First Time-Restricted Eating Trial in HD Shows Promise

Time-restricted eating (TRE, or intermittent fasting) is safe and tolerable in patients with early-stage Huntington disease (HD) and was associated with improved cognitive and motor function, a new pilot trial suggested. The diet was also linked to a decrease in plasma neurofilament light chain (NfL) levels, an indicator of slower disease progression.TRE has shown promise in animal models of HD, but this 12-week trial marks the first time the diet has been studied in humans.Although HD is known for associated weight loss, study results showed stability in both weight and fat-free mass with daily food consumption limited to just a 6- to 8-hour period. There were also no reports of moderate-to-serious adverse events (AEs).Self-reported physical activity (PA) increased significantly, and high retention and adherence rates were achieved, meeting the study’s primary outcome.“I was a little surprised that people were able to maintain their weight as well as they did in the study,” lead author Russell Wells, fourth-year medical student at Oregon Health and Science University (OHSU) in Portland, told Medscape Medical News. “But the really intriguing part was the significant NfL improvement for almost every member of the study.”The findings were published online on September 17 in Nature Metabolism.Neuroprotective Effects?There are currently no approved treatments in the US for slowing or stopping the progression of HD, which affects about 41,000 Americans.Wells was a lead author of a 2024 review that discussed the potential of fasting and restricted eating for treating HD, as well as possible underlying mechanisms. The summary showed that, at the time, there had only been four animal studies and one small case report evaluating this intervention in these patients.TRE “activates adaptive cellular stress response mechanisms and has demonstrated neuroprotective effects in preclinical HD models,” the current investigators noted.However, there have been concerns about assessing this intervention in a human clinical trial because of worries that it could trigger weight loss, which is associated with worse disease outcomes.The researchers sought to evaluate the safety and feasibility of TRE in a 12-week open-label trial, which included 20 patients with early-stage HD (mean age, 45 years; 50% women). The median cytosine, adenine, and guanine count for the group of patients was 42.All participants were allowed to select a 6- to 8-hour eating window that worked best for their daily lives. During the study, they all chose start times ranging from 10 AM to 1 PM and ending times that ranged from 6 PM to 8 PM.Dietary guidance handouts were provided at baseline. Adherence, body weight, AEs, dietary composition, and PA were tracked throughout the study.Adherence was the primary outcome, while secondary outcomes included the composite Unified Huntington Disease Rating Scale (cUHDRS) scores and changes in NfL levels and fat-free body mass. Investigators also collected data on motor function and cognitive function, including processing speed and verbal memory.‘Encouraging Improvements’Results showed adherence to an 8-hour or less TRE interval was achieved with a mean of 75.6 days by the full group. Body weight only decreased by 1.3% between baseline and post-intervention, and fat-free mass decreased by 0.9%.Although there were no serious or moderate AEs, one participant reported fatigue during fasting.During the TRE phase, participants reported significant decreases in mean daily caloric intake (-168; P = .02) and significant increases in PA (37 min/wk; P = .04).Several efficacy outcomes showed improvement after the intervention, including overall disease severity and progression (average cUHDRS increase, 0.5 points; P = .003). Processing speed also improved (Symbol Digit Modalities Test, 3.6 points; P = .01), as did verbal memory (Verbal Fluency Test, 6.55 points; P < .001) and motor function (Total Motor Score, -1.50 points; P = .03).Among the more surprising findings, investigators noted, was a 12.6% decrease in plasma NfL, a marker of disease progression (mean decrease, 16.41 pg/mL; P = .002).“Moreover, the 12.6% reduction in plasma NfL, a biomarker not susceptible to placebo or practice effects, is remarkable given that it is reported to increase by 10%-18% annually across HD stages,” researchers wrote.Researchers also found improved mitochondrial function, marked by increased basal cellular respiration (by 38.5 pmol O2/min; P = .007), adenosine triphosphate-linked respiration (15.7 pmol O2/min; P = .02), maximal respiration (60.3 pmol O2/min; P = .005), and nonmitochondrial respiration (83.0 pmol O2/min; P = .004). These outcomes persisted even after multiple adjustments.The results, however, should be interpreted with caution because of the small size of the study and the fact that no comparison group was included, the investigators noted.“This study laid the foundation for the next step and for a larger, longer randomized controlled trial. And we’re now in the middle of writing the proposal for that next step,” Wells told Medscape Medical News.‘Interesting’ ApproachClaudia Testa, MD, PhD, director of the Huntington’s Disease Program at the University of North Carolina at Chapel Hill, called the study “an interesting idea” and noted that there’s currently a lot of research out there regarding diet and brain health.However, concerns about unintentional weight loss may have hindered nutrition studies in patients with HD, noted Testa, who was not involved with the research. The current study “had a really interesting way of addressing those concerns,” she told Medscape Medical News.Given the small study size, Testa urged caution when interpreting the efficacy findings.“What I do appreciate in this paper is the level of transparency and that they show each patient’s data points, showing variability and trends,” she said.“The most exciting thing for me was that it appeared safe and very well tolerated and therefore something you could push forward with. Also, it’s something that’s really accessible,” Testa added. “Sometimes the things that are most accessible can make a big impact.”Some of the results were presented previously at the American Academy of Neurology 2026 Annual Meeting and at the International Congress of Parkinson’s Disease and Movement Disorders 2025 Annual Meeting.The study was funded by the OHSU Parkinson Center of Oregon; the Parkinson’s Disease Research, Education and Clinical Centers at the VA Portland Health Care System; and the National Center for Advancing Translational Sciences. The investigators and Testa reported no relevant financial relationships.