The main findings of this study are: 1) As hypothesized, compared to SN and regardless of MJ use status, HIV + group had poorer cognitive performance. 2) In contrast, regardless of HIV-serostatus, MJ users and non-users had similar cognitive performance; hence, no interactions or additive deleterious effects were found in HIV + MJ on cognitive test scores. 3) Similarly, DTI measures in HIV + group, regardless of MJ use status, had lower FA and higher diffusivities than SN controls in multiple white matter and subcortical brain regions, indicating greater neurodegeneration and neuroinflammation. 4) Regardless of HIV-serostatus, MJ users had lower AD in the right UNC than Nonusers. Furthermore, we observed a trend for HIV-by-MJ interaction in the right GP_MD, indicating possible differential MJ effects on neuroinflammation in this brain region of HIV patients compared to SN controls.
Cognitive Performance in Chronic MJ Users with and without HIV-infection
The poorer performance in HIV + compared to SN controls, regardless of MJ Use, in the Fluency, Attention/Working Memory, Learning, Memory, and Global Function, domains are consistent with prior studies in HIV + individuals (1). These persistent cognitive abnormalities were attributed primarily to ongoing neuroinflammation (23–26). Also similar to prior reports (7–10), regardless of HIV status, MJ users had similar performance across all cognitive domains as Nonusers. The lack of cognition deficits in our adult MJ users suggest little or no neurotoxic effects associated with chronic MJ use, which is supported by the lack of decline in IQ in adult onset MJ users (14). In contrast, the developing brain of adolescents may be more vulnerable to the neurotoxic effects of MJ, since earlier onset or regular (weekly) MJ use was associated with lower cognition (15, 16), decline in IQ and cognitive function (between ages 13–38 years) (14).
In the current study, although no significant HIV-by-MJ interaction was found in any of the cognitive domains, SN + MJ tended to have poorer performance than SN Nonusers in Learning, Memory and Motor domains, while HIV + MJ tended to perform better than HIV + Nonusers in Fluency, executive function and speed of information processing. These trends are consistent with a recent large study that found MJ use was associated with lower odds of neurocognitive impairment, and higher verbal fluency and learning performance, in PLWH, but not in the SN participants (11). This paradoxical effect of MJ use in SN and HIV + individuals might be related to the anti-inflammatory effects from some of the MJ constituents on the neuroinflammation in PLWH (32, 33). For example, Δ9-THC suppresses cytokine-induced T-cell activation (32, 33) and lowers the monocyte-derived pro-inflammatory factor IP-10 in vitro (33). Furthermore, MJ-using HIV + participants showed faster decline of cellular HIV DNA levels during the first 4 months of cART, compared with those who did not use MJ or used other substances (34). In addition, HIV + light MJ users had better verbal fluency than SN light users (9), but this advantage was not found in HIV + heavy MJ users (8), How the dosage and the potency of Δ9-THC in MJ, which has quadrupled in the past two decades (35), may impact cognition in PLWH will need to be evaluated in future studies.
DTI Metrics in Chronic MJ Users with and Without HIV-infection
Consistent with prior DTI studies (2, 36–38), our HIV + participants, regardless of MJ use, had lower FA and/or higher diffusivities in the corpus callosum, coronal radiata, internal capsule, the cingulum, SLF, SFO and SS. Lower FA and higher diffusivities in HIV + individuals most likely reflect disrupted white matter microstructure, perhaps due to neurodegeneration and chronic neuroinflammation induced by ongoing HIV + infection (39). Our HIV + participants also showed lower FA in the caudates and higher MD in subcortical gray matter (caudate, globus pallidus and thalamus), suggesting lesser microstructural integrity and possible demyelination in these regions. The elevated MD in the caudates of our HIV + individuals is consistent with the findings in early HIV infection (40), while the elevated MD in the GP is consistent with higher 18 kDa translocator protein (TSPO) binding, reflecting microglial activation, in this region in PLWH (39). Furthermore, relatively lower FA in the globus pallidus, along with poorer motor skills, were found in HIV + women, but not HIV + men (41).
In contrast, the right uncinate fasciculus (UNC) was the only brain region that showed abnormally lower AD in MJ users, regardless of HIV status. The lower AD in the UNC indicates reduced water movement along the axonal fibers, suggesting lesser axonal fiber density, accumulated cellular debris from damaged axonal, or extracellular space tortuosity (42). In preclinical studies, reduced AD was consistently found at early stages of brain injury from models of multiple sclerosis, and correlated with the axonal damage or loss (42, 43). Furthermore, the UNC in MJ users were found to have reduced FA and elevated MD (25). as well as shorter than normal fiber bundle (44). Lower FA in the UNC was also associated with higher scores for apathy in MJ users (25). The UNC fasciculi are long-range projecting fibers that connect the orbitofrontal cortex with entorhinal and fusiform cortices, which have densely localized CB1 receptors that are target receptors for Δ9-THC (44). Lower AD in the UNC might lead to lesser connectivity among these regions, which were found to have abnormally thinner cortices and associated poorer verbal memory in cannabis users (44).
The right globus pallidus showed a trend for HIV-by-MJ interaction on diffusivity, with relatively lower MD in SN + MJ users but relatively higher MD in the HIV + MJ users. This trend parallels the interactive effects in an earlier study that showed relatively lower levels of myoinositol, a glial marker, in the basal ganglia of SN + MJ users but relatively higher myoinositol levels in HIV + MJ users (7). In HIV + patients, higher diffusivity was associated with higher myoinositol level, indicating greater neuroinflammation, which in turn correlated with poorer cognitive performance (45). Therefore, this interactive trend suggests while chronic MJ use might suppress glial activation in the GP of SN, chronic MJ use might exacerbate the glial activation in HIV + users. However, future studies with other glial markers to assess these possible differential effects of MJ use on neuroinflammation in the GP between PLWH and SN are needed.
DTI Metrics Predicted Cognitive Performance in HIV + individuals and MJ users
Microstructural abnormalities predicted poorer cognitive function in our HIV + and SN + MJ groups. Specifically, in our HIV + group, the higher MD in thalamus, suggesting lesser microstructural integrity or greater neuroinflammation, predicted poorer fluency, learning and verbal memory. Consistent with our study, a [(11)C]PBR28 PET study that measured the 18 kDa TSPO found greater binding in several subcortical regions, including the thalamus, suggesting greater microglial activation; the higher tracer binding also correlated with higher MD on DTI, as well as poorer memory, verbal learning and global function (39). Also consistent with our findings, lower FA in the thalamic radiation predicted greater intra-individual variability on neuropsychological performance in HIV patients (46). Lastly, higher RD in posterior corona radiata (PCR) in our MJ users predicted poorer learning, similar to the correlations between higher MD in corona radiata and slower processing speed in the aging population (47), as well as between higher ACR_AD and poorer learning in HIV + participants (37).
Age-Related and MJ-Related Changes in DTI Metrics in HIV + individuals and MJ users
Our HIV + participants had greater than normal age-dependent declines in FA in the ACR, CC and SS, regardless of MJ usage; this is consistent with findings in prior DTI studies (36, 48). In addition, we observed greater than normal age-related FA decline in the EC and SLF of MJ users regardless of HIV-serostatus, which is consistent with the greater than normal age-related FA decline in multiple white matter regions in MJ users (24). Lastly, age-dependent decline was observed in the right globus pallidus FA only in SN-MJ users, but not in the other three groups (HIV, HIV + MJ or MJ), since they already had lower GP_FA, indicating lesser microstructural integrity, at younger ages. However, due to the limited sample size in each of the subgroups, these exploratory observations will need to be confirmed in future studies.
Our study has several limitations. 1) Our cohort included primarily men; therefore, we were not able to assess sex-specific differences on brain microstructure in relation to the possible additive or interactive effects of HIV-infection and chronic MJ use. 2) Since this is a cross-sectional study, we could not determine the causality of chronic MJ use on altered DTI metrics or cognitive deficits in HIV + individuals. Future longitudinal studies are necessary to further delineate the independent and combined effects of chronic MJ use and HIV-infection on brain microstructure. 3) Self-report of MJ use or other substances used may be inaccurate or under-reported, and might have confounded our results.