Ketogenic-Mimicking Diet as a Therapeutic Modality for Bipolar Disorder: Biomechanistic Rationale and Protocol for a Pilot Clinical Trial.

There is growing interest in the investigation of ketogenic diets as a potential therapy for bipolar disorder. The overlapping pharmacotherapies utilized for both bipolar disorder and seizures suggest that a mechanistic overlap may exist between these conditions, with fasting and the ketogenic diet representing the most time-proven therapies for seizure control. Recently, preliminary evidence has begun to emerge supporting a potential role for ketogenic diets in treating bipolar disorder. Notably, some patients may struggle to initiate a strict diet in the midst of a mood episode or significant life stressors. The key question addressed by this pilot clinical trial protocol is if benefits can be achieved with a less restrictive diet, as this would allow such an intervention to be accessible for more patients. Recent development of so-called ketone esters, that once ingested is converted to natural ketone bodies, combined with low glycemic index dietary changes has the potential to mimic two foundational components of therapeutic ketosis: high levels of ketones and minimal spiking of glucose/insulin. This pilot clinical trial protocol thus aims to investigate the effect of a 'ketogenic-mimicking diet' (combining supplementation of ketone esters with a low glycemic index dietary intervention) on neural network stability, mood, and biomarker outcomes in the setting of bipolar disorder. Positive findings obtained via this pilot clinical trial protocol may support future target engagement studies of ketogenic-mimicking diets or related ketogenic interventions. A lack of positive findings, in contrast, may justify a focus on more strict dietary interventions for future research.

Ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease: A systematic review and critical appraisal.

Background: There is increasing interest in therapeutic ketosis as a potential therapy for neurodegenerative disorders-in particular, mild cognitive impairment (MCI), Alzheimer's disease (AD), and Parkinson's disease (PD)-following a proof-of-concept study in Parkinson's disease published in 2005. Methods: To provide an objective assessment of emerging clinical evidence and targeted recommendations for future research, we reviewed clinical trials involving ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease reported since 2005. Levels of clinical evidence were systematically reviewed using the American Academy of Neurology criteria for rating therapeutic trials. Results: 10 AD, 3 MCI, and 5 PD therapeutic ketogenic trials were identified. Respective grades of clinical evidence were objectively assessed using the American Academy of Neurology criteria for rating therapeutic trials. We found class "B" evidence (probably effective) for cognitive improvement in subjects with mild cognitive impairment and subjects with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele (APOε4-). We found class "U" evidence (unproven) for cognitive stabilization in individuals with mild-to-moderate Alzheimer's disease positive for the apolipoprotein ε4 allele (APOε4+). We found class "C" evidence (possibly effective) for improvement of non-motor features and class "U" evidence (unproven) for motor features in individuals with Parkinson's disease. The number of trials in Parkinson's disease is very small with best evidence that acute supplementation holds promise for improving exercise endurance. Conclusions: Limitations of the literature to date include the range of ketogenic interventions currently assessed in the literature (i.e., primarily diet or medium-chain triglyceride interventions), with fewer studies using more potent formulations (e.g., exogenous ketone esters). Collectively, the strongest evidence to date exists for cognitive improvement in individuals with mild cognitive impairment and in individuals with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele. Larger-scale, pivotal trials are justified in these populations. Further research is required to optimize the utilization of ketogenic interventions in differing clinical contexts and to better characterize the response to therapeutic ketosis in patients who are positive for the apolipoprotein ε4 allele, as modified interventions may be necessary.

Mentally stimulating activities associate with better cognitive performance in Parkinson disease.

Subjects at risk of dementia benefit from participation in mentally stimulating activities, but no prior studies have investigated similar associations in Parkinson disease (PD). The aim of this study was to investigate the relationship between times spent engaging in mentally stimulating activities and cognitive functions in PD while accounting for the degree of primary neurodegenerations. PD patients (N = 41, 33 males; age 68.5 ± 7.2; Hoehn and Yahr stage 2.6 ± 0.6) completed the Community Health Activities Model Program for Seniors questionnaire, mini-mental state examination (MMSE), and [11C]dihydrotetrabenazine dopaminergic and [11C]piperidinyl propionate acetylcholinesterase PET imaging. The subset of mentally stimulating activity items of the Community Health Activities Model Program for Seniors questionnaire was used to develop a rating scale as primary outcome variable in this study. Findings showed that mean rating scale score of time spent in mentally stimulating activities over a 4-week timespan was 20.0 ± 8.3 h and mean MMSE score was 28.4 ± 1.9. Regression analysis showed that duration of participation in mentally stimulating activities was a significant predictor of MMSE scores (standardized ß = 0.39, t = 2.8, p = 0.009; total model: F (6,34) = 3.5, p = 0.005) independent from significant effects for cortical cholinergic activity (ß = 0.35, t = 2.4, p = 0.024). Caudate nucleus dopaminergic activity, age, education, or duration of disease were not significant regressors. Post hoc analysis did not show significant effects of motor disease severity or level of physical activities. We conclude that engagement in mentally stimulating activities is associated with better cognitive abilities in PD, independent of education, severity of motor disease, nigrostriatal dopaminergic and cortical cholinergic degenerations.