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ALZHEIMER’S DISEASE
Dr. A. Sreekumar MBBS; DLO; FACNEM; FINEM; FSAAARMM
SOUKHYA INTERNATIONAL COPY RIGHTS RESERVED
Dr.A.Sreekumar,
M.B.B.S,D.L.O;FACNEM,FINEM;FSAAARMM
1

WORLD
ALZHEIMER’S
DAY
SEPTEMBER 21
Dr.A.Sreekumar,
2

ALOIS ALZHEIMER
• 1905 German Psychiatrist – autopsied cognitive
decline patient
• 1910 Kraepelin – defined dementia as Alzheimer’s
• Even after 100 years, today AD is poorly understood
• Progressive & fatal brain disease – first sign is loss of
smell followed by rapidly declining functional status.
• Between diagnosis & death – 7 years
Dr.A.Sreekumar,
3

SIGNIFICANCE TODAY
• 46.8 million globally in 2015 - one new case every 3.2
seconds.
• May double every 20 years reaching 74.7 million in 2030 and
131.5 million in 2050.
• 58% of people with dementia live in low and middle income
countries.
• The total estimated worldwide cost of dementia is US$818
billion in 2015, which represents 1.09% of global GDP.
Dr.A.Sreekumar,
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STAGES
•Early warning signs
•Mild
•Moderate
•Advances
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PRESENTATIONS
• Increasing forgetfulness or mild confusion may be the only
symptoms for some time and may last few years
• But over time, the disease robs you of more of your memory,
especially recent memories. The rate at which symptoms
worsen varies from person to person.
• One may not recognize that anything is wrong, even when
changes are noticeable to your family members, close
friends or co-workers.
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6

COURSE
• Repeat statements and questions over and over, not realizing that
they've asked the question before
• Forget conversations, appointments or events, and not remember
them later
• Routinely misplace possessions, often putting them in illogical locations
• Get lost in familiar places
• Eventually forget the names of family members and everyday objects
• Have trouble finding the right words to identify objects, express
thoughts or take part in conversations
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REASONING & JUDGEMENT
• Alzheimer's disease causes difficulty concentrating and thinking,
especially about abstract concepts like numbers.
• Multitasking is especially difficult, and it may be challenging to
manage finances, balance check books and pay bills on time. These
difficulties may progress to inability to recognize and deal with
numbers.
• Responding effectively to everyday problems, such as food burning
on the stove or unexpected driving situations, becomes increasingly
challenging.
• Advanced – forget bathing & even dressing
Dr.A.Sreekumar,
8

SIGNS & SYMPTOMS
• Depression
• Apathy
• Social withdrawal
• Mood swings
• Distrust in others
• Irritability and
aggressiveness
• Changes in sleeping
habits
• Wandering
• Loss of inhibitions
Dr.A.Sreekumar,
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RISK FACTORS
• Genetics
• Age
• Sex
• Head Injury
• Educational level
• Mental activity
• Drug abuse
• Physical activity
• Vascular factors
• Alcohol
• Physical Illness
• Toxic Metals
• Poor Nutrition
• Iatrogenic
Dr.A.Sreekumar,
10

LIFESTYLE FACTORS
• Lack of exercise
• Obesity
• Smoking or exposure to second hand smoke
• High blood pressure
• High blood cholesterol
• Poorly controlled type 2 diabetes
• Diet lacking in fruits and vegetables
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COMPLICATIONS
• Communicate that he or she is
experiencing pain — for
example, from a dental problem
• Report symptoms of another
illness
• Follow a prescribed treatment
plan
• Notice or describe medication
side effects
• Aspiration of food or liquid into
the lungs.
• Pneumonia and other infections
• Falls
• Fractures
• Bedsores
• Malnutrition or dehydration
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THEORIES
• Cholinergic
• Amyloid plaque
• Tau hypothesis
• Inflammation
• Oxidative Stress theory
• Metal metabolism theory
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CHOLINERGIC THEORY
• Predominant in 80s
• Believes begin with depletion od Ach
• Due to deficiency of enzymes –
• Choline acetyl transferase
• Acetylcholine esterase
• Later understood – low enzymes are not present in early stages, but only
appear in later stages.
• So, medicines increasing these enzymes (Aricept) & Ach enhancing
medications have only limited role.
Dr.A.Sreekumar,
14

AMYLOID PLAQUE
• Beta – amyloid, the main protein plaque found in AD brain.
• Believe that this is the key event in brain cell destruction
• Early strategy of removing plaque – immunization
• This though was successful in mice, but failed in humans
• It was successful in containing amyloid, but the disease progressed
• This also suggest that beta amyloid is the result of disease
•
Dr.A.Sreekumar,
15

TAU THEORY
• A protein that normally helps organize and stabilize
cell’s internal skeleton (microtubules vehicle for
transporting vesicle & enzymes)
• In AD, tau become chemically modified & clump
together
• So, loss of nutrient transport and death of brain cells.
Dr.A.Sreekumar,
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STUDIES
• Dysfunction of the para-vascular pathway may
serve as an early biomarker of Alzheimer disease
(Peng et al.,2016)
• Exercise & Omega 3 have been associated with
improved glymphatic Aβ removal (He et al.,2017.
Ren et al.,2017)
Dr.A.Sreekumar,
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STUDY
Well established that the glymphatic system participates in
the removal of amyloid beta (Aβ), a pathological hallmark of
Alzheimer disease
Tarasoff-Conway et al., 2015; Simon and Iliff, 2016
Iliff and Nedergaard originally demonstrated that the
clearance of radio-labelled Aβ injected into brain
parenchyma was cleared via para-vascular routes.
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INFLAMMATION
• 2004 Scripps Research Institute proposed chronic
inflammation central
• Suggest that amyloid is modified as a result of this
inflammation. This causes them to mis-fold &
accumulate like plaques
• Research still going to unfold the molecular theory
Dr.A.Sreekumar,
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OXIDATIVE STRESS
• Chronic excess of free radicals lead to brain damage
• Source of free radicals
• Physical injury
• Bacteria
• Viruses
• Inflammation
• Heavy metals
• Radiation
Dr.A.Sreekumar,
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DIABETES
• The link between Alzheimer’s disease and diabetes continues to
grow stronger. A new study presented at the Society for Neuroscience
shows that the disease may actually be the late stages of type 2
diabetes.
• People who develop type 2 diabetes often experience a sharp
decline in cognition and almost 70% of them ultimately develop
Alzheimer’s.
• Insulin resistance increases risk for Alzheimer's disease, study finds
Watson GS, Craft S CNS Drugs 2003;17(1):27-45.
Dr.A.Sreekumar,
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DIABETES – STUDY
The link between Alzheimer’s and diabetes continues to grow
stronger with a new paper by Professor Melissa Schilling, a
strategy and innovation expert at the NYU Stern School of
Business. The paper, recently published in The Journal of
Alzheimer’s Disease, found that hyperinsulinemia, caused by
early or undiagnosed diabetes, obesity or prediabetes is also
found in nearly half of all people with Alzheimer’s. Schilling
reviewed hundreds of published articles about the pathway
between insulin and Alzheimer’s, leading her to a new
understanding of the connections between the two disease.
Dr.A.Sreekumar,
22

FOOD
• Although food has classically been perceived as a means to
provide energy and building material to the body, its ability
to prevent and protect against diseases is starting to be
recognized.
• In particular, research over the past 5 years has provided
exciting evidence for the influence of dietary factors on
specific molecular systems and mechanisms that maintain
mental function.
Dr.A.Sreekumar,
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GUT & COGNITION
• In addition to the capacity of the gut to directly stimulate
molecular systems that are associated with synaptic plasticity
and learning, several gut hormones or peptides, such as leptin,
ghrelin, glucagon-like peptide 1(GLP1) and insulin have been
found to influence emotions and cognitive processes.
• Neural circuits that are involved in feeding behaviour show
precise coordination with brain centres that modulate energy
homeostasis and cognitive function.
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MANAGEMENT
Hypo Metabolism as a therapeutic target
in Alzheimer's disease.
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HYPO METABOLISM – TARGET THERAPY
The pathology of Alzheimer's disease (AD) is characterized by cerebral atrophy in
frontal, temporal, and parietal regions, with senile plaques, dystrophic neurites, and
neurofibrillar tangles within defined areas of the brain. Another characteristic of AD
is regional hypometabolism in the brain. This decline in cerebral glucose metabolism
occurs before pathology and symptoms manifest, continues as symptoms progress,
and is more severe than that of normal aging. Ketone bodies are an efficient
alternative fuel for cells that are unable to metabolize glucose or are 'starved' of
glucose. AC-1202 is designed to elevate serum ketone levels safely. We previously
showed that treatment with AC-1202 in patients with mild-to-moderate AD improves
memory and cognition. Treatment outcomes were influenced by apolipoprotein E
genotype status. These data suggest that AC-1202 may be an effective treatment
for cognitive dysfunction by providing an alternative substrate for use by glucose-
compromised neurons.
Dr.A.Sreekumar,
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HEALTHY BRAIN
•Need
• Competent Blood Brain Barrier
• Enough antioxidant protection inside brain
• Some of the antioxidants including Vitamin E,
selenium, CoQ10, glutathione, lipoic acid
therapies showed that life span improvement
and stop advancing death of brain cells.
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METALLOTHIONEIN
• Autopsy studies showed that MT levels decrease in AD
• MT protein have several protective functions –
• Prevention of toxic metals from passing BBB
• Regulation of Copper levels
• Powerful antioxidant action against free radicals
• Protective action depends on Glutathione and Selenium
• Gene expression of MT is Zn dependent
Dr.A.Sreekumar,
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METALLOTHIONEIN
• Cysteine rich protein
• Found in higher levels in limbic area of brain
• Generated in response to various factors
• Weakened MT function result in problems in any
areas of limbic system.
Dr.A.Sreekumar,
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METALLOTHIONEIN – ROLE
• Early brain development
• Powerful antioxidant
• Detox heavy metals – Hg & other toxic metals
• Reduce inflammation after injury
• Improve leaky gut
• Improve immune system
• Balacing Copper/Zinc
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METALLOTHIONEIN – ROLE
• Regulate stomach acid
• Regulate taste sensation
• Protection of enzymes
• Gene regulation
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BLOOD BRAIN BARRIER
• The endothelial cells forming the blood-brain barrier are
highly specialized to allow precise control over the
substances that enter or leave the brain.
• The discovery of the BBB dates back more than 100 years
when, in the 1880s, Paul Ehrlich
• The BBB in adults consists of a complex cellular system of a
highly specialized basal membrane, a large number of
pericytes embedded in the basal membrane and astrocytic
end feet.
Dr.A.Sreekumar,
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BLOOD BRAIN BARRIER
• The brain endothelial cells differ from endothelial cells from
other organs in two important ways.
• Continuous tight junctions are present between brain
endothelial cells. These tight junctions prevent para-
cellular movement of molecules.
• There are no detectable trans-endothelial pathways such
as intracellular vesicles.
• These properties of brain endothelial cells provide a
barrier between the blood and the brain.
Dr.A.Sreekumar,
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BLOOD BRAIN BARRIER
• The continuous tight junctions that join the endothelial cells in the brain
capillaries limit the diffusion of molecules across the BBB.
• The basement (basal) membrane provides structural support for the capillary
and specific proteins present in the basement membrane have been
proposed to be involved in the development of the BBB.
• Astrocytic foot processes release specific factors and are necessary for the
development of the BBB. Astrocytic foot processes contain water channels
(aquaporin-4) that allow water uptake and contribute to brain swelling.
• Transport carriers for glucose and essential amino acids facilitate the
movement of these solutes into the brain. Since brain cells cannot synthesize
these essential amino acids, it is taken up from the blood.
Dr.A.Sreekumar,
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BLOOD BRAIN BARRIER
• Secondary transport systems appear to cause efflux of small
molecules and nonessential amino acids from the brain to the blood.
• Sodium ion transporters on the luminal membrane and Na,K-ATPase
on the anti-luminal membrane account for movement of sodium from
the blood to the brain. The large number of mitochondrias present in
the brain endothelial cells provide energy for the function of this Na,K-
ATPase.
• The "enzymatic blood-brain-barrier": Metabolic processes within the
brain capillary endothelial cells are important to blood-brain function
and control the entry of neurotransmitters into the brain.
Dr.A.Sreekumar,
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AREA WITHOUT BBB
• The structures located at strategic positions in the midline of the ventricular
system lack the BBB are collectively referred to as circumventricular organs.
• In these non-barrier regions, the tight junctions between
endothelial cells are discontinuous thus allowing entry of
molecules. Many of these areas participate in hormonal
control.
• Pituitary gland Median eminence
• Area postrema Preoptic recess
• Paraphysis Pineal gland
• Endothelium of choroid plexus
Dr.A.Sreekumar,
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THEORIES
• Copper & Iron overload increase beta amyloid deposit in
brain
• Metallothionein & Cu/Zn SOD protect against Cu free
radicals
• Deficiency or excess of Cu can be toxic to brain (studies)
• Brain Insulin resistance has been studied as the mechanism
behind neuro degeneration and some call it brain diabetes
Dr.A.Sreekumar,
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NT – NUTRIENT RELATIONSHIP
Neurotransmitter
• Serotonin
• Dopamine
• Nor
Epinephrine
Increased activity
• Methionine, SAMe, 5HTP,
Inositol, Ca,
• Mg, Vitamin B2, B6 & D
• Tyrosine, Phenyl Alanine,
B1, B6, SAMe,
Methionine
• Tyrosine, Phenylalanine,
Copper, B6, Vit C
Decreased activity
• Folic acid, DMAE, Vitamin
B5, Niacinamide, CoA
• Folic acid, B5, C, Choline,
DMAE, Mn, C,
Niacinamide, CoA, Mn,
GABA
• GABA, Folic acid, DMAE,
Mg, CoA, Niacinamide, Zn,
B5, Choline
Dr.A.Sreekumar,
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NT – NUTRIENT RELATIONSHIP
Neurotransmitter
NMDA
GABA
Increased activity
Glutamine,
Glutathione, Glycine,
Se, D Cycloserine,
Sarcosine, Dserine.
P5P, Zinc
Decreased activity
Low glycine, Low
glutathione, High
oxidative stress
Aspartic Acid
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CLUES – CHEMICAL IMBALANCE
• Copper Zinc ratio
• Hormonal imbalance
• Under methylation
• Over methylation
• Pyrolle disorder
• Toxic metal overload
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MT – MECHANISM
• GSH is first line of defense against toxic metals.
• When 10-20% of GSH is oxidized, toxic metals are
transferred from GSH to MT.
• Selenium increases kinetics of the GSH/MT
antioxidant system by more than 50%.
• Most toxic metals depart body in MT form.
Dr.A.Sreekumar,
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MT & HEAVY METALS
• 95% of ingested Hg, Pb, Cd is stopped by MT & GSH
combination at the intestinal mucosa.
• 80% of toxic metals entering portal blood stream
become bound to MT/GSH in liver.
• 95% of remaining toxic metals are sequestered at
B/B barrier by MT & GSH.
• Additional MT & GSH are present in the brain and
provide antioxidant neuroprotection.
Dr.A.Sreekumar,
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LAB TESTING
• Whole blood histamine
• Plasma Zinc
• Plasma Copper
• Urine Pyrroles
• Serum Ceruloplasmin
• Thyroid panel
• Liver enzymes
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WELLNESS CARE
•General
• Detox
• Hormonal balancing
• Biochemical balancing
• Specific biochemical balancing
• Prevention of toxic metals crossing BBB
• Regulation of Cu overload
• Powerful antioxidant therapy
• Metallothionein promotion
Dr.A.Sreekumar,
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MT – MANAGEMENT
• Amyloid plaques are known to result from interaction
of metal free-radicals with natural substances in the
brain.
• Metallothionein proteins provide natural protection
against free-radical metal ions
• Metallothionein protein levels are less than 1/3 of
normal levels in Alzheimer brains.
Dr.A.Sreekumar,
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SUPPLEMENTS
Zinc Picolinate
P-5-P (a form of B6)
Magnesium Gluconate
Magnesium Ascorbate
Pyridoxine Hydrochloride
Glutathione
Selenium
Vitamins C & E
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PROTEIN SUPPLEMENTS
Cysteine*
Serine
Lysine
Alanine
Valine
Glycine
Threonine
Proline
Aspartic Acid
Isoleucine
Asparagine
Glutamic Acid
Methionine
Glutamine
Dr.A.Sreekumar,
47

MCT
• MCT – Medium Chain Triglycerides
• Abundant in coconut oil
• In healthy individuals -
• glucose supplies almost all of the brain's energy.
• However, in certain patient populations (e.g. those with or
developing Alzheimer's disease, type II diabetics) the ability of
the brain to use glucose is impaired.
• Ketones are an alternative energy source for the brain and
might be able to compensate for this impairment
Dr.A.Sreekumar,
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RESEARCH
• One clinical trial in elderly individuals with age-
related cognitive decline reported no cognitive
improvement with an MCT supplement (here).
• However, another small clinical trial in diabetic
patients reported that MCT supplements preserved
cognitive function in conditions of artificial
hypoglycemia (where glucose levels were held low)
• No human studies have examined whether MCTs
can prevent or delay dementia.
Dr.A.Sreekumar,
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RESEARCH
• Two clinical trials reported that MCT supplements
improved cognitive function in mild cognitive
impairment (MCI) and Alzheimer's disease patients who
do not carry the APOE4 genotype but were ineffective
for APOE4 carriers
• Two clinical trials suggest that an MCT supplement
(Axona®) may provide an acute benefit in patients with
MCI and Alzheimer's disease. However, these
improvements were short-lived and disappeared 14
days after the supplement was stopped.
Dr.A.Sreekumar,
50

MCT
MCTs can be found in certain foods, as supplements,
and as medical foods. Coconut oil has the highest
naturally occurring percentage of MCTs, which make
up nearly 60 percent of its total fat content. Palm oil
and butter also contain significant amounts of MCTs.
In most studies, individuals have taken 10-40g of MCTs
per day.
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REFERRENCES
• Cunnane SC, Courchesne-Loyer A, St-Pierre V et al. (2016) Annals of the
New York Academy of Sciences 1367, 12-20.
• Castellano CA, Nugent S, Paquet N et al. (2015) Journal of Alzheimer's
disease : JAD 43, 1343-1353.
• Page KA, Williamson A, Yu N et al. (2009) Diabetes 58, 1237-1244.
• Pan Y, Larson B, Araujo JA et al. (2010) The British journal of nutrition 103,
1746-1754.
• Kashiwaya Y, Bergman C, Lee JH et al. (2013) Neurobiology of aging 34,
1530-1539
• Henderson ST, Vogel JL, Barr LJ et al. (2009) Nutrition & metabolism 6, 31.
Dr.A.Sreekumar,
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REFERRENCES
• Reger MA, Henderson ST, Hale C et al. (2004) Neurobiology of aging 25, 311-
314.
• Yin JX, Maalouf M, Han P et al. (2016) . Neurobiology of aging 39, 25-37.
• Nosaka N, Kasai M, Nakamura M et al. (2002) Biosci Biotechnol Biochem 66,
1713-1718.
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53

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