Caudate blood flow and volume are reduced in HIVⴙ neurocognitively impaired patients B.M. Ances, MD, PhD*; A.C. Roc, MS*; J. Wang, PhD; M. Korczykowski, MA; J. Okawa, MSN; J. Stern, MD; J. Kim, PhD; R. Wolf, MD; K. Lawler, DPhil; D.L. Kolson, MD, PhD; and J.A. Detre, MD
Abstract—Objective: To evaluate the effects of HIV-associated neurocognitive impairment on caudate blood flow and volume. Methods: The authors performed continuous arterial spin labeled MRI on 42 HIV⫹ patients (23 subsyndromic and 19 HIV neurosymptomatic) on highly active antiretroviral therapy and 17 seronegative controls. They compared caudate blood flow and volume among groups. Results: A stepwise decrease in both caudate blood flow and volume was observed with increasing HIV-associated neurocognitive impairment. Compared with seronegative controls, baseline caudate blood flow was reduced in HIV⫹ neurosymptomatic patients (p ⫽ 0.001) with a similar decreasing trend for subsyndromic HIV⫹ patients (p ⫽ 0.070). Differences in caudate volume were observed only for neurosymptomatic HIV⫹ patients compared with controls (p ⫽ 0.010). A Jonckheere–Terpstra test for trends was significant for both caudate blood flow and volume for each of the three subgroups. Pearson product moment correlation coefficients were not significant between caudate blood flow and volume for each group. Conclusions: Decreasing trends in caudate blood flow and volume were associated with significantly increasing HIV-associated neurocognitive impairment (HNCI), with the greatest decreases observed for more severely impaired patients. However, reductions in caudate blood flow and volume were poorly correlated. Changes in residual caudate blood flow may act as a surrogate biomarker for classifying the degree of HNCI. NEUROLOGY 2006;66:862–866
HIV-associated neurocognitive impairment (HNCI) is characterized by deficits in memory, attention, and reasoning.1 Disease severity is classified by neuropsychological performance (NP) as assessed by a Global Deficit Score (GDS).2-4 Highly active antiretroviral therapy (HAART) has decreased HNCI incidence but not prevalence.5 HIV preferentially affects the caudate,6,7 leading to psychomotor retardation.8 Previous qualitative volumetric neuroimaging studies used caudate atrophy to measure integrity8-11 with HNCI severity correlating with bicaudate ratios.12,13 However, bicaudate ratios cannot differentiate volume loss from surrounding white matter changes. Using 99m Tc-HMPAO SPECT, several groups demonstrated regional perfusion defects in HIV⫹ patients.14-17 However, relative perfusion was assessed by visual interpretation, not quantification. Observed abnormalities within a single patient may not be consistent across groups.18 Studies that quantified blood flow in HIV⫹ patients have produced contrasting results. In one study, no regional flow differences occurred between
HIV⫹ patients and seronegative controls.19 However, blood volume was increased in subcortical gray matter of HIV⫹ patients.20 A recent study showed regional flow reductions in frontal and parietal lobes of HIV⫹ patients.21 We quantified blood flow in patients with HNCI with use of continuous arterial spin labeled (CASL) MRI. CASL-MRI uses magnetically labeled arterial water as an endogenous tracer to provide rapid noninvasive blood flow measurements.22 It has been validated with other neuroimaging techniques22-24 in healthy individuals25 and patients.26 We examined whether baseline caudate blood flow could serve as a surrogate biomarker for HNCI. Methods. Subjects. Forty-two HIV⫹ patients and 17 seronegative healthy subjects were recruited and studied using CASL-MRI. Serologic status was confirmed by a documented positive Western blot or plasma HIV PCR result. Typical laboratory screening evaluations performed in close temporal proximity to scans included basic metabolic panel, complete blood count, thyroid panel, syphilis, CD4 level, and plasma viral load (table 1). All seropositive HIV patients fulfilled the following inclusion criteria: a recent history of CD4 ⬍ 500 cells/mm3, negative urine toxicology screen, no other chronic medical or psychiatric ill-
* These authors contributed equally to this work. From the Department of Neurosciences and Radiology (B.M.A.), University of California at San Diego, San Diego, CA; Departments of Neurology (A.C.R., J.W., M.K., J.K., K.L., D.L.K., J.A.D.) and Radiology (K.K., J.A.D.), Hospital of the University of Pennsylvania, Philadelphia, PA; and Department of Infectious Diseases (J.O., J.S.), Pennsylvania Hospital, Philadelphia, PA. Supported by a grant at the University of Pennsylvania Center for AIDS Research (B.A., J.D.), Universitywide AIDS Research Program Fellowship (CF05-SD-301) (B.A.), and the University of Pennsylvania AIDS Clinical Trials Unit (NIH AI 32783) (B.A., D.K., J.O., J.S., J.D.). Disclosure: The authors report no conflicts of interest. Received August 31, 2005. Accepted in final form November 18, 2005. Address correspondence and reprint requests to Dr. Beau M. Ances, HIV Neurobehavioral Research Center, 150 W. Washington, 2nd Floor, San Diego, CA 92119; e-mail: [email protected]
Copyright © 2006 by AAN Enterprises, Inc.
Comparisons of clinical characteristics and laboratory values for subjects Controls, n ⫽ 17
Subsyndromic, n ⫽ 23
Neurosymptomatic, n ⫽ 19
43 ⫾ 8
45 ⫾ 10
44 ⫾ 7
13 ⫾ 2
14 ⫾ 3
12 ⫾ 2
352 ⫾ 214
400 ⫾ 249
Laboratory results CD4, cells/mm3 % Log copies Viral load, copies/mL
60 ⫾ 174
22 ⫾ 12
4,152 ⫾ 8,376
14,357 ⫾ 59,642
13 ⫾ 2
13 ⫾ 2
40 ⫾ 4
40 ⫾ 4
Medical status % on HAART regimens Age and education are expressed in years ⫾ SD; laboratory results are ⫾ SEM. [Hb] ⫽ hemoglobin concentration; [Hct] ⫽ hematocrit concentration; HAART ⫽ highly active antiretroviral therapy.
nesses, and MRI without major structural abnormalities. Patients continued their HAART regimens, with most patients using at least three medications (table 1). Healthy age and educationmatched seronegative controls from the general population were recruited. These controls required no medications and had no history of substance abuse. Before participating, all subjects were informed of the protocol and completed signed consent as required by the Human Subjects Institutional Review Board at the Hospital of the University of Pennsylvania. Neuropsychological and neurologic examination. HIV⫹ patients were classified into subgroups using neurobehavioral assessments described in detail elsewhere.4,27 Seronegative control subjects were screened with a basic questionnaire including neuropsychological history. In addition, 9 of the 17 subjects completed neurologic and neuropsychological examinations. A neurologist (B.A.) performed a detailed standardized neurologic examination that included testing of cranial nerve function, motor strength and coordination, reflexes, gait, and sensation, as well as an interrogative assessment of mood, bowel/bladder dysfunction, and difficulties with activities of daily living on all HIV⫹ patients and controls.28 Participants who completed neuropsychological evaluations were tested on a comprehensive neuropsychometric battery that was designed to assess functioning in verbal memory and recall, psychomotor skills, motor skills and praxis, and executive functioning.29 This NP test battery included the Rey Auditory Verbal Learning, Symbol-Digit Task, Trailmaking A, Grooved Pegboard Dominant and Non-Dominant hands, Trailmaking B, and Stroop Color, Word, and Interference tasks. Raw scores were then converted into T scores by applying demographic corrections for age, sex, and education.4,30 T scores from each test were subsequently transformed into GDS, with GDS 0 for T ⱖ 40, GDS 1 for 39 ⱖ T ⱖ 35, GDS 2 for 34 ⱖ T ⱖ 30, GDS 3 for 29 ⱖ T ⱖ 25, GDS 4 for 24 ⱖ T ⱖ 20, and GDS 5 for T ⱕ 19.4 GDSs from each test were then averaged to derive an average GDS for each participant, with patients classified as either subsyndromic (GDS ⱕ 1.0) or neurosymptomatic (GDS ⬎ 1.0). This cutoff was chosen because it has been demonstrated to have higher likelihood ratio and positive predictive value for differentiating these two HIV⫹ subgroups.4 Imaging protocol. MRI was performed on a Siemens 3.0-Tesla Trio scanner with a standard clinical quadrature head coil. The imaging protocol consisted of the following: a localizer (TR/TE ⫽ 20/5 milliseconds, 144 ⫻ 192, 3 slices, 9.6 mm thick, 2 minutes in duration), a T1-weighted magnetization-prepared rapid acquisition gradient echo (MPRAGE) (TR/TE ⫽ 1,620/3 milliseconds, 192 ⫻ 256, 160 slices, 1 mm isotropic, 6 minutes in duration), and a CASL sequence using gradient echo echoplanar imaging. CASLMRI was performed with a 0.16-G/cm gradient and 22.5-mG RF
irradiation applied 8 cm beneath the center of the acquired slices. Control pulse applied was applied using an amplitude modulated version of the labeling pulse and had a sinusoid function. The tagging/control duration was 2 s. Interleaved images with and without labeling were acquired using a gradient echo echoplanar imaging sequence. A delay of 1.2 seconds was inserted between the end of the labeling pulse and image acquisition to reduce transit artifact. Acquisition parameters were as follows: FOV ⫽ 22 cm, matrix ⫽ 64 ⫻ 64, TR ⫽ 4 seconds, TE ⫽ 17 milliseconds, flip angle ⫽ 90 °. Twelve slices (6-mm thickness with 1.5-mm gap) were acquired from inferior to superior in a sequential order. The CASL scan took 5 minutes 30 seconds and resulted in 80 acquisitions. Data analysis. Images were processed off-line using a program written in Interactive Data Language (IDL) software (Research Systems, Boulder, CO). The CASL image series were first corrected for motion using a routine based on the principle component analysis.31 The label and control images were pairwise subtracted and averaged to generate the mean difference image (⌬M).22 Caudate blood flow quantification followed a singlecompartment perfusion model assuming the labeled blood spins remain primarily in the vasculature rather than exchanging completely with tissue water: f ⫽
⌬M R1␣ 2␣Mcon关exp共 ⫺ wR1␣兲 ⫺ exp共 ⫺ 共 ⫹ w兲R1␣兲兴
where f is blood flow, R1a (⫽ 0.67 seconds⫺1) is the longitudinal relaxation rate of blood, Mcon is the average control image intensity, ␣ (0.68) is the tagging efficiency, (⫽ 2 seconds) is the duration of the labeling pulse, w (⫽ 1.2 seconds) is the postlabeling delay time, and (⫽ 0.9 g/mL) is blood/tissue water partition coefficient. Blood flow images were subsequently coregistered with structural T1 images using SPM99 (www.fil.ion.ucl.ac.uk/spm) (figure 1). The caudate region was manually segmented for each subject on high-resolution T1 images using anatomic landmarks and guided by an MRI atlas.32 The location and accuracy of caudate segmentations were verified by a neuroradiologist (R.W.). Care was taken to ensure that the manually drawn caudate regions did not include the lateral ventricles. Caudate size was measured as the number of voxels within the region and expressed in mm3 (e.g., 1 voxel ⫽ 1 mm3). Within the same caudate region, quantitative blood flow was calculated and expressed in milliliters per 100 g caudate volume per min (mL/ 100 g/minute). Statistics. To determine whether differences were present across groups, a one-way analysis of variance (ANOVA) was perMarch (2 of 2) 2006
Figure 1. Representative T1 images and coregistered blood flow maps for a seronegative control, a subsyndromic patient, and a neurosymptomatic patient. The caudate was manually segmented (red line) on T1 images, and both caudate blood flow and volume measurements were extracted from this region. CBF ⫽ cerebral blood flow.
formed (p ⬍ 0.05) followed by pairwise multiple comparisons using the Student–Newman–Keuls method (p ⬍ 0.05). To test for trends in caudate blood flow and volume with increasing HNCI, the nonparametric Jonckheere–Terpstra test for ordered alternatives (p ⬍ 0.05) was used. In this test, the null hypothesis assumed that the distribution of the dependent variables, caudate blood flow and volume, did not differ among the subgroups. The null hypothesis was rejected if the median caudate blood flow and volume for each group decreased in an orderly fashion with increasing neurocognitive impairment. To determine whether a relationship exists between blood flow and volume, Pearson product moment correlations (p ⬍ 0.05) were conducted for each group between the two variables. Table 2
Results. Neuropsychological performance. Table 2 shows NP and GDS results for each of the tasks. These test results, along with the directed neurologic examinations, were used for classifying HIV⫹ patients as either subsyndromic (GDS ⱕ 1) or neurosymptomatic (GDS ⬎ 1). Nine of the 17 seronegative controls had complete NP testing. There were no significant differences within the control group in regard to the general neurologic examination, education, age, race, or sex of subjects irrespective of formal NP testing.
Comparisons of neuropsychological performance and global deficits for subjects Controls, n ⫽ 9
Subsyndromic, n ⫽ 23
Neurosymptomatic, n ⫽ 19
RAVL average of 5 trials, %
RAVL 6th trial, %
RAVL 7th trial, %
Symbol Digit, %
Trailmaking A, %
Motor skills and praxis Grooved Pegboard Dominant, %
Grooved Pegboard Non-Dominant, %
Executive function Trailmaking B, % Stroop Color, seconds
58 ⫾ 12
66 ⫾ 14
90 ⫾ 23
Stroop Word, seconds
44 ⫾ 6
52 ⫾ 12
78 ⫾ 28
115 ⫾ 15
123 ⫾ 27
172 ⫾ 64
WAIS-R Vocabulary, %
90 ⫾ 20
85 ⫾ 27
36 ⫾ 28
0.3 ⫾ 0.2
0.5 ⫾ 0.1
2.0 ⫾ 0.2
Stroop Interference, seconds
Stroop tests are expressed in raw mean scores ⫾ SD. RAVL ⫽ Rey Auditory Verbal Learning Test; WAIS-R ⫽ Wechsler Adult Intelligence Scale Revised; % ⫽ standardized percentile scores; GDS ⫽ Global Deficit Scale. 864
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Figure 2. Baseline caudate cerebral blood flow (CBF) (A) and volume (B) for controls (white bars), subsyndromic patients (gray bars), and neurosymptomatic patients (black bars). Data are presented as mean and SEM. * p ⬍ 0.05.
Caudate CBF and volume measurements. Both changes in caudate blood flow and volume were significant across groups by one-way ANOVA (p ⫽ 0.03 for cerebral blood flow [CBF] and p ⫽ 0.05 for volume). Post hoc multiple comparisons by the Student–Newman–Keuls method further showed a decrease in caudate blood flow between neurosymptomatic HIV patients and controls (p ⫽ 0.02, figure 2A) and a reduction in caudate volume between the same two groups (p ⫽ 0.05, figure 2B). Within the neurosymptomatic group, nine patients who had a GDS of 2 or greater had both diminished caudate blood flow and volume. However, these differences were not significant compared with neurosymptomatic patients with a GDS of less than 2. Neither caudate blood flow nor volume was different between subsyndromic HIV⫹ patients and controls (p ⫽ 0.13 for blood flow and p ⫽ 0.55 for volume). An association of stepwise decreases in caudate blood flow and volume (Jonckheere–Terpstra test, p ⫽ 0.005 for blood flow and p ⫽ 0.02 for volume) was present with increasing degree of HNCI. Pearson product moment correlation was performed to determine whether changes in caudate blood flow were comparable with volume changes. Correlation coefficients were not significant for all three groups.
Discussion. Our study using CASL-MRI demonstrates significant reductions in caudate blood flow and volume in patients with HNCI compared with controls. In particular, neurosymptomatic HIV⫹ patients were characterized by significantly lower caudate baseline blood flow and smaller caudate volumes compared with controls. Between subsyndromic HIV⫹ patients and seronegative controls, caudate blood flow changes seemed greater than volume changes, although neither blood flow nor volume was significantly different between the two groups. These results suggest that the severity of both reductions in residual caudate blood flow and volume loss increases with increasing HNCI severity. In HIV⫹ patients, residual blood flow changes may precede the loss of structural integrity as measured by caudate volume.21,33 Longitudinal studies are clearly necessary to address this hypothesis directly. We have used standardized NP tests to characterize the degree of cognitive impairment in these HIV⫹ patients. Our results are consistent with previous
studies using these measures to classify HIV⫹ patients into certain subtypes.2,30,34 As such, it is generally accepted that HIV infection within the brain primarily leads to a subcortical dementia with significant impairments in memory, attention, and psychomotor skills. More recently, the GDS scale, which incorporates multiple aspects of this NP battery, has been devised and provides an overall measure of cognitive dysfunction.2-4 Although administration of this battery of tests provides an important means for classifying HIV patients, it can be laborious and often does not reflect degree of functional disability.34 Noninvasive rapid neuroimaging techniques such as structural MRI and CASL-MRI provide anatomic and perfusion information that can be used in conjunction with NP results for assessing longitudinal follow-up of HIV⫹ patients.18 Previous studies of cerebral blood flow in HIV⫹ patients using SPECT have been invasive and time-consuming. Unlike CASL-MRI, SPECT provides only relative ratios and not quantifiable measurements of perfusion. Accordingly, our determination of caudate CBF values in seronegative control subjects were comparable to previous subcortical measures obtained in humans using CASL-MRI25 as well as animal studies that have used either autoradiography or SPECT.35 Similarly, reduced caudate blood flow values in patients with HNCI are consistent with perfusion MRI measurements that demonstrated areas of relative hypoperfusion in mild cognitively affected HIV patients on HAART compared with seronegative controls.21 This suggests a possible reproducibility of CASLMRI for quantification of blood flow across controls and HIV⫹ patients. The current study extends previous qualitative volumetric based neuroimaging studies in HIVinfected individuals.10,36,37 Initial studies have shown a correlation between bicaudate ratios and AIDS stage by the Centers for Disease Control criteria.8,10 A more recent study has shown a very weak correlation between caudate volume and NP performance in HIV patients.21 In this study, we found significant associations between caudate blood flow and volume and HIV subgroup based on GDS score, with a stepwise decrease in caudate blood flow and volume occurring with increasing degree of HNCI. Within the neurosymptomatic HIV⫹ patients, less than half had a GDS of greater than 2. No significant differences were seen between this particular subgroup and other neurosymptomatic patients with a GDS of less than 2. The relative paucity of these patients may reflect the decreasing number of patients now seen with significant neurocognitive deficits since the introduction of HAART. Within this study, no correlation was seen between caudate blood flow changes and volume changes. Notably, while caudate volumes reflected the degree of tissue loss, perfusion measurements reflected flow within the residual caudate volume rather than effects of volume loss per se. Therefore, although both volume and blood flow in the residual March (2 of 2) 2006
caudate were found to correlate with CBF, there is no reason to expect that caudate volume and blood flow within the residual volume are correlated. Because caudate blood flow and GDS were significantly correlated, our results suggest that caudate perfusion may serve as a surrogate biomarker of disease progression, independent of volume. Future studies that include a larger sample size may provide further insight into the relationships between blood flow, volume, and NP impairment. The exact mechanisms for regional hypoperfusion and atrophy, especially for HIV⫹ neurosymptomatic impaired patients, remain unknown. HIV-associated brain injury may develop from the combined effects of viral (e.g., gp120, tat, gp41) and cellular factors (e.g., cytokines, nitric oxide) that are either neurotoxic or act as mediators of inflammation rather than direct infection of neurons.38-40 A combination of these mechanisms may be responsible for the observed perfusion abnormalities and subsequent decreased metabolic demands within the caudate of HIV neurosymptomatic patients.41,42 Acknowledgment The authors thank Norman Butler, Doris Cain, and Tonya Kurtz for help with MRIs.
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Caudate blood flow and volume are reduced in HIV+ neurocognitively impaired patients B. M. Ances, A. C. Roc, J. Wang, et al. Neurology 2006;66;862-866 DOI 10.1212/01.wnl.0000203524.57993.e2 This information is current as of March 27, 2006 Updated Information & Services
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