Beta hydroxybutyrate does make you smarter

Someone tweeted this study which I have read before, but unfortunately lost. I find this paper rather exceptional because of the perspective of the authors regarding congition and mental health. Most researchers only agree that a KD is efficient for seizure control, not so much for neuroprotection and neuroregeneration. The notion that the brain only functions with glucose coupled with the idea that not eating glucose is metabolically stressful (next post is about this) has deviated attention from ketone bodies as memory enhancing agents. This, I think, is one of the reasons for the very little attention given to KD for Alzheimer and Parkinson, considering the very promising results of studies done on the subject. Maybe because it is not a drug...

Back to the study. 23 older adults with mild cognitive impairment (MCI) were assigned to either a very low carbohydrate diet (VLCD) or to a high carbohydrate diet (HCD) for 6 weeks. Carbohydrate calories were 5-10% on the VLCD and 50% in the HCD. They do not controlled calories, fat or protein*. Some interesting facts from the dietary intevention:

- "The high carbohydrate diet approximated the macronutrient profile consumed at the time of enrollment for most subjects, which included at least 50% of calories from carbohydrates."
< - "We advised the high carbohydrate subjects to consume fruits and vegetables as carbohydrate sources as much as possible.Those in the low carbohydrate diet were restricted from fruit and instructed to limit carbohydrate consumption to small portions of vegetables."

Let's look at the results. 

Memory performance was only increased significantly in the low carbohydrate group. Ok, but maybe the VLCD performed better because of the changes in weight or calorie intake and not necessarily because of the diet being ketogenic. 

(I'm omitting some statistical data on the text). 

"There were significant changes in anthropometric and metabolic values and in dietary parameters. After the intervention, weight (81 kg vs. 77 kg, adjusted means) and waist circumference (95 cm vs. 90 cm, adjusted means) were reduced for the low carbohydrate group. Likewise, fasting glucose (96 mg/dL vs. 86 mg/dL, adjusted means) and fasting insulin values (14.5 /mL vs. 11.9 /mL, adjusted means) were lower for the low carbohydrate but not high carbohydrate group. Urinary ketone bodies were not detected for the high carbohydrate subjects but were present for the low carbohydrate subjects (Table 2), and ketone body levels were related to memory performance."

Table 2:

The VLCD group reduced their calorie intake considerably compared to the HCD group. Note that pre intervention energy intake was 1697 kcal for the HCD and 1762 kcal for the VLCD. There was a slight increase in protein (and fat) intake, but not sufficient to be the responsible of the sudden drop of calories. What about insulin?

"(...) semipartial correlations indicated weak and nonsignificant relationships to memory performance for each of these factors: change in calories (rsp = -0.16, p = 0.46); change in insulin (rsp =-0.26, p = 0.24); and change in weight (rsp = 0.28, p = 0.20). However, within the low carbohydrate group, the relationship between change in insulin and change in memory performance was stronger although not statistically significant, r = 0.47, p = 0.11."

Ok so there was a weak relationship between insulin levels and memory performance, but only in the VLCD. In the end, the parameter that was best correlated to memory performance was ketone body levels. 

Interesting discussion excerpts:

"A number of mechanisms might be considered with respect to our memory finding. There are indications that central ketone metabolism may confer neurocognitive benefit and mitigate neurodegenerative processes in conjunction with, but also independent of, effects on insulin. Mean fasting insulin levels prior to the intervention indicated that, on average, subjects were hyperinsulinemic. We observed a significant reduction of insulin among the low carbohydrate subjects, suggesting that the memory improvement was related, in part, to increased insulin transport into the central nervous system (CNS) as a consequence of correction of peripheral hyperinsulinemia. The trend toward a moderate relationship between fasting insulin and memory performance within the low carbohydrate group would be expected to reach statistical significance in a larger sample.It is noteworthy that a recent trial involving 12 weeks’ calorie restriction in a sample of 50 middle-aged and older adults demonstrated improvement in memory function related to change in fasting insulin (Witte et al., 2009)."

"The absence of a strong relationship between insulin reduction and memory improvement suggests that neurocognitive benefit also might be associated with other aspects of the ketotic condition. Ketone metabolism has been shown to protect hippocampal neurons from Abeta toxicity (Kashiwaya et al., 2000), glutamate toxicity, and apoptosis (Noh et al., 2006), as well as other insults such as kainic acid (Noh et al., 2003) and hypoxia (Puchowizt et al., 2005). As compared with glucose metabolism, central ketone metabolism generates lower levels of oxidative stress (Prins, 2008) and has been shown to produce greater cellular energy output and antioxidant capacity, the latter by increasing glutathione peroxidase in hippocampal cells (Veech et al., 2001; Ziegler et al.. 2003). In addition, the presence of cerebral ketones is associated with decreased apoptosis and inflammation (Gasior et al., 2006; Malouf et al., 2009), which along with oxidative stress, have been identified as fundamental factors contributing to neurodegeneration (Cotman, 2000)."

Some final notes:

- Ketone body levels were measured with urinary strips, and BOHB was not measured directly.

- The KD was by not means a high fat diet (maybe if we consider the % of calories from fat). 

* As per the authors: "Very high levels of fat (90% of total calorie intake) have been prescribed traditionally to induce ketosis for seizure management (Vining, 1998). However, recent trials have indicated that protein restriction is not necessary to achieve ketosis (Boden et al., 2005; Cassady et al., 2007) or effective seizure control (Kossoff and Dorward, 2008; Kossoff et al.,2003), allowing for a less severe regimen." More on protein intake & Ketosis here.

Krikorian R, Shidler MD, Dangelo K, Couch SC, Benoit SC, & Clegg DJ (2010). Dietary ketosis enhances memory in mild cognitive impairment. Neurobiology of aging PMID: 21130529