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Published online before print May 20, 2003, 10.1148/radiol.2281010683
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(Radiology 2003;228:185-192.)
© RSNA, 2003

Neuroradiology

Human Immmunodeficiency Virus 1–associated Minor Motor Disorders: Perfusion-weighted MR Imaging and 1H MR Spectroscopy1

Frank Wenserski, MD, Hans-Juergen von Giesen, MD, Hans-Joerg Wittsack, PhD, Albrecht Aulich, MD and Gabriele Arendt, MD

1 From the Departments of Diagnostic Radiology (F.W., H.J.W., A.A.) and Neurology (H.J.v.G., G.A.), Heinrich-Heine-University, Moorenstr 5, 40225 Duesseldorf, Germany. Received October 15, 2001; revision requested January 8, 2002; final revision received October 11; accepted October 31. Address correspondence to F.W. (e-mail: wensersk@uni-duesseldorf.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To investigate whether advanced magnetic resonance (MR) imaging techniques such as diffusion-weighted (DW) and perfusion-weighted (PW) MR imaging and hydrogen 1 (1H) MR spectroscopy can depict functional and pathophysiologic mechanisms in patients who have minor motor deficits (MMDs) associated with human immunodeficiency virus 1 (HIV-1).

MATERIALS AND METHODS: Thirty-two patients with results seropositive for HIV-1 and different degrees of HIV-1–related MMD underwent conventional brain MR imaging, as well as DW and PW MR imaging and 1H MR spectroscopy of the basal ganglia. PW MR imaging data were computed pixel by pixel for creation of time-to-peak, relative regional cerebral blood volume, and bolus amplitude parameter maps. In addition, quantitative regional cerebral blood flow (rCBF) maps were calculated with respect to the arterial input function by using the singular value decomposition algorithm. For 1H MR spectrocopy, a stimulated echo acquisition mode 20, or STEAM 20, sequence was used. Spectra were fit for determination of the signal intensities of the different metabolites. According to psychomotor testing results, patients were divided into three groups: group 1, 10 patients with normal motor function; group 2, eight patients with psychomotor slowing for the first time; and group 3, 14 patients who had had sustained pathologic psychomotor slowing for at least 6 months before the MR imaging examination.

RESULTS: No patients had an abnormality at either conventional or DW MR imaging. PW MR imaging depicted significantly elevated rCBF in group 2 patients (P = .039, analysis of variance [ANOVA]) and significantly elevated myo-inositol–to-creatine ratio levels in group 3 patients (P = .020, ANOVA).

CONCLUSION: Quantitative PW MR imaging and 1H MR spectroscopy can depict pathologic changes in patients who have HIV-1–related MMD but normal clinical examination and conventional MR imaging findings.

© RSNA, 2003

Index terms: Acquired immunodeficiency syndrome (AIDS), 13.2068 • Brain, MR, 13.121411, 13.121412, 13.121413, 13.121416, 13.12143, 13.12144, 13.12145 • Magnetic resonance (MR), diffusion study, 13.12144 • Magnetic resonance (MR), perfusion study, 13.12144 • Magnetic resonance (MR), spectroscopy, 13.12145


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Minor motor deficits (MMDs) related to human immunodeficiency virus 1 (HIV-1) are a clearly defined preclinical manifestation of HIV-1 in the human brain (1). Although different examination paradigms have been used to assess HIV-1–related MMD, the results of both European (2) and large American studies (eg, Multicenter AIDS Cohort Study) (3) have demonstrated that HIV-1–related MMD indicates the progression of HIV-1–associated brain disease toward dementia and death. The adequate assessment in individual patients is therefore crucial.

The diagnosis of HIV-1–related MMD can be confirmed by performing electrophysiologic motor tests to quantify psychomotor speed before any abnormality is identified at either routine imaging procedures, such as magnetic resonance (MR) imaging of the brain, or clinical examination. A defined motor test battery to quantify motor dysfunction in extrapyramidal disorders such as Parkinson or Wilson disease has been developed (4,5). This test battery has been proven to not only enable detection of abnormalities early during the individual course of the disease (6) but also yield sensitive parameters for monitoring the therapeutic and prophylactic effects of antiretroviral therapy on the central nervous system (7–9).

In a previously performed positron emission tomographic (PET) study (10), initial hypermetabolism in the basal ganglia was seen in association with HIV-1–related MMD, and pseudonormalization and finally hypometabolism at the stage of clinically overt acquired immunodeficiency syndrome–related dementia followed. On the basis of the results of that study, our purpose in this study was to investigate whether diffusion-weighted (DW) MR imaging, perfusion-weighted (PW) MR imaging, and hydrogen 1 (1H) MR spectroscopy have the potential to depict the functional and pathophysiologic mechanisms of HIV-1–related MMD.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patients and Control Subjects
Fourteen healthy volunteers with findings seronegative for HIV-1 served as control subjects (hereafter referred to as HIV-1–seronegative volunteers or control subjects) who underwent 1H MR spectroscopy. All of these volunteers were white men with a mean age of 33.6 years ± 6.5 (SD). All of these volunteers were employees of the diagnostic radiology and neurology departments of Heinrich-Heine-University and had undergone a complete medical examination in the year before the MR imaging examinations. These examinations included a medical history, a clinical examination, routine blood tests, and chest radiography. None of these volunteers had a history of substance abuse.

To avoid the assessment of signal intensity changes caused by entities other than HIV-1–related MMD, we recruited a homogeneous patient group that consisted of 32 white homosexual men who had findings positive for HIV-1. All of these patients were recruited from the neurologic acquired immunodeficiency syndrome outpatient clinic of the neurology department of Heinrich-Heine-University. Written informed consent was obtained in accordance with the guidelines of the 1975 Declaration of Human Rights of Helsinki. The study was approved by the local ethics committee. Patients with any of the following characteristics were excluded: history of drug abuse, HIV-1–associated dementia (1), clinical signs of basal ganglial dysfunction, and evidence of either HIV-1–associated myelopathy or HIV-1–associated peripheral polyneuropathy. None of the patients had ever had a cerebral opportunistic infection or a cerebral lymphoma. All but three patients were undergoing highly active antiretroviral therapy.

All patients were clinically and electrophysiologically monitored every 3 months. This monitoring included evaluation of unified Parkinson disease rating scale motor scores (11) and human immunodeficiency virus dementia scale scores (12) and testing of psychomotor speed. Electrophysiologic assessment of psychomotor speed included tests of most rapid voluntary isometric index finger extensions. The parameters measured in this context were simple reaction time and contraction time. In brief, the reaction time (in milliseconds) is the time between an acoustic trigger signal and the onset of movement, whereas the contraction time (in milliseconds) is the time between the onset of a rapid extension of the index finger and the time at which maximum movement occurs. The methodologic details of these tests are described elsewhere (6). Contraction times were rated as pathologic when the motor test results for at least one hand were outside the range of the mean ± 2 SDs. Normal values are reported elsewhere (13).

According to the results of psychomotor testing, the patients were divided into three groups: Group 1 consisted of 10 patients who had had normal motor function for at least 1 year. Group 2 consisted of eight patients who had manifestations of psychomotor slowing for the first time after at least 1 year of normal motor function (ie, incipient MMD). Group 3 consisted of 14 patients who had had sustained pathologic psychomotor slowing for at least 6 months before they underwent the MR imaging examinations (ie, sustained MMD). These levels of psychomotor function have been shown to characterize distinct subgroups of patients with findings seropositive for HIV-1 (hereafter referred to as HIV-1–seropositive patients) (9).

The three patient groups were homogeneous and did not differ with respect to age, duration of HIV-1 seropositivity, or CD4 cell count. All patients in each of the three groups had some stage of acquired immunodeficiency syndrome, and the human immunodeficiency virus– related dementia scale and unified Parkinson disease rating scale scores did not differ among the groups. The demographic data for these patients have been published previously (29) and are listed in Table 1.


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  		TABLE 1. Demographic Data for All HIV-1-Seropositive Patients

 
MR Imaging and 1H MR Spectroscopy
All MR imaging measurements were performed with a 1.5-T whole-body clinical MR imaging unit (Magnetom Vision; Siemens, Erlangen, Germany) equipped with a gradient overdrive and by using a standard head coil. The routine MR imaging protocol for the patients and control subjects consisted of a transverse T2-weighted turbo-gradient spin-echo sequence (7,040/115 [repetition time msec/echo time msec], 20 sections, 6-mm section thickness, 345 x 512 matrix, 230-mm field of view) followed by a transverse fluid-attenuated inversion-recovery sequence (9,000/105, 2,200-msec inversion time, 18 sections, 6-mm section thickness, 144 x 256 matrix, 230-mm field of view) and a coronal T1-weighted spin-echo sequence (560/17, 20 sections, 6-mm section thickness, 144 x 256 matrix, 230-mm field of view). Abnormalities such as infarcts, arteriovenous malformations, tumors, and edema led to exclusion from MR imaging.

If the conventional MR images appeared to be normal, a transverse DW single-shot spin-echo echo-planar MR imaging sequence (103-msec echo time, 20 sections, 5-mm section thickness, 96 x 128 matrix, 240-mm field of view) was performed with diffusion weighting factors, or b values, of 0 and 1,000 sec/mm2; the high b value measurements were performed with diffusion gradients in three orthogonal directions (ie, read, section, and phase directions) in space. Then, transverse, coronal, and sagittal T1-weighted MR images were obtained by using a two-dimensional fast low-angle shot gradient-echo sequence (300/6, 20 sections, 6-mm section thickness, 144 x 256 matrix, 230-mm field of view).

For 1H MR spectroscopy, we chose a spectroscopic volume of 2 x 2 x 2 cm, which yielded a sufficient signal-to-noise ratio within a reasonable measurement time. Because there is unequivocal evidence that the basal ganglia has a pivotal role in human immunodeficiency virus infection in the brain (14,15) and because in a previously performed PET study (10), the patients with HIV-1–associated MMD especially had disturbances in the basal ganglia, we presumed that the placement of the 1H MR spectroscopic target volume within this region would improve our chances to detect metabolic changes during this very early stage of HIV-1–associated central nervous system dysfunction. Owing to technical reasons, however, our sample volume included regions of less interest, such as parts of the thalamus and the striatum. Any other placement would have led to either an inhomogeneous sampling volume that included not only gray and white matter but also cerebrospinal fluid or shim adjustment problems caused by structures of the skull.

When psychomotor testing revealed a pathologic contraction time for both hands, the more marked prolongation was chosen and 1H MR spectroscopy of the contralateral basal ganglia was performed.

Spectroscopic data were acquired with a stimulated echo acquisition mode, or STEAM (16–18), sequence by using 1,500/20 and 256 acquisitions. The spectral line widths were 8–9 Hz for the H2O resonance that resulted from the preceding shimming procedure. Water suppression was performed by using a frequency-selective 90° prepulse with a Gaussian pulse shape. The total acquisition time for 1H MR spectroscopy was 6.5 minutes.

In all 32 HIV-1–seropositive patients who underwent 1H MR spectroscopy, an additional perfusion study that consisted of 40 T2*-weighted gradient-echo echo-planar MR imaging (54-msec echo time, 12 sections, 5-mm section thickness, 128 x 128 matrix, 240-mm field of view) measurements at 2-second intervals was performed. Fifteen milliliters of gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany) was injected at a rate of 5 mL/sec at the time of the fourth MR image acquisition, and an intravenous injection of 15 mL of sodium chloride at the same rate immediately followed.

After the PW MR imaging examination, we performed a T1-weighted spin-echo MR imaging sequence (560/17, 6-mm section thickness, 144 x 256 matrix, 230-mm field of view) in all patients to exclude the enhancing lesions.

Postprocessing and MR Image Analysis
To evaluate the DW and PW MR imaging data, we used commercially available software (Microsoft Windows Stroketool, version 1.02; Digital Image Solutions, Cologne, Germany) that runs on a personal computer. By using this software, we calculated the DW MR image data by averaging the image data obtained at DW MR imaging in the section, read, and phase directions. Trace apparent diffusion coefficient maps also were calculated from the DW MR imaging data.

We computed PW MR imaging data pixel by pixel to create color-coded time-to-peak maps. Parameter maps indicating the relative regional cerebral blood volume and the bolus amplitude also were calculated. In addition to creating these nonquantitative perfusion maps, we quantified the regional cerebral blood flow (rCBF) in the basal ganglia by using Stroketool, because this computer software implements the singular value decomposition algorithm described by Østergaard et al (19). In brief, Stroketool, in a first step, automatically detects the arterial input function, taking into account only those pixels that show the deepest and earliest decrease in signal intensity in the corresponding time frame. In a second step, the blood flow in brain tissue is calculated pixel by pixel with respect to the arterial input function by using the singular value decomposition algorithm.

Assuming that the microvascular hematocrit level is constant throughout the brain (20), we used normal-appearing occipital white matter as an internal standard that is said to have a fairly constant age-independent flow volume of 22 mL/100 mL/min (21). Three independent observers (F.W., H.J.W., H.J.v.G.) chose and manually marked regions of interest within the basal ganglia on the resulting rCBF quantitative maps three times (multiple measurements). Because the regions of interest had to be adjusted to the anatomy of individual patients, they ranged in size from 15 to 30 pixels. Mean rCBF values and SDs for the regions of interest were calculated.

The 1H MR spectroscopic data were transferred to a workstation (Sun Ultra Sparc1; Sun Microsystems, Palo Alto, Calif) for postprocessing. The residual signal intensity of suppressed water was subtracted by using the Hankel Lanczos singular values decomposition algorithm (22). An exponential line broadening of 1 Hz was performed. To determine the signal intensity of the different metabolites, spectra were fitted by using the variable projection time-domain fitting algorithm (23,24) and the tool kit of MR user interface software. Because we used the variable projection time-domain fitting method, there was no need to perform any baseline correction or other preprocessing, especially since phase is also a fitting parameter. We used the time-domain fitting technique (27) because the evaluation of short-echo in vivo spectra is difficult owing to the overlapping resonances of different metabolites and possible background problems (25–27).

To obtain stable results, in a first step we fitted the resonance of creatine-phosphocreatine to determine the line width of this peak. The only prior knowledge for the final fitting procedure was to fix all resonances to this constant line width. This procedure was described previously by Mierisova and co-workers (28). The determined signal intensities of the following metabolite level peaks were relevant to the statistical analysis: glutamine-glutamate level, which peaked at 3.65–3.80 ppm; myo-inositol level, which peaked at 3.54 ppm; choline-containing compound level, which peaked at 3.20 ppm; creatine-phosphocreatine level, which peaked at 3.00 ppm; and N-acetylaspartate level, which peaked at 2.02 ppm.

All conventional, DW, and PW MR images were analyzed for possible abnormalities by two experienced neuroradiologists (F.W., 7 years experience; A.A., 30 years experience) who were not involved in patient or volunteer recruitment and were blinded to all clinical and electrophysiologic data. Interpretations were made by consensus.

Additionally, on the apparent diffusion coefficient maps obtained for all patients, regions of interest were traced within the regions of the basal ganglia and the occipital white matter, and the so-obtained mean apparent diffusion coefficients for each region were statistically evaluated. These regions of interest also were adjusted to the anatomy of individual patients, and they ranged in size from 12 to 33 pixels.

Statistical Analysis
Statistic analyses were performed by using a commercially available software package (Statview, version 5.0.1; SAS Institute, Cary, NC). We performed analysis of variance to test for differences between groups, and the Fisher protected least significant difference was used for post hoc testing for significance adjusting in multiple comparisons among the groups. The level of significance was set at P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Patient Imaging
The conventional MR images obtained in all patients were normal—notably, we observed no pathologic contrast enhancement or structural abnormalities at any of the examinations. There were no abnormalities at visual analysis of the DW MR maps or nonquantitative PW MR maps. The quantitative data generated from the different MR imaging examinations are presented in Table 2. Evaluation of the regions of interest on the apparent diffusion coefficient maps at analysis of variance revealed no significant differences among the three patient groups (ie, patients with normal motor function, patients with incipient MMD, and patients with sustained MMD).


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  		TABLE 2. Group Statistical Comparisons among Patient Groups

 
In contrast, quantification of the perfusion data at analysis of variance revealed significant differences among the patient groups (P = .039)—specifically, increased rCBF in the basal ganglia in the group 2 patients, as compared with the basal ganglial rCBF in the group 1 patients, and decreased rCBF in the basal ganglia in the group 3 patients, as compared with the basal ganglial rCBF in the group 1 patients. Although these changes were not significant at post hoc testing, the rCBF values in the group 2 patients were significantly higher than those in the group 3 patients (P = .012, Fisher protected least significant difference). This significant difference is illustrated on an individual patient basis in Figure 1.



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  		Figure 1. Transverse rCBF maps for, A, a patient with incipient HIV-1-related MMD (group 2) and, B, a patient with sustained HIV-1-related MMD (group 3). Circles are regions of interest. Quantitative evaluation revealed a higher mean blood flow volume in the basal ganglia in the group 2 patient (81.3 mL/100 mL/min ± 5.3) compared with that in the group 3 patient (39.6 mL/100 mL/min ± 3.3). PW MR imaging data were acquired by using a gadopentetate dimeglumine-enhanced, single-shot T2*-weighted gradient-echo echo-planar sequence (54-msec echo time, 12 sections, 5-mm section thickness, 128 x 128 matrix, 240-mm field of view) performed in 2-second intervals.

 
1H MR Spectroscopy
We previously reported the 1H MR spectroscopy data (29). On a group statistical level, no significant differences in either metabolite ratio levels or single metabolite levels were observed between the HIV-1–seronegative volunteers (ie, control subjects) and the HIV-1–seropositive—but neurologically asymptomatic— patients. No significant differences between the analyzed right and left basal ganglial regions of interest were detected.

We were interested in determining whether 1H MR spectroscopy would depict differences in findings between the HIV-1–seropositive patients with and those without HIV-1–associated MMD. At 1H MR spectroscopy, the patients with sustained HIV-1–related MMD (group 3) had significantly elevated myo-inositol–to-creatine ratios (P = .020, analysis of variance). Post hoc testing with the Fisher protected least significant difference, with adjustments made for multiple comparisons among groups, revealed that the patients in group 3 had higher myo-inositol–to-creatine ratios than the patients in group 2 (P = .012). No significant differences in the levels of the other metabolites, especially not the N-acetylaspartate–to-creatine ratio, were observed among the groups (29) (Fig 2, Table 2).



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  		Figure 2a. (a, b) 1H MR spectra for two patients. The substantial decline in myo-inositol (mI) signal intensity in the group 3 patient (a), as compared with the normal spectrum of this metabolite in the group 1 patient (b), is obvious. Cho = choline, Cr/PCr = creatine-phosphocreatine, Glx = glutamine-glutamate, NAA = N-acetylaspartate. (c) Placement of target volumes (squares) on sagittal (left), coronal (middle), and transverse (right) T1-weighted two-dimensional fast low-angle shot MR images (300/6, 6-mm section thickness, 144 x 256 matrix, 230-mm field of view) obtained in the group 3 patient (a).

 


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  		Figure 2b. (a, b) 1H MR spectra for two patients. The substantial decline in myo-inositol (mI) signal intensity in the group 3 patient (a), as compared with the normal spectrum of this metabolite in the group 1 patient (b), is obvious. Cho = choline, Cr/PCr = creatine-phosphocreatine, Glx = glutamine-glutamate, NAA = N-acetylaspartate. (c) Placement of target volumes (squares) on sagittal (left), coronal (middle), and transverse (right) T1-weighted two-dimensional fast low-angle shot MR images (300/6, 6-mm section thickness, 144 x 256 matrix, 230-mm field of view) obtained in the group 3 patient (a).

 


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  		Figure 2c. (a, b) 1H MR spectra for two patients. The substantial decline in myo-inositol (mI) signal intensity in the group 3 patient (a), as compared with the normal spectrum of this metabolite in the group 1 patient (b), is obvious. Cho = choline, Cr/PCr = creatine-phosphocreatine, Glx = glutamine-glutamate, NAA = N-acetylaspartate. (c) Placement of target volumes (squares) on sagittal (left), coronal (middle), and transverse (right) T1-weighted two-dimensional fast low-angle shot MR images (300/6, 6-mm section thickness, 144 x 256 matrix, 230-mm field of view) obtained in the group 3 patient (a).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
HIV-1–associated MMDs, as assessed by using electrophysiologic psychomotor tests, are a common complication in patients with HIV-1; however, little is known about the underlying pathomechanisms, time course, or possible reversibility or irreversibility of these disorders within certain time windows. Because conventional imaging techniques do not yield any clue, the present study was designed to answer the question of whether the advanced MR imaging modalities—specifically, DW MR imaging, PW MR imaging, and 1H MR spectroscopy—have the potential to depict the abnormalities that constitute possible pathophysiologic and functional correlates of HIV-1–associated MMDs. We, therefore, defined the groups evaluated in this study according to the very first subtle but electrophysiologically detectable manifestation of psychomotor slowing (1), which is known to be highly predictive of subsequent HIV-1–related dementia (2,3). We recognize that with this approach, there is a risk that patients will be examined at such an early stage in the course of the disease that minor abnormalities may not be detected.

With regard to the described series of patients, who had no lesions at conventional MR imaging, neither the DW MR image findings, apparent diffusion coefficient maps of the whole brain, nor apparent diffusion coefficients for the basal ganglia and occipital white matter indicated any abnormality in those patients with electrophysiologically defined HIV-1–related MMD. However, during the later stages of the disease, DW MR imaging is reported to yield information that is essential to the differentiation between intracranial neoplasms and infection (30).

In contrast, we observed significant differences, in both PW MR imaging data and 1H MR spectroscopic data, among the patients with HIV-1–associated MMD. These differences were compatible with the proposed multiphasic course of HIV-1–associated brain disease, in which the focus is the basal ganglia and their function (10). According to this hypothesis, the first stage of the disease is characterized by hypermetabolism within the basal ganglia. This hypermetabolism, as assessed with PET, correlates with hyperperfusion of the basal ganglia, as indicated by the PW MR imaging data for the group 2 patients. At the time of the first manifestation of psychomotor slowing (in group 2), there were no sustained functional deficits, and, accordingly, 1H MR spectroscopy depicted no findings of longer-lasting structural alterations.

Abnormalities depicted at PW MR imaging in patients with HIV-1–associated minor cognitive motor disorders have also been described by another group (31). However, those abnormalities were observed in clinically already compromised patients and not in clinically yet unaffected patients, and the basal ganglia were not examined.

The next stage of HIV-1–associated MMD, as assessed with PET, is characterized first by a metabolic pseudonormalization and then by a secondary hypometabolism. In this study, this stage was reflected by the substantial hypoperfusion of the basal ganglia depicted at PW MR imaging in the group 3 patients, as compared with the PW MR imaging–depicted perfusion in the group 2 patients. This stage is consistent with sustained motor dysfunction, and 1H MR spectroscopy depicts substantial changes in the myo-inositol–to-creatine ratio level that are suggestive of astrogliosis.

In most studies, MR spectroscopy has been performed for evaluation of HIV-1–seropositive patients with manifestations of dementia (32–35). In patients with dementia, reduced N-acetylaspartate levels and increased choline levels have been observed in white matter regions (32, 36,37), and the metabolic changes appeared to be more marked in the patients who had more advanced stages of dementia (32). An increased choline level was observed to precede the N-acetylaspartate level decrease (38). According to these findings, both increased and decreased ratios of N-acetylaspartate–to-creatine and choline-to-creatine have been described in patients with dementia (35,39). Because N-acetylaspartate is a marker for mature neurons (40), the N-acetylaspartate level decrease has been interpreted as a sign of neuronal loss during relatively late stages of HIV-1–associated brain damage. However, focusing on the earlier and subclinical stages of the disease rather than on the late stages, when extensive neuronal death has possibly already occurred, may enable one to obtain better information concerning the underlying pathomechanisms and therefore help in the identification of earlier treatment indications from a neurologic point of view (41).

The patients in this study had no substantial metabolic abnormalities at MR spectroscopy on a group statistical basis; P values were not significant at unpaired t testing (29). However, after categorizing the patients into the earlier defined groups, we observed significantly higher myo-inositol–to-creatine ratios in the group 3 patients. In our opinion, despite the very strict selection criteria used to select the patients in this study, there are two main reasons that the MR spectroscopic changes were not substantial overall:

1. Focusing exclusively on the striatum might have led to more substantial differences; however, this was impossible because of technical reasons.

2. All but three patients were undergoing highly active antiretroviral therapy, and a decrease in initially elevated myo-inositol levels in response to this treatment has been described (42).

However, the fact that we observed substantial changes among only the electrophysiologically distinguishable yet clinically not compromised patients makes the explanation that we suggest even more probable. Furthermore, our findings are in good agreement with those of Ernst and co-workers (43), who observed reduced creatine and myo-inositol concentrations in the basal ganglia in HIV-1–positive patients at MR spectroscopy and declared these decreases to be early findings of human immunodeficiency virus–related cognitive motor complex (43).

In another study, Chang et al (44) described an increased choline-to-creatine ratio level in the middle-frontal white matter and the basal ganglia and elevated myo-inositol–to-creatine ratio and myo-inositol concentrations in the basal ganglia in patients with mild human immunodeficiency virus–related dementia. High choline concentrations in the subcortical regions of the brain have been observed during the early stages of HIV-1 disease, whereas low N-acetylaspartate levels in this region have been observed in individuals with severe neuropsychologic impairments (45). It has been reported that while undergoing highly active antiretroviral therapy, patients have decreases in initially elevated myo-inositol levels (42) and improved psychomotor function in response to this treatment (8,46–49).

We conclude that sustained HIV-1–related MMDs are associated with slight but MR spectroscopically measurable increases in myo-inositol levels. Conversely, HIV-1–related MMDs are not associated with N-acetylaspartate level decreases (44). Myo-inositol can be seen only in short-echo-time spectra of the brain, because the peak concentration of this marker is modulated by J coupling, which causes severe signal intensity attenuation with longer echo times. The definite biologic role of this metabolite is unclear; however, there is strong evidence that myo-inositol is a glia-specific marker that may participate in the osmoregulatory system in astrocytes (50). Our study findings emphasize the important role of disturbances in astrocyte function in the pathogenesis of HIV-1–related brain disease. Therefore, our findings are in good agreement with those of Lipton (51–53) and Koeller et al (54), the latter group of which observed an alteration in astrocyte function in rat cell cultures that was provoked by the cerebrospinal fluid from HIV-1–infected patients with brain involvement.

The results of another study (55) involving HIV-1–seropositive patients without associated dementia revealed significant increases in myo-inositol–to-creatine ratio levels in the white matter compared with the levels of this metabolite in this region in healthy control subjects. The study population in that study may have comprised patients with pathologic motor slowing. In contrast, the myo-inositol–to-creatine ratio levels in both the gray matter and white matter of the patients with dementia in that study were almost normal. However, those patients had a substantial decrease in N-acetylaspartate–to-creatine ratio levels in the gray matter compared with both the control subjects and the patients without dementia. These myo-inositol–to-creatine ratio level changes seem to parallel the dynamics recently proposed for regional glucose metabolism, as assessed at fluorodeoxyglucose PET (10). Initial astroglial hypermetabolism and probably gliosis are followed by a final hypometabolic phase that is characterized by neuronal loss and clinical manifestations of HIV-1–related dementia. On the basis of the findings just described, there appears to be a need for continuous follow-up examinations in patients, especially since it is known that incipient MMD may be reversible in certain circumstances (8). Thus, there is the need to determine the best moment during an individual course of this disease to start specific therapy.

Because changes in rCBF and in MR spectroscopically detectable metabolite levels generally occur long before clinical examination, conventional MR imaging, or DW MR imaging reveals any abnormalities, our findings suggest that in addition to measurements of psychomotor speed, metabolite concentrations observed at short-echo-time 1H MR spectroscopy and basal ganglial rCBF are adequate surrogate markers for HIV-1–associated brain disease, as well as adequate therapy control parameters.

As discussed in the Materials and Methods section, the 1H MR spectroscopic sample volume had to include regions of less interest, such as parts of the thalamus, the internal capsule, and the striatum. Therefore, the exact origin of the observed changes remains unclear, because we cannot reject the proposal that 1H MR spectroscopic changes occur in the thalamus and internal capsule as well. However, considering all of the information together, we believe that there are good reasons to propose the basal ganglia as the origin of the detected metabolic changes, because the observed changes in cerebral perfusion were also restricted to the basal ganglia. Nevertheless, we have no doubt that the explanation for the phenomenon of MMD itself is dysfunction of the basal ganglia. We, therefore, believe that focusing exclusively on the striatum probably would have led to even more marked differences in 1H MR spectroscopic findings.


   ACKNOWLEDGMENTS
 
The authors thank E. Raedisch for her skillful technical assistance.


   FOOTNOTES
 
Abbreviations: DW = diffusion weighted, HIV-1 = human immunodeficiency virus 1, MMD = minor motor deficit, PW = perfusion weighted, rCBF = regional cerebral blood flow

Author contributions: Guarantor of integrity of entire study, G.A.; study concepts, A.A., F.W., H.J.v.G.; study design, F.W., H.J.v.G., H.J.W.; literature research, F.W., H.J.v.G.; clinical studies, G.A., H.J.v.G.; experimental studies, H.J.v.G., F.W., H.J.W.; data acquisition, F.W., H.J.W.; data analysis/ interpretation, F.W., H.J.v.G., H.J.W.; statistical analysis, H.J.v.G.; manuscript preparation, F.W., H.J.v.G.; manuscript definition of intellectual content, all authors; manuscript editing, F.W.; manuscript revision/review and final version approval, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
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