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Neurology 2001;56:112-115
© 2001 American Academy of Neurology
Brief Communications

Clinical and spectroscopic improvement in HIV-associated cognitive impairment

B. Stankoff, MD*;, A. Tourbah, MD, PhD*;, S. Suarez, PhD;, E. Turell, MD;, J.L. Stievenart, MD;, C. Payan, MD, PhD;, A. Coutellier, MD;, S. Herson, MD;, L. Baril, MD;, F. Bricaire, MD;, V. Calvez, MD, PhD;, E.A. Cabanis, MD;, L. Lacomblez, MD, PhD and C. Lubetzki, MD, PhD

From the Fédération de Neurologie I (Drs. Stankoff, Tourbah, Turell, and Lubetzki), Laboratoire de Neuropathologie R. Escourolle (Dr. Suarez), Fédération de Neurologie Mazarin II (Dr. Lacomblez), and Service de Pharmacologie (Drs. Payan and Lacomblez,), Service de Médecine Interne (Drs. Coutellier and Herson); Service des Maladies Infectieuses (Drs. Baril and Bricaire), Laboratoire de Virologie CERVI (Dr. Calvez), Hôpital Pitié Salpêtrière, AP-HP and University Paris VI; and Service de Neuroradiologie (Drs. Tourbah, Stievenart, and Cabanis), Centre Hospitalier National des Quinze-Vingts, Paris, France.

Address correspondence and reprint requests to Prof. C. Lubetzki, Fédération de Neurologie, Hôpital de la Salpêtrière, 47 Bld de l’Hôpital, 75651 Paris Cedex 13, France; e-mail: catherine.lubetzki{at}psl.ap-hop-paris.fr


   Article Abstract
Top.
 Article Abstract
Introduction
 Methods.
 Results.
 Discussion.
 References
 
To assess the impact of highly active antiretroviral therapy (HAART) on AIDS-associated cognitive impairment, 22 patients with AIDS with (n = 11) and without (n = 11) cognitive deficit were evaluated clinically and by MRS every 3 months for 9 months. Nineteen patients were on HAART at study entry, 21 after 2 months. Cognitively impaired patients presented with a subcorticofrontal deficit and decreased N-acetyl-aspartate in frontal white matter. These clinical and metabolic abnormalities reversed partially on HAART, whereas they remained within normal limits in cognitively unimpaired patients.


   Introduction
Top.
 Article Abstract
 Introduction
Methods.
 Results.
 Discussion.
 References
 
Whether highly active antiretroviral therapy (HAART) treats or prevents AIDS-associated cognitive impairment is a critically important issue in neuro-AIDS. Since HAART was first widely used, a major decline in the incidence of this complication has been reported.1 Few studies, however, have analyzed the impact of HAART on cerebral dysfunction.2-4


   Methods.
Top.
 Article Abstract
 Introduction
 Methods.
Results.
 Discussion.
 References
 
We prospectively studied 22 AIDS patients (20 men and two women) without previous or ongoing neurologic disease, major psychiatric disorder, or current alcohol or drug addiction. All had a CD4 cell count below 200/mm3 at study entry or at anytime during the preceding year. The study was approved by the ethical committee of our institution and all patients provided informed consent prior to enrollment.

Using Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for AIDS dementia, 11 patients were classified as cognitively unimpaired (CU), and 11 as cognitively impaired (CI). Of the latter, nine had a mild cognitive impairment and two were demented.

Neuropsychological and MRS evaluations were performed at study entry (M0), then every 3 months (M3, M6, and M9) for 9 months. CD4 cell count and plasma HIV-1 RNA level were obtained at M0, then when requested by the treating physician.

The neuropsychological battery, already described,5,6 comprised the Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale, Trail Making A and B, Purdue Pegboard, and Grober and Buschke tests. Depression was evaluated with Montgomery and Asberg Depression Rating Scale (MADRS).

MRI (1.5 T) was performed using axial fluid-attenuated inversion recovery (FLAIR) sequences. MRS spectra were acquired and analyzed as previously described,7 with three volumes of interest: two in the white matter (centrum semi-ovale and frontal white matter) and one in the medial parieto-occipital gray matter. The following ratios were analyzed: area of NAA/Cr (N-acetylaspartate to Creatine), Cho/Cr (Choline to Creatine), and amplitude of Myo/Cr (Myoinositol to Creatine) ( figure 1). Mean (±SEM) ratios of a reference control group7 were 2.11 ± 0.05 (range: 1.86 to 2.48) for NAA/Cr, 1.09 ± 0.03 (range: 0.92 to 1.24) for Cho/Cr, and 0.93 ± 0.08 (range: 0.49 to 0.87) for Myo/Cr.



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  		Figure 1. Brain MRI showing on axial fluid-attenuated inversion recovery sequences the two volumes selected in the white matter, one in the centrum semi-ovale and the other in the frontal white matter (a) and the volume selected in the medial parieto-occipital gray matter (b). (c) Spectrum at ET = 136 ms showing the NAA and Cho peaks; (d) spectrum at ET = 18 ms showing the Myo peak; (e) spectrum at ET = 30 ms.

 
Statistical analysis was performed with BMDP software. Groups were compared using non-parametric tests (Mann–Whitney U test). Correlations were calculated using the Spearman coefficient. Results are presented as mean ± SEM.


   Results.
Top.
 Article Abstract
 Introduction
 Methods.
 Results.
Discussion.
 References
 
Mean age was 36.4 years (range: 26 to 44 years) and the mean educational level was 10.7 years (range: 2 to 20 years). Mean duration of disease was 10 years (range: 4 to 12 years). No statistical difference between groups was found in terms of age, educational level, or HIV infection duration. Nine patients were HIV-infected through homosexual contact, six through heterosexual transmission, and four had a history of drug addiction for several years. For three patients, the cause of HIV transmission was unknown.

At baseline, 19 patients received HAART with at least one protease inhibitor, and duration of HAART before inclusion was one to 15 months. In the CI group, two patients had no antiretroviral treatment, one was on bitherapy with nucleosides. One patient remained untreated; and in the two other cases, HAART was initiated during the first 2 months of the study.

Mean duration of treatment was 10 months (range: 1 to 19) in the CU group and 6 months (range: 0 to 15) in the CI group. Mean CD4 cell count was 241 ± 53 in the CU group, and 117 ± 35 in the CI group. Plasmatic HIV RNA level (log10) was 3.87 ± 1.6 in the CU group, and 4.58 ± 1.2 in the CI group.

Neuropsychological data for the 22 patients (11 CI and 11 CU) at baseline are detailed in table 1. The 11 CI patients had a subcorticofrontal deficit with bradykinesia, verbal slowing, and sensitivity to semantic cues, as compared to CU patients. Mattis subtests and the Grober and Buschke test showed that memory was more affected than other cognitive performances, and was different between groups (p < 0.01) (not shown). MADRS score was significantly higher in the CI group, although not exceeding 28, reflecting the absence of severely depressed patients.


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  		Table 1. Neuropsychological data
 
Brain atrophy was detected in two CU patients and seven CI patients. Diffuse white matter abnormalities suggestive of HIV leuco-encephalopathy was detected in three cases (one CU and two CI), who were analyzed separately at M0.

Baseline MRS data were collected in 15 (eight CI and seven CU) patients without white matter abnormalities ( table 2). In the frontal white matter, mean NAA/Cr levels were within normal range in the CU group, whereas they were below normal range in the CI group. Mean posterior white matter NAA/Cr levels were within normal range in both groups. Cho/Cr levels were elevated for all patients in both areas. Myo/Cr levels were above the normal range in the posterior white matter of CI patients, and normal for all patients in the frontal white matter. Gray matter values were within normal limits (not shown).


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  		Table 2. White matter MRS ratios at M0
 
Seventeen patients were evaluated neuropsychologically at least twice ( figure 2,A and B). Of the eight CU patients, Mattis scores remained stable in seven cases, and declined in one case. Of the nine CI patients, Mattis scores improved in six cases, including the two patients who received HAART after study entry, and remained unchanged in three cases. Despite this neuropsychological improvement, no CI patient had a normalization of his cognitive status. The only untreated CI patient had no cognitive change between M0 and M9 (not shown).



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  		Figure 2. Individual neuropsychological and MRS data: longitudinal study. Mattis score (A, B) and frontal NAA/Cr (C, D) evolution in cognitively unimpaired (CU) (A, C) and impaired (B, D) patients. Normal mean (black arrow) and range (white arrowhead) of NAA/Cr. White circles correspond to the three patients with leukoencephalopathy. White triangles correspond to the single CU patient with cognitive decline. Note that he was also the only CU patient with a decrease of NAA/Cr ratio throughout follow-up.

 
Fifteen patients had a MRS follow-up (figure 2,C and D). Of the seven CU patients, frontal NAA/Cr ratios remained stable in three cases, increased in three cases, and decreased in one case, which was the only CU patient to develop a cognitive deficit. Of the eight CI patients, NAA/Cr increased in six cases, and decreased in the two cases who started HAART after study entry. Improvement of clinical and MRS data were detected at M3 in most cases and continued thereafter.

In addition to this individual analysis, a comparison of neuropsychological and spectroscopic variables between M0 and M9 was performed on the subgroup of patients who completed the study. Fourteen patients completed the neuropsychological evaluation. In the CI group (n = 8), the mean Mattis score improved (134.5 ± 1.9 at M0, and 138.0 ± 1.1 at M9). All other neuropsychological tests improved, significantly for attention and memory evaluation. In the CU group (n = 6), Mattis scores remained unchanged.

Eleven patients completed the MRS study. In the CU group (n = 5), mean frontal NAA/Cr levels remained within normal range (1.95 ± 0.22 at M0, and 1.83 ± 0.17 at M9), whereas they increased from 1.67 ± 0.06 (below the normal range) to 1.86 ± 0.08 (within the normal range) in the CI group (n = 6). Cho/Cr levels remained elevated in the frontal anterior white matter in both groups. Posterior Myo/Cr normalized in CI patients. Gray matter values (n = 5) remained within normal limits (not shown).

At M0, white matter NAA/Cr or Cho/Cr levels did not correlate with total Mattis or Mattis subtests. Myo/Cr levels in white matter did not correlate with the total Mattis score, but correlated inversely with the Mattis memory score (r = -0.52 for frontal Myo/Cre, p < 0.05) as well as with NAA/Cr level (r = -0.58 for frontal ratios, p < 0.05; and r = -0.79 for posterior ratios, p < 0.005). No correlation between cognitive status and disease duration was found.

At M0, mean CD4 cell count correlated with the Mattis memory subtest (r = 0.52, p < 0.02), and weakly with the total Mattis score (r = 0.46, p < 0.05). HIV RNA level correlated inversely with the memory subtest of the Mattis scale (r = -0.47, p < 0.05), but not with the total Mattis score.


   Discussion.
Top.
 Article Abstract
 Introduction
 Methods.
 Results.
 Discussion.
References
 
This study confirms reported metabolic abnormalities of HIV encephalopathy,8-10 with decreased N-acetylaspartate and increased choline, and underscores their regional (frontal) or diffuse distribution. The longitudinal evaluation demonstrated that HAART partially reverses both clinical and metabolic abnormalities. Long-term follow-up will be needed to determine if patients with cognitive deficits recover.


   Acknowledgments
 
Supported by a grant from ANRS (Agence Nationale de Recherche sur le SIDA) and DRC-APHP (Délégation à la Recherche Clinique–Assistance Publique des Hôpitaux de Paris).

The authors thank B. Dubois for advice on the neuropsychological evaluation; C. Jangal, C. Brançon, and G. Aymard for excellent technical assistance; and E. Waubant and J. Wainer for careful reading of the manuscript.


   Footnotes
 
*These authors contributed equally to the work.

Presented in part at the 51st annual meeting of the American Academy of Neurology; Toronto, Ontario, Canada; April 1999.


   References
Top.
 Article Abstract
 Introduction
 Methods.
 Results.
 Discussion.
 References
 

  1. Clifford DB. Human immunodeficiency virus–associated dementia. Arch Neurol 2000; 57: 321–324.[Free Full Text]
  2. Tozzi V, Balestra P, Galgani S, et al. Positive and sustained effect of highly active antiretroviral therapy on HIV-1–associated neurocognitive impairment. AIDS 1999; 13: 1889–1897.[Medline]
  3. Sacktor N, Lyles R, Skolasky R, et al. Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men. Neurology 1999; 52: 1640–1647.[Abstract/Free Full Text]
  4. Chang I, Ernst T, Leonido-Yee M, et al. Highly active antiretroviral therapy reverses brain metabolic abnormalities in mild HIV dementia. Neurology 1999; 53: 782–789.[Abstract/Free Full Text]
  5. Suarez S, Conqui L, Rosenblum O, et al. Similar subcortical pattern of cognitive impairment in AIDS patients with and without dementia. Eur J Neurol 2000; 7: 151–158.[Medline]
  6. Stankoff B, Calvez V, Suarez S, et al. Plasma and cerebrospinal fluid human immunodeficiency virus type-1 (HIV-1) RNA levels in HIV-related cognitive impairment. Eur J Neurol 1999; 6: 669–675.[Medline]
  7. Tourbah A, Stievenart J, Gout O, et al. Localized proton magnetic resonance spectroscopy in relapsing remitting versus secondary progressive multiple sclerosis. Neurology 1999; 53: 1091–1097.[Abstract/Free Full Text]
  8. Salvan A, Vion-Dury J, Confort-Gouny S, Nicoli F, Lamoureux S, Cozzone P. Brain proton magnetic resonance spectroscopy in HIV-related encephalopathy: identification of evolving metabolic patterns in relation to dementia and therapy. AIDS Res Hum Retroviruses 1997; 13: 1055–1066.[Medline]
  9. Barker RL, McArthur JC. AIDS dementia complex: evaluation with proton MR spectroscopic imaging. Radiology 1995; 195: 58–64.[Abstract/Free Full Text]
  10. Lopez-Villegas D, Lenkinski R, Frank I. Biochemical changes in the frontal lobe of HIV-infected individuals detected by magnetic resonance spectroscopy. Proc Natl Acad Sci USA 1997; 94: 9854–9859.[Abstract/Free Full Text]
Received March 6, 2000. Accepted in final form August 24, 2000.




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