Table 2.
Current SCD disease-modifying therapies and experimental cognition-specific targets.
| Agent | Evidence for neuroprotection | Current use |
|---|---|---|
| SCD disease-modifying therapies | ||
| Chronic transfusion therapy (CTT) | STOP Trial showed normalization of elevated TCD velocities and decreased risk for stroke; 22 STOP 2 showed need for continued CTT to prevent recurrence of elevated TCD velocities; 89 CTT significantly reduces risk for secondary stroke and SCI (SIT Trial)37,93 | Primary and secondary stroke prophylaxis35,94 |
| Hydroxyurea | Decreases rate of new SCI development; 91 normalizes and stabilizes cerebral oxygen saturation; 101 observational studies showed higher scores on cognition measures in children on HU vs not;13,88 likely due to increase in total hemoglobin concentration90,92 | Recommended for all patients with higher risk genotypes beginning at nine months of age 94 |
| Experimental agents specifically targeting cognitive function | ||
| Cholinesterase inhibitors (donepezil and galantamine) | Efficacy for donepezil and galantamine in RCTs of vascular dementia, although clinical benefit questionable;102–106 no current studies in SCD | Not currently in use or under investigation for SCD |
| NMDA receptor antagonist (memantine) | Modest cognitive benefit in vascular dementia;107,108 in pilot phase II trial, four patients with SCD treated with memantine × 12 months with improved RBC hydration, decreased sickling and hemolysis, but no assessment of neurological change109,110 | Not currently in use or under further investigation for SCD |
| Minocycline (tetracycline antibiotic) | In preclinical mice models, inhibition of activated microglia and improved cognition in aged SCD mice; 15 MADE Trial in AD showed tolerability, but no difference in slowing rate of cognitive decline vs placebo 113 | Phase I trial of tolerability to open in SCD |
| Etanercept (TNF-α inhibitor) | In AD patients, high TNF-α levels associated with faster cognitive decline vs low baseline levels. 116 Phase II trial in AD showed tolerability, but no difference in change in cognitive measures over six months in treated vs placebo 117 | Not currently in use or under investigation for SCD |
SCD: sickle cell disease; NMDA: N-methyl-D-aspartate; AD: Alzheimer’s disease; TNF-α: tumor necrosis factor alpha; RBC: red blood cell; RCT: randomized controlled trial; STOP: The Stroke Prevention Trial in Sickle Cell Anemia; TCD: transcranial Doppler; MADE: Minocycline in Alzheimer Disease Efficacy.