Share

February 22, 2000; 54 (4) Articles

Cerebrovascular changes in the basal ganglia with HIV dementia

J.R. Berger, A. Nath, R.N. Greenberg, A.H. Andersen, R.A. Greene, A. Bognar, M.J. Avison
First published February 22, 2000, DOI: https://doi.org/10.1212/WNL.54.4.921
Full PDF
Citation
Permissions

Make Comment

See Comments

Downloads
438

Share

Abstract

Background: HIV dementia is a form of subcortical dementia. Clinical, radiologic, pathologic, and biochemical studies suggest a major contribution of basal ganglia dysfunction to the pathogenesis of this disorder. Many investigators have proposed a contribution of a disrupted blood–brain barrier (BBB) to the pathogenesis of HIV dementia.

Objective: To identify microvascular abnormalities in vivo in basal ganglia or white matter of persons with HIV dementia.

Methods: Time course of MRI postcontrast enhancement was determined in basal ganglia and white matter of HIV-infected persons without dementia (Memorial Sloan Kettering [MSK] score of 0; n = 4); HIV-infected persons with mild dementia (MSK score of 0.5; n = 2); and HIV-infected persons with moderate-to-severe dementia (MSK ≥ 1.0; n = 6).

Results: Increased basal ganglia enhancement was observed in individuals with moderate-to-severe dementia relative to nondemented individuals, both immediately and 30 minutes after contrast administration. Decline of basal ganglia enhancement was slower in the moderately to severely demented patients and, when normalized to intravascular enhancement of sagittal sinus, suggested leakage of contrast agent, consistent with increased permeability of BBB. A significant correlation between the postcontrast fractional enhancement at 30 minutes (FE30) and the MSK score was noted. White matter showed no significant differences in postcontrast enhancement among the three groups.

Conclusion: Increased early enhancement in basal ganglia of the HIV dementia group is consistent with increased regional cerebral blood volume (rCBV). Increased late enhancement is strongly suggestive of BBB disruption. Similar abnormalities were absent in the white matter adjacent to the caudate nucleus.

Disruption of the blood–brain barrier (BBB) has been postulated as one of the mechanisms contributing to the development of HIV dementia.1-3 Consistent with this view are the CSF analyses showing living patients to have an association between an alteration of the BBB and the presence of HIV dementia, as determined by clinical criteria.4,5 This has been confirmed by histopathologic studies showing an influx of serum proteins in brain parenchyma of persons with HIV encephalitis.1,6,7

Clinical and neuropathologic data support the view that HIV dementia is principally subcortical in origin, with significant impairment of subcortical motor and dopamine systems.8 Functional imaging studies show significant changes in basal ganglia metabolism after HIV infection.9-12 However, direct evidence of microvascular or BBB changes in the basal ganglia after HIV infection has remained elusive. In the current study, we test the hypothesis that the time course of postcontrast enhancement in the basal ganglia of HIV-infected patients is related to the presence and severity of HIV dementia.

Methods.

Study design.

On the basis of the neurologic examination, patients were placed prospectively in one of three groups for MRI study and analysis: 1) nondemented (Memorial Sloan Kettering [MSK] = 0; n = 4); 2) mildly demented (MSK = 0.5; n = 2); or 3) moderately to severely demented (MSK ≥ 1.0, n = 6). Within 2 weeks of the neurologic examination, each patient was studied using a series of MRI scans to determine the time course of postcontrast signal enhancement in key structures.

Patients.

Patients were recruited for this study from the Infectious Disease Clinic and the Neurology service at the University of Kentucky Medical Center using a protocol approved by the University of Kentucky’s Medical Institutional Review Board. Each patient’s seropositive status was established by HIV ELISA (Abbott Diagnostics, Chicago, IL) and confirmed by Western blot analysis. Patients with other CNS illnesses, which may result in cerebrovascular or BBB abnormalities, were excluded. A detailed neurologic examination and initial standard MRI scans were used to screen for opportunistic infections or malignancies. Any patients showing unexplained MRI abnormalities connected with these disorders were excluded.

Neurologic examination.

Each patient had an extensive history, general physical examination, and detailed neurologic examination. This included assessment of HIV dementia using the MSK Scale.13 Select individuals also had comprehensive neuropsychological testing.

MRI.

Patients were scanned on a 1.5-tesla Siemens Magnetom Vision MR system (Siemens Medical Systems, Iselin, NJ) using a standard, circularly polarized head coil. The following sets of MR images were collected initially to rule out the presence of neurologically significant structural lesions:

  • • T1-weighted spin-echo (sagittal): TR/TE = 500/14 msec, FA = 70°, THK = 5 mm, 3% interslice gap, field of view (FOV) = 230 mm, MA = 192 × 256.

  • • PD/T2-weighted spin-echo (axial): TR/TE1/TE2 = 2,000/20/80 msec, FA = 65°, FOV = 256 × 256 × 180 mm, MA = 128 × 128 × 90.

  • • T1-weighted 3D FLASH: TR/TE = 21/6 msec, FA = 30°, THK = 5 mm, 30% interslice gap, FOV = 230 mm, MA = 192 × 256.

  • • PD-weighted spin-echo (axial): TR/TE = 2,000/14 msec, FA = 62°, THK = 5 mm, 3% interslice gap, FOV = 230 mm, MA = 192 × 256.

  • • T1-weighted spin-echo (axial, precontrast, and postcontrast): TR/TE = 610/14 msec, FA = 62°, THK = 5 mm, 3% interslice gap, FOV = 230 mm, MA = 192 × 256. Fixed receiver and reconstruction gains.

The axial T1-weighted spin-echo sequence was used to measure the time course of cerebral postcontrast enhancement. A minimum of three precontrast images were acquired and averaged to improve the estimate of the precontrast image intensities. The precontrast images were also used to obtain an estimate of the precontrast variance for each pixel in the image. The individual images had sufficient signal to noise to detect fractional enhancements (FEs) of 1% or greater. Contrast agent (gadolinium-DTPA; Magnevist 0.1 mmol/kg IV) was then administered, and collection of postcontrast T1-weighted images using identical acquisition conditions was begun. Collection of images continued without interruption (one set every 2 minutes) for at least 30 minutes postcontrast unless an earlier termination was requested by the patient.

Data analysis.

For a given region of interest (ROI), the FE at time t postcontrast was defined as FE(t) = (S(t) − S(pre))/S(pre), where S(t) was the mean MRI signal in the ROI at time t postcontrast and S(pre) was the mean MRI signal in the same ROI before contrast administration. As noted earlier, a minimum of three precontrast images were acquired and averaged to improve the estimate of S(pre). Mean FE was determined for the basal ganglia and adjacent white matter as follows: ROI measurements for each timepoint precontrast and postcontrast were collected using a mask traced to outline basal ganglia structures (figure 1). These ROI measurements were combined to determine the mean FE in subcortical gray for each subject. Circular ROIs placed bilaterally in the anterior white matter tracts adjacent to the head of the caudate were used to assess white matter enhancement. As with the subcortical gray ROIs, the white matter ROI measurements were combined to determine a mean white matter FE for each subject. To account for patient-to-patient variations in contrast dose and to assess the contribution of differences in regional cerebral blood volume (rCBV) in demented and nondemented individuals to the postcontrast enhancement, we also determined the FE in the sagittal sinus as a function of time postcontrast.

Figure

Figure 1. Axial T1-weighted spin-echo MRI at the level of the lenticular nuclei showing the regions of interest (ROI) used for determination of postcontrast fractional enhancement. ROI for sagittal sinus is indicated by an arrow (see Methods for MRI details).

Statistical analysis.

All data are reported as mean ± SEM. Intergroup differences were tested for significance using the Kruskal–Wallis Test and one-way analysis of variance, with Mann–Whitney U and Fischer’s Protected Least Significant Difference used for post hoc testing.

Results.

The table summarizes the pertinent clinical characteristics of the patients studied. The size and time course of the postcontrast FE in the sagittal sinus were the same in all three groups of patients (figure 2), confirming the absence of significant differences in intravascular contrast concentration or clearance among the three groups. Figure 3 shows the time course of postcontrast FE in the basal ganglia. In all three groups, there was an initial rapid enhancement, which reached a maximum (FEmax) within 4 minutes of contrast administration. There was no significant difference in basal ganglia FEmax between the nondemented (FEmax = 0.042 ± 0.007) and the mildly demented patients (FEmax = 0.041 ± 0.011). However, in patients with moderate-to-severe dementia, the basal ganglia FEmax was elevated (0.068 ± 0.015; p < 0.05 versus nondemented). Furthermore, in the moderately to severely demented patients, the decline in postcontrast basal ganglia FE was slower than in nondemented and mildly demented patients and was slower than the rate of FE decline in the sagittal sinus (FEss). Thus, 30 minutes postcontrast, FE in the basal ganglia was greater in moderately to severely demented patients (FE30 = 0.037 ± 0.008) than in mildly demented (FE30 = 0.006 ± 0.003; p < 0.05) and nondemented (FE30 = 0.016 ± 0.007) patients. These differences are greater than can be explained by any differences in basal ganglia parenchymal volume or differences in degree of basal ganglia atrophy between the groups. Despite the small number of subjects, regression analysis showed a significant dependence of basal ganglia FE30 postcontrast on dementia severity (figure 4).

View this table:
Table 1.

Pertinent clinical characteristics

Figure

Figure 2. Time course of postcontrast fractional enhancement (FE) in sagittal sinus of the nondemented (Memorial Sloan Kettering [MSK] = 0), mildly (MSK = 0.5), and moderately to severely demented (MSK ≥ 1.0) patients. There was no significant difference in peak FE nor in the rate of FE decline postcontrast, confirming there was little variation in contrast dose, and no significant difference between the demented and nondemented patients in the rate of renal clearance of contrast agent. Error bars are ±SEM.

Figure

Figure 3. Time course of postcontrast fractional enhancement (FE) in basal ganglia of nondemented (Memorial Sloan Kettering [MSK] = 0), mildly demented (MSK = 0.5), and moderately to severely demented (MSK ≥ 1.0) patients. Although there was no major difference between the nondemented and mildly demented patients, patients in the moderate–severe dementia group showed a significantly greater FE at all timepoints postcontrast. Error bars are ±SEM.

Figure

Figure 4. Dependence of the basal ganglia fractional enhancement (FE) 30 minutes postcontrast (FE30) on the Memorial Sloan Kettering (MSK) dementia rating. Regression analysis showed a strong correlation of the basal ganglia FE30 with the dementia rating (FE30 = 0.010 + 0.019 MSK; r = 0.746, p < 0.01). One of the subjects in the moderate-to-severe dementia group (HF121098) was unable to complete the study and is not included in the analysis.

In contrast, there were no significant differences in white matter FEmax between nondemented (FEmax = 0.017 ± 0.002), mildly demented (FEmax = 0.013 ± 0.003), or moderately to severely demented patients (FEmax = 0.014 ± 0.009). No significant intergroup differences in white matter fractional enhancement 30 minutes postcontrast (FE30 = 0.003 ± 0.001, nondemented; FE30 = 0.003 ± 0.002, mild dementia; FE30 = 0.017 ± 0.016, moderate-to-severe dementia) were detected either.

Discussion.

The significantly greater initial maximal enhancement (FEmax) in the basal ganglia of the moderately to severely demented patients suggests an increased vascularity of the basal ganglia in this group. This interpretation is consistent with previous reports of increased rCBV in patients with advanced HIV dementia.14,15 In a regression analysis including all patients studied, the dependence of basal ganglia FEmax on dementia severity (MSK rating) failed to achieve significance in this study (data not shown). This result is consistent with a previously reported relationship between the severity of dementia and the increase in rCBV in deep gray matter structures.14

Several caveats are appropriate in the discussion of these data. First, the groups were not age matched, and patients in the moderate-to-severe dementia group were on average 13.6 years older than those in the nondemented group (p < 0.01). Studies in humans and animals have found microvascular histologic changes associated with increasing age, as well as decreases in a variety of selective transport systems.16 Thus, it is possible that the differences in postcontrast enhancement observed reflect age-associated rather than HIV-dementia-associated changes. It is unlikely that the difference in early fractional enhancement, if attributable to increased vascularity, is caused by this age difference because rCBV decreases with increasing age.17 The increased late FE seen in the moderately to severely demented subjects relative to the nondemented patients may arise from an age-associated increase in BBB permeability. However, this seems unlikely because human and animal data suggest that age-associated changes in BBB passive permeability are relatively minor over the age range of patients in the current study.18-20 Thus, contrast-enhanced MRI studies of the aging canine brain in vivo found no age-associated changes in BBB function or cerebrovascular volume,20 and studies of insulin permeability in the squirrel monkey CNS found no difference between adult and senescent animals.

Second, the CD4 count remained quite high in several of the demented patients, which would seem to be at odds with previous data indicating an inverse correlation between dementia and CD4 count.21 However, the correlation between CD4 count and severity of dementia generally was poor. Furthermore, recent studies show a marked increase in median CD4 count at diagnosis of dementia since the introduction of highly active antiretroviral therapy (HAART).22 This suggests that HAART may lead to a decoupling/weakening of the correlation between ADC and CD4 observed in the pre-HAART era and that the CD4 counts in the current study may be somewhat misleading as an index of CNS compromise.

The lack of clear evidence for age-associated cerebrovascular alterations in young-to-middle-aged adults, together with the absence of significant differences in CD4 counts or viral load among the three groups in this study, suggests that the differences in subcortical postcontrast enhancement observed in the moderately to severely demented group may be associated with HIV dementia.

Thus, the observation of significantly greater FEmax and FE30 and a slower decline in FE after contrast administration in HIV-infected patients with moderate-to-severe dementia all point to microvascular changes in the basal ganglia. In particular, the significantly increased FE30 and the slower postcontrast decline in basal ganglia FE suggest compromise of the BBB in the basal ganglia in advanced stages of HIV dementia. Therefore, when the FE in the basal ganglia was normalized to that in the sagittal sinus, there was a trend to increasing FE at later timepoints in the moderately to severely demented group, whereas the nondemented and mildly demented patients showed a decrease in FE at later times (figure 5). The relationship between BBB abnormalities in the basal ganglia and the development of HIV dementia remains obscure. Although it is possible that the loss of integrity of the BBB is an epiphenomenon related to high levels of virus in the basal ganglia and plays no role in the development of dementia, this seems unlikely in light of our observation of a correlation between FE30 in the basal ganglia and the dementia rating. Rather, it seems likely that BBB disruption, resulting from direct infection of endothelial cells6 or apoptotic changes in endothelial cells caused by blood-borne factors,23 may play an important early role in the development of HIV dementia. Early BBB disruption may facilitate entry of free virus or virus-infected cells increasing the viral burden in this region of the brain. Alternatively, the increased BBB permeability may permit entry from the blood of substances with a pernicious effect on basal ganglia neurons, such as activated monocytes, chemokines, and cytokines, in the course of HIV infection. Viral products released from HIV-infected cells in basal ganglia may also damage the BBB by either causing direct endothelial injury24 or inducible nitric oxide synthase (iNOS)25,26 or chemokines,27 thus causing a positive feedback loop in advancing stages of dementia.

Figure

Figure 5. Time course of postcontrast fractional enhancement (FE) in the basal ganglia normalized to that in the sagittal sinus. Note the difference in time course in the Memorial Sloan Kettering ≥1.0 group relative to the nondemented and mildly demented patients. Error bars are ±SEM.

The abnormalities detected in the basal ganglia are consistent with the clinical, radiologic, and metabolic findings in HIV dementia. Bradyphrenia, forgetfulness, apathy, and poor sequential processing are cognitive disturbances that parallel those seen in PD and are observed in HIV dementia.28 Among the earliest manifestations is impaired psychomotor speed.29 Other parkinsonian features include bradykinesia, impaired manual dexterity, postural instability, gait abnormalities, rigidity, hypomimetic facies, hypophonia, poorly articulated speech, and seborrheic dermatitis.28,30 Ocular motility disorders in HIV dementia31 are suggestive of striatal lesions. It is estimated that 5% of patients presenting to the Neuro-AIDS clinic have Parkinsonism and another 10% have parkinsonian features.30

In radiologic studies comparing three groups (HIV-seronegative individuals, HIV-seropositive individuals without dementia, and HIV-seropositive individuals with dementia), the presence of smaller basal ganglia volumes after corrections were made for intracranial volume separated the demented group from the other two groups.32 Significant correlations exist between central atrophy determined on CT and impairment on neuropsychological tests33 and between progressive caudate atrophy as determined by a bicaudate ratio on cranial MRI and the presence of AIDS dementia.34

Metabolic studies have shown abnormalities in basal ganglia metabolism. Studies of the cerebral metabolic rate of glucose using {18F}2-fluoro-2-deoxy-d-glucose have shown hypermetabolism of the basal ganglia in early HIV-1-associated dementia.9,11,35 With advanced dementia, basal ganglia hypometabolism is noted.11 Proton MR spectroscopy has shown a decreased N-acetyl-aspartate/choline (NAA/Cho) ratio in the lenticular nuclei of HIV-positive individuals when compared with that of normal controls.10 CSF studies have found significantly diminished dopamine levels in the presence of HIV-associated neurologic disease36 and reduced levels of homovanillic acid, the major metabolite of dopamine, in both HIV-seropositive subjects and those with features of HIV dementia.37

Pathologic studies also support the presence of basal ganglia involvement in AIDS dementia. Reactive cell changes, multinucleated giant cells, and glial-microglial collections are seen in subcortical gray matter.38 Immunohistochemistry for HIV-1 envelope glycoprotein, gp41, and p24 shows its presence in high concentrations of infected macrophages, microglia, and multinucleated giant cells in the basal ganglia.39,40 Other studies have also shown high viral load in the brains of patients with AIDS with universal and preferential involvement of deep gray matter nuclei.41,42 There is an average decline of 25% in the number of neuronal cell bodies in the substantia nigra of patients with AIDS.43 Stereologic studies of other structures of the basal ganglia have been technically difficult because of the smaller size of the neuronal cell body, making it difficult to differentiate from glial cells.

Particularly relevant to this study is the recently reported correlation40 between the expression of iNOS in the basal ganglia and the presence and severity of AIDS dementia as determined by the MSK scale of Price and Brew.13 The NOS expression has been associated with a disruption of the BBB in a number of conditions, including viral encephalitis,44 bacterial meningitis,45 hypoxia,46 and hyperthermia.47 As discussed above, HIV proteins Tat, gp41, and gp120 can induce iNOS and, hence, may play a critical role in regulating the BBB function.

Although abnormalities of the BBB have been reported in the orbitofrontal white matter,48 no abnormalities suggestive of either increased rCBV or increased BBB permeability were detected in the white matter adjacent to the caudate nucleus in our study. Conceivably, the degree of alteration was of an insufficient magnitude to permit detection using the current MRI approach. Such a possibility is consistent with the four-fold to five-fold lower rCBV found in white matter. Additional studies are required to determine the specific relationship between the disruption of the BBB in the basal ganglia and the genesis of HIV dementia.

  • Received May 27, 1999.
  • Accepted October 15, 1999.

References

  1. ↵
    Petito CK, Cash KS. Blood–brain barrier abnormalities in the acquired immunodeficiency syndrome: immunohistochemical localization of serum proteins in postmortem brain. Ann Neurol 1992;32:658–666.
    OpenUrlCrossRefPubMed
  2. Power C, Kong PA, Crawford TO, et al. Cerebral white matter changes in acquired immunodeficiency syndrome dementia: alterations of the blood–brain barrier. Ann Neurol 1993;34:339–350.
    OpenUrlCrossRefPubMed
  3. ↵
    Smith TW, DeGirolami U, Henin D, Bolgert F, Hauw JJ. Human immunodeficiency virus (HIV) leukoencephalopathy and the microcirculation. J Neuropathol Exp Neurol 1990;49:357–370.
    OpenUrlCrossRefPubMed
  4. ↵
    McArthur JC, Nance Sproson TE, Griffin DE, et al. The diagnostic utility of elevation in cerebrospinal fluid beta 2-microglobulin in HIV-1 dementia. Multicenter AIDS Cohort Study. Neurology 1992;42:1707–1712.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Singer EJ, Syndulko K, Fahy Chandon B, Schmid P, Conrad A, Tourtellotte WW. Intrathecal IgG synthesis and albumin leakage are increased in subjects with HIV-1 neurologic disease. J Acquir Immune Defic Syndr 1994;7:265–271.
  6. ↵
    Moses AV, Nelson JA. HIV infection of human brain capillary endothelial cells—implications for AIDS dementia. Adv Neuroimmunol 1994;4:239–247.
    OpenUrlPubMed
  7. ↵
    Rhodes RH. Evidence of serum-protein leakage across the blood–brain barrier in the acquired immunodeficiency syndrome. J Neuropathol Exp Neurol 1991;50:171–183.
    OpenUrlPubMed
  8. ↵
    Berger JR, Nath A. HIV dementia and the basal ganglia. Intervirology 1997;40:122–131.
    OpenUrlPubMed
  9. ↵
    Hinkin CH, van Gorp WG, Mandelkern MA, et al. Cerebral metabolic change in patients with AIDS: report of a six-month follow-up using positron-emission tomography. J Neuropsychiatry Clin Neurosci 1995;7:180–187.
    OpenUrlPubMed
  10. ↵
    Pavlakis SG, Lu D, Frank Y, et al. Magnetic resonance spectroscopy in childhood AIDS encephalopathy. Pediatr Neurol 1995;12:277–282.
    OpenUrlCrossRefPubMed
  11. ↵
    Rottenberg DA, Sidtis JJ, Strother SC, et al. Abnormal cerebral glucose metabolism in HIV-1 seropositive subjects with and without dementia. J Nucl Med 1996;37:1133–1141.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Tracey I, Carr CA, Guimaraes AR, Worth JL, Navia BA, Gonzalez RG. Brain choline-containing compounds are elevated in HIV-positive patients before the onset of AIDS dementia complex: a proton magnetic resonance spectroscopic study [published erratum appears in Neurology 1996;46:1787]. Neurology 1996;46:783–788.
    OpenUrlFREE Full Text
  13. ↵
    Price RW, Brew BJ. The AIDS dementia complex. J Infect Dis 1988;158:1079–1083.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Tracey I, Hamberg LM, Guimaraes AR, et al. Increased cerebral blood volume in HIV-positive patients detected by functional MRI. Neurology 1998;50:1821–1826.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Chang L, Speck O, Walot I, Ernst T. Perfusion MRI detects regional cerebral blood flow abnormalities in patients with early stages of HIV dementia (abstract). Neurology 1999;52 (suppl2): A254–A255.
    OpenUrl
  16. ↵
    Mooradian AD. Potential mechanisms of the age-related changes in the blood–brain barrier. Neurobiol Aging 1994;15:751–755.
    OpenUrlCrossRefPubMed
  17. ↵
    Leenders KL, Perani D, Lammertsma AA, et al. Cerebral blood flow, blood volume and oxygen utilization. Normal values and effect of age. Brain 1990;113:27–47.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Mackic JB, Weiss MH, Miao W, et al. Cerebrovascular accumulation and increased blood–brain barrier permeability to circulating Alzheimer’s amyloid beta peptide in aged squirrel monkey with cerebral amyloid angiopathy. J Neurochem 1998;70:210–215.
    OpenUrlPubMed
  19. Kalaria RN. Cerebral vessels in ageing and Alzheimer’s disease. Pharmacol Ther 1996;72:193–214.
    OpenUrlCrossRefPubMed
  20. ↵
    Su MY, Head E, Brooks WM, et al. Magnetic resonance imaging of anatomic and vascular characteristics in a canine model of human aging. Neurobiol Aging 1998;19:479–485.
    OpenUrlCrossRefPubMed
  21. ↵
    Royal W 3rd, Selnes OA, Concha M, Nance Sproson TE, McArthur JC. Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) p24 antigen levels in HIV-1-related dementia. Ann Neurol 1994;36:32–39.
    OpenUrlCrossRefPubMed
  22. ↵
    Dore GJ, Correll PK, Li Y, Kaldor JM, Cooper DA, Brew BJ. Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 1999;9:1249–1253.
    OpenUrl
  23. ↵
    Shi B, De Girolami U, He J, et al. Apoptosis induced by HIV-1 infection of the central nervous system. J Clin Invest 1996;98:1979–1990.
    OpenUrlPubMed
  24. ↵
    Hofman FM, Dohadwala MM, Wright AD, Hinton DR, Walker SM. Exogenous tat protein activates central nervous system-derived endothelial cells. J Neuroimmunol 1994;54:19–28.
    OpenUrlCrossRefPubMed
  25. ↵
    Kruman II, Nath A, Mattson MP. HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol 1998;154:276–288.
    OpenUrlCrossRefPubMed
  26. ↵
    Adamson DC, Wildemann B, Sasaki M, et al. Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV-1 gp41. Science 1996;274:1917–1921.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    Conant K, Garzino Demo A, Nath A, et al. Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci USA 1998;95:3117–3121.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I. Clinical features. Ann Neurol 1986;19:517–524.
    OpenUrlCrossRefPubMed
  29. ↵
    Selnes OA, Galai N, Bacellar H, et al. Cognitive performance after progression to AIDS: a longitudinal study from the Multicenter AIDS Cohort Study. Neurology 1995;45:267–275.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    Mirsattari SM, Power C, Nath A. Parkinsonism with HIV infection. Mov Disord 1998;13:684–689.
    OpenUrlCrossRefPubMed
  31. ↵
    Johnston JL, Miller JD, Nath A. Ocular motor dysfunction in HIV-1-infected subjects: a quantitative oculographic analysis. Neurology 1996;46:451–457.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    Aylward EH, Brettschneider PD, McArthur JC, et al. Magnetic resonance imaging measurement of gray matter volume reductions in HIV dementia. Am J Psychiatry 1995;152:987–994.
    OpenUrlPubMed
  33. ↵
    Jakobsen J, Gyldensted C, Brun B, Bruhn P, Helweg Larsen S, Arlien Soborg P. Cerebral ventricular enlargement relates to neuropsychological measures in unselected AIDS patients. Acta Neurol Scand 1989;79:59–62.
    OpenUrlPubMed
  34. ↵
    Hestad K, McArthur JH, Dal Pan GJ, et al. Regional brain atrophy in HIV-1 infection: association with specific neuropsychological test performance. Acta Neurol Scand 1993;88:112–118.
    OpenUrlPubMed
  35. ↵
    van Gorp WG, Mandelkern MA, Gee M, et al. Cerebral metabolic dysfunction in AIDS: findings in a sample with and without dementia. J Neuropsychiatry Clin Neurosci 1992;4:280–287.
    OpenUrlPubMed
  36. ↵
    Berger JR, Kumar M, Kumar A, Fernandez JB, Levin B. Cerebrospinal fluid dopamine in HIV-1 infection. AIDS 1994;8:67–71.
    OpenUrlCrossRefPubMed
  37. ↵
    Larsson M, Hagberg L, Forsman A, Norkrans G. Cerebrospinal fluid catecholamine metabolites in HIV-infected patients. J Neurosci Res 1991;28:406–409.
    OpenUrlCrossRefPubMed
  38. ↵
    Navia BA, Cho ES, Petito CK, Price RW. The AIDS dementia complex: II. Neuropathology. Ann Neurol 1986;19:525–535.
    OpenUrlCrossRefPubMed
  39. ↵
    Brew BJ, Rosenblum M, Cronin K, Price RW. AIDS dementia complex and HIV-1 brain infection: clinical-virological correlations. Ann Neurol 1995;38:563–570.
    OpenUrlCrossRefPubMed
  40. ↵
    Rostasy K, Monti L, Yiannoutsos C, et al. Human immunodeficiency virus infection, inducible nitric oxide synthase expression and microglial activation: pathogenetic relationship to the acquired immunodeficiency syndrome dementia complex. Ann Neurol 1999;46:207–216.
    OpenUrlCrossRefPubMed
  41. ↵
    Wiley CA, Soontornniyomkij V, Radhakrishnan L, et al. Distribution of brain HIV load in AIDS. Brain Pathol 1998;8:277–284.
    OpenUrlPubMed
  42. ↵
    Neuen Jacob E, Arendt G, Wendtland B, Jacob B, Schneeweis M, Wechsler W. Frequency and topographical distribution of CD68-positive macrophages and HIV-1 core proteins in HIV-associated brain lesions. Clin Neuropathol 1993;12:315–324.
    OpenUrlPubMed
  43. ↵
    Reyes MG, Faraldi F, Senseng CS, Flowers C, Fariello R. Nigral degeneration in acquired immune deficiency syndrome (AIDS). Acta Neuropathol Berl 1991;82:39–44.
    OpenUrlCrossRefPubMed
  44. ↵
    Komatsu T, Ireland DD, Chung N, Dor A, Yoder M, Shoshkes Reiss C. Regulation of the BBB during viral encephalitis: roles of IL-12 and NOS. Nitric Oxide 1999;3:327–339.
    OpenUrlCrossRefPubMed
  45. ↵
    Jaworowicz DJ Jr, Korytko PJ, Singh Lakhman S, Boje KM. Nitric oxide and prostaglandin E2 formation parallels blood–brain barrier disruption in an experimental rat model of bacterial meningitis. Brain Res Bull 1998;46:541–546.
    OpenUrlCrossRefPubMed
  46. ↵
    Fischer S, Clauss M, Wiesnet M, Renz D, Schaper W, Karliczek GF. Hypoxia induces permeability in brain microvessel endothelial cells via VEGF and NO. Am J Physiol 1999;276:C812–C820.
    OpenUrlAbstract/FREE Full Text
  47. ↵
    Alm P, Sharma HS, Hedlund S, Sjoquist PO, Westman J. Nitric oxide in the pathophysiology of hyperthermic brain injury. Influence of a new anti-oxidant compound H-290/51. A pharmacological study using immunohistochemistry in the rat. Amino Acids 1998;14:95–103.
    OpenUrlPubMed
  48. ↵
    Sacktor NC, Bacellar H, Hoover DR, et al. Psychomotor slowing in HIV infection: a predictor of dementia, AIDS and death. J Neurovirol 1996;2:404–410.
    OpenUrlPubMed

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
Advertisement

Related Articles

  • No related articles found.

Alert Me

Recommended articles