Development of neuroprotective therapies for neurodegenerative disease face extraordinary challenges, related to both the complexity of neuropathogenesis, bioavailability of drugs in vulnerable brain regions and timing of treatment. For example, AD and PD likely begin many decades before a clinically significant phenotype is noticeable; thus therapeutic strategies face an uphill battle because damage to vulnerable neuronal pathways may have passed a critical point for repair and return to pre-morbid homeostasis. In contrast, HAND provides some unique opportunities for therapeutic intervention not least because (i) the onset of HIV-1 infection is usually a definable event that can be routinely tested and (ii) early events in HAND likely involve reversible synaptic injury (see above).
Despite this, previous trials of adjunctive therapy for HAND have been unsuccessful. As noted above, a recent meta-analysis of the published outcomes of ten trials of adjunctive therapies involving 711 people with HIV-1 and neurologic disease, concluded that there was no evidence for efficacy in terms of cognitive improvement. While many of these agents had not been evaluated in an appropriate in vivo
model of HAND, a notable exception was memantine. Memantine blocks the NMDA receptor-associated ion channel only when it is excessively (i.e. pathologically) open, and as such, does not remain in the channel long enough to block normal excitatory neurotransmission. Despite success in preclinical small animal models,[11
] memantine failed to significantly improve any
neuropsychologic indices in a phase II double-blind, randomized, placebo-controlled, multi-center trial (plus best anti-retroviral therapy) in patients with HAND.[12
] Interestingly, this was the first clinical study of HIV-associated dementia in which surrogate markers (magnetic resonance spectroscopy, i.e. MRS) were validated with clinical presentation, as quantified by neurocognitive testing, and in which the surrogate markers appeared to be even more sensitive than the cognitive testing or neurologic examination. MRS was used to quantify N-acetylaspartate (NAA), a metabolite that is chiefly found in neurons in the adult brain, and the ratio of NAA to creatine (Cr) was used as an index of neuronal function and viability. Significant increases in NAA/Cr were observed in the multivariate analysis among individuals receiving memantine compared to placebo in the frontal white matter and the parietal cortex. Thus, memantine’s failure to elicit clinical improvements in neuropsychologic parameters despite an increase in the MRS parameter NAA that was presumably indicative of preserved neuronal integrity in corresponding brain regions, may reflect the fact that neuroinflammation can prevent activity-dependent (i.e. LTP) processes both upstream and downstream of the NMDA-R channel.[13
This emphasizes the need to design adjunctive therapies that take into account both neuroinflammation caused by HIV-1 viral products and pro-inflammatory mediators, and the activity-dependent nature of neuronal networks vulnerable to these neurotoxins, rather than simply quantifying neuronal apoptosis or even synaptic transmission as a therapeutic endpoint.