infection. Mean values are indicated
concentrations of HVA in our patients with AIDS than in the patients at earlier stages of HIV infection. The most drastic reductions in HVA levels were seen in the patients with dementia syndrome, but reduced HVA levels were also found in 2 patients showing virtually no sign of the AIDS dementia complex. Clinical manifestations of senile dementia and Parkinson’s disease do not appear until there is a pronounced reduction in the neurotransmitters (Bondareff et al., 1982; Hornykiewicz, 1983). It is feasible, however, that individuals with a lesser reduction in transmitter levels might be at risk of reaching symptomatic thresholds for dementia or movement disorder. AIDS patients are susceptible to a considerable array of opportunistic infections, and opportunistic CNS infections may play a role in the progression of disease, but no patient in our study showed signs of additive CNS infection, and the HVA deficiencies observed were therefore ascribed to the HIV infection. The HIV pathogenesis in the nervous system is still unknown. Most evidence suggest that cells of the monocyte/macrophage lineage are the primary target cells in CNS, and that neural glia cells and neuronal cells only rarely are directly infected by HIV (Wiley et al., 1986). The clinical and pathological types of brain abnormalities seen in AIDS are compatible with a generalized toxic effect. It is possible that monocytes and macrophages may activate toxic factors, such as inappropriate secretions of cytokines, which may affect the catecholamine metabolism. Gallo et al. (1989) have reported high CSF levels of the cytokine IL-6 in HIV-seropositive individ-
uals. CNS symptoms may to some extent be reversible with antiviral treatment (Schmitt et al., 1988). If there is a link between the catecholamine deficiency and the clinical symptoms, such treatment should result in restored concentrations of catecholamine metabolites, at least during the earlier stages of CNS engagement. The fact that the HIV-infected patients in this study who had not yet developed AIDS had catecholamine levels within the range of normal subjects indicates that significant changes in this parameter do not occur until the HIV infection has reached an advanced stage.
ACKNOWLEDGMENTS Our coworkers in the laboratory, Birgitta Hallberg and Anita Andrkasson, are gratefully acknowledged for valuable assistance with the sample analyses. Our sincere thanks are also due to Agneta Brimse for her help in preparing this report. The study was supported by the Swedish Medical Research Council (project numbers 5996 and 7746) and by the University of Goteborg.
REFERENCES Adolfsson R, Gottfries CG, Oreland L (1978): Reduced levels of catecholamines in the brain and increased activity of monoamine oxidase in platelets in Alzheimer’s disease: Therapeutic implications. Age Ageing 7:441-451. Aronow H , Brew B, Price R (1988): The management of the neurological complications of HIV infection and AIDS. AIDS 2: 15 1-1 59.
CSF Catecholamine Metabolites in HIV Patients Bondareff W, Mountjay CQ, Roth M (1982): Loss of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology 32: 164-168. Chiodi F, Albert J , Olausson E, Norkrans G, Hagberg L, Sonnerborg A, Asjo B, Fenyo EM (1988): Isolation frequency of human immunodeficiency virus from cerebrospinal fluid and blood of patients with varying severity of HIV infection. AIDS Res Hum Retro 5:351-358. Gallo P, Frei K, Rordorf C, Lazdins J , Tavolato B, Fontana A (1989): Human immunodeficiency virus type I (HIV-I) infection of the central nervous system: an evaluation of cytokines in cerebrospinal fluid. Neuroimmunology 23: 109-1 16. Goethe K, Mitchell J, Marshall D (1989): Neuropsychological and neurological function of human immunodeficiency virus seropositive asymptomatic individuals. Arch Neurol 46: 129-1 33. Hornykiewicz 0 (1983): Parkinson’s disease and the ageing basal ganglia. Dev Neurol 7:253-260. Larsson M, Hagberg L. Norkrans G , Forsman A (1989): Indolamine deficiency in blood and cerebrospinal fluid from patients with human immunodeficiency virus infection. J . Neurosci Res 23: 44 1-446. Navia BA, Jordan BD, Price RW (1986): The AIDS dementia complex. I. Clinical features. Ann Neurol 19517-524.
409
Popovic M, Mellert W, Erfle V, Gartner S (1988): Role of mononuclear phagocytes and accessory cells in human immunodeficiency virus type I infection of the brain. Ann Neurol [Suppll 23:74-77. Price R, Brew B, Sidtis J (1988): The brain in AIDS: Central nervous system HIV-1 infection and AIDS dementia complex. Science 239:586-589. Scheinin M (1987): Determination of monoamine metabolites in cerebrospinal fluid and plasma: liquid chromatographic methods and pharmacological applications. Thesis, University of Turku, Finland. Schmitt FA, Bigley JW, McKinnis R, Logue PE, Evans RW, Drucker JL (1988): Neuropsychological outcome of zidovudine (AZT) treatment of patients with AIDS and AIDS-related complex. N Engl J Med 319:1573-1578. Wiley C, Schrier R, Nelson J (1986): Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA 83:7088-7093. Winblad B, Hardy J, Backman L, Nilsson L (1985): Memory function and brain biochemistry in normal aging and in senile dementia. Ann NY Acad Sci 444:255-268.
Cerebrospinal Fluid Catecholamine Metabolites in HIV-Infected Patients M. Lacsson, L. Hagberg, A. Forsman, and G. Norkrans Department of Psychiatry, Lillhagen Hospital (M.L., A.F.) and Department of Infectious Diseases, East Hospital (L.H., G.N.), University of Goteborg, Goteborg, Sweden Twenty-eight HIV-seropositive individuals-11 asymptomatic cases, 8 with lymphadenopathy syndrome (LAS), and 9 with A I D S w e r e investigated. Clinical staging of the AIDS dementia complex was done in the 9 AIDS patients. The catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol(MHPG) and homovanillic acid (HVA) in CSF were determined in all the HIV patients and in 20 healthy volunteers. The CSF MHPG levels did not differ significantly between healthy subjects and HIV-infected patients at any stage of the infection. The CSF concentrations of HVA differed between the groups only during the AIDS stage. The mean CSF HVA value in the AIDS patients was 42% lower than in the healthy subjects and significantly lower than in any other stage of HIV infection (I' < .01). Patients with signs of the AIDS dementia complex had reduced CSF HVA levels, but there was no clear relationship between HVA concentration and stage of the AIDS dementia complex.
stages of the disease (Navia et al., 1986). We have recently reported deficiencies in the CSF and serum indole amine system in HIV-infected patients (Larsson et al., 1989). Deficient catecholaminergic neurons are often observed in non-HIV-related psychiatric and neurological diseases (Adolfsson et al., 1978; Winblad et al., 1985; Hornykiewicz, 1983). Aiming to gain further insight into the implications of these facts and theories, we have investigated the dopamine and noradrenaline metabolites homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) in HIV-seropositive individuals with and without clinical manifestations of the AIDS dementia complex.
SUBJECTS AND METHODS Subjects Twenty-eight HIV-seropositive individuals, 25 men and 3 women, aged 24-68 years (mean age 40), were included in the study. Classification according to the Center for Disease Control (CDC) criteria showed Key words: AIDS dementia complex, neurotransCDC stage I1 (asymptomatic) in 11 of the patients, CDC mitters, HVA, MHPG stage I11 (LAS) in 8, and CDC stage IV-Cl (AIDS) in 9. All 9 AIDS patients had pneumocystis carinii pneumoINTRODUCTION nia, in one case with concomitant Kaposi's sarcoma and in another with CNS lymphoma. Two of the patients Human immunodeficiency virus type 1 (HIV-1) inwere blood transfusion recipients, 6 were heterosexual, duces a slow degeneration of the immune system, and and 20 were homosexual. No clinical or laboratory findthe late stages of HIV infection are often associated with ings indicated opportunistic CNS infections such as toxneuropsychiatric disorders (Navia et al., 1986). A cur, cryptococcal meningitis, cytomegalovirus , oplasmosis rent hypothesis suggests that infected macrophages, or progressive multifocal leukoencephalopathy . No pawhich are able to penetrate the blood-brain barrier, carry tient was treated with antiviral or CNS-active drugs durthe virus into the brain where it may cause subsequent ing the month preceding the investigation. A group of 20 dysfunction (Wiley et al., 1986; Popovic et al., 1988). healthy and drug-free volunteers, aged 20-60 years The detection of HIV-positive isolates from the cerebrospinal fluid (CSF) in asymptomatic HIV-seropositive (mean age 38), was used for comparative analyses of the individuals indicates that the virus replication may start a CSF samples. latent and slowly progressing infection in the central nervous system (CNS) long before other manifestations of disease appear (Chiodi et al., 1988). Abnormalities in Received April 17, 1990; accepted July 16, 1990. cognitive, behavioural , and motor functions are fre- Address reprint requests to Margareta Larsson, M.D., Department of quently reported in patients with AIDS (Goethe et al., Psychiatry, Lillhagen Hospital, Box 3005, 422 03 Hisings Backa, 1989), and dementia is commonly seen during the late Sweden. 0 1991 Wiley-Liss, Inc.
CSF Catecholamine Metabolites in HIV Patients
407
TABLE I. CSF Catecholamine Metabolites in Healthy Subjects and Patients at Various Stages of HIV Infection CSF concentrations of
No. of aubiects Healthy subjects CDC I1 stage (asymptomatic) CDC I11 stage (LAS) CDC IV C1 stage (AIDS)
HVA (ngiml) Mean
20 11
8 9
+ SD
38 t 12 42 t 17 36 2 10 22 2 8*
Range 25-13 30-84 25-52 1-34
MHPG (ngiml) Mean
2
SD
*4
10 8 + 1 + 8 2
2 2 4
Range
6-16 5-12 5-10 5-14
*Significance of difference in HVA value between AIDS patients and any other group of subjects: P < .01.
AIDS Dementia Complex Clinical staging of the AIDS dementia complex on a scale of 0-4 (Aronow et al., 1988) was done in the 9 patients with AIDS. Stage 0 = normal mental and motor functions, stage 1 = mild symptoms of impairment, stage 2 = moderate symptoms, stage 3 = severe symptoms, and stage 4 = the final stage.
RESULTS The AIDS Dementia Complex The clinical staging of AIDS dementia complex in our 9 AIDS patients showed 3 cases at stage 0, 3 cases at stage 1, 1 case at stage 2, and 2 cases at stage 3 .
CSF Values of HVA and MHPG CSF concentrations of HVA and MHPG in the HIV patients and in the healthy volunteers are given in Table CSF Samples 1. The mean HVA concentration in the group of AIDS CSF samples were collected from patients and volpatients was 42% lower than in the healthy subjects and unteers in the morning before breakfast, and 22 ml CSF significantly lower than in any other category ( P < .01) was obtained from each subject, The CSF flow was di(Fig. 1). There were no other significant differences bevided into fractions for use in various analyses; the contween the groups in HVA or MHPG concentrations. centrations of HVA and MHPG were determined in the HVA levels within normal limits were seen in 3/9 first 12 ml fraction. Samples were frozen at -70°C imAIDS patients, 2 of whom were at the AIDS dementia mediately after collection and stored until analysed. stage 0 and 1 who was at stage 1. One of the 6 AIDS patients with HVA levels below normal was at the AIDS dementia stage 0 , 2 were at stage 1, 1 was at stage 2, and Analytical Techniques The analyses of catecholamine metabolites in CSF 2 were at stage 3. The severity of AIDS dementia comwere performed by means of high-performance liquid plex was not significantly correlated to CSF concentrachromatography (HPLC) technique with electrochemical tions of HVA, but each of the 3 patients at the most severe stages in our study had decreased HVA levels. detection, based upon Scheinin (1987) and with some Three subjects-I asymptomatic case, 1 with modifications. The Waters Associates M460 detector LAS, and 1 with AIDS-had subnormal CSF concentrawas set to 0.75 V. The column was a 10 p m tions of MHPG. pBondapack C,, (3.9 mm X 30 cm) at a flow rate of 2.0 ml/min. The mobile phase consisted of a 0.01 M citric acid monohydrateitri-sodium citrate 2-hydrate buffer at DISCUSSION pH = 4.1, and CH,OH (90: 10). Immediately after thawDisturbed monoamine metabolism has been found ing, 0.5 ml CSF was extracted with 1 ml ethylacetate in the presence of 100 pl 1 M sodium-acetate at pH = 4.1. in patients with dementia and motor dysfunction. Low A sample of 200 p l organic layer was evaporated to CSF levels of monoamine metabolites are thus common dryness, resolved in mobile phase, and injected into the in, for instance, Parkinson’s and Alzheimer’s diseases (Adolfsson et al., 1978; Winblad et al., 1985; Hordescribed HPLC system. nykiewicz, 1983). Progressive dementia, a frequent manifestation of HIV- 1 infection, has been associated Statistical Analyses with the presence of HIV in the brain (Price et al., 1988), Statistical evaluations of differences between where the virus may affect neuronal functions and transmitter substances. We found significantly lower CSF groups of values were performed by means of a t-test.
408
Larsson et al.
.
.
.
....
.
..
*.
u
.
**
.*
0 ‘
I
1
HEALTIIY SUBJECTS ln=201
1
I
1
ASYMPTOMATIC PATIENTS i n = l l i
1
LAS PATIENTS in%
. . .
0 .
CI
1
1
AIDS PATIENTS in=9)
Fig. 1. CSF concentrationsof HVA in healthy subjects and in patients at various stages of HIV infection. Mean values are indicated
concentrations of HVA in our patients with AIDS than in the patients at earlier stages of HIV infection. The most drastic reductions in HVA levels were seen in the patients with dementia syndrome, but reduced HVA levels were also found in 2 patients showing virtually no sign of the AIDS dementia complex. Clinical manifestations of senile dementia and Parkinson’s disease do not appear until there is a pronounced reduction in the neurotransmitters (Bondareff et al., 1982; Hornykiewicz, 1983). It is feasible, however, that individuals with a lesser reduction in transmitter levels might be at risk of reaching symptomatic thresholds for dementia or movement disorder. AIDS patients are susceptible to a considerable array of opportunistic infections, and opportunistic CNS infections may play a role in the progression of disease, but no patient in our study showed signs of additive CNS infection, and the HVA deficiencies observed were therefore ascribed to the HIV infection. The HIV pathogenesis in the nervous system is still unknown. Most evidence suggest that cells of the monocyte/macrophage lineage are the primary target cells in CNS, and that neural glia cells and neuronal cells only rarely are directly infected by HIV (Wiley et al., 1986). The clinical and pathological types of brain abnormalities seen in AIDS are compatible with a generalized toxic effect. It is possible that monocytes and macrophages may activate toxic factors, such as inappropriate secretions of cytokines, which may affect the catecholamine metabolism. Gallo et al. (1989) have reported high CSF levels of the cytokine IL-6 in HIV-seropositive individ-
uals. CNS symptoms may to some extent be reversible with antiviral treatment (Schmitt et al., 1988). If there is a link between the catecholamine deficiency and the clinical symptoms, such treatment should result in restored concentrations of catecholamine metabolites, at least during the earlier stages of CNS engagement. The fact that the HIV-infected patients in this study who had not yet developed AIDS had catecholamine levels within the range of normal subjects indicates that significant changes in this parameter do not occur until the HIV infection has reached an advanced stage.
ACKNOWLEDGMENTS Our coworkers in the laboratory, Birgitta Hallberg and Anita Andrkasson, are gratefully acknowledged for valuable assistance with the sample analyses. Our sincere thanks are also due to Agneta Brimse for her help in preparing this report. The study was supported by the Swedish Medical Research Council (project numbers 5996 and 7746) and by the University of Goteborg.
REFERENCES Adolfsson R, Gottfries CG, Oreland L (1978): Reduced levels of catecholamines in the brain and increased activity of monoamine oxidase in platelets in Alzheimer’s disease: Therapeutic implications. Age Ageing 7:441-451. Aronow H , Brew B, Price R (1988): The management of the neurological complications of HIV infection and AIDS. AIDS 2: 15 1-1 59.
CSF Catecholamine Metabolites in HIV Patients Bondareff W, Mountjay CQ, Roth M (1982): Loss of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology 32: 164-168. Chiodi F, Albert J , Olausson E, Norkrans G, Hagberg L, Sonnerborg A, Asjo B, Fenyo EM (1988): Isolation frequency of human immunodeficiency virus from cerebrospinal fluid and blood of patients with varying severity of HIV infection. AIDS Res Hum Retro 5:351-358. Gallo P, Frei K, Rordorf C, Lazdins J , Tavolato B, Fontana A (1989): Human immunodeficiency virus type I (HIV-I) infection of the central nervous system: an evaluation of cytokines in cerebrospinal fluid. Neuroimmunology 23: 109-1 16. Goethe K, Mitchell J, Marshall D (1989): Neuropsychological and neurological function of human immunodeficiency virus seropositive asymptomatic individuals. Arch Neurol 46: 129-1 33. Hornykiewicz 0 (1983): Parkinson’s disease and the ageing basal ganglia. Dev Neurol 7:253-260. Larsson M, Hagberg L. Norkrans G , Forsman A (1989): Indolamine deficiency in blood and cerebrospinal fluid from patients with human immunodeficiency virus infection. J . Neurosci Res 23: 44 1-446. Navia BA, Jordan BD, Price RW (1986): The AIDS dementia complex. I. Clinical features. Ann Neurol 19517-524.
409
Popovic M, Mellert W, Erfle V, Gartner S (1988): Role of mononuclear phagocytes and accessory cells in human immunodeficiency virus type I infection of the brain. Ann Neurol [Suppll 23:74-77. Price R, Brew B, Sidtis J (1988): The brain in AIDS: Central nervous system HIV-1 infection and AIDS dementia complex. Science 239:586-589. Scheinin M (1987): Determination of monoamine metabolites in cerebrospinal fluid and plasma: liquid chromatographic methods and pharmacological applications. Thesis, University of Turku, Finland. Schmitt FA, Bigley JW, McKinnis R, Logue PE, Evans RW, Drucker JL (1988): Neuropsychological outcome of zidovudine (AZT) treatment of patients with AIDS and AIDS-related complex. N Engl J Med 319:1573-1578. Wiley C, Schrier R, Nelson J (1986): Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA 83:7088-7093. Winblad B, Hardy J, Backman L, Nilsson L (1985): Memory function and brain biochemistry in normal aging and in senile dementia. Ann NY Acad Sci 444:255-268.
