The prevalence of Parkinson’s disease (PD) has doubled in the last 25 years and is estimated to affect 8.5 million individuals globally (1). It is the second most common neurodegenerative disease after Alzheimer’s disease (2). Although the exact pathogenesis is unclear, PD is characterized by misfolded alpha-synuclein protein accumulation leading to neuronal death, particularly in the substantia nigra’s dopaminergic neurons (3). Exacerbating this neurodegeneration are the involvement of pro-oxidant pathways, decreased mitochondrial function (4–6), inflammatory responses associated with elevated proinflammatory cytokines, increased levels of circulating insulin and glucose (7), and inflammasome alteration of the gut microbiota that may be both activated by and promote further alpha-synuclein aggregations (3). This energy dysregulation seen in PD may partially explain why the switch in cellular energy substrate from glucose to triglycerides associated with a ketogenic diet (KD) may be neuroprotective and potentially mitigate symptoms (8).

During a prolonged restriction or starvation of carbohydrate intake, ketone bodies become the primary energy source of adenosine triphosphate (ATP) for cells, including neurons. Hepatically produced beta-hydroxybutyrate (BHB) and acetoacetate are the two primary ketones of nutritional ketosis; with BHB having the neuroprotective benefit of crossing the blood–brain barrier and preventing hippocampal neuron death (4). Other neuro-beneficial effects of a predominantly ketone-predominant metabolism are increased central nervous system (CNS) adenosine, increased gamma- aminobutyric acid (GABA) levels, and decreased glutamate levels, all of which directly affect ion channels, increase mitochondrial ATP production, and have anti-inflammatory and antioxidant effects (Figure 1) (9).

Traditionally, a KD includes significant portions of animal dairy foods as a fat source. While the relationship between dairy, gut microbiota, and PD is not fully elucidated, we propose dairy is an important factor to consider when designing a KD for these patients due to studies showing high dairy product consumption, particularly low-fat, is associated with an increased risk for PD. (10, 11).

Although there are pharmaceutical treatments for PD, many patients feel overwhelmed by managing polypharmacy over the disease course and may experience adverse events, functional decline, cognitive impairment, falls, and other negative health outcomes (12). Therefore, patients are increasingly advocating for non-pharmacological treatment options that may be used alongside other interventions. This study was initiated by a patient support group whose members were investigating additional options for managing disease progression and discovered two articles about the neuroprotective effects of a KD (5, 8). The group collectively expressed interest to their physician and local researchers to investigate whether a KD could positively impact quality of life and help control certain aspects of their disease process. The novel KD designed for this study has an important distinction of limiting dairy due to evidence linking high dairy intake with increased PD risk. The primary aim of this 12-week, patient-initiated, mixed-methods, exploratory study was to evaluate the feasibility and acceptability of an innovative, modified KD. A secondary aim included assessing the potential impact of this diet on the quality of life and functional movements in patients with PD.

To our knowledge, this mixed-methods exploratory pilot study is the first to test a modified, low dairy KD on people with PD. Results demonstrated a modified, low dairy KD was feasible and acceptable for our study sample. As expected, results demonstrated this study’s participants found this intervention tolerable and were highly motivated since this was a participant-initiated study. All predetermined criteria for feasibility were met. Attrition was very low, reported adherence to dietary intake was > 75%, and the recommended daily intake of 80% fat, 15% protein, and 5% carbohydrates was largely followed by participants. When participants ate less fat than recommended, this was replaced with protein rather than carbohydrate content, which may have contributed to the weight loss noted during this study. Urinalysis BHB levels indicated that most participants maintained a ‘nutritional level’ of ketosis by Week 4, with BHB levels reaching at least 3 mM/L.

Predetermined acceptability criteria were met. PDQ-39 scores indicated all participants maintained or improved quality of life. Most subjects experienced no change in constipation, with one subject reporting improvement, and four reporting a slight worsening. It is difficult to determine whether changes in self-reported constipation scores can be solely attributed to the KD, as constipation in PD can be impacted by numerous factors such as natural disease progression (21), stress (22), and microbiome composition (23). Additionally, the pre-study questionnaire asked subjects (n = 8) about the number and frequency of bowel movements. Three subjects reported 2 movements per day, while the other 5 subjects had one movement every other day and 5 of the subjects took a stool softener or supplement to help with constipation. It is interesting to note the range of what subjects felt was “normal” for bowel movements, as this may have implications for how constipation was reported in the UPDRS.

Predetermined safety criteria were also met, including subject’s baseline concerns regarding constipation, weight loss and blood lipid concentrations. While all participants experienced some weight loss by week 12, none lost more than 10% of their baseline weight, thus meeting our safety criteria for this time period. Additionally, while neither HDL nor triglycerides changed, both average total cholesterol and average LDL showed a non-significant increase by Week 12 (Figure 2C). Some individuals in this study had a more significant increase in cholesterol. If people are consuming a KD for a longer period, cholesterol should be monitored. Increased levels of total cholesterol and LDL are associated with a reduced risk of PD but increased risk of cardiovascular disease (24), underscoring the importance of monitoring blood lipids.

Although not statistically significant, these subjects had elevated eosinophil and basophil counts not reported in other studies (Figure 2D), but which showed KD alone can increase T cells and natural killer cells (25). It is possible these elevated immune cells were caused by seasonal allergies, as the study was conducted in the spring when pollen counts are high (26).

Regarding the secondary outcomes of this study, several improvements in quality of life and functional movement were noted. To avoid relying on statistical differences that do not involve a clear clinical impact, the concept of minimal clinically important differences (MCID) was employed (27) as is commonly used in PD drug trials and observational studies (28–30). MCID were identified in 8 of the 12 participants in motor function, quality of life, dynamic balance, and self-reported freezing behaviors. On average, the cohort’s UPDRS scores for non-motor experience of daily living (Part I), motor experience and activities of daily living (Part II), and motor examination (Part III) all improved by Week 12. The greatest improvement was seen in Activities of Daily Living (section 2) and Cognition (section 6) of the PDQ-39; however, these were not statistically significant. No significant changes were observed in Mobility, Emotional Well-being, Stigma, and Communication. There was no change in the cohort’s mean for motor complications (UPDRS Part IV).

To our knowledge, five other small clinical trials have investigated the effects of the KD on PD. (5, 31–35) Consistent with our study results, these studies suggest non-motor symptoms may be more likely to improve than motor symptoms when utilizing a KD, at least in the short-term. One randomized trial assigned patients with PD (n = 47) to either an 8-week KD or low-fat diet (31) and reported a greater improvement in nonmotor symptoms with the KD, although both groups improved overall motor and nonmotor symptoms. The other four trials, like ours, are single arm trials. Krikorian et al. (32) followed 14 patients with PD-associated mild cognitive impairment during an 8-week KD and found an improvement in lexical access and memory, and a nonsignificant trend toward reduced memory interference (32). Another study used a 12-week KD in patients with PD (n = 16) and reported improvements in Part I of the UPDRS and anxiety scores, with no change in motor function (33). The smallest study, a 28-day KD in five patients with PD, reported improved UPDRS scores (5). Finally, Choi et al. (34) utilized a 3-week KD plus medium-chain triglyceride supplementation in 15 patients with PD. They found the diet was feasible and acceptable, and reported a reduced non-motor symptom severity score, with no change in UPDRS, 3-back, and rs-EEG results. As non-motor symptoms are affected by changes in neurotransmitter and inflammation signaling, it is possible they exhibit more plasticity than symptoms resulting from the loss of dopaminergic cells in the substantia nigra that control movement, muscle control, and balance. Dopaminergic decline or restoration of function of injured neurons in PD is not generally considered possible, although mechanistically a KD may favorably impact mechanisms of neurotoxicity and slow disease progression (36).

Several biological mechanisms of a KD may be relevant to PD therapy, including mitochondrial energy production, immunomodulation, reduced circulating insulin and glucose, and altered gut microbiota. A subgroup of patients with PD have been found to have a defect in cellular energy production specifically related to respiratory chain complex I, which requires glucose as a substrate. A KD switches primary energy consumption from glucose to ketones, bypassing the need to utilize the defective complex I and instead primarily utilizing complex II, which may help restore appropriate mitochondrial function and energy production (37). Several murine models showed improved mitochondrial function, increased ATP production, and protection of dopaminergic neurons when KD or ketogenic supplements were utilized after a complex I inhibitor (4, 5, 38–41). These improvements in energy synthesis and protection of dopamine production may be influenced by the activation of the Nrf2-ARE pathway. The KD induces an initial mild oxidative stress, stimulating innate antioxidant responses through Nrf2-ARE signaling. Ultimately, this leads to an overall reduction of oxidative stress (41–44).

Additionally, a KD may modulate the immune system and result in reduced inflammation. A decrease in pro-inflammatory cytokines was observed in preliminary human studies (41, 45), with a decrease in both proinflammatory cytokines and microglia activation noted in murine models (4, 42, 45–47). This combination of reduced oxidative stress, rescued respiratory chain complexes, and decreased inflammation and inflammatory cytokine reduction improved spatial learning and memory, cognitive function, and motor control in KD mouse models (5, 40, 43–45, 47–49).

Since insulin resistance and diabetes mellitus are risk factors for PD (50) and are associated with disease progression and severity, a KD’s significantly reduced carbohydrate consumption may result in improved disease outcomes. Clinical and in vivo PD studies using repurposed anti-diabetic medications report mixed results but suggest an overall potential modest benefit (50) in motor and cognitive symptoms with GLP-1 receptor agonists taken for at least 12 months (51). By limiting dietary carbohydrate intake and increasing fat and protein consumption, ketone bodies become the primary source of ATP for tissues, including the brain. Not only could the decrease in circulating glucose potentially alleviate neuronal glucotoxicity, but hepatically produced BHB (one of the two primary endogenous ketones derived from fats) can cross the blood–brain barrier and reduce hippocampal neuron death (4).

Finally, a KD may also modify the gut microbiota due to the significant shift in dietary macronutrient intake. Gastrointestinal symptoms often present years before motor symptoms in PD and evidence suggests gut microbes play a role in PD pathogenesis via the microbiota-gut-brain axis (52). Several studies highlight altered gut microbial populations in PD patients, which may be positively associated with more severe postural instability and gait difficulty (53, 54). Some researchers have recently proposed the potential origination of pathogenic alpha-synuclein proteins in the gastrointestinal tract (54), and transfer to the central nervous system via trans-synaptic cell-to-cell transmission in the vagal nerve. Although this is currently theoretical, the deposition of alpha-synuclein aggregations like those found in the brain have been found in the enteric nervous system.

Our decision to modify the KD by reducing dairy was based on evidence suggesting consumption of higher amounts of certain animal dairy products may increase risk and disease progression in PD (55–57). A meta-analysis of epidemiological data from the US, Finland, and Greece, found a positive, dose–response association between dairy consumption (especially milk and cheese) and the incidence of PD in men (55). Subsequent studies, however, have shown less (57) to no association (58), associations only with certain types of dairy (e.g., milk) (59), or differing associations by fat-content of milk such as positive association with low-fat milk (58) and inverse association with high-fat milk (58). For the purposes of this study, reduction of dairy intake to minimal levels was deemed to be a reasonable modification. Future studies investigating modified KD for individuals with PD should consider subcategorization factors such as: sex, location (pesticide (60) use in different countries/regions), type (fermented vs. non-fermented dairy products), and content (e.g., high fat, low sugar dairy products).

This exploratory study investigated a modified KD limiting animal dairy products for 3 months in 12 individuals with PD. Initial results were promising, showing this modified KD is acceptable and feasible for individuals with PD. Clinical improvements were also found in total UPDRS, UPDRS Part III, miniBEST, Freezing of Gait, and quality of life, without an increase in constipation or significant weight loss, both of which are concerns in PD. This study shows the modified KD is safe for this duration, may have similar benefits to a traditional KD, and may potentially reduce the risk of symptom exacerbation associated with traditional KD by limiting consumption of animal dairy products. To further elucidate the beneficial biological mechanisms of a KD in individuals with PD, future studies with larger cohorts and longer follow-up times are needed to objectively measure changes in the gut microbiome, circulating metabolic markers, and immunomodulation.