Background & Aims

Approximately 38 million people worldwide live with human immunodeficiency virus (HIV). A common neurological complication of HIV and its treatment in people living with HIV (PWH) is HIV-associated sensory neuropathy, with neuropathic pain being its most highly prevalent and debilitating symptom. Our group has previously observed elevated levels of the 18kDa translocator protein (TSPO), a marker of neuro-glial dysfunction, in human chronic pain1 and HIV2, as compared to healthy controls, using [11C]PBR28 positron emission tomography/magnetic resonance imaging (PET/MRI). In this study, we used [11C]PBR28 PET/MRI to evaluate the hypothesis that PWH with neuropathic pain (PWHpain) may exhibit greater levels of TSPO expression or neuro-glial dysfunction compared to PWH without pain (PWHnopain).

Methods

Eleven PWHpain (age: 58±6 y/o; sex: 8M, 3F) and 15 PWHnopain (age: 52.5±8 y/o; sex: 14M, 1F) completed [11C]PBR28 3T PET/MRI scans. PWH were included if they were high- (PWHpainN=8, PWHnopainN=7) or mixed- (PWHpainN=3, PWHnopainN=8) affinity binders, based on their polymorphism in the TSPO gene. PWH completed the PainDETECT neuropathic pain questionnaire and were stimulated with a 300g Von Frey filament on the volar forearm and dorsum foot to test sensitivity to mechanical prick pain. Standardized uptake values ratio (SUVR) was generated using the 60-90min post-injection data normalized using the whole-brain signal, spatially smoothed (FWHM=8mm), and normalized to the MNI template. A T1-weighted volume (TR/TE1/TE2/TE3/TE4=2530/1.64/3.5/5.36/7.22ms, flip angle=7º, voxel size=1x1x1mm3) was used for attenuation correction and spatial normalization to the MNI space. Whole-brain voxel-wise analyses were run with a z=2.3 cluster-forming threshold, including genotype as a covariate.

Results

PWHpain had a higher [11C]PBR28 signal compared to PWHnopain in the anterior and posterior midcingulate (aMCC and pMCC, respectively) and posterior cingulate cortices, dorsolateral and dorsomedial prefrontal cortices (dLPFC and dMPFC, respectively), precentral gyrus, superior parietal lobule (SPL), supplementary motor area (SMA), and primary somatosensory and motor cortices (S1 and M1, respectively). Similarly, in PWHpain, [11C]PBR28 signal in the cingulate, somatosensory, and motor cortices was also positively correlated with the average Von Frey arm pain ratings, but not the foot pain ratings and not in PWHnopain.
In 25 PWH (excluding 1 PWHnopain with missing PainDETECT data), [11C]PBR28 signal was positively correlated with PainDETECT scores in the cuneus, aMCC, pMCC, SMA, dMPFC, dLPFC, SPL, S1, and M1.

Conclusions

PWHpain had higher [11C]PBR28 signals in various brain regions, including the cingulate and prefrontal cortices and somatosensory and sensorimotor areas, compared to PWHnopain. Positive correlations between [11C]PBR28 signal and the average Von Frey arm pain ratings were found in the aforementioned regions in PWHpain, but not in PWHnopain. In PWH, [11C]PBR28 signal was positively correlated with PainDETECT neuropathic pain scores in the prefrontal, cingulate, and primary somatosensory and motor cortices. Together, these results suggest an association between neuropathic pain and neuro-glial dysfunction in PWH. Future research with a larger sample size is required to assess the generalizability and validity of these observations.

References

1Loggia et al. (2015). Evidence for brain glial activation in chronic pain patient. Brain, 138(3), 604-615.
2Sari et al. (2022). Multimodal investigation of neuroinflammation in aviremic patients with HIV on antiretroviral therapy and HIV elite controllers. Neurol Neuroimmunol Neuroinflamm, 9(2), e1144.
3Owen et al. (2012). An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. Journal of Cerebral Blood Flow and Metabolism, 32(1), 1-5.

Presenting Author

Minhae Kim

Poster Authors

Minhae Kim

OTHR

Massachusetts General Hospital

Lead Author

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Angelica Sandström

PhD

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

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Aarushi Tandon

BS

A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

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Akila Weerasekera

PhD

A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

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Kelly Castro-Blanco

BS

A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

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Yang Lin

BS

A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

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Ludovica Brusaferri

London South Bank University

Lead Author

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Zeynab Alshelh

PhD

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

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Erin J. Morrissey

BA

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

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Shibani Mukerji

MD

Massachusetts General Hospital, Harvard Medical School

Lead Author

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Emily Rudmann

BS

Massachusetts General Hospital, Harvard Medical School

Lead Author

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Rajesh Gandhi

MD

Massachusetts General Hospital, Harvard Medical School

Lead Author

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Richard Ahern

CNP

Massachusetts General Hospital, Harvard Medical School

Lead Author

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Vitaly Napadow

Spaulding Rehabilitation Hospital

Lead Author

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Robert Edwards

PhD

Brigham & Women's Hospital/Harvard Medical School

Lead Author

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Eva Ratai

PhD

Harvard Medical School

Lead Author

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Marco L. Loggia

PhD

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

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Topics

  • Pain Imaging