Parkinson’s disease (PD) is a frequently observed neurodegenerative disease of the brain, the incidence of which has doubled since 1990. It develops particularly in elderly people, namely, in 1% of individuals aged over 60 years, although it is increasingly diagnosed in persons at a young age. It is a significant cause of disability worldwide since in 2019, it was responsible for 5.8 million disability-adjusted life years (increased by 81% in relation to 2000). At least 53 million people worldwide struggle with that disease, and in 2019, it was the cause of 329 thousand deaths, which was an increase of over 100% in relation to the year 2000. The disease is manifested with motor sluggishness, tremor, equilibrium disturbances and dysaesthesia or neuropsychiatric signs. The cause of these signs is damage to the neurons in the substantia nigra responsible, inter alia for dopamine production [1,174,175,176,177,178,179]. In this case, the ketogenic diet also may prove effective, and that effect is more and more frequently the subject of studies.
The ketogenic diet can affect Parkinson’s disease (PD) through several mechanisms resulting from the nature of the disease. Although specific unequivocal causes have still not been established, a persistent inflammatory condition of the nervous system, mitochondrial dysfunction, reactive oxygen species (ROS) excess, a reduced ability to produce dopamine, abnormal cerebral glucose metabolism and the accumulation of damaged proteins, so-called Lewy bodies composed of misfolded α-synuclein, have been observed [180,181]. It has been found that the ketogenic diet can affect each of the aspects mentioned. The anti-inflammatory effect in all neurodegenerative diseases has been described earlier, and in this respect, the diet has a multifaceted activity [182]. However, studies are available on the anti-inflammatory effect of the diet strictly in PD. Among other studies, a publication in 2022 demonstrated that the anti-inflammatory effect of the ketogenic diet in the disease is related to a modulation of the Akt/GSK-3β/CREB signalling pathway, mediated by the acetylation of metabotropic glutamate receptor 5 (mGluR5) promoter region histones in a rat Parkinson’s disease model [183]. This study confirmed mainly the neuroprotective effect of preventive ketosis compared to receiving KD as a therapeutic diet in the lipopolysaccharide (LPS)-induced rat PD model. After the induction of PD (with LPS), the model showed an increased regulation of proinflammatory mediators (TNF-α, IL-1 and IL-6), the loss of dopaminergic neurons, a reduction in mGluR5+ microglial cells, an increase in TSPO+ microglial cells, a reduction in H3K9 acetylation in the mGluR5 promoter region, and mGluR5 mRNA reduction with a decrease in the phosphorylation levels of the Akt/GSK-3/CREB pathway. These disturbances were improved by the dietary intervention of preventive KD in particular. PET imaging enabled the noninvasive detection and monitoring of the anti-inflammatory effect on PD (via the KD diet) related to histone acetylation or the DNA methylation of the mGluR5 gene.
KD suppressed the inflammatory response (neuroinflammation) relevant to microglial activation and had a neuroprotective influence. The anti-inflammatory effect of KD on PD was related to the modulation of the mGluR5/Akt/GSK-3β/CREB signalling pathway by increasing the level of histone acetylation of the mGluR5 promoter region.
In addition, the pathological processes of neuroinflammation connected with PD are supposed to ameliorate by the multiple neuroprotective mechanisms of KD-induced ketosis involving the inhibition of proinflammatory mediator gene expression, the inhibition of the NLRP3 inflammasome assembly, epigenetic adaptations associated with calorie restriction, polyunsaturated fatty acids, ROS reduction, and the gut microbiome. Ketone bodies serve not only as an energy substrate but also as a signalling molecule. Finally, microglial cells can be modulated by various epigenetic mechanisms (DNA methylation and histone acetylation) and, thus, regulate neuroinflammation, resulting in neuroprotection [183].
Damaged mitochondria, ROS excess and abnormal glucose metabolism are closely interrelated, and the ketogenic diet can have an influence on those as well. Ketone bodies show an ability to rebuild new mitochondria to increase mitochondrial respiration and the production of ATP molecules. The reduction of free radicals thus also results from the improved efficiency of the respiratory chain in mitochondria [45,81,184]. The main ketone body, β-hydroxybutyrate, can also reduce the dopaminergic neurodegeneration and mitochondrial deficit observed in PD [38,185]. The neuroprotection of dopaminergic neurons seems to be of great importance, taking into account the scale of the problem of dopamine deficiency. Levodopa (L-DOPA), i.e., a dopamine precursor, has been, for years, one of the main drugs prescribed for PD. That drug can, however, contribute to the increased aggregation of α-synuclein, which, abnormally tangled, causes the formation of the Lewy bodies present in PD [186]. It has been found, however, that when using levodopa together with a ketogenic diet, the results can be far more favourable than those of the treatment with the drug alone (through an improvement of its bioavailability) [187,188,189].
Studies on PD animal models have clearly demonstrated that ketone bodies reduce dopaminergic neuronal death (BHB administered in vitro to cortical neurons and subcutaneously infused in mice) [38,190], decrease the number of proinflammatory cells in the brain and improve motor functions [62]. Another potentially possible mechanism of the ketogenic diet’s influence on PD is the indirect effect mediated by changes in the intestinal microbiome. It is known that diet significantly influences intestinal microbiome remodelling; on the other hand, it is known that the microbiome plays a great role in the pathogenesis and course of PD [191].
In 2018, a randomised controlled study was conducted on 47 patients with PD (38 of whom completed the study), who were divided into two groups: a group in which the ketogenic diet was applied and a group on a low-fat and high-carbohydrate diet.
Although, after eight weeks, an improvement was observed in both groups, it was more pronounced in the group of patients on the ketogenic diet. In Part I of the Unified Parkinson’s Disease Rating Scale (UPDRS), the results in the ketogenic diet group improved by 41% in relation to the initial values (−4.58 ± 2.17 points), while those in the low-fat group improved by 11% (−0.99 ± 3.63 points). That was true of non-motor signs, while, in respect of motor signs, both groups presented a similar significant improvement. The adverse effects observed in both groups included increased sensations of hunger in the low-fat group and periodical exacerbations of tremor and/or stiffness in the ketogenic diet group [192].
A study in 2022 conducted on 16 patients with PD observing a ketogenic diet for 12 weeks also demonstrated its favourable effects. A significant improvement was noted on the Parkinson Anxiety Scale (PAS). At the same time, an improvement was observed in body mass, BMI, waist circumference, the concentrations of C-reactive protein (CRP), glycated haemoglobin, fasting insulin, HDL cholesterol and triglycerides. On the Center for Epidemiologic Studies Depression Scale (CESD-R-20), no major changes in depression symptoms were found [193].
In another study, among other findings, it was demonstrated that in PD patients, ketogenic diet application resulted in a mean reduction in Unified Parkinson Disease Rating Scale (UPDRS) result values by 10.72 points (a reduction by almost half compared with the initial results). An improvement was observed in respect of posture equilibrium, gait, resting tremor, mood and energy level, and it was achieved in just 28 days [188].
Another study comparing the ketogenic diet with a high-carbohydrate diet in PD patients demonstrated that in spite of the absence of motor function differences in the UPDRS between the groups, in the group of patients on the ketogenic diet, better results were observed in respect of short-term memory and verbal fluency [194].
In 2022, a case report was published on a 69-year-old woman with PD and mild depression and anxiety symptoms, to whom the ketogenic diet had been applied. A reduction in depression symptoms by 8 points on the Center for Epidemiologic Studies Depression Scale (CESDR) (from 42 to 34) and an improvement in the Parkinson Anxiety Scale (PAS) by 6 points (from 23 to 17) were noted. A significant improvement occurred in all health biomarkers, including a reduction in cardiovascular disease risk. On the other hand, in the UPDRS, an increase was observed from 24 to 33 points [195].
An improvement in UPDRS also occurred in all five study participants with PD, strictly complying with ketogenic diet requirements (fats 90%, proteins 8%, carbohydrates 2%) for 28 days [194]. Włodarek also referred to these results in his publication in 2019 [36].
Another study assessed the effect of the ketogenic diet on the quality of voice, which is decreased in PD patients. A Voice Handicap Index (VHI) test was used, and an improvement was observed in voice quality parameters in patients with PD, suggesting a possible alternative therapy for the improvement of that parameter in PD patients [196]. Taking into account the wide range of the effect on many aspects and potential therapeutic possibilities of the ketogenic diet in PD, further studies in this respect seem extremely necessary.
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