Naturopathic Nutrition Year 2

© CNM: Nutrition 2 ― Ageing, Alzheimer’s, MS & Parkinson’s. RG.1

Ageing, Alzheimer’s,

MS and Parkinson’s Disease

Naturopathic Nutrition Year 2


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Learning Outcomes

In today’s lecture you will learn about:

• Ageing: Main theories

and causes.

• Alzheimer’s disease.

• Multiple sclerosis.

• Parkinson’s disease.


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The Main Causes of Ageing

Ageing:

• The main theories and causes of ageing.

• How the body defends against ageing.

• Hormesis: How a little stress increases

the lifespan or ‘healthspan’.

• The impact of ageing and inflammation

on the brain — and how they play out

in MS, dementia, Alzheimer’s and

Parkinson’s diseases.

hormesis = to ‘excite’. How

mild stress triggers anti-

ageing reactions in our cells


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‘Allostatic load’ or ‘overload theory’:

• Social, psychological, lifestyle and nutritional

factors all interact with our genome to

create either healthy resilience to ageing

or accelerated deterioration with age.

• Exposure to toxins (environment,

household, cosmetics), inadequate

exercise, poor nutrition, high stress,

genetic susceptibility, chronic inflammation

and dysbiosis all play a role at a

physiological and molecular level.(Shiels et al. 2019)

allostasis = remaining

stable by being variable

© CNM: Nutrition 2 ― Ageing, Alzheimer’s, MS & Parkinson’s. RG.

Mitochondrial theory:

• Mitochondria are considered to be

the main source of ROS in a cell.

• Oxidative stress within mitochondria leads to

mtDNA mutations, reduced ATP and energy.

• Mitochondrial dysfunction leads to

apoptosis (programmed cell death).

• Mitochondrial dysfunction is linked to MS,

Alzheimer’s and Parkinson’s diseases

and many chronic inflammatory diseases.5

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(Nissanka & Moraes, 2018)

mtDNA = mitochondrial DNA




Inflammageing:

• Chronic low-grade inflammation increases as we age

(inflammageing) leading to many age-related diseases.

• Pathogens, damaged tissues,

altered gut microbiota, antibiotics,

steroids, and antihistamines all

promote chronic inflammation.

• Inflammageing is the result of pathological

stimulation of the innate immune system.

• Alzheimer’s disease is associated with inflammageing of the brain.(Franceschi et al. 2018;

Giunta et al. 2008)


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Why Do We Live So Long?

Maximum lifespan potential (MLSP):

• Ageing is mostly considered in a negative

way but, in general, humans are exceptionally

good at dealing with the ageing process.

• Humans have a maximum lifespan potential (MLSP)

of over 100 years. This is FOUR times higher

than expected for a mammal of our size!

• Understanding and implementing human

anti-ageing strategies will improve our

‘healthspan’ as well as lifespan. (Bruns et al. 2015)


Hormesis:

• Definition: “A process in which exposure to

a low level of stress or toxicity induces an

adaptive beneficial effect in a cell or organism”.

• Calorie restriction, phytochemicals, exercise,

cognitive stimulation, intermittent cold and

heat mildly stress the body — they can all

extend lifespan and healthspan.

• A healthy body responds to mild stress by increasing

the production of endogenous antioxidants and

cellular quality control mechanisms.8

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Hormesis

(Mattson, 2008)


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Hormesis

Mild

Stress

Increased production of glutathione, catalase,

superoxide dismutase and phase II detoxification

enzymes.


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Hormesis

Oxidative Stress

Zone ofHormesis

Ha

rmH

ea

lth

The surprising health benefit of mild amounts of oxidative stress.


Nrf2:

• Nrf2 is a transcription factor which senses cellular

stress and then responds by upregulating genes

relating to the production of endogenous antioxidants.

• Nrf2 attaches to the ARE within DNA and

increases the expression of glutathione

enzymes, superoxide dismutase, catalase

and phase II detoxification enzymes.

• Long-lived species, such as humans,

have an increased activity of Nrf2.11

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Hormesis

(Mattson, 2008; Bruns et al. 2015)

Nrf2 = nuclear factor erythroid 2-related factor 2

ARE = antioxidant response element.


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Hormesis

(Jung & Kwak, 2010)

ROS

Mild

stressNrf2

ARE

Direct

antioxidant

Indirect

antioxidant

The antioxidant power of phytochemicals: Direct and indirect.

= Blocking effect of antioxidants on ROS


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Calorie restriction and exercise:

• Calorie restriction and exercise

induce stress partly by depleting cellular

energy ATP ADP NADH NAD.

• Low cellular energy activates AMPK,

a pro-longevity protein.

• Low cellular energy also

activates the sirtuins (SIRT 1-7),

a family of anti-ageing proteins.

(Burkewitz et al. 2014)

AMPK = AMP-activated protein kinase

sirtuins = the anti-ageing proteins

called SIRT 1-7

Hormesis


Autophagy and mitophagy:

• AMPK and sirtuins initiate numerous processes

that improve health and prolong life. This

occurs at a tissue, cellular and molecular level.

• During a period of low cellular energy, AMPK

and sirtuins initiate a process called autophagy

(self-eating), where worn-out or damaged

cellular components are digested to improve

the quality of the whole organism.

• Autophagy of mitochondria is known as mitophagy. 14

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Quality Control for Longevity

(Bareja et al. 2019)

autophagy = ‘self-

eating’ or digestion

of worn-out cell

components


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Fusion

Fission

Mitophagy

Mitochondrial

Biogenesis

Mitochondrial quality control or ‘mitochondrial dynamics’.


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Mitochondrial quality control or ‘mitochondrial dynamics’.

• In a healthy cell, mitochondria undergo

mitophagy every few days.

• Depending on the type of tissue, mitochondria

are digested between 9 and 25 days after their

biogenesis to maintain their ability to produce energy.

• Liver mitochondria are turned over more rapidly

than heart, kidney and brain mitochondria.

• Mitophagy is defective in Alzheimer’s and

Parkinson’s disease, resulting in low brain energy.(Lee & Kim, 2014;

Cai & Jeong, 2020)

Mitophagy


Autophagy defends against the 9 key signatures of ageing:

• Genome instability.

• Telomere shortening.

• Epigenetic alterations.

• Loss of protein regulation and disposal — a

hallmark of Alzheimer’s and Parkinson’s diseases.

• Insulin resistance and poor nutrient sensing.

• Cell senescence (biological ageing).

• Stem cell loss.

• Altered intercellular communication.17

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(Bareja et al. 2019)


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Social Connection and Ageing

Social connection and stress have a lifelong impact on health:

• Social connection is most important

for children and the elderly.

• Poor childhood social connection or

trauma predisposes a person to

inflammatory diseases in later life.

• In the elderly, social connection is a

powerful anti-inflammatory — in fact, it is

as strong as smoking cessation or exercise!

• BMI, blood pressure and inflammation can all be reduced by

good social connections — social stress has the opposite effect.(Yang et al., 2016)


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Excess phase I detoxification linked to ageing and cancer:

• Phase I detoxification enzymes transform

xenobiotics, steroid hormones and drugs into

reactive intermediates by the addition of oxygen.

• Hydrocarbons from smoked and cooked foods are common

xenobiotics which induce phase I detoxification enzymes.

• Phase I detoxification enzymes are mainly found in the

liver but are also found in the kidneys, lung, gut and brain.

• Cells detect many xenobiotics via the aryl hydrocarbon receptor

AhR which binds to the DNA xenobiotic response element

(XRE) to drive gene expression of phase I enzymes.(Hodges & Minich, 2015;

Brinkmann et al. 2020)

Detoxification and Ageing


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Excess phase I detoxification linked to ageing and cancer:

• Over-activation of the aryl hydrocarbon

receptor (AhR) leads to accelerated ageing,

cardiovascular disease and cancer.

• Phase I detoxification is important — but not too quickly!

• Green tea, turmeric, quercetin and resveratrol desensitise

the AhR, slow down phase I and protect against cancer.

Garlic and ginger are thought to do the same.

• Neanderthals had 100–1000 times more active

hydrocarbon detoxification which made the

invention of fire and cooked food lethal for them! (Eckers et al. 2016; Caspermeyer, 2016;

Fukuda et al. 2003; Donovan et al. 2018)

aryl hydrocarbon

receptor = cell

environmental

toxin sensor



.

Phase I

detoxification

enzymes

Smoke-

cooked meats;

environmental

hydrocarbons

Aryl

hydrocarbon

receptor

Green tea, turmeric

quercetin and resveratrol

Xenobiotic

response

element

Accelerated ageing and increased risk of

cardiovascular disease and cancer.

CYP1A1

CYP1A2

CYP1B1



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Hormesis supports phase II and III detoxification:

• Through anti-ageing Nrf2 activation, plant compounds

help to induce phase II and III detoxification.

• Phase II conjugates or binds to the reactive

intermediates of phase I detoxification.

• Phase III removes detoxified

metabolites from cells.

• Upregulation of Nrf2 and phase II has

been found to be neuroprotective in

Alzheimer’s and Parkinson’s diseases.(Zhang et al. 2013;

Panieri et al. 2020)



Healthy exercise regimes extend life:

• Exercise mitigates all the hallmarks of ageing.

• Exercise improves brain, cardiovascular, lung,

muscle, body composition and metabolic function.

• Through hormesis and Nrf2, exercise induces

endogenous antioxidant enzymes and

anti-ageing proteins.

• Exercise increases levels of PGC1-alpha, a protein

that enables the synthesis of brand new mitochondria

through mitochondrial biogenesis.23

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Exercise

(Garatachea et al. 2015;

Vargas-Mendoza et al. 2019)


Examining the diet of the world’s longest lived people:

The island of Okinawa, off the coast of Japan, has one of

the highest concentrations of centenarians in the world.

The Okinawan diet:

• High in unrefined carbohydrates.

• Small / moderate amounts of lean meat and fish.

• High intake of vegetables / legumes.

• High in monounsaturated / polyunsaturated fats.

• Low in saturated fats.

• Only eat until 80% full — a philosophy termed ‘hara hachi bu’.

• Eat off small plates. 24

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Diet and Ageing

(Willcox et al. 2014; Buettner and

Skemp, 2016; Willcox et al. 2017)


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Fasting and Ageing

Calorie restriction, intermittent fasting and fasting:

• Activate sirtuins, the anti-ageing proteins.

• Sirtuins improve insulin sensitivity, mitochondrial

activity, cardiovascular health, fat metabolism,

DNA integrity and also lower inflammation.

• Promote autophagy to aid cellular rejuvenation.

• Increase adiponectin, an adipokine associated

with longevity.

• Ketogenic diets may mimic some of the health benefits

of fasting by shifting metabolism toward beta-oxidation

and ketone synthesis. Ketones protect an ageing brain.(Golbidi et al. 2017;

Mujica-Parodi et al. 2020)

adipokine = cytokine

of adipose tissue


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Obesity and Glycation

Obesity and insulin-resistant individuals present with:

• Mitochondrial dysfunction and reduced biogenesis.

• Loss of viable stem cells, hindering

tissue repair and renewal.

• Increased inflammageing.

Advanced glycation end products or AGEs:

• Proteins modified by glycation are able to bind to

AGE receptors (RAGEs) and promote inflammation.

• AGEs are strongly associated with accelerated ageing,

neurodegeneration, diabetes and cancer.(Salvestrini et al. 2019; Sang, 2019)


• Toxins.

• Inadequate exercise.

• Poor nutrition.

• High stress.

• Dysbiosis of microbiome.

• Medication, especially

over-the-counter drugs.

• Antibiotics.

• Alcohol and smoking.

• Coffee, sugars.27

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What to Avoid


• B vitamins.

• Omega-3 fatty acids.

• Magnesium.

• Vitamin D.

• Vitamin K.

• CoQ10.

• Shiitake and reishi mushrooms.

• Extra virgin olive oil.

• Beetroot.

• Wheatgrass and barley grass.28

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Nutrients for Anti-ageing

• Resveratrol.

• Alpha-lipoic acid.

• Green tea.

• Berries.

• Pomegranate.

• Cruciferous vegetables.

• Garlic and onions.

• Turmeric and ginger.

• Nuts and seeds.


Ageing Questions

1. Name THREE ways to activate hormesis in our body.

2. Name THREE poor lifestyle choices which add to

our allostatic load and accelerate ageing.

3. How much longer do humans live compared

to other mammals of our size?

4. What health issues can a good social connection help prevent?

5. Name THREE dietary habits which help many

Okinawan people to live beyond 100 years of age.

6. Name FOUR anti-aging nutrients.

7. What health conditions are AGEs associated with?


Dementia and Alzheimer’s Disease

Dementia:

Dementia describes a syndrome of cognitive

impairment that affects memory recall, cognitive

abilities and behaviour, and significantly interferes

with a person’s ability to perform daily activities.

• Alzheimer’s disease (AD) is the most common form of

dementia and accounts for 60–80% of all dementia cases.

• 50 million people worldwide are presently suffering from dementia.

• Nearly 10 million people are diagnosed with dementia each year,

with over 60% residing in the world’s poorest countries.


Dementia risk factors:

• Chronic / acute stress.

• Proton pump inhibitor medication.

• Poor diet (junk food, sugars).

• Vitamin and nutritional deficiencies,

e.g., vitamin A, D, C, B6, B9, B12 etc.

• Poor lifestyle (e.g., smoking and

drinking alcohol)

• Vaccinations.

• Hypertension and diabetes.

• Mental inactivity.31

• Obesity.

• Physical inactivity.

• Social isolation.

• Environmental toxins.

• ApoE4 polymorphism.

• Mid-life depression.

Dementia and Alzheimer’s Disease

(Mielich et al. 2020)

APoE

(apolipoprotein E)


The four main types of dementia:

• Frontotemporal dementia: Behavioural, language and movement

difficulties, driven by atrophy of frontal and temporal lobes.

• Vascular dementia: Impaired blood flow to the brain leading to

cognitive decline. Often associated with cardiovascular disease.

• Lewy body dementia: Lewy bodies are abnormal clumps of protein

that cause alterations in thoughts, perceptions and movement.

Lewy bodies are also found in Parkinson’s disease patients.

• Alzheimer’s disease: Amyloid beta and tau are two proteins

which are correlated with Alzheimer’s disease pathology. Patients

suffer progressive loss of memory, language and reasoning.32

Dementia


• Infection, inflammation and oxidative

stress drive amyloid production.

• Amyloid beta is now thought to

be the brain’s protective response

to a threat rather than the cause

of Alzheimer’s disease.

33

Alzheimer’s Disease

Build up of misfolded amyloid beta and tau proteins:

• Amyloid plaques and misfolded tau proteins are characteristic

of AD pathology. Note: They are symptoms and not the cause!



(Bredesen, 2017;

Zukotynski et al. 2018)

Brain HQ: (Online headquarters for brain training).

• Dr Dale Bredesen, a world leader in Alzheimer’s research,

recommends Brain HQ, an online brain training app that

assesses and helps to improve cognitive function. brainhq.com

Diagnosis:

Brain scans:

• Combined CT scan (computerised tomography)

and MRI for excluding other brain disorders and

monitoring brain atrophy as AD progresses.

• Combined PET scan (positron emission tomography) and CT scan

help to identify dementia type and style of management required.


Dr Bredesen’s three categories of Alzheimer’s:

• Inflammation or ‘hot’: Associated with increased

innate immune system activation, inflammation,

pro-inflammatory microglia (M1) and reduced

sirtuin (SIRT1) activity compared to NF kappa B.

• Atrophic or ‘cold’: Loss of trophic support from neurotrophins

such as brain-derived neurotrophic factor (BDNF).

• Cortical or ‘toxic’: Dr Bredesen considers this subtype

to be associated with environmental toxins, leading

to chronic inflammation and general brain atrophy.

35


(Bredesen, 2017)

microglia = resident immune cells of the brain


Microglia — the resident immune cells of the brain:

• In addition to an M1 (pro-inflammatory) type,

microglia can be polarised to an M2

(anti-inflammatory) type. Promoting a shift

from M1 to M2 microglia has been found to be

a supportive strategy in Alzheimer’s disease.

• Nrf2 is the transcription factor which

supports a shift from M1 to M2.

• The inflammatory transcription factor NF Kappa B

promotes the neuroinflammatory M1 phenotype.36

(Minter et al. 2016;

Rojo et al. 2014)

Microglial

activation

to an M1

phenotype

Microglia


Microglia

M1 microglia;

pro-inflammatory,

drives neurodegeneration.

M2 microglia;

anti-inflammatory,

neuroprotective.

NF kappa B Nrf2

Amyloid

plaque


Pathogens cause cell damage which is communicated to

TLRs; its impact may be mitigated by social connection.

• Dysbiosis of gut microbiota leads to pro-inflammatory communication

to TLRs on brain microglia via the microbiota-gut-brain axis.

• TLRs on brain microglia are sensitive to our own damaged tissue,

leading to a spiral of inflammation and neuronal loss.

• Oxytocin, produced during enriched social

interactions, can act through the Vagus nerve

to suppress microglia-related inflammation.

• Oral dysbiosis: P. gingivalis (from periodontitis)

is associated with a significantly ↑ Alzheimer’s risk.

38(Zhang et al. 2017; Lin et al. 2019;

Matsushita et al. 2021)

Microglia

TLR = toll-like receptor

Hence gut protocols for dysbiosis (e.g., 5R) and oral hygiene /probiotics might be applicable.


Neurogenesis occurs in the hippocampus:

• The hippocampus is the seahorse-shaped

structure in our brain involved in memory

storage, mood and cognitive functions.

• In Alzheimer’s, cholinergic hippocampal neurons

are lost and there is also a reduced ability to

grow new neurons through neurogenesis.

• Every day there are 700 new neurons created in the

hippocampus but they will not survive if inflammation is high.

• Depression increases the risk of Alzheimer’s in later life.39(Berger et al. 2020)

Growing New Neurons


Neurotrophins are our brain nourishers:

• BDNF (brain-derived neurotrophic factor) is a neuroprotective

protein essential for the survival of cholinergic neurons.

• In Alzheimer’s disease BDNF levels

are significantly decreased.

• BDNF supports cognitive ability, memory,

neurogenesis and synapse function.

• Healthy gut microbiota support BDNF.

• Yoga has been found to triple BDNF

levels in participants.40

(Ng et al. 2019; Heyck and

Ibarra, 2019; Cahn et al. 2017)

Neurotrophins

BDNF gene variants can ↓ support

for neuronal and synaptic growth and

protection. Consider SNP testing.


• Mediterranean diet.

• Pomegranate, raspberry,

strawberry, walnut, blackberry,

pecan and cranberry.

• Omega-3 fatty acids.

• Vitamin B12.

• Lactobacillus and bifidobacterium.

• Rutin and hesperidin.

• Curcumin (turmeric).

• Calorie restriction.

Diet and lifestyle to support BDNF:

• Exercise, yoga, dance.

• Oxygen, fresh air, nature.

• Environmental enrichment.

• Social enrichment.

• Music, singing, laughing.

• Reduced stress.

• Cultural excursions.

• Polyphenols — resveratrol,

catechins / epicatechins, e.g.,

green tea, blueberries, cocoa.41

(Griffiths, 2019)

Neurotrophins


Alzheimer’s drugs prescribed in medicine:

• Donepezil is widely used to raise levels of acetylcholine by

inhibiting acetylcholinesterase. Side effects are nausea and

incontinence as increased acetylcholine can disrupt peristalsis.

The drug is ineffective at delaying the decline seen in AD.

• Drugs have been developed to remove

amyloid beta but failed to show any benefit.

• Dr Bredesen states: “Patients who had their

amyloid removed by antibody drugs did much

worse when they had that removed, so you

want to remove the cause, the inducers, first”.42

Alzheimer’s Drugsacetylcholine = neurotransmitter that supports memory recall


Diet, lifestyle and BDNF support acetylcholine:

• Acetylcholine, essential for mood, memory

and learning, is made from mitochondrial

acetyl-CoA and dietary choline.

• Healthy diet, lifestyle and BDNF support

acetylcholine though stimulation of the Vagus

nerve, which then releases acetylcholine.

• Acetylcholine is a brain anti-inflammatory

and supports mitochondrial health.

• Therefore, the brain needs an enriched diet, lifestyle, environment

and good people to maintain its integrity and sanity! 43

(Ferreira-Vieira et al. 2016;

Marosi & Mattson, 2014)

Natural Acetylcholine

© CNM: Nutrition 2 ― Ageing, Alzheimer’s, MS & Parkinson’s. RG.44(Exley & Clarkson, 2020; Jones,

2018; Igbokwe et al. 2020)

Aluminium

Aluminium is a neurotoxin implicated in Alzheimer’s disease:

• Aluminium concentrations are significantly raised

in the brains of patients with Alzheimer’s disease.

• Aluminium easily complexes with cellular components,

becoming a burden to neurons, and depleting them of vital ATP.

• Aluminium absorption rates:

– 0.1% from food. 0.3% from water. 100% from vaccine adjuvants.

• Silica-rich water chelate aluminium due to high silica content.

Herbal chelators include cilantro and chlorella.

• Heavy metals (e.g., aluminium, lead, mercury)

contribute to AD — consider chelation therapy.


Obesity, diabetes and insulin resistance linked to Alzheimer’s:

• The strong association between insulin

resistance and Alzheimer’s has led to it

being described as ‘Type 3 diabetes’.

• Obese individuals have increased peripheral

inflammation and neuroinflammation.

• Obesity over-activates the sympathetic

nervous system, suppressing

parasympathetic acetylcholine activity.

• Obesity, therefore, stresses and

inflames the entire body and brain.45

(Esler et al. 2006; Won & Kim,

2016; Kandimalla et al. 2017)

Type 3 Diabetes


Type 3 Diabetes

Sympathetic tone

Vagus nerve activity

BDNF

Acetylcholine

Neuroinflammation

increased AD risk

Parasympathetic tone

Vagus nerve activity

BDNF

Acetylcholine

Oxytocin

Decreased

neuroinflammation;

decreased AD risk

Obesity vs healthy diet and lifestyle and Alzheimer’s risk:


Dr David Perlmutter advises:

• Whole unprocessed foods.

• Low GI foods such as green leafy vegetables, kale,

broccoli, cauliflower, beans, blueberries and apples.

• Healthy fats from olive oil, avocado, nuts and seeds.

• Fatty fish such as salmon, herring, sardines and mackerel.

• Choose free range, pasture-fed,

organic animal produce.

• Drink plenty of water — the brain is 80%

water and can shrink if dehydrated.47(Perlmutter, 2019)

Diet and Brain Health

Dr Perlmutter: Neurologist

and author. An expert on

the subject of brain health

and preventing Alzheimer’s

disease.


The MIND diet:

• The MIND diet is a hybrid of the Mediterranean and

DASH (Dietary Approaches to Stop Hypertension)

diets. Designed to help protect against Alzheimer’s disease,

and improve the health of patients with Alzheimer’s disease.

• The MIND diet has 15 dietary components, including

10 ‘brain-healthy food groups’ — green leafy vegetables,

other vegetables, nuts, berries, beans, whole grains, fish,

poultry and olive oil … and excluding five unhealthy

groups that comprise red meats, butter and margarine,

cheese, pastries and sweets and fried or fast food.48(Morris et al. 2015)

Diet and Alzheimer’s


Dr Dale Bredesen advises a mild ketogenic diet — Ketoflex 12 / 3.

• ‘12’ means leaving 12 hours between

the last meal of the day and the first

meal the day after.

• ‘3’ means leaving 3 hours between the

last meal of the day and bedtime.

• The 12 / 3 action will put the body into

a mild state of ketosis which is healing

for the brain and mitochondria.

• Simple carbohydrate intake will rapidly halt ketosis.49

(Bredesen, 2017)



Coconut oil will support Alzheimer’s by boosting ketones.

• Alzheimer’s patients present with compromised brain glucose

metabolism although ketone metabolism remains intact.

• Consumption of 20 g / day of organic coconut oil raises blood

ketone levels and correlates with improved cognitive performance.

• Coconut oil is rich in MCTs (medium chain

triglycerides) which are an easily absorbable

• form of saturated fatty acids.

• Strict ketogenic diets are not recommended

for Alzheimer’s patients due to potential

gastrointestinal disturbances and loss of appetite.50(Chatterjee et al. 2020)



Goal: Approach: Rationale:

Optimise diet Fresh whole foods — low GI

Eat to 80% full and not too late

Reduce inflammation,

improve insulin sensitivity

Exercise, reduce stress Exercise 1 hour per day, consider

yoga

Reduce inflammation and

promote neurogenesis

Brain stimulation, oxygen

and adequate sleep

Mental challenges and restful sleep Maintain cognitive ability and

sleep allowing for brain repair

Test for raised C-reactive

protein (CRP)

If high, follow above goals —

particularly omega-3 fatty acids and

curcumin from turmeric

Reduce inflammation:

Inflammageing is a major

health issue in AD

Test B5, B6, B12 and

folate

Pantethine, P5P, hydroxocobalamin

or methycobalamin and

methylfolate

Support methylation,

mitochondria and

neurotransmitter function

GI health Repair gut and use probiotics Gut-brain issues in AD

Metabolic enhancement for neurodegeneration (MEND):

51(Bredesen, 2017)

The MEND Protocol 1



Optimise fasting glucose

and insulin

Diet, exercise and stress

reduction

AD is recognised as Type 3

diabetes

Optimise vitamin D status

Blood: 50-100 nmol / L

Sunlight, fish and vitamin D3

supplement

Reduce inflammation: Vitamin

D often low in AD and ageing

Provide synaptic

components

Supplement citicoline and DHA Promote synapse formation

and support mitochondria

Optimise antioxidants Fruit and vegetables, berries,

ascorbate, lipoic acid, vitamin E

Protect against oxidative and

nitrosative stress

Support mitochondria CoQ10, ascorbate, B vitamins,

lipoic acid, DHA, citicoline

Neurons are totally dependent

on mitochondria for energy

Check for heavy metal

toxicity

Hair mineral analysis Accelerate amyloid misfolding

MCTs Coconut oil Support brain energy


52(Bredesen, 2017)

The MEND Protocol 2


David ― retired office manager:

• Diagnosed with AD a year after losing his wife to cancer.

• Stopped taking AD medication as he found the side

effects of urinary and faecal incontinence intolerable.

• Tests revealed poor blood sugar regulation, BMI in

the obese range, cortisol dysregulation, chronic

inflammation, low vitamin D and gut dysbiosis.

• Followed MEND protocol, Perlmutter diet and

Bredesen Ketoflex 12 / 3 with 20 g / day coconut oil.

• After three months, David saw improvements in memory recall.

After a year, he was able to engage with friends and family.53(Bredesen, 2017;

Perlmutter, 2019)

Case Study: Alzheimer’s


Supplement and dosage per day: Benefit:

Vitamin C (500 mg), alpha lipoic acid

(300 mg) and taurine (1000 mg)

Glucose metabolism support and general

antioxidants

Lactobacillus acidophilus and

salivarius (1 and 4 billion)

Reduces gut permeability and dysbiosis

CoQ10 (600 mg), vitamin B complex

and vitamin E (1000 iu)

Mitochondrial support

Citicoline (250 mg) Synapse and mitochondrial support and CNS

anti-inflammatory.

Curcumin (500 mg), vitamin D (2000

iu) and omega-3 fatty acids (750 mg)

Anti-inflammatory

Resveratrol (100 mg) Protects against misfolded amyloid and tau

Recommended supplements:

Case Study: Alzheimer’s


AD and Dementia Questions

1. Name THREE diet and lifestyle interventions to support BDNF (brain-derived neurotrophic factor).

2. What category of Alzheimer’s does Dr Bredesen ascribe to patients presenting with low BDNF?

3. The MEND protocol suggests supporting mitochondria — what would be your approach and why?

4. What percentage of aluminium is absorbed from food and vaccine adjuvants and why is there such a vast difference?

5. Name good food sources of healthy fats for the Alzheimer’s diet.

6. Which neurotransmitter is supported by an enriched diet, lifestyle, environment and good people?


MS is an autoimmune disease:

• The myelin sheath is a fat and protein

compound which wraps around a

nerve to support nerve impulses.

• The myelin sheath is produced by

cells called oligodendrocytes.

• In MS, autoreactive and inflammatory

immune cells infiltrate the blood-brain

barrier and attack the myelin sheath.

• If sustained, this attack can lead to the loss

of oligodendrocytes and neurodegeneration.10

56

Multiple Sclerosis


Types of MS:

• 85% of patients present with the relapsing

remitting form of MS where the disease

alternates between relapse / myelin loss and

periods of remission. The average age of

diagnosis for relapsing-remitting MS is 30.

• 10–15% of patients present with the primary

progressive form of MS where there is a

continuous and progressive loss of neurological

function with no remission. The average age

of diagnosis for progressive MS is 45. 57

Multiple Sclerosis


Symptoms:

• Visual impairment ― optic neuritis.

• Nerve tingling and numbness.

• Intestinal and urinary problems.

• Fatigue and weakness.

• Poor co-ordination and balance.

• Speech difficulties.

• Learning and memory issues.

• Difficulty walking.

• Emotional difficulties.

• Muscle spasm or tremors.

• Pain.58

Multiple Sclerosis


Prognosis:

• If the symptoms of MS occur only once,

this is known as ‘clinically isolated

syndrome’ (CIS). If a further relapse

occurs then the condition is viewed

as relapsing-remitting MS (RRMS).

• RRMS often deteriorates to secondary

progressive MS (SPMS) after 10–30 years.

• MS is 2.5 times more prevalent in

women, but men progress from RRMS

to SPMS more rapidly than women.59

Multiple Sclerosis


MS considered to be a T-cell mediated disease:

• Shift in T-cell subpopulations away from anti-inflammatory T-

regulatory cells (T-regs), towards autoreactive Th17 T cells.

60

(Hayes & Ntambi, 2020; Shaw et

al. 2017; Sadeghian et al. 2016)

Multiple Sclerosis

• Proposed risk factors for MS include:

– Vitamin D deficiency, raised BMI.

– Infections such as Epstein-Barr virus.

– Childhood trauma / stress.

– Homocysteine, mitochondrial dysfunction.

– Cigarette smoke exposure.

– Certain autoimmune diseases.

– Environmental toxins, e.g. dioxins, air pollution.


Vitamin D deficiency associated with MS:

• MS is more prevalent in countries further away from the equator.

• Vitamin D helps shift adaptive immune system expression away

from autoreactive T-cells and toward anti-inflammatory T-regs.

• Doubling vitamin D level decreases MS relapse risk by 27%.

• MS patients with low vitamin D were found to have

more brain lesions and increased numbers of relapses.

• Sufficient vitamin D during pregnancy and at

birth protects child from MS in later years.

• Serum vitamin D levels of 75–100 nmol / L have been proposed to

protect against MS development and / or MS relapse.61

Hayes and Ntambi, 2020;

Sintzel et al. 2018)

Vitamin D


Vitamin K deficiency found in MS patients:

• Key aim of MS therapy is to promote the

regeneration of oligodendrocytes and

remyelination in the central nervous system.

• Gas 6 (growth arrest specific 6) is a vitamin

K-dependent anti-inflammatory protein which

protects oligodendrocytes and promotes remyelination.

• MS patients are frequently vitamin K deficient, with blood

levels around one-third of those expected.

• Deficiency thought to be due to poor microbial synthesis in

the gut, low absorption or low dietary intake.62

(Goudarzi et al. 2016;

Lasemi et al. 2018)

Vitamin K


Vitamin B12 also found to be deficient in MS patients:

• Studies show B12 supplementation improves neuron

growth and survival and regenerates the myelin sheath.

• B12 deficiency leads to many health symptoms

that are shared with MS thereby making it

difficult to differentiate between them.

• The phospholipids contained within the

myelin sheath are methylated, and so

require B12 to support methylation.

• Many MS patients present with high homocysteine and low B12.63

(Nemazannikova et al. 2018)

Vitamin B12


Obesity and a high BMI are risk factors for MS:

• Obese RRMS patients have

a higher level of disability.

• Obesity during childhood is a risk factor for MS.

• Obesity makes the blood-brain barrier more

permeable leading to CNS inflammation.

• The adipokine leptin, raised during obesity,

is associated with CNS inflammation.

• Leptin increases levels of Th17 autoreactive T-cells. 64

(Stampanoni et al. 2019;

Yamamoto et al. 2019;

Guerrero-García et al. 2016)

Obesity and BMI


Inflammation and obesity in MS:

• Obesity leads to an upregulation of M1

microglia overwhelming the protective M2.

• M1 microglia are proinflammatory and

drive oligodendrocyte loss.

• M2 microglia are anti-inflammatory,

support oligodendrocytes and remyelination.

• Obesity-driven BBB permeability leads to

infiltration of peripheral macrophages from

general circulation driving further inflammation.65

(Pegoretti et al. 2020; Tang & Le,

2016; Guerrero-García et al. 2016)

Inflammation and Obesity


A traumatic childhood increases MS risk:

• Childhood adversity is linked to MS onset.

• Childhood neglect or abuse leads to

thymic involution or atrophy.

• Thymic involution amplifies the production

of autoreactive T-cells and predisposes a

person to MS.

• Research suggests that early life stress has a

negative impact on oligodendrocytes, which

then becomes problematic in early adulthood.66

(Shaw et al. 2017; Tanegashima et al. 1999;

Coder et al. 2015; Artemiadis et al. 2011)

Childhood Adversity


Autonomic nervous system (ANS) effects on T-cells:

• The sympathetic and parasympathetic arms of the

ANS regulate inflammation by interacting with T-cells.

• The parasympathetic arm operates

primarily via the Vagus nerve.

• Stimulating the Vagus nerve (see next slide)

decreases proinflammatory microglia,

autoreactive T-cells and increases

myelination and anti-inflammatory T-regs.

• Chronic stress can undermine ANS connection

to T-cells and so drive up inflammation.67

(Di Bari et al. 2016; Hamlin

et al. 2019; Leal et al. 2018)

Stress and MS


Vagal nerve stimulation ― anti-inflammatory effects on T-cells:

68(Hamlin et al. 2019)

Stress and MS

Vagal nerve stimulation

Acetylcholine

receptors

T-regs

Proinflammatory

Microglia

Autoreactive

Th17 T cells


Supplements which support MS patients (per day):

• Vitamin D (2000 iu).

• Vitamin K (90 mcg).

• Hesperidin (500 mg).

• Quercetin (500 mg).

• Sulforaphane (250 mg).

• Alpha lipoic acid (300 mg).

• Citicoline (250 mg).

• Omega-3 fatty acids (750 mg).

• Vitamin B12 (1000 mcg) and methyl folate (500 mcg).

69

Supplements for MS

(Goudarzi et al. 2016; Yoo et al. 2019; Solanki et al. 2015; Hajialyani et al. 2019; Li et al. 2013;

Li et al. 2018; Skripuletz et al. 2015; AlAmmar et al. 2019; Gomez-Pinedo et al. 2020; Li et al. 2020)


(Swank MS Foundation, 2015;

Jelinek, 2106; Senanayake et al. 2015)

MS Diet — The Swank Diet

The Swank diet was devised by Dr Roy Swank in 1949:

• Dr Roy Swank observed 70 years ago that his MS patients

thrived on a low saturated fat diet —— under 15 g / day.

• We now know that many MS patients have difficulty

metabolising saturated fat in mitochondria — and

the poorly metabolised fat disrupts the myelin sheath.

• Fruit and vegetables.

• No red meat permissible in the first year; pork also excluded.

• White meat poultry and white fish — under 50 g / day.

• Dr Swank’s work has now been expanded by Professor

George Jelinek, who also suffers from MS.


Dr Terry Wahls is in MS remission after following a paleo diet:

• Green leafy vegetables.

• Sulphur-rich vegetables, such as cabbage, onions and asparagus.

• Colourful fruits and vegetables due to their phytonutrient content,

such as beetroot, oranges, berries and carrots.

• Omega-3 fatty acids. Sources:

Salmon, herring, and sardines.

• Grass-fed meats and organ meats.

• Seaweed.

• Dr Wahls’ diet is less strict on saturated fat intake. However grass-

fed meats are lower in saturated fat than intensively farmed animals.71

(Wahls, Chenard & Snetselaar,

2019)

MS Diet — The Wahls Diet


MS Questions

1. Name THREE vitamins considered to be supportive for MS.

2. Name THREE lifestyle interventions to stimulate

the Vagus nerve and reduce inflammation.

3. How much saturated fat does the Swank diet

suggest consuming per day?

4. How does obesity drive up brain inflammation in MS?

5. On average, how deficient in vitamin K are MS

patients compared to normal?

6. What are the suggested optimum blood levels of

vitamin D to protect against MS and MS relapse?


Parkinson’s Disease (PD)

What is Parkinson’s disease?

• Parkinson’s disease (PD): The second most common

neurogenerative disorder after Alzheimer’s disease.

• In the disease there is a gradual loss of

dopamine-producing neurons in a part of the

brain called the substantia nigra.

• Neurons of the substantia nigra normally supply

or enervate a part of the brain called the striatum.

• Loss of dopamine supply to the striatum leads

to the characteristic tremor and movement

disorders seen in the disease.


What are the symptoms of Parkinson’s disease?

• Characteristic tremor — often called ‘pill rolling’,

which looks as if a patient is rolling a pill

between their index finger and thumb.

• Muscle rigidity or dystonia — stiff or weak

muscles and difficulty maintaining posture.

• Shuffling gait (dragging feet).

• Constipation and loss of sense of smell — may

occur many years before Parkinson’s disease diagnosis.

• Bradykinesia or slowness of movement. Affects

handwriting (micrographia), facial expression and speech.74

Parkinson’s Disease


Causes and risk factors for Parkinson’s disease:

• Age, hereditary, sex.

• Mitochondrial dysfunction,

inflammation and oxidative stress.

• Traumatic brain injury.

• Pesticides and herbicides.

• Manganese, iron, mercury, lead

and aluminium toxicity.

• Poor calcium metabolism.

• Stress and depression.

• Recreational drugs, especially amphetamines.75


(Griffiths, 2019)



Tests for Parkinson’s disease:

• A diagnosis of Parkinson’s disease and

diagnosis is based on symptoms, medical

history and physical examination.

• DaT scan — helps to differentiate between

Parkinson’s disease and essential tremor.

Essential tremor is a condition that can

easily be mistaken for Parkinson’s.

• PET scan — identifies irregularities in the parts

of the brain affected by Parkinson’s disease.(Bajaj et al. 2013; Peng et al. 2013;

NHS, 2019)


Alpha synuclein is the signature misfolded protein

in Parkinson’s disease:

• Similar to Alzheimer’s disease, Parkinson’s disease

has a misfolded protein associated with its pathology.

• Misfolded alpha synuclein is thought to become

misfolded due to excess oxidative stress.

• Once misfolded, alpha synuclein can form

protein aggregates called Lewy bodies.

• Lewy body accumulates in and around dopamine

neurons leading to further oxidative stress,

mitochondrial dysfunction and finally dopamine neuron loss.77


(Griffiths, 2019)


• Manganese has been linked to PD. Welders in particular

have high occupational exposure. Caution should be exercised

with high supplemental intake, as this may increase PD risk.

• Post-mortem studies reveal high levels of iron deposits in the

brains of PD patients. Iron and manganese supplementation

have been found to double the risk of PD in some people.

• Higher blood levels of mercury are seen in PD patients.

Mercury exposure can lead to an 8-fold increase in risk of PD.

• Aluminium, cadmium, cobalt, copper, iron, and

manganese all accelerate the misfolding of

alpha synuclein into toxic aggregates. 78

Metals

(Powers et al. 2003; Harischandra et al. 2019;

Wang et al. 2016; Bjorklund et al. 2018)


• Rotenone is a natural pesticide used until recently in

organic farming. Rotenone causes mitochondrial

dysfunction and increases the risk of PD.

• Paraquat is a herbicide which increases PD risk by

dramatically increasing oxidative stress in the host.

• Maneb is a manganese containing fungicide also

associated with increased PD risk.

• Rotenone, paraquat and maneb have all been

found to block mitochondrial transport to dopaminergic

neuron synapses in a cell-based study.79

Agrochemicals

(Choi et al. 2011; Tanner et al. 2011; Stykel et al. 2018)


L-dopa is the drug / protein derivative most

commonly prescribed to PD patients:

• Dopamine cannot cross the blood-brain

barrier (BBB). L-dopa can cross into the

CNS where it converts into dopamine.

• Serotonin-producing neurons also convert L-dopa to

dopamine by using amino acid decarboxylase — the same

enzyme is used to make both dopamine and serotonin.

• Serotonin neurons can be damaged by L-dopa,

resulting in some negative psychological effects.

80

Parkinson’s Drugs

(Stansley & Yamamoto, 2015;

Choi et al. 2017)


L-dopa (cont.):

• L-dopa drugs also include another drug called a

decarboxylase inhibitor — this drug inhibits L-dopa

dopamine conversion outside the brain, resulting

in a higher level of dopamine reaching the brain.

• Vitamin B6 should be taken away from L-dopa medication

as it may interfere with decarboxylase inhibitors.

• L-dopa is derived from the amino acid tyrosine. Some

patients benefit from eating protein-containing meals

after their medication, as it may facilitate easier

L-dopa passage into the brain.81

(Stansley & Yamamoto, 2015;

Sato et al. 2017; Freitas et al. 2017)

Parkinson’s Drugs


Dopamine degrades in the cytosol of a neuron to toxic DOPAL:

• Dopamine is degraded by the enzyme monoamine oxidase B

(MAO-B) in the cytosol to a toxic intermediate called DOPAL.

• Worryingly, L-dopa medication can increase DOPAL levels x 18.

• DOPAL interacts with the protein alpha synuclein leading to its

misfolding and the formation of toxic Lewy bodies. Misfolded

alpha synuclein further accelerates toxic DOPAL formation.

• Slowing down MAO-B and speeding up DOPAL

detoxification to its metabolite DOPAC, is

considered to be protective for dopaminergic neurons.82

Catecholaldehyde Theory of PD

(Griffiths, 2019)


Catecholaldehyde Theory of PD

(Griffiths, 2019)

Dopamine

DOPAL

DOPAC

MAO-B

Aldehyde

Dehydrogenase

Slowing down MAO-B and speeding up DOPAL

detoxification is considered to be a protective

strategy for dopaminergic neurons.

Rasagiline, blackcurrant,

blueberry, blackberry

1000 x toxicity

of dopamine

CoQ10, taurine, alpha

lipoic acid, pantetheine


70% of dopaminergic neurons may already be lost by time of

diagnosis so awareness of early warning signs is important.

• Many PD patients lose their sense of smell several

years before diagnosis, or before motor signs first appear.

• It is common for PD patients to have suffered

from constipation for up to 10 years before diagnosis.

• The Braak hypothesis of PD theorises that misfolded alpha

synuclein travels from an inflamed gut to the brain over

a period of 10 years, leading to PD in some people.

• Obviously, not everyone suffering from constipation

and loss of smell will be diagnosed with PD — but

these issues should still be acted upon early in everyone. 84

Early Warning Signs (Prodrome)

(Griffiths, 2019)


Dr David Perlmutter advises:

• Whole unprocessed foods.

• Low GI foods such as green leafy

vegetables, kale, broccoli, cauliflower,

beans, blueberries and apples.

• Healthy fats from olive oil, avocado, nuts and seeds.

• Fatty fish such as salmon, herring, sardines and mackerel.

• Choose free-range, pasture-fed, organic animal produce.

• Drink plenty of water — the brain is

80% water. It can shrink if dehydrated.85(Perlmutter, 2019)




Optimise diet Fresh whole foods ― low GI

Eat to 80% full and not too late

Reduce inflammation, improve

insulin sensitivity

Exercise, reduce stress Exercise 1 hour per day, consider

yoga

Reduce inflammation and

promote neurogenesis

Brain stimulation, oxygen and

adequate sleep

Mental challenges, and restful

sleep

Maintain cognitive ability and

sleep allowing for brain repair

Test for raised C reactive

protein

If high, follow above goals ―

particularly omega-3 fatty acids

and curcumin from turmeric

Reduce inflammation —

inflammageing is a major health

issue in PD

Test B5, B6, B12 and folate Pantethine, P5P,

hydroxocobalamin or

methycobalamin and methylfolate

Support methylation,

mitochondria and

neurotransmitter function

GI health Repair and use probiotics Gut-brain issues in PD


86(Bredesen, 2017)

The MEND Protocol 1



Optimise fasting glucose and

insulin

Diet, exercise and stress reduction AD is recognised as Type 3

diabetes

Optimise vitamin D status

Blood: 50–100 nmol / L

Sunlight, fish and vitamin D3

supplement

Reduce inflammation — vitamin

often low in PD and ageing

Provide synaptic components Supplement citicoline and DHA Promote synapse formation

and support mitochondria

Optimise antioxidants Fruit and vegetables, berries,

ascorbate, lipoic acid, vitamin E

Protect against oxidative and

nitrosative stress

Support mitochondria CoQ10, ascorbate, B vitamins,

lipoic acid, DHA, citicoline

Neurons are totally dependent

on mitochondria for energy

Check for heavy metal toxicity Hair mineral analysis Accelerate protein misfolding

MCTs Coconut oil Support brain energy


87(Bredesen, 2017)

The MEND Protocol 2


• Hyperbaric oxygen (breathing pure oxygen in a pressurised room)

— can lessen psychiatric symptoms associated with PD.

• Avoid EMFs from mobile phones and microwaves. EMFs have

been found to disrupt cell membrane calcium channels leading to

oxidative / nitrosative stress in the CNS.

• Chelation of aluminium with Volvic, Fiji water and other

chelators such as chlorella and coriander. Aluminium

has been shown to displace iron from its stores leading

to increased oxidative stress and protein misfolding.

• Alpha lipoic acid can chelate damaging

iron deposits from ageing brains.88

Other Considerations

(Pall, 2016; Xu et al. 2018; Inan-Eroglu &

Ayaz, 2018; Jones, 2018; Tai et al. 2020)


John — retired oil tanker engineer:

• Exposed to petrochemicals all working life. Developed Parkinson’s

after falling off a ladder at home and suffering a head injury.

• His neurologist prescribed L-dopa and rasagaline.

• Tests revealed poor blood sugar regulation, gut dysbiosis,

increased gut permeability, petrochemical exposure,

low vitamin D, high homocysteine, MTHFR polymorphism

(genetic difficulty in making active folate) and mitochondrial

dysfunction (e.g., Great Plains organic acid test).

• Followed MEND protocol, Perlmutter diet and Bredesen

Ketoflex 12 / 3 with 20 g / day coconut oil.89

Case Study: Parkinson’s

(Bredesen, 2017; Perlmutter,

2019; Griffiths, 2019)


Supplement and dosage per day: Benefit:

Vitamin C (500 mg), alpha lipoic acid (300

mg) and taurine (1000 mg)

Dopamine and glucose metabolism,

petrochemical detox

Lactobacillus acidophilus and salivarius (1

and 4 billion)

Reduces gut permeability and dysbiosis

CoQ10 (600 mg), vitamin B complex and

vitamin E (1000 iu)

Mitochondrial support

Citicoline (250 mg) Synapse and mitochondrial support and CNS

anti-inflammatory.

Curcumin (500 mg), vitamin D (2000 iu) and

omega-3 fatty acids (750 mg)

Anti-inflammatory

Methyl folate (500 mcg) Homocysteine reduction

Recommended supplements:

Case Study: Parkinson’s


Herbs that can help repair the blood brain barrier:

91

Herbs for Brain Health

• Gotu kola and guggul — also neuroprotective (reversing neuronal

damage), anti-oxidants, shown to inhibit acetylcholinesterase.

• Rosemary — diterpenes shown to inhibit neuronal cell death.

• Gingko biloba — circulatory stimulant, tissue perfusion enhancing.

• Ashwagandha: Substantial research supports its use in Alzheimer’s.

Specifically indicated for Parkinson’s disease:

• Mucuna pruriens (kapikachu or velvet bean): Contains L-dopa

which crosses the blood-brain barrier and converts into

dopamine. Caution: Possible additive effects with pharmaceutical

dopaminergics, although may reduce need for high doses.


Parkinson’s Questions

1. Name THREE metals associated with an increased risk of PD.

2. What are TWO early warning signs that PD patients might have several years before diagnosis?

3. Which berries are MAO-B inhibitors and what toxic compound do they protect against?

4. Up to what length of time can constipation often precede a diagnosis of PD?

5. Name an agrochemical associated with PD.

6. What supplements might you choose to support mitochondria of a PD patient?


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