| PMC full text: | Nat Rev Drug Discov. Author manuscript; available in PMC 2021 Mar 11. Published in final edited form as: Nat Rev Drug Discov. 2020 Sep; 19(9): 609–633. Published online 2020 Jul 24. doi: 10.1038/s41573-020-0072-x |
Table 2 |
Clinical trials reporting improved brain function and/or energetics in NDAs
| Disorder | Study details | Results and comments | Ref. |
|---|---|---|---|
| AD | Single-blind RCT of (S)-equol (n = 15) or placebo (n = 15) for 2 weeks (NCT02142777) | Well tolerated. More participants showed ↑ cytochrome oxidase activity with (S)-equol than with placebo; no cognitive change. First study of a mitochondrial intervention as a direct biomarker of mitochondrial engagement in AD | 137 |
| Mild-to-moderate AD and MCI | RCT in individuals with AD (n = 21) or MCI (n = 39) receiving long-acting intranasally administered insulin (20 or 40 IU) or placebo for 4 months (NCT01595646) | Dose-dependent ↑ memory composite score on regular but not long-acting intranasal insulin in ApoE4+ individuals. No change in functional autonomy or executive function | 38 |
| AD | RCT of liraglutide (n = 14) or placebo (n = 20) for 26 weeks (NCT01469351) | No change in Aβ load or cognitive scores. ↓ brain glucose uptake over 26 weeks only with placebo. Underpowered for cognitive outcomes. Liraglutide may delay metabolic decline in brain | 194 |
| AD or MCI | RCT (n = 20) of metformin (500 mg) or placebo for 8 weeks (NCT01965756) | ↑ Executive function. No change in cerebral blood flow | 182 |
| AD | Double-blind RCT of C8 at 20 g per day (n = 77) or placebo (n = 63) for 90 days (NCT00142805) | ADAS-Cog score ↑ by 3.4 points in ApoE4− individuals. Cognitive score varied directly as ketones. ↑ cognition in mild-to-moderate AD | 119 |
| Mild-to-moderate AD | Open label study (n = 10) of KD ± C8C10 for 12 weeks (NCT03690193) | ↑ ADAS-Cog score; no cardiovascular safety or other metabolic concerns. First reported clinical use of a KD in AD including medium-chain triglyceride supplementation | 157 |
| AD and MCI | RCT of KD (n = 9) or NIA low-fat diet (n = 5) for 12 weeks (NCT02521818) | ↑ composite cognitive score, particularly memory domain, only in adherent participants and only with KD. First reported clinical use of a KD without medium-chain triglyceride supplementation. Feasibility is very challenging but beneficial effects of ketones were clearly present | 162 |
| Mild-moderate AD | Open-label study of C8C10 (n = 11) or C8 (n = 6) at 30 g per day for 4 weeks (NCT02709356) | ↑ ketones twofold. Brain ketone uptake ↑ in direct proportion to ↑ ketone and brain glucose utilization. In AD, the brain can utilize additional ketones provided as C8C10 | 270 |
| Mild-to-moderate ApoE4− AD | Crossover RCT of medium-chain triglycerides (17.3 g) (n = 24) or placebo (canola oil) (n = 25) for 30 days (ChiCTRIOR6009737) | 2.62-point increase on ADAS-Cog (Chinese version) for medium-chain triglycerides, 2.57-point reduction for placebo. Study restricted to ApoE4− patients. Inverse correlation between cognitive changes and plasma lysophosphatidylcholine species | 120 |
| PD | RCT of exenatide at a dosage of 2 mg once per week (n = 31) or placebo (n = 29) for 48 weeks plus a 12-week washout (NCT 01971242) | UPDRS motor subscale at 60 weeks:↑ by 1.0 point for drug and ↓ by 2.1 points for placebo. ↓ motor symptoms | 97 |
| PD | RCT of KD (n = 20) or low-fat diet (n = 20) for 8 weeks (ACTRN 12617000027314) | ↑ UPDRS score in both groups, but 41% more for the KD. 86% adherence; tremor ± rigidity intermittently ↑ for KD. First RCT of KD in PD. A KD and low-fat diets are safe in PD | 160 |
| HD | Open-label study in individuals with HD (n = 10) and controls (n = 13) receiving triheptanoin at 1 g kg−1 for 1 month (NCT01696708) | MRS: ↑ levels of brain high-energy phosphates including ↑ inorganic phosphate/phosphocreatine during visual stimulation | 271 |
These studies reported statistically significant improvements in primary or secondary end points with novel treatments or drugs approved for other indications and repurposed for treatment of neurodegenerative disorders of ageing (NDAs). The low-fat diet162 was a modified Atkins diet. The three ketogenic diet (KD) trials were all principally feasibility studies not powered for cognitive or metabolic outcomes157,161,163. ↑, increase; ↓, decrease; Aβ, amyloid-β; AD, Alzheimer disease; ADAS-Cog, Alzheimer Disease Assessment Scale — Cognitive Subscale; ApoE4, E4 isoform of apolipoprotein E; C8, octanoic acid; C8C10, octanoic acid plus decanoic acid; HD, Huntington disease; MCI, mild cognitive impairment; MRS, magnetic resonance spectroscopy; NIA, National Institute on Aging; PD, Parkinson disease; RCT, randomized controlled trial; UPDRS; Unified Parkinson Disease Rating Scale.