NWT-03 and Brain Function
Condition: Brain Vascular Function; Cognition
Study type: Interventional

Summary: 
      Age-related chronic diseases including dementia, type II diabetes mellitus (T2DM) and
      cardiovascular disease (CVD) become more prevalent and of increasing societal concern. Common
      denominators of these co-morbidities are insulin-resistance and impaired vascular function.
      Animal and short-term human studies now suggest that NWT-03 - an egg-protein hydrolysate -
      improves insulin-sensitivity and peripheral vascular function, which are risk markers for the
      development of T2DM and CVD. Insulin-resistance is also associated with cognitive decline,
      while impaired brain vascular function is an important event preceding the development of
      impaired cognitive performance. The investigators have already shown in a shorter-term trial
      (12 weeks) beneficial effects of a daily dose of 5.0 g of NWT-03 on cognitive performance.
      However, underlying mechanisms have not yet been addressed, while the long-term effects
      remain unknown. Thus, the investigators now hypothesize that NWT-03 beneficially affects
      cognitive performance and brain vascular function following long-term daily intake.

      The primary objectives of this trial are to evaluate in overweight or obese adults (aged
      60-75) with subjective cognitive decline (SCD) the effects of a 36-weeks NWT-03 intervention
      on (1) cognitive performance using a neurophysiological test battery, and (2) cerebral blood
      flow, as quantified by the current non-invasive gold standard magnetic resonance imaging
      (MRI) perfusion method Arterial Spin Labeling (ASL). Secondary study objectives are to
      examine effects on insulin-sensitivity and peripheral vascular function.

      This intervention study will have a randomized, controlled, parallel design. The total study
      duration will be 36 weeks. Forty-four older adults (aged 60-75 years) with a Body Mass Index
      (BMI) between 25-35 kg/m2 (overweight or obese) and subjective cognitive decline (SCD), as
      assessed with the cognitive failure questionnaire, will participate. These study individuals
      are known to be at increased risk of cognitive impairment, allowing for improvement by the
      intervention. During the study, subjects will receive daily (in the morning) 5.0 g NWT-03 or
      placebo powders for 36 weeks.
    

Detailed description: 
      Due to the aging population, the number of people with cognitive impairment will have doubled
      by the year 2035. Also, the number of individuals with type-2 diabetes mellitus (T2DM) and
      cardiovascular disease (CVD) will have increased substantially. Common denominators of these
      age-related co-morbidities in humans are insulin-resistance and an impaired vascular
      function.

      Newtricious (NWT)-03 is a novel dietary egg-protein hydrolysate that has proven benefits on
      glucose and insulin metabolism, as the investigators have recently shown in overweight or
      obese individuals with T2DM or impaired glucose tolerance. Furthermore, peripheral vascular
      function was improved. The potential explanation of these effects may arise from the finding
      that NWT-03 blocks the enzyme dipeptidyl peptidase (DPP)-IV (7) - a pharmaceutical target for
      the treatment of T2DM and CVD - that beneficially affects insulin metabolism. Compared to the
      wealth of knowledge about the impact of insulin-sensitivity and peripheral vascular function
      on the risk of T2DM and CVD, emerging evidence also indicates that these risk markers affect
      cognitive performance. This is of great interest, since the brain is an insulin sensitive
      organ and insulin-resistance is associated with cognitive decline, while impaired brain
      vascular function is a key pathophysiological event preceding the development of an impaired
      cognitive performance. A study in mice also showed effects of NWT-03 on neuro-inflammation
      and oxidative stress in the brain. In fact, a decreased expression of TNF-α and improved
      expression of enzymes involved in anti-oxidative processes were observed. The investigators
      have also shown in a similar - but shorter-term (12 weeks) - trial beneficial effects of
      NWT-03 on executive function, as the latency of response was reduced (manuscripts in
      preparation). In addition, the hen egg-white hydrolysate (i.e. LumiVida) also improved
      reaction time in middle-aged women. Underlying mechanisms of these hydrolysates on cognitive
      performance were however not addressed. In our review the investigators summarized the impact
      of dietary factors and exercise on brain vascular function in adults and discussed the
      relation between these effects with changes in cognitive performance. It was concluded that
      studies on the longer-term effects of lifestyle factors, including diet and physical
      exercise, can improve brain vascular function, which may contribute to the beneficial effects
      observed on cognitive performance. In addition, longer-term effects remain unknown and only a
      limited number of parameters related to cognitive performance were studied. Therefore, the
      investigators propose to perform a long-term placebo-controlled double blind intervention
      study including functional outcome parameters and study in vivo effects of NWT-03 on brain
      vascular function, which is a potential target to prevent or slow-down cognitive impairments,
      and improve cognitive performance. Focus will be on older adults (aged 60-75 years) with a
      Body Mass Index (BMI) between 25-35 kg/m2 (overweight or obese) and subjective cognitive
      decline (SCD), as assessed with the cognitive failure questionnaire. These individuals are
      known to be at increased risk of cognitive impairment, allowing for improvement by the
      intervention.

      Secondary study endpoints are effects on insulin-sensitivity and peripheral vascular
      function, which are risk markers that may affect cognitive performance. Finally, the
      investigators will focus on other potential mechanisms underlying effects on brain function
      (i.e. ambulatory blood pressure, structural brain status, humoral factors, and the more
      conventional cardiometabolic risk markers) and other perceivable benefits, including general
      well-being (quality of life, sleep characteristics and mood) and physical fitness.

      Effects will be investigated using innovative and emerging non-invasive brain magnetic
      resonance imaging (MRI)-perfusion methods, while focusing on whole brain and
      cognitive-control brain areas plus cognitive performance tests. Furthermore, the
      investigators have reviewed that cerebral blood flow in gray matter is a sensitive and
      straightforward marker of brain vascular function, which correlates with cognitive
      performance. Of note, lower cerebral blood flow is associated with accelerated cognitive
      decline and increased risk of dementia in the general population based on results of the
      Rotterdam prospective cohort study. Cerebral blood flow changes will be quantified on a
      Siemens 3 Tesla Magnetom Prisma Fit scanner at the Scannexus research facilities by the
      non-invasive gold standard approach: the MRI perfusion method pseudo-continuous Arterial Spin
      Labeling.Cognitive performance will be assessed using CANTAB (i.e. Cambridge
      Neuropsychological Test Automated Battery). These validated assessments for state-of-the-art
      cognitive testing focus on the main cognitive domains (i.e. executive function, attention and
      memory). Brain vascular function will be investigated using innovative and emerging
      non-invasive brain magnetic resonance imaging (MRI)-perfusion methods, while focusing on
      whole brain and cognitive-control brain areas plus cognitive performance tests. Furthermore,
      the investigators have reviewed that cerebral blood flow in gray matter is a sensitive and
      straightforward marker of brain vascular function, which correlates with cognitive
      performance. Of note, lower cerebral blood flow is associated with accelerated cognitive
      decline and increased risk of dementia in the general population based on results of the
      Rotterdam prospective cohort study. Cerebral blood flow changes will be quantified on a
      Siemens 3 Tesla Magnetom Prisma Fit scanner at the Scannexus research facilities by the
      non-invasive gold standard approach: the MRI perfusion method pseudo-continuous Arterial Spin
      Labeling.

      Considering the background information given in the previous paragraph, the following
      research questions are formulated:

      Primary research question:

      What are the effects in older adults with a BMI between 25-35 kg/m2 and SCD of a 36-weeks
      NWT-03 intervention on (i) cognitive performance using a neurophysiological test battery, and
      (ii) cerebral blood flow, as quantified by the MRI-perfusion method Arterial Spin Labelling?

      Major null hypotheses, H0:

        1. A 36-weeks NWT-03 intervention does not significantly affect cognitive performance in
           older adults with a BMI between 25-35 kg/m2 and SCD.

        2. A 36-weeks NWT-03 intervention does not significantly affect cerebral blood flow, as
           assessed by Arterial Spin Labelling, in older adults with a BMI between 25-35 kg/m2 and
           SCD.

      Major alternate hypotheses, Ha:

        1. A 36-weeks NWT-03 intervention significantly affects cognitive performance in older
           adults with a BMI between 25-35 kg/m2 and SCD.

        2. A 36-weeks NWT-03 intervention significantly affects cerebral blood flow, as assessed by
           Arterial Spin Labelling, in older adults with a BMI between 25-35 kg/m2 and SCD.

      Secondary research question:

      What are the effects in older adults with SCD of a 36-weeks NWT-03 intervention on insulin
      sensitivity and peripheral vascular function, which are risk markers for T2DM and CVD?

      Exploratory research questions:

      What are the effects in older adults with subjective cognitive decline (SCD) of a 36-weeks
      NWT-03 intervention on;

        -  mechanisms underlying effects on brain function, including structural brain status,
           humoral factors, and the more conventional cardiometabolic risk markers;

        -  perceivable (consumer) benefits, including physical fitness and general well-being.

      A randomized, placebo-controlled trial with a parallel design will be conducted.

      Before screening, subjects will be informed about the procedures and informed consent will be
      obtained. Following screening, study participants that fulfill all inclusion criteria and are
      willing to participate will be asked to participate in this study.

      Subjects will be informed about their screening results, including anthropometric measures
      (weight, length, body mass index), systolic and diastolic blood pressure (SBP and DBP), serum
      total cholesterol and triacylglycerol concentrations, and plasma glucose concentrations. When
      treatment with drugs or lifestyle interventions is indicated according to the Standards of
      the Dutch general practitioners' community (NHG), subjects will be advised to consult their
      general practitioner. Study results obtained during the intervention trial (i.e. brain
      vascular function) will be reported in a descriptive way at a group level, for example:
      "brain vascular function is improved". because no accepted normal ranges exist for these
      measurements.

      On the days before blood sampling, adults are asked not to perform any strenuous physical
      exercise or to consume alcoholic beverages. On the morning of blood sampling - after a
      12-hour overnight fast (from 8.00 PM) - study subjects are only allowed to drink a glass of
      water. Subjects are also asked not to change their habitual diet during the study. Finally,
      subjects are asked to come to the Metabolic Research Unit (MRUM) by public transport or car
      (and not by foot or bike) to standardize research measurements as much as possible

      At baseline and after 18 weeks, anthropometric measurements will be performed, and a fasting
      blood sample will be drawn. At baseline and after 36 weeks, subjects have to attend two times
      the research facilities to perform the follow-up measurements: once for the "Day A"
      measurements and once for the "Day B" measurements. During these tests, study participants
      have to stay at the university and are not allowed to eat. These test days will take place
      with an interval of three days.
    

Intervention name(s): An egg-protein hydrolysate (NWT-03); Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): As described in the experimental arm; As described in the Control arm
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Cerebral Blood Flow; Cognitive Performance