A Study of N-Acetyl aspartic acid/Creatine Ratio in the White Matter of HIV Positive Patients and Its Application

Abstract: A total of 50 patients were enrolled in the study, and MRI brain with MR spectroscopy was done. Tuberculosis was the most common neurologic disease found in the HIV positive group, consisting of 9 patients. Seven of these patients had tuberculous meningitis amongst which a further 2 had vasculitic infarcts.PML was seen in 6 patients. NAA to Cr ratio was found to be reduced in all the patients, and in fact the value was further reduced compared to the HIV positive group as a whole. Raised choline and myoInositol peaks were also found in all the patients. MR Spectroscopy showed lipid lactate peaks confirming the diagnosis. 2 patients had HIV encephalopathy on the imaging study. Their spectra also revealed lowered NAA peaks along with raised choline peaks. 2 patients with cryptococcosis showed characteristic imaging finding of enlarged Virchow Robin (perivascular) spaces. They revealed elevated choline peaks in addition to reduced NAA. The values of NAA to Cr ratio were determined after duly processing the spectroscopic data from both cases and controls. Each group (Cases and controls) were divided on the basis of age into two age groups: Lesser than or equal to 40 years, and greater than 40 years. In all three groups the values of the mean NAA to Cr ratio ratio was significantly (p-value less than 0.05) reduced in comparison to controls. An ancillary finding was the reduction of NAA to Cr ratio further in cases of PML. Combined use of both the conventional and advanced MRI sequences is advisable as spectroscopy helps in confirming the diagnosis of opportunistic infection of the CNS in HIV positive patients. NAA to Cr ratio ratio is reduced in HIV positive patients and is a marker for HIV infection of the brain even in the absence of imaging findings of HIV encephalopathy or when the patient is symptomatic due to neurological disease of other etiologies.

• The paper demonstrates significantly lower NAA/Cr ratios in HIV-positive patients versus controls (p < 0.05), indicating early CNS damage.
• The study uses multivoxel MRS on a 1.5T scanner to detect subclinical changes even when conventional MRI shows no focal lesions.
• MRS effectively differentiates opportunistic infections like tuberculosis and PML, enhancing diagnostic precision in HIV-related CNS pathologies.

This study investigated the utility of Magnetic Resonance Spectroscopy (MRS), particularly the N-Acetyl aspartate/Creatine (NAA/Cr) ratio, in diagnosing and evaluating Central Nervous System (CNS) involvement in HIV-positive patients (1502.07848). The research aimed to compare NAA/Cr ratios in the white matter of HIV-positive individuals with HIV-negative controls and to assess the role of MRS in characterizing various CNS pathologies common in HIV infection.

Methods:

The prospective observational study enrolled 50 participants: 35 HIV-positive patients with neurological symptoms (cases) and 15 HIV-negative individuals undergoing MRI for unrelated reasons (controls). All participants underwent brain MRI on a 1.5T scanner, including standard sequences (T1W, T2W, FLAIR, DWI, post-contrast T1W) and multivoxel MRS with a short echo time (TE=30ms). MRS voxels were placed in brain lesions (if present) and normal-appearing white matter (centrum semiovale). The NAA/Cr ratio from the white matter was calculated for all participants. Cases and controls were further divided into two age groups: ≤ 40 years and > 40 years. Statistical analyses (Runs test, Anderson-Darling test, Welch's t-test) were performed to compare NAA/Cr ratios between groups. MRS spectra from focal lesions were analyzed qualitatively based on the final clinical diagnosis.

Key Findings:

1. NAA/Cr Ratio: The mean NAA/Cr ratio was significantly lower (p < 0.05) in the white matter of HIV-positive patients compared to controls across all age groups.
   • Overall: Cases (1.623 ± 0.423) vs. Controls (1.986 ± 0.293)
   • Age ≤ 40: Cases (1.669 ± 0.374) vs. Controls (2.120 ± 0.221)
   • Age > 40: Cases (1.567 ± 0.481) vs. Controls (1.869 ± 0.310)
2. Asymptomatic Changes: Reduced NAA/Cr ratios were observed even in 7 HIV-positive patients who had no focal lesions identified on conventional MRI sequences, suggesting MRS can detect early or subclinical brain injury.
3. Opportunistic Infections and Other Pathologies:
   • Tuberculosis (n=9): Most common pathology. MRS of tuberculomas showed prominent lipid-lactate peaks, aiding diagnosis.
   • Progressive Multifocal Leukoencephalopathy (PML) (n=6): MRS showed reduced NAA/Cr (mean 1.427, lower than the overall HIV+ group mean), elevated Choline (Cho), and elevated myo-Inositol (mI).
   • Toxoplasmosis (n=4): Spectra were characterized by marked elevation of lipid and lactate peaks with reduced levels of other metabolites, helping differentiate it from lymphoma.
   • Pyogenic Abscess (n=1): MRS confirmed the diagnosis by showing a lactate peak and characteristic amino acid resonances (valine, leucine, isoleucine) around 0.9 ppm.
   • HIV Encephalopathy (n=2): Spectra revealed lowered NAA peaks and raised Cho peaks.
   • Cryptococcosis (n=2): MRS showed reduced NAA and elevated Cho; specific trehalose peaks were not identified.
   • Stroke (n=4): MRS findings were non-specific in this study, although reduced NAA was noted in arterial infarcts.
4. MRS Utility: Spectroscopy proved valuable as a problem-solving tool, particularly in differentiating lesions with similar appearances on conventional MRI, such as toxoplasmosis vs. lymphoma, tuberculoma vs. tumor, and tuberculous vs. pyogenic abscess.

Conclusion:

The study concludes that MRI, complemented by MRS, is the optimal imaging approach for evaluating CNS disease in HIV-positive patients. MRS is particularly useful for characterizing focal lesions and confirming diagnoses of opportunistic infections. Crucially, the NAA/Cr ratio is significantly reduced in the white matter of HIV-positive individuals compared to controls, serving as a potential marker for HIV-related brain injury even before structural changes are visible on conventional MRI. The authors recommend including MRS in the routine evaluation of HIV patients, as it may detect early HIV encephalopathy and potentially monitor treatment response.