LipiDiDiet finds broadly sustainable effects of nutrient intervention in early Alzheimer's

by Saarland University

Credit: CC0 Public Domain

Trial participants who received a multinutrient formulation over an extended period of time showed a significantly less rapid deterioration in cognitive performance than the patients in a control group, who received only a placebo. These findings are from an ongoing European study LipiDiDiet in which 311 patients in eleven hospitals have been monitored for three years. The research results have been published in the highly ranked international journal Alzheimer's & Dementia, the Journal of the Alzheimer's Association.

05 november 2020--The early stages of Alzheimer's disease are characterized by a decline in brain and memory function, with short-term memory loss particularly affected. Patients and their families recognize these symptoms long before dementia occurs. "By examining the cerebrospinal fluid and by using magnetic resonance brain imaging techniques that can show the hippocampal shrinkage that is so typical of Alzheimer's disease, we are able to identify patients who are at this early (prodromal) stage," explains Tobias Hartmann, Professor of Experimental Neurology at Saarland University, who coordinates the European LipiDiDiet project. LipiDiDiet is a broad-based, long-term study of over three hundred participants who originally showed initial symptoms of memory impairment. The study was designed to investigate the effects of treating patients with a specially formulated medical food.

The previously published preliminary results showed that this nutrition-based intervention has a positive impact on the progression of the disease. "But it is only now, after three years of treatment, that we are seeing how extensive the significant differences between trial participants who received the active nutrient drink and those in the control group really are," explains Hartmann. Participants in the control group were given a placebo drink that was identical in terms of taste, texture and appearance. Neither the patients, nor the doctors and researchers knew who had been given the placebo and who had received the multinutrient drink. "We found that there was 20 percent less brain shrinkage in patients with Alzheimer's disease who received the nutrient cocktail than in those in the control group, which represents a significant slowing in the rate of brain atrophy. More importantly, we have demonstrated that over the three years of treatment, patients who were given the multinutrient drink suffered between 40 and 70 percent less cognitive impairment than those who received the placebo," says Hartmann.

"The positive effects of the treatment were most pronounced in those patients who began taking the multinutrient formulation at the earliest prodromal stage of Alzheimer's disease. We were particularly surprised to discover that these positive effects increased the longer treatment continued and that this finding was observed not only with respect to memory, but also with other cognitive abilities," explains Professor Hartmann. Compared with those in the control group, the subjects who received the multinutrient drink were better able to master typical day-to-day challenges, such as paying a bill, remembering a route or dealing with emergencies.

The multinutrient formulation given to the Alzheimer's patients in the LipiDiDiet study was the commercially available medical food "Fortasyn Connect," which contains a specific combination of essential fatty acids, vitamins and other nutrients. Specifically, Fortasyn Connect contains docosahexaenoic acid, eicosapentaenoic acid, uridine monophosphate, choline, vitamins B12, B6, C, E, and folic acid, phospholipids and selenium. Earlier preclinical research by the LipiDiDiet consortium and other laboratories, such as the Massachusetts Institute of Technology (MIT), has shown that these nutrients can reduce a number of the changes typically seen in the brains of Alzheimer's disease patients. Subsequent clinical studies demonstrated positive results from memory and EEG measurements that indicate increased brain activity in the trial participants that were given the nutrient drink.

Globally, around 47 million people are currently suffering from Alzheimer's disease or a similar neurodegenerative dementia, for which there is at present no known cure. Over the next 20 years, scientists expect this number to double, with forecasts suggesting that there will be around 130 million sufferers in 2050. "Despite significant research efforts, we still do not have any medications that can cure early-stage Alzheimer's disease. Some of these drugs are able to provide temporary relief for certain symptoms, but after a while the patients usually return to their earlier pre-treatment state. In light of this, the positive effects that we have been able to achieve with our special multinutrient drink are a major success. Our hope is that the significantly slower progression that we see in our patients will continue so that they can maintain their independence well into old age," says Tobias Hartmann.

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More information: Hilkka Soininen et al. 36‐month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer's disease, Alzheimer's & Dementia (2020). DOI: 10.1002/alz.12172

Provided by Saarland University 

Research lays groundwork for promising Alzheimer's-fighting drink

A nutrient mix based in part on research from the lab of MIT Professor Emeritus Richard Wurtman has shown promise in treating the early stages of Alzheimer’s disease. 

Much of Professor Emeritus Richard Wurtman's career in MIT's Department of Brain and Cognitive Sciences revolved around developing new treatments for diseases and conditions by modifying chemicals produced in the brain.

01 nov 2017--Since coming to MIT in 1970, Wurtman and his research group have generated more than 1,000 research articles and 200 patents, laying the groundwork for numerous successful medical products.
 "I'm very interested in using basic knowledge to ameliorate the human condition, to make living better," says Wurtman, who is also a medical doctor.
Now a nutrient mix based on essential research contributions by Wurtman has shown promise in treating the early stages of Alzheimer's disease, according to a new clinical trial funded by the European Union.
In the mid-2000s, Wurtman developed a nutrient cocktail aimed at treating what he considers "the root cause" of Alzheimer's: loss of brain synapses. The mixture increases production of new synapses and restores connectivity between brain regions, improving memory and other cognitive functions. A French company then combined this research with a multinutrient it was developing along with the LipiDiDiet consortium—a European collaboration of 16 universities and research centers—to create a drink, called Souvenaid, for Alzheimer's patients.
Over the years, Souvenaid has been the focus on several clinical trials to validate its efficacy. The mixture is not yet available in the United States, but it is being sold as a "medical food"—a category of regulated and safe foods that are designed for dietary management of diseases—in a number of countries across the globe.
In the new clinical trial, published in today's issue of Lancet Neurology, patients with prodromal Alzheimer's—the predementia stage of Alzheimer's with mild symptoms—were given either Souvenaid or a placebo. Compared to people who drank the placebo, patients who drank Souvenaid throughout the trial showed less worsening in everyday cognitive and functional performance and significantly less atrophy of the hippocampus, which is caused early in Alzheimer's by brain tissue loss.
"It feels like science-fiction, where you can take a drink of Souvenaid and you get more synapses … for improved cognitive function," Wurtman says. "But it works."
The co-authors of the study are from the University of Eastern Finland, Kuopio University Hospital, Karolinska Institutet and Karolinska University Hospital, the University of Masstricht, the VU University Medical Centre, Pentara Corporation, the University of Gothenburg, Sahlgrenska University Hospital, and Saarland University and the LipiDiDiet study group.

Making Souvenaid

Souvenaid's popularity may be on the rise today, but the product would not be possible without years of MIT research, Wurtman says.
In the mid-2000s, Wurtman's research led him to seek the mechanisms behind the body's production of phosphatides, a class of lipids that, along with proteins, form biological membranes. Production of these phosphatides, Wurtman discovered, depends on a set of nutrient precursors.
Specifically, Wurtman homed in on three naturally occurring dietary compounds: choline, uridine, and the omega-3 fatty acid DHA. Choline is found in meats, nuts, and eggs. Fish, flaxseeds, and certain meats contain omega-3 fatty acids. Uridine is mostly produced in the liver.
All those compounds taken simultaneously boost production of phosphatides, encouraging membrane development, which is critical in creating new synapses. Knowing that Alzheimer's-affected brains continuously lose synapses, Wurtman patented the work through MIT's Technology Licensing Office in hopes of using some version of the cocktail to treat Alzheimer's and any disease that leads to loss of synapses.
Then, in 2003, Wurtman presented the work at a meeting in Europe. Attending the event was a representative from Nutricia—a unit of Danone, a French company known as Dannon in the United States—which was experienced in making medical foods. Wurtman was invited to the company's headquarters, where a deal was hashed out to combine Wurtman's findings with a multinutrient the company was working on to create a new treatment for Alzheimer's.
By 2008, Danone had licensed the patent and Souvenaid was already a product. But Wurtman and several graduate students continued basic research behind Souvenaid, which gave the product a boost. "We were much more able to do the basic research at MIT," Wurtman says. "As soon as we found something in the research, we'd patent it. We never had the lag time. If you work in entrepreneurship and innovation that lag time could be the downfall of a prospective product."
Among the group's key discoveries was the finding that Souvenaid boosted the number of structures called dendritic spines, found in brain cells. When spines from one neuron contact another, a synapse is formed.
A 2010 study detailing those findings in Alzheimer's and Dementia indicated that Souvenaid improved verbal memory in patients with mild Alzheimer's. A 2012 study published in the Journal of Alzheimer's Disease confirmed and expanded these findings. Over six months, patients with mild Alzheimer's were given Souvenaid or a placebo. Patients taking the placebo deteriorated in their verbal-memory performance in the final three months of the study, while the Souvenaid patients continued to improve. Both trials were conducted by Philip Scheltens of the Alzheimer Center of the VU University Medical Centre in Amsterdam.

Future of Souvenaid

In the new clinical trial by the LipiDiDiet consortium, researchers conducted a 24-month trial, where more than 300 patients with prodromal Alzheimer's were randomly assigned Souvenaid or a placebo. The patients taking Souvenaid showed about 45 percent less cognitive decline than people taking the placebo, according to a measure known as the clinical dementia rating sum of boxes.
But the surprising finding, Wurtman says, is that the patients taking Souvenaid showed a substantial reduction is the loss of hippocampal volume. In early stages of Alzheimer's, the hippocampus—which plays an important role in memory—shrinks as tissue is destroyed. But rates of deterioration for those taking Souvenaid were about 26 percent lower than the control group.
"That's remarkable," Wurtman says. "I never would have guessed that something like that could happen. But if you suppress the loss of the hippocampus, it makes sense that you'd have better retention of cognitive function."
The results indicate that Souvenaid may be able to slow or stop full progression of very early Alzheimer's into full-blown Alzheimer's, Wurtman says.
With this new study, Wurtman has high hopes for Souvenaid. First, he says the findings could encourage more researchers to view synapse restoration as a treatment for Alzheimer's, which isn't a popular area of study. Most research today, he says, focuses on reducing the accumulation of amyloid plaques or minimizing damage caused by toxic metabolites in Alzheimer's-affected brains.
"Everyone who writes about Alzheimer's knows there's a synapse deficiency, and this impairs connections between brain regions," he says. "Even if the amyloid or another problem gets solved, one way or another, you'll have to replace these synapses."
Wurtman also hopes the study will "catalyze the rapid appearance of Souvenaid in the American market" and become a very early treatment for suspected Alzheimer's patients. Several potential biomarkers are being studied as indicators of early Alzheimer's. But it's somewhat useless to detect these biomarkers if nothing can be done about the disease at that point, Wurtman says. With Souvenaid, he says, that can change.
"Most people don't do a biomarker test, because … there's been nowhere to go from there. Now, it will be possible, I believe, for a doctor to tell a patient that, even though they have early Alzheimer's, they can take Souvenaid chronically to suppress the development of the disease."

This story is republished courtesy of MIT News (web.mit.edu/newsoffice/), a popular site that covers news about MIT research, innovation and teaching.

Provided by Massachusetts Institute of Technology

Research consortium LipiDiDiet finds a way to impact Alzheimer's disease before it's too late

Professor Tobias Hartmann, Saarland University in Germany.

The pioneering clinical trial is part of a large European Union funded project and involved 311 patients across 11 sites in four countries (Finland, Germany, the Netherlands and Sweden). The trial involved patients with prodromal Alzheimer's (often referred to as Mild Cognitive Impairment or MCI). Patients were randomised to receive either the nutritional intervention or an iso-caloric control drink for 24 months.

31 oct 2017--The study's primary endpoint, impact on NTB, was not met. The decline in the NTB of the control group was less than anticipated rendering this analysis statistically underpowered. However, key secondary endpoints showed significant advantages for nutrient-treated patients with 45% less worsening in the Clinical Dementia Rating-Sum of Box (CDR-SB). This measure is especially important because it tracks the patient's disease progression based on performance in managing everyday life, such as handling household emergencies, handling financial transactions or forgetting a major event. Furthermore, there was less brain atrophy in the active group, with 26% difference for the hippocampus and 16% for the ventricular volume. Progressive brain degeneration is typical for Alzheimer's, with hippocampal damage being responsible for many of the associated memory deficits. Over the 24-month period the incidence of any adverse events were similar between the active and control groups.
Professor Hilkka Soininen, Professor in Neurology MD, PhD from the University of Eastern Finland, who headed the clinical trial as part of the LipiDiDiet project, said: "Today's results, published in The Lancet Neurology, are extremely valuable as they bring us closer to understanding the impact of nutritional interventions on prodromal Alzheimer's, which we are now better at diagnosing but unable to treat due to a lack of approved pharmaceutical options. The LipiDiDiet study illustrates that this nutritional intervention can help to conserve brain tissue and also memory and patients' ability to perform everyday tasks - possibly the most troubling aspects of the disease."
The LipiDiDiet trial is now the third clinical trial on this nutritional intervention to show favourable effects on memory performance. The two previous clinical trials involved patients with mild Alzheimer's dementia and reported that daily intake of the nutritional intervention improved memory performance and increased measures of synaptic and functional connectivity in the brain.
Professor Tobias Hartmann, the project's coordinator, said: "While this nutritional intervention is not a cure for Alzheimer's, it effectively shows that the earlier in the disease process we intervene, the greater the advantage for the patient. Importantly, reduced atrophy in the patient's brain shows that the benefit extends beyond symptomatic effects, something never before achieved."

More information: The Lancet (2017). DOI: 10.1016/S147


Provided by Saarland University

Nutritional drink can help to conserve memory in case of prodromal Alzheimer's disease

Professor Tobias Hartmann, Saarland University. Credit: Saarland University

The study did not find a significant benefit in broad cognitive function (the study primary endpoint). Cognitive decline over the study period was less than originally expected when it was designed ten years ago, so differences found between the two groups were too small to be statistically significant. Project coordinator Professor Tobias Hartmann, Saarland University Germany, explained that this is the most likely reason the primary endpoint was not met.

01 july 2016--Professor Hilkka Soininen, Professor in Neurology MD, PhD from the University of Eastern Finland, who headed the clinical trial as part of the LipiDiDiet project, said: "Today's results are extremely valuable as they bring us closer to understanding the impact of nutritional interventions on prodromal AD which we are now better at diagnosing but unable to treat due to a lack of approved pharmaceutical options.
The LipiDiDiet study illustrates that this nutritional intervention can help to conserve brain tissue and also memory and patients' ability to perform everyday tasks—possibly the most troubling aspects of the disease. We look forward to the results of subsequent analyses and the six year extension study which will provide further insights".
The clinical trial, headed by Professor Hilkka Soininen is part of a large EC project (LipiDiDiet) to explore the therapeutic and preventative impact of nutrition on neuronal and cognitive performance in ageing, AD and vascular dementia. LipiDiDiet is funded by the seventh Framework Programme (FP7) of the European Commission (EC) and coordinated by Professor Hartmann, Saarland University in Germany.
Fortasyn Connect was selected by a consortium of leading researchers from 19 European institutes, for this 24-month, randomised, controlled, double-blind, multicentre study involving 311 patients - on the basis of its results in a previous EU project (LipiDiet).
Nearly 47 million people have Alzheimer's or a related dementia for which there is currently no cure.2 This number is expected to double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050.2

Study details

The trial was the first to investigate the impact of Fortasyn Connect on patients with prodromal AD who were randomised to receive either Fortasyn Connect or an iso-caloric control drink once daily.
The primary outcome parameter was selected to assess the effect on cognitive function (a broad measure of thinking) during 24 months intake of Fortasyn Connect compared with a control product. This was a cognitive composite score consisting of the CERAD 10-word immediate recall, delayed recall and recognition, category fluency and letter digit substitution test.
Secondary outcome parameters were brain volumes (total hippocampal, whole-brain & ventricular volumes), the Clinical Dementia Rating Sum of Boxes (CDR-SB), Neuropsychological Test Battery composite scores: episodic memory, executive function/working memory composite and a complete composite score consisting of 16 subtests, progression to (AD) dementia, blood and CSF biomarkers, tolerance and safety.
No significant difference was observed for the cognitive composite score. Predefined analyses showed significant differences between active and control study groups for hippocampal and whole-brain atrophy, and favourable effects for CDR Sum of Boxes and episodic memory (both were most pronounced in patients with high baseline cognition with regular intake). Analyses are ongoing for progression to (AD) dementia and blood and CSF biomarkers.
Tobias Hartmann, the project's coordinator, said "We have known for a while that diet can reduce the risk of developing dementia. Indeed, certain nutrients have been found to have a neuroprotective effect on the brain. However translating this into an effective intervention hasn't been easy because single nutrients simply aren't powerful enough to fight a disease like Alzheimer's alone. Today's clinical trial results have shown that the key is combining certain nutrients, in order to increase their effect.
This is exciting because it shows that in the absence of effective drug options, we really have found something that can help slow down some of the most distressing symptoms in prodromal AD; especially in those who started the intervention early. Indeed those patients who have lost the least cognitive function, have the most to gain".


Provided by Saarland University