Victoria Johnson

 found that a ketogenic medium chain triglyceride (kMCT) drink improved executive function, episodic memory, and language by increasing blood ketone levels and brain energy status in patients with evidence of mild cognitive impairment (MCI). These findings reinforce the potential of brain energy rescue as a strategy to reduce cognitive decline in MCI and Alzheimer Disease (AD).

The brain energy rescue process is achieved by offering the brain more ketones to metabolize when brain glucose metabolism decreases, which is a common effect of these disorders. Study author Stephen Cunnane, PhD, Research Center on Aging, Universite de Sherbrooke, and colleagues found that when compared to placebo, the kMCT group scored higher on free and cued recall (

 = .017) after a 6-month randomized, controlled trial.

This study followed up the Brain Energy, Functional Imaging, and Cognition (BENEFIC) study (NCT02551419) that showed a kMCT drink improved brain energy status and aimed to assess the effect of kMCT on cognitive outcomes. 

 spoke with Cunnane to learn more about the ketogenic drink used in the study and the potential of ketogenic diets to mediate Alzheimer Disease.

: How does the kMCT drink work to initiate brain energy rescue?

: It should be able to replicate what happens during fasting, and what happens in infant brain development. In fact, the supply of ketones during infant brain development comes from medium chain triglycerides in mother's milk. The mother will produce medium chain triglycerides in the mammary gland, and they will be supplied to the baby and converted to ketones. This is nature's solution to meeting the energy challenge of early development. So, we took the same approach with MCT in Alzheimer's disease. We were able to show with PET imaging that the ketones are taken up by the brain normally and increasing proportion in relation to the level in the plasma or in the diet. There absolutely was the same relationship, as you would see in the young, healthy adult, across brain regions, across gray matter and white matter. And we've been detailing these results over the past 5 years.

Do you believe ketogenic diets could be complimentary to brain energy rescue and do they have potential to be prescribed to patients suffering from MCI?

The answer is yes, and no. Ketogenic diets have been around for 100 years. They’re initially and still predominantly used for epilepsy, and that strikes more in children—it's easier in some ways to control the diets of children than it is in adults and in older people. So, it becomes a logistical problem, how do you actually reduce the carbohydrate intake to well below 10% of our calorie intake? It’s very difficult for most people to adapt to reducing bread, pasta, rice, potatoes, and refined sugar, of course, so dessert, too. 

Scientifically, I think it is an effective approach. It's a question of the practical elements and the logistics of it that that make it very challenging. But there are clinics that specialize in this now and some even have remote sites you can find online, so you don't have to physically go to the clinic. You can buy a sort of subscription and get medical support at home to manage this type of approach yourself—and with your family because they have to get involved, too. If you're living with someone else, cooking 2 sets of meals every time is going to be a nightmare, and it's simply not going to work. So, this is an adjustment for the person who has Alzheimer's disease, or MCI, but it's an adjustment for their family, too. And the physician often needs to learn more about the merits of this approach because ketogenic diets are very high fat, and high fat has been always been associated with gaining weight and cardiovascular risk. In fact, ketogenic diets are now used for weight loss. They're used for type 2 diabetes control, because they reduce the carbohydrate and the strain on insulin. People have shown for up to 12 weeks now in older people that the cardiovascular risk simply does not materialize in any measurable fashion. So, I think there's a learning curve that we as scientists, clinicians, patients, and families that are affected, need to adapt to. And if the ketogenic diet is not something that can be managed, for various reasons, a ketogenic supplement becomes a practical alternative.

1. Fortier M, Castellano CA, Croteau E, et. al. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. 

. 201915(5):625-634. doi: 10.1016/j.jalz.2018.12.017 
2. Fortier M, Castellano CA, St-Pierre V, et. al. A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT. 

. Published online Oct 26, 2020. doi: 10.1002/alz.12206

Articles

Stephen Cunnane, PhD, Research Center on Aging, Universite de Sherbrooke, discussed the ketogenic drink used in his recent study and the action of ketogenic diets. 

The Use of Ketogenic Triglycerides to Improve Cognitive Function

A recent study published in Neurology suggests that progressive brain atrophy predictive of 

 (AD) is associated with late-life exposure to particulate matter with aerodynamic diameters <2.5-μm (PM

Longitudinal analyses showed that for each interquartile range (IQR) increase (IQR, 2.82- μg/m

, the associated risk of developing AD increased by 24% (hazard ratio [HR], 1.24; 95% CI, 1.14–1.34) over a 5-year period, as assessed by increased AD pattern similarity (AD-PS) scores. This association remained within levels of PM

 below US regulatory standards (<12-μg/m

Principal author Diana Younan, PhD, research associate, University of Southern California, stated in a related release that the “findings have important public health implications because not only did we find brain shrinkage in women exposed to the highest levels of PM

 pollution but we also found it in women exposed to levels lower than those that the EPA considers safe.”

Younan and colleagues investigated data from 1365 women free of dementia with a mean age of 77.9 years (standard deviation [SD], 2.7) that participated in the WHIMS Magnetic Resonance Imaging (WHIMS MRI) study. MRI data at baseline and after 5 years was investigated. AD-PS scores—which have been shown to be associated with known risk factors of AD and poor cognitive function—were developed by a supervised machine learning algorithm by comparison of MRI data from the AD Neuroimaging Initiative of gray matter atrophy in areas vulnerable to AD such as the amygdala, hippocampus, thalamus, midbrain, parahippocampal gyrus, and inferior temporal lobe areas.

Midlife Hypertension Linked to Increased Risk of Later Life Brain Damage

In longitudinal analysis, IQR-increments were significantly associated with a 0.031 (β = 0.031; 95% CI, 0.017–0.046) increase in AD-PS score. In fully adjusted models the association was 0.026 (95% CI, 0.009–0.043), which correlates to the 24% increase of AD risk. This association remained after adjusting for socio-demographics, lifestyle, and clinical characteristics including cerebrovascular factors such as white matter lesion volume and stroke, challenging previous studies that have proposed a cerebrovascular mechanism of PM

 damage leading to brain atrophy. Instead, Younan and colleagues favor the theorized mechanism that PM

 directly contributes to the neurodegenerative process of dementia via a neurotoxic effect on brain structure.

Sensitiviy analyses confirmed the positive association between PM

 and AD-PS score after adjusting for baseline AD-PS scores. No association was seen between PM

 and baseline AD-PS score in cross sectional analyses (β = –0.004; 95% CI, –0.019 to 0.011). 

Previous analyses of WHIMS MRI include region-of-interest analyses that showed residence in areas with higher PM

 was associated with smaller total brain and white matter volumes, and that residing in places with >12-μg/m

 increased the risk of global cognitive decline by 81% and all-cause dementia by 92%.

Younan and colleagues call for future studies “to fully investigate whether the neurodegenerative effects of late-life exposures to airborne particles may be contributed by or independent of cerebrovascular damage before or during late life...to replicate these results and to thoroughly explore other measures of cerebrovascular damage that may not be captured by white matter lesions and were not explored in our study (e.g., microbleeds; lacunar infarcts).”

1. Younan D, Wang X, Casanova R, et al. PM2.5 associated with gray matter atrophy reflecting increased Alzheimers risk in older women. 

. Published online November 18, 2020. doi: 10.1212/WNL.0000000000011149
2. Hopper L. Does air pollution increase women’s risk of dementia? 

. November 20, 2020. Accessed December 2, 2020. 

https://hscnews.usc.edu/does-air-pollution-increase-womens-risk-of-dementia


3. Chen J, Wang X, Wellenius GA, et al. Ambient air pollution and neurotoxicity on brain structure: Evidence from women’s health initiative memory study. 

. 2015;78(3):466–476. doi: 10.1002/ana.24460

Researchers from USC propose a direct neurotoxic effect of particulate matter smaller than 2.5 μm. 

Levels of Particulate Matter Below Regulatory Standards Increase Risk of Alzheimer Disease 

A new post hoc analysis suggests that fremanezumab may help increase reversion of 

 (CM) to episodic migraine (EM) for patients with the headache disorder.

Rates of reversion from CM to EM (CM-EM), measured in 2 ways, were higher in fremanezumab-treated patients with CM than placebo. Under a less-strict definition, 50.5% of patients treated quarterly (1 dose; n =185; 

 = .108) and 53.7% of patients treated monthly (n = 196; 

 = .012) reverted to EM versus placebo (44.6%; n = 159). Under another more stringent definition, 31.2% of patients treated quarterly (n = 114; 

 = .008) and 33.7% of patients treated monthly (n = 123; 

 = .001) reverted to EM versus placebo (22.4%; n = 80).

Richard B. Lipton, MD, Edwin S. Lowe Professor and vice chair of neurology, professor of epidemiology and population health, and professor of psychiatry and behavioral sciences, Albert Einstein College of Medicine, and director, Montefiore Headache Center, and colleagues state in their paper that “fremanezumab is efficacious as a preventive therapy for CM, based on significantly reduced frequency of headache and migraine days compared with placebo.” They note that their analysis shows “the potential [of fremanezumab] for reversion from a CM to an EM classification, a clinically relevant goal of preventive therapy.”

Reversion from CM to EM was defined 2 ways: 1, a less strict definition, as a reduction in the monthly average number of headache days over the 3 months of treatment; and 2, in a more stringent way, requiring a reduction in headache days from baseline for each month of treatment.

Fremanezumab Efficacy Shows Consistency Across Monthly, Quarterly Dosing Regimens

Lipton and colleagues analyzed the randomized, double-blind, placebo-controlled, parallel group HALO CM (NCT02621931) trial of fremanezumab which included data from 1088 patients with CM. These patients were randomized to receive placebo (n = 357), quarterly treatment (n = 366), or monthly treatment (n = 365) over the course of 3 months. Following ICHD-3 criteria, patients had to have migraine for at least 12 months, at least 15 headache days and 8 migraine days per month.

 A reduction of migraine required patients to experience less than 15 headache days per month.

The primary analysis of HALO CM previously showed significant reductions in monthly average headache days from baseline, with quarterly patients experiencing a mean reduction of 4.3 days (standard deviation [SD], 0.3) and monthly patients experiencing a mean reduction of 4.6 days (SD, 0.3). Placebo patients experienced a reduction of 2.5 days (SD, 0.3; 

Lipton and colleagues found some negative predictors of (CM-EM) that need to be further studied. In patients who did not revert to EM (CM-CM), rates of onabotulinumtoxinA use (CM-CM, 20% [n = 108]; CM-EM, 10% [n = 55]), topiramate use (CM-CM, 33% [n = 182]; CM-EM, 27% [n = 248]), and concomitant preventive medication use (CM-CM, 24% [n = 132]; CM-EM, 18% [n = 98]) were higher than those of CM-EM patients. In CM-CM patients, 57% (n = 314) also had medication overuse as compared to 50% (n = 268) of CM-EM patients. Medication overuse was defined as the use of acute headache medication on at least 15 days of the month, use of migraine-specific medication on at least 10 days, or use of combination medications on at least 10 days.

 These data show medication use may likely be associated with baseline migraine severity.

CM-EM patients experienced fewer monthly average headache days at baseline (mean, 18.4 days; SD, 2.9) than those who did not (mean, 22.6 days; SD, 3.9), which may also support the need to consider initial migraine severity as an additional variable.

“Future studies with fremanezumab should evaluate whether certain acute medications are more likely to predict failure to revert than others, though this may represent a treatment-resistant population. Further work would be needed to elucidate the relationship between medication overuse and reversion from CM to EM,” Lipton and colleagues wrote.

1. Lipton RB, Cohen JM, Bibeau K, et al. Reversion from chronic migraine to episodic migraine in patients treated with fremanezumab: Post hoc analysis from HALO CM study. 

. Published online November 11, 2020. doi:10.1111/head.13997
2. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. 

. 2018;38(1):1-211. doi: 10.1177/0333102417738202

A new post hoc analysis following the HALO CM study that showed a reduction in headache days with use of fremanezumab. 

Fremanezumab Aids Reversion from Chronic Migraine to Episodic Migraine

 that investigated 1-year outcomes of minimally invasive surgical treatment with laser interstitial thermal therapy (LITT) found it to be a safe and effective treatment option for patients with drug resistant epilepsy (DRE), with 64% of patients free of seizures at the end of the study period.

Additionally, the study assessed quality of life with the Quality of Life in Epilepsy questionnaire (QOLIE-31). The median score increased by 14.1 points at 1-year follow up, driven by improvements in seizure worry and social functioning. Although this total score change was not statistically significant, it is still clinically meaningful, according to Patrick Landazuri, MD, associate professor of neurology, University of Kansas Medical Center, and colleagues. 

They examined these 1-year outcomes from patients enrolled in the multicenter, prospective LAANTERN registry (Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System; NCT02392078) specifically for epilepsy treatment. They looked at the 60 LITT procedures performed for DRE. Patients with mesial temporal lobe epilepsy/mesial temporal sclerosis (MTLE/MTS) made up the majority of procedures but other etiologies were assessed, too. 

 talked to Landazuri to learn more about the LITT procedure, future studies and outcomes, and deciding the best options for patients.

: How do you think LITT could be further improved?

: It's still a relatively new technique in terms of epilepsy surgery. The story of LITT for epilepsy treatment began in 2013, or 2014. So it's only 6 or 7 years old, and LAANTERN is the first multicenter and prospective study. I think as we gather more and more data, we’ll be guided to different directions to pursue. Mesial temporal lobe epilepsy is easily the most studied epilepsy type for LITT therapies, and our paper contributes to that literature. The next steps will be understanding how effective it may be with extra temporal lobe epilepsy, which is also generally harder to surgically treat compared to MTLE. So far, our paper looks at our 1-year outcomes, but the study is slated to go for 5 years, and hopefully we will see that these outcomes are durable. Another important consideration is identifying different patient characteristics and epilepsy etiologies that may or may not make patient better candidates for LITT versus other therapies. I think as we expand our own cohort and LAANTERN, we’re trying to find trends to determine if, let’s say, cortical dysplasia patients would be better candidates or maybe people with cavernoma instead. There are other centers doing single center studies reporting their cohorts, and I think that's valuable as well.

What further research would you like to see conducted to investigate LITT?

In an ideal world, we would do randomized control trials, but I think that's going to be very difficult in epilepsy surgery. There was a study published several years ago that compared stereotactic radiosurgery to open craniotomy for mesial temporal lobe epilepsy, and when you read that paper you see there was a significant struggle in recruiting people. This was at least due in part to patients' decisions about what they wanted in the first place. You could tell in that manuscript that some patients really just wanted one surgery or the other. I'm not sure if that that kind of research will ever be truly feasible in epilepsy surgery. Some patients are going to gravitate towards an open surgery, which have so far been shown to be a bit more effective than more minimally invasive techniques. Other patients don’t want to do open craniotomy, even if it would be more effective, and may elect to do a more minimally invasive surgery – which is an equally valid decision. For these patients, there’s no one size that fits all epilepsy surgery, and I think it's appropriate to provide different options for patients to consider.

Is there anything else you want clinicians to know about laser ablation?

I'd like physicians and patients alike to know that it's a good option, but that doesn’t mean it's the only option. I know that I've had patients come to our clinic here and say, “Well, I really want to have a laser ablation.” And then they go through the presurgical evaluation and we identify that perhaps a different treatment option would be best for them, whether for medical or personal reasons. And so, I would encourage physicians and patients alike to be open to different options. I mean, the goal is to investigate individual patient characteristics and then make a decision that's appropriate for them because again, every patient has different priorities. Every patient has different epilepsy types, and I think it's making that individual decision between the physician and the patient that really makes the best care.

Landazuri P, Shih J, Leuthardt E, et. al. A prospective multicenter study of laser ablation for drug resistant epilepsy – One year outcomes. 

. 2020; 167. doi: 10.1016/j.eplepsyres.2020.106473

In this interview, Patrick Landazuri, MD, discusses the validity of laser ablation as an option for epilepsy surgery. 

Victoria Johnson

Articles

The Use of Ketogenic Triglycerides to Improve Cognitive Function

Levels of Particulate Matter Below Regulatory Standards Increase Risk of Alzheimer Disease

Fremanezumab Aids Reversion from Chronic Migraine to Episodic Migraine

Determining the Best Surgery for Drug Resistant Epilepsy