Multinutrient Intervention in the Prevention and Treatment of Dementia

C H A P T E R

22 Multinutrient Intervention in the Prevention and Treatment of Dementia Blanka Klimova1 and Kamil Kuca2 1

2

University of Hradec Kralove, Hradec Kralove, Czech Republic University Hospital Hradec Kralove, Hradec Kralove, Czech Republic

INTRODUCTION As a result of an increase in the older population groups, one of the social and economic issues nowadays is the growth of aging diseases such as dementia.1,2 Dementia is closely linked to aging. It is a consequence of the brain disease and it results in the deterioration of mental and cognitive activities. Symptoms of dementia are altogether defined in detail, but it is very difficult to distinguish whether those are dementia symptoms or manifestations of physiological aging. Most symptoms such as memory loss, orientation difficulties, communication disorders, or worsening decision-making process, refer to cognitive impairment, but dementia also affects behavior and self-sufficiency.3 Dementia can be diagnosed if there are cognitive and behavioral symptoms which should include at least two of the following aspects:4 • worsened ability to gain and recall a new source of information (e.g., disorientation in well-known places, forgetting appointments or asking the same questions several times); • worsened reasoning and judgment (e.g., low decision-making processes, tendency to safety risks or inability to conduct complex tasks); • worsened visuospatial skills (e.g., failure to recognize familiar faces or things, inability to dress appropriately or to find things); • worsened language (e.g., difficulties finding the right words, name the objects correctly, making hesitations or writing mistakes); and • behavioral changes (e.g., frequent changes in mood, social exclusion, or apathy).

Role of the Mediterranean Diet in the Brain and Neurodegenerative Diseases DOI: http://dx.doi.org/10.1016/B978-0-12-811959-4.00022-5

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Dementia is caused by several reasons such as an impediment of blood flow which circulates into the brain, multiple small strokes, malnutrition, brain tumors, metabolic diseases, or trauma. The most frequent type of dementia is Alzheimer’s disease (AD) which covers 70% of all dementia cases. The second most frequents type is vascular dementia (17% of all dementia cases), and the third one is dementia with Lewy bodies (10% 25% of all dementia cases). These are then followed by Parkinson’s disease dementia, and frontotemporal dementia/degeneration (FTD).5 Table 22.1 then provides an overview of these main types of dementia, the pace of cognitive decline in each type and the description of the most common symptoms of each dementia. Currently, there are about 47.5 million people living with dementia worldwide and this number is expected to triple by 2050.7 Although there already exist a few effective drugs to delay the development of dementia,8 these drug therapies still have quite modest benefits and they are rather expensive.9 Therefore there is ongoing effort to minimize agerelated cognitive decline and dementia by using nonpharmacological approaches, which can be good alternative tools in the treatment of dementia5,10 and have a positive impact health lifestyle, which is one of the modifiable risk factors. Recent randomized clinical trials11 22 have provided evidence-based results about several such approaches. These approaches especially include sports activities such as aerobic exercises, music therapy such as listening to Buddhist hymns, cognitive training such as solving crosswords, Mediterranean diet (MedDi), and medical foods such Souvenaid. The last two strategies— MedDi and medical foods—are discussed in this study since research studies indicate that TABLE 22.1 An Overview of the Main Types of Dementia and Their Symptoms Cognitive Decline

Type of Dementia

Common Symptoms

Alzheimer’s disease

Memory loss, problems with orientation, language disorders, changes Gradual in mood, loss of motivation, inability to manage self-care, behavioral disorders, and later on eating and walking problems

Vascular dementia

Impairment in attention, recalling new events, recognizing familiar objects, thinking difficulties, impaired communication, organizational difficulties, learning new things, or motor coordination

Stepwise and/or gradual

Dementia with Lewy bodies

Decline of reasoning and thinking, balance problems or stiff muscles, visual hallucinations, delusions, loss of memory, a lack of attention, or acting on dreams

Gradual but fluctuating

Parkinson’s disease dementia

Impairment of executive and visuospatial function, tremors, especially in hands, slow movements, stiffness of limbs, and balance problems, neuropsychiatric symptoms such as depression, anxiety, hallucinations or apathy; autonomic symptoms such as low blood pressure, constipation, difficulties in swallowing, increased sweating or sexual dysfunction; sleep disorders; or loss of smell

Gradual

Frontotemporal dementia/degeneration

changes in behavior, language disorders, neuropsychiatric disorders such as depression, hallucinations or delusions, or problems with spatial orientation

Gradual but fast

Source: Authors’ own processing based on [6].

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especially multinutrient dietary approaches seem to be play a crucial role in the delay of cognitive decline.23 van de Rest et al.24 state that the evidence for combined effects such as multinutrient approaches is growing. Thus, the purpose of this study is to explore the issue of multinutrient intervention as one of the lifestyle modifiable risk factors in the prevention and treatment of dementia.

DIETARY SUPPLEMENTS, MEDITERRANEAN DIET, MEDICAL FOODS, AND COGNITIVE DECLINE Research studies24 26 reveal that certain dietary patterns may reduce the risk of cognitive decline and delay the development of dementia. As Klimova and Kuca23 report, currently, there are several dietary supplements offered on the market to enhance memory and help delay the cognitive decline. However, some of these products might not be safe and effective and cause negative interactions if they are taken with prescribed drugs.27 In addition, they are not approved by the US Food and Drug Administration. These dietary supplements are products which are not pharmaceutical drugs, food additives like spices or preservatives, or conventional food. They are products which should supplement a person’s diet; they are or include a vitamin, dietary element, herb used for herbalism or botanical used as a medicinal plant, amino acid, any substance which contributes to other food eaten, or any concentrate, metabolite, ingredient, extract, or combination of these things; and they are labeled as a dietary supplement.28 The most frequent are, for example, caprylic acid and coconut oil, concerns, coenzyme Q10, coral calcium, ginkgo biloba, huperzine A, Omega-3 fatty acids, phosphatidylserine, and tramiprosate.23 Nevertheless, the findings of their efficacy on the enhancement of cognitive reserve have not been conclusive. Most of the research studies seems to be skeptical about their effects.29 31 However, in the area of multinutrient intervention studies recent research studies24,32 35 have provided quite convincing evidence about the adherence to MedDi in the prevention and delay of cognitive decline and early stages of dementia, respectively, AD. Mediterranean diet is distinguished by abundancy in nutrients such as fruit, vegetables, fish, nuts, whole grains, and olive oil, by moderate wine consumption, low consumption of processed foods, dairy products, red meat and vegetable oils.36 Trichopoulou et al.37 in their study propose to follow the traditional Greek menu, which could be a representative of the MedDi. Thus, for instance, breakfast should consist of herbal tea, sugar/honey, feta cheese/black olives, bread, and grapes/apple. Lunch should then include green beans, or lentils with tomato, or lamb, or fish, or chicken, and always bread, red wine, some vegetable or fruit. Dinner should comprise some kind of pie (e.g., spinach or cheese pie), Greek salad and bread. Knight et al.35 in their study list all the related nutrients in the typical traditional MedDi pattern. These include monounsaturated fatty acids, polyunsaturated fatty acids, antioxidants (e.g., allium sulfur compounds, anthocyanins, beta-caroteneflavonoids, catechins, carotenoids, indoles, or lutein), vitamins (A, B1,6,9,12, D, E), minerals (magnesium, potassium, calcium, iodine, zinc, selenium). Furthermore, they explain that the synergy of specific foods and nutrients in MedDi is more powerful on the aging brain than individual nutrients or a low fat diet. This combination of nutrients have a positive effect on pathological neurodegenerative processes such as oxidative stress,

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neuroinflammation, insulin resistance, or reduced cerebral blood flow.38 Hardman et al.39 discovered that the adherence to the MedDi led to the improved memory (delayed recognition, long-term, and working memory), executive function, and visual constructs. MedDi also appears to be less costly, free of negative side effects and with more persuasive epidemiological outcomes.40 Thus, the synergy of different nutrients seems to be a relevant intervention tool for the reduction of cognitive decline. The same can be true for the so-called medical foods because they also consist of various nutrients.41 The US Food and Drug Administration40 defines them as follows: a product is labeled as a medical food provided that it possesses a specific formulation (as opposed to a naturally occurring foodstuff in its natural state) for oral or tube feeding; it is labeled for the dietary management of a specific medical disorder, disease, or condition with distinctive nutritional requirements; it is intended for use under medical supervision; and it is intended only for a patient receiving active and ongoing medical supervision for a condition requiring medical care on a recurring basis so that instructions on the use of the medical food can be provided. It is probably Souvenaid which offers most of the evidence on medical foods in the reduction of cognitive decline and delay of dementia.17 19,42 Souvenaid was developed by the Advanced Medical Nutrition Division of Nutricia in 2002. It is a medical drink which is administered once a day in a 125-mL dose. It has either a vanilla or strawberry flavor. So far Souvenaid has been prescribed in the USA and in some countries of Europe such as England, Germany, Netherlands, or Italy.43 Its effect on the reduction of cognitive decline consists in the specific nutrient combination Fortasyn Connect, which was designed to improve synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. Fortasyn Connect includes uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium.42

METHODS The methodology was based on Moher et al.44 This study applied a method of literature search of available sources exploring the issue of multinutrient intervention in the prevention and early stages of dementia. Moreover, a method of comparison of findings from different research studies analyzing this topic was used. The selection criterion of the research studies was based on the research topics (i.e., dementia, AD, multinutrient intervention, nutrition, medical foods, Souvenaid, Mediterranean diet, alternative treatment) found in several world’s acknowledged databases PubMed, Web of Science, Springer and Scopus in the period of 2015 16. The reason for the selection of such a short period was that several review studies on this topic already covered the previous period, cf. [23 26,45]. Furthermore, other relevant studies were reviewed on the basis of the reference lists of the research articles from the searched databases. Altogether 60 research studies were identified for the full-text analysis. For the final detailed analysis only four latest studies on the research topic were detected. The other full-text studies were then used for the description of the research topic and comparison of the findings in other parts of the manuscript. The study was included if it was written in English, focused on multinutrient

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intervention in the prevention of cognitive decline and early stages of dementia, respectively AD, and was randomized controlled trial (RCT)19 22 or an intervention study.46

FINDINGS FROM THE MOST RECENT STUDIES As other researchers23,35 point out, there are only very few RCTs exploring the issues of multinutrient dietary intervention in the prevention and early stages of dementia. Most of the studies on this topic are observational studies, e.g., [47 50]. Thus, only four clinical studies were identified in the period of 2015 and 2016. Three studies were randomized clinical trials20 22 and one was a study that included two randomly allotted intervention groups.46 Two studies examined the intervention effect of Souvenaid in patients with mild AD20 and in patients with frontotemporal dementia,46 one study22 investigated the impact of MedDi supplemented with antioxidants on healthy older individuals at high cardiovascular risk, and one study21 explored the effect of a combination of different intervention activities on cognitive functioning. A Dutch study by Von Straaten et al.20 examined the value of magnetoencephalohraphy (MEC) with higher spatial resolution than encephalography (EEG) in detecting intervention effects of Fortasyn Connect, which is present in the medical food Souvenaid and should improve synaptic functioning. The intervention period lasted 24 weeks and 55 drug naı¨ve older adults participated in this project. The intervention group consisted of 27 people taking Souvenaid and the control group was comprised of 28 people who were receiving an isocaloric control product. The results were based on comparing MEC spectral measures, functional connectivity, and networks between the intervention and control group. The findings of the study revealed neither any statistically significant intervention effects, nor difference in sensitivity between MEG and EEG peak frequency. The authors suggest that this might have been caused by methodological issues such as small and unbalanced study groups or incompatible data from different centers when applying the latest analysis techniques. The Italian researchers Pardini et al.46 also explored the impact of Souvenaid, in their case on social cognition and behavioral disturbances in patients with the behavioral variant of frontotemporal dementia (bvFTD). Altogether 26 older patients with bvFTD were randomly divided into the intervention group taking Souvenaid and the control group receiving placebo. The intervention lasted for 12 weeks, and after this period, patients switched groups and for another 12 weeks they were receiving the set treatment. Patients were tested after 12 weeks as well as after 24 weeks. The results of the study showed that Souvenaid had a significant impact on the reduction of behavioral symptoms and on the increase of their mind skills. Unfortunately, no effect was observed on their executive functions. Valls-Pedret et al.22 in their study on multinutrient intervention focused on the impact of MedDi supplemented with antioxidant rich foods on cognitive functions among older people in Spain. Altogether 447 healthy older individuals at high cardiovascular risk participated in the study. Participants were randomly divided into two intervention groups; one with the adherence to MedDi supplemented with extravirgin olive oil (1 l/weeks, 127 subjects) and one with the adherence to MedDi supplemented with mixed nuts (30 g/day, 112 subjects); and into one control group (95 subjects) advised to reduce dietary fat. The

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project lasted from 2003 to 2009 and the participants were tested 4.1 years after the intervention. The results were based on neuropsychological test battery. The research revealed that participants with the adherence to MedDi plus olive oil scored better on the RAVLT (P 5 0.049) and Color Trail Test part 2 (P 5 0.04) compared with controls. In addition, there were no between-group differences for the other cognitive tests. Similarly adjusted cognitive composites (mean z scores with 95% Confidence Interval - CIs) for changes above baseline of the memory composite were 0.04 (20.09 to 0.18) for the adherence to MedDi plus olive oil, 0.09 (20.05 to 0.23; P 5 0.04 vs controls) for the adherence to MedDi plus nuts, and 20.17 (20.32 to 20.01) for the control diet. Thus, the findings indicate that adherence to MedDi plus olive oil or mixed nuts has a positive impact on the enhancement of cognitive functions among healthy older individuals. A Swedish-Finnish RCT study conducted by Ngandu et al.21 explored a combination of different intervention activities: diet, exercise, cognitive training, and vascular risk monitoring. They assessed a multidomain approach to prevent cognitive decline among older people at-risk of dementia from the general population. Altogether 1260 older adults aged 60 77 years participated in the study. There were 631 subjects in the intervention group and 629 subjects in the control group. The intervention period lasted 2 years. The primary outcome was measured by comprehensive neuropsychological test battery. Estimated mean change in neuropsychological test battery (NTB) total Z score at 2 years was 0.20 (standard error - SE 0.02, standard deviation SD 0.51) in the intervention group and 0.16 (0.01, 0.51) in the control group. Between-group difference in the change of NTB total score per year was 0.022 (95% CI 0.002 0.042, P 5 0.030). The findings suggest that a multidomain intervention might improve or maintain cognitive functioning among older people at risk of dementia.

DISCUSSION The findings described above show that the studies exploring the impact of the medical food Souvenaid have not brought the desired effect on the delay of cognitive decline among patients with dementia. This was also confirmed in the study by Shah et al.18 who indicated that Souvenaid in the course of 24 weeks had not delayed or slowed the cognitive decline, but it was well tolerated. However, other clinical trials conducted, for instance, by de Waal et al.,17 Olde Rikert et al.,51 or Scheltens et al.,52 imply that Souvenaid improves memory among patients with mild-to-moderate AD. Cummings et al.19 analyzed three RCT with Souvenaid (Souvenir I, Souvenir II, and S-Connect) among patients with mild and mild-to-moderate AD in order to determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm. They found out that that the effect sizes had been 0.21 (95% confidence intervals: 20.06, 0.49) for the primary outcome in Souvenir II (neuropsychological test battery memory z-score) and 0.20 (0.10, 0.34) for the coprimary outcome of Souvenir I (Wechsler memory scale delayed recall) among the patients with mild AD. However, they did not observe any effect on cognition in patients with mild-to-moderate AD (S-Connect). The number required to treat (6 and 21 for Souvenir I and II, respectively) and high number required to harm values suggested a favorable harm benefit ratio for Souvenaid vs control among the patients with mild AD. Thus, the findings indicate that Souvenaid may have positive

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effects especially for the patients for mild AD, i.e., the early stage of this neurodegenerative disease. Furthermore, the results from the study by Pardini et al.46 imply the impact of the administration of Souvenaid on the enhancement of behavior and social cognitive skills in case of bvFTD. The study by Valls-Pedret et al.22 then brings evidence about the positive effects of the adherence to MedDi in the enhancement of cognitive functions. This is in fact consistent with the findings of the second only RCT focused on the impact of MedDi, which was conducted again in Spain by Martinez-Lapiscina et al.16 In their study with 285 healthy older adults at high vascular risk, they found out that after 6.5 years of the adherence to MedDi supplemented extravirgin olive oil and mixed nuts led to better cognitive performance of the intervention group with MedDi 1 extravirgin olive oil especially in the area of fluency and memory tasks. Researchers32,33,53 also emphasize that MedDi is effective in the prevention of cognitive delay if there is a high adherence to this diet. There is general consensus that MedDi may be effective in the delay of cognitive decline but its effect on dementia, respectively on AD, is still uncertain.24,54 However, for instance, Cao et al.26 claim that MedDi and higher consumption of unsaturated fatty acids, antioxidants, and B vitamins lower the risk of dementia while smoking and higher consumption of aluminum raise the risk of dementia. Low levels of vitamin D are then connected with cognitive decline. The effect of fish, vegetables, fruits, and alcohol needs to be researched. Nevertheless, it seems that investigating the whole diet approaches instead of individual nutrients, especially the MedDi pattern might clarify the link between the dietary patterns and cognitive decline and the onset of dementia.24,55 The study by Ngandu et al.21 then suggests that especially the multinutrient MedDi as part of other multidomain intervention activities may have a far more significant effect on the enhancement of cognitive functions among the healthy generation groups at risk of dementia. For example, Coley et al.45 argue that there is very little evidence that nutritional interventions can be beneficial in the delay of cognitive decline in aging. However, they admit that the nutritional interventions may be effective as part of multidomain interventions targeting multiple lifestyle factors. For example, the International Conference on Nutrition and the Brain in Washington in 2013 set the following principles for a health/ lifestyle, which might contribute to the better quality of life. They are as follows:56 • • • • • • • •

to minimize an intake of saturated fats and trans fats; to replace meats and dairy products with vegetables, legumes, fruits, and whole grains; to eat food rich in vitamin E; to include vitamin B12 in a daily diet, at least as a supplement; to choose multiple vitamins rich in iron and copper; attempt to avoid the products that contain aluminum; to include aerobic exercise in ones routine, equivalent to 40 min of brisk walking 3 times per week.

Table 22.2 then summarizes the main benefits and limitations of multinutrient intervention in the prevention and treatment of dementia. Limitations of this study obviously still reflect a lack of RCT in this field and methodological inconsistencies, which may result in the overestimated effects of the discussed

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TABLE 22.2 An Overview of the Main Benefits and Limitations of Multinutrient Intervention in the Prevention and Treatment of Dementia Benefits

Limitations

Less invasive approach

A lack of RCT

None or only very few side effects, well tolerated

A lack of rigorous methodologies

Cost-effectiveness, lower costs of treatment, institutionalization, and care

A low awareness of multinutrient approaches among public

Quite convincing positive results of RCTs on cognitive decline in aging Some possible efficacy of multinutrient approach in the early stages of dementia Source: Authors’ own processing.

findings and have a negative impact on the validity of these reviewed studies.57,58 In addition, more educational studies about the awareness of positive effects of medical foods and MedDi are needed. Researchers call for collaboration and action on the part of policy makers both at the political and social level.59

CONCLUSION One of the top 10 priorities set at the First WHO Ministerial Conference on Global Action against Dementia in March 2015 is the reduction of dementia risk,60 which might be achieved by the multinutritional intervention described in this manuscript. The findings of this study also indicate that multidomain intervention approach to the delay of cognitive decline, including the adherence to multinutrient diet, may also protect against the onset of dementia, respectively AD, as well as other diseases such as vascular diseases and diabetes61 and in this way decrease the economic burden of the pharmacological treatment and care.62,63

Disclosure The authors have no conflicts of interest to declare.

Acknowledgments This paper was supported by the research project Excellence 2017, Faculty of Informatics and Management, University of Hradec Kralove, Czech Republic, and by the long-term development plan FNHK.

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Further Reading Thaipisuttikul P, Galvin JE. Use of medical foods and nutritional approaches in the treatment of Alzheimer’s disease. Clin Pract (Lond). 2012;9(2):199 209.

ROLE OF THE MEDITERRANEAN DIET IN THE BRAIN AND NEURODEGENERATIVE DISEASES