The Integrative Management of
Neurodegenerative Disorders
– Nutritional Perspective
神經內科
張嘉祐 醫師
Neurodegenerative diseases
• Neurodegenerative Diseases
( Alzheimer's Disease, Parkinson's
Disease, amyotrophic lateral
sclerosis (ALS), prion diseases,
frontotemporal dementia (FTD), and
Huntington's Disease. )
• Age-related disorders
• Cancer, cerebrovascular disease, and
heart disease account 75% of all death
of age 65 and older.
• Neurodegenerative pathologies such as
Alzheimer’s disease will increase and
become a significant cause of mortality.
• Senile dementia increase 24 % between
2000 to 2010 and 26 % between 2010 to
2020
• It costs about $ 60 billion a year to care
for AD patients. If we could delay the
onset by just 5 years, we could cut that
cost in half.
It is not aging to which many
neurological signs should be
attributed, but rather to the
neurodegenerative syndromes
that accompany aging.
慢性病
生活習慣病
日野原重明
飲食
遺傳
老化
生活型態
生活型態
壓力
心理
SIGNS
SYMPTOMS
MEDIATORS
TRIGGERS
DIATHESIS & ANTECEDENTS
Patient Centered Assessment
Diathesis and Antecedents
• Every aspect of the patient’s life that
may have predisposed him or her
toward an illness is gathered together
under the concept of diathesis.
• Personal and individual (biochemical
individuality, genetic uniqueness)
Genotype VS Phenotype
Basic points about genes
• Your genes are unique and not identical to
anyone else’s even if you are an identical
twins.
• All the genetic messages you need to remark
yourself are present in every cell of your body.
• At any one time some genes are being
expressed and others are not.
• Genetic messages may be partially expressed.
• You can modify the expression of many genes
through diet, nutrients, exercise, life style
and environment.
Triggers and Mediators
• Triggers may be located either inside
(endogenous) or outside(exogenous) the body.
• Triggers include exposure to microbes (viruses,
bacteria, parasites, etc) and exposure to specific
food or food components like lectins or antigens.
• Mediators are always inside the body .
• Hormones, neurotrasmitters, reactive oxygen
species, cytokines, kinins, eicosanoids, and ions
are important mediators
PATIENT WORKUP
Nutritional Status
Immune/Inflammation
GI Function
Oxidative stress
Detoxification
Structural
Neuro-Endocrine
Mind－Body
Apoptosis
Xenobiotics
Drugs
Oxidant stress
and mitochondrial Alcohol
damage
ApoE, cytokines
GI permeability
Immune
Cells
“dysbiosis”
NO/alteration of
detoxification
Airborne
pollutants
Alzheimer’s disease
Alzheimer’s disease prevalence
9
8
7
6
affected
individuals
(millions)
5
4
3
2
1
0
1930 1950 1970 1990 2010 2030
Alzheimer’s disease -pathology
• The neuropathological hallmarks of
neurofibrillary tangles and senile plaques
were described by a German psychiatrist,
Alois Alzheimer, in 1907
• Senile (neuritic) plaques result from the
accumulation of several proteins and an
inflammatory reaction around deposits of
b-amyloid
Mechanisms of Neurodegenerative Disorders
– Protein Aggregates
Commonalities between genetics of
cardiovascular disease and
neurodegenerative disorders
Current Opinion in Lipidology 2004, 15:121–127
• The intensive search conducted in the past
year gave rise to many publications, more
than half of which were related to genes
common to cardiovascular and
neurodegenerative disorders.
• The majority of the genes studied are
involved in cholesterol metabolism,
hypertension, lipid oxidation and detoxication
or inflammatory processes.
Atorvastatin for the Treatment
of Mild to Moderate Alzheimer Disease
Preliminary Results
Arch Neurol.
2005;62:753-757
• Epidemiological studies suggest that prior
statin use in treating risk of coronary
artery disease may reduce the risk of AD
later in life.
• Atorvastatin reduced circulating
cholesterol levels and produced a positive
signal on each of the clinical outcome
measures compared with placebo.
• Apolipoprotein E (APOE), the susceptibility gene
locus for late-onset (55 and older) AD affecting the
risk and age of onset distribution in the population
• APOE has three common alleles, designated e2, e3,
and e4 .
• Familial late-onset AD, the e4 allele frequency was
found to be 0.50, compared to 0.16 for age-matched
controls.
• Saunders et al then looked at a very large series of
176 autopsy-confirmed sporadic patients with AD
who had the clinical syndrome and pathological
confirmation, but no known family history . The e4
allele frequency in this sporadic series was 0.40, highly
significantly different from controls.
ApoE and Abeta 1-42 interactions: effects of
isoform and conformation on structure and
function.
J Mol Neurosci. 2004;23(3):235-46.
.
The hypothesis is that apoE has two general
functions in relation to A beta :
• First, apoE interacts with oligomeric A beta via
an apoE receptor-mediated process to inhibit
neurotoxicity and neuroinflammation (apoE3 >
apoE4) a process possibly related to binding and
clearance of apoE3:oligomer complexes.
• Second, apoE facilitates the deposition of A beta
as amyloid (apoE4 > apoE3).
1) Inflammatory molecules and mechanisms
are uniquely present or significant elevated
in the AD brain
2) Inflammation may be a necessary
component of AD pathogenesis
3) Inflammation may be sufficient to cause AD
neurodegeneration.
4) Retrospective and direct trials suggest a
therapeutic benefit of conventional
antiinflammatory medications in slowing the
progress or even delaying the onset of AD
Effect of non-steroidal anti-inflammatory drugs on
risk of Alzheimer's disease: systematic review and
meta-analysis of observational studies
BMJ. 2003 Jul 19;327(7407):128
• The pooled relative risk of Alzheimer's disease among users of
NSAIDs was 0.72 (95% confidence interval 0.56 to 0.94).
• The risk was 0.95 (0.70 to 1.29) among short term users (< 1
month)
• 0.83 (0.65 to 1.06) among intermediate term (mostly < 24
months)
• 0.27 (0.13 to 0.58) among long term (mostly > 24 months) users .
• The pooled relative risk in the eight studies of aspirin users was
0.87 (0.70 to 1.07).
• NSAIDs offer some protection against the development of
Alzheimer's disease. The appropriate dosage and duration of
drug use and the ratios of risk to benefit are still unclear.
The influence of systemic inflammation on
inflammation in the brain: implications for
chronic neurodegenerative disease.
Perry VH.
Brain Behav Immun. 2004 Sep;18(5):407-13
•Systemic inflammation may impact on local
inflammation in the diseased brain leading to
exaggerated synthesis of inflammatory cytokines and
other mediators in the brain, which may in turn influence
behaviour.
•Systemic infections, or indeed any systemic challenge
that promotes a systemic inflammatory response, may
contribute to the outcome or progression of chronic
neurodegenerative disease.
The incidence of Alzheimer’s disease is
highest in carriers of the apolipoprotein
(APO) E-ε4 allele who harbour HSV-1
DNA in the CNS, so it is possible that
these agents are co-factors for the disease.
Lancet Neurology 2003: 2: 425–28
A recent prospective study (S Seshadri and
colleagues N Engl J Med; 2002 346: 476–83)
showed hyperhomocysteinaemia to be a strong,
independent risk factor for dementia and AD. The
researchers found a graded increase in risk of
both outcomes with rising plasma concentration
of homocysteine after multivariate control for
putative risk factors for AD.
A placebo-controlled, double-blind randomized
trial of an extract of Ginkgo biloba for dementia
Le Bars, P JAMA October 22, 1997
137 patients, 52 weeks, Egb 120mg/d
 27 % treated group improved on
standardized cognitive testing
 Egb actions: homeostasis of inflammation,
membrane protection, neurotransmission
modulation

The use of melatonin in Alzheimer's disease
Neuro Endocrinol Lett. 2002 ;23 Suppl 1:20-3
• Melatonin improved sleep and suppressed
sundowning agitation, an effect seen
regardless of the concomitant medication
employed to treat cognitive or behavioral
signs of AD.
• Melatonin treatment seems to constitute
a selection therapy to ameliorate sundowning
and to slow evolution of cognitive impairment in
AD patients.
• Metatonin has the capacity to interchelate into bpleated sheet structures and break them up.
• Melatonin is also an antioxidants.
Curcumin (薑黃) inhibits formation of amyloid
beta oligomers and fibrils, binds plaques, and
reduces amyloid in vivo
J Biol Chem. 2005 280(7):5892-901
• The phenolic yellow curry pigment curcumin has
potent anti-inflammatory and antioxidant
activities
• Curcumin was a better A beta 40 aggregation
inhibitor than ibuprofen and naproxen
• Curcumin directly binds small beta-amyloid
species to block aggregation and fibril formation
in vitro and in vivo.
Prevention of Alzheimer’s disease: Omega-3 fatty acid
and phenolic anti-oxidant interventions
Neurobiology of Aging 26S (2005) S133–S136
• Because of its availability and low cost, coupled with
preclinical data showing its potential for intervention at
multiple sites inAD pathogenesis, curcumin is now
in clinical trials in mild to moderate AD patients under
an FDA approved IND by theUCLA Alzheimer Center
• Epidemiology shows risk reduction of 60% associated
with modest increases in DHA intake or plasma levels.
DHA works well in slowing AD pathogenesis in mice
with a human AD gene and is safe enough to include in
infant formula. It should be a strong candidate for use
in primary prevention.
Supplements Regimen for
Alzheimer’s Patients
Supplement
A.M
GLA
300 mg
P.M
3-9 mg at bed time
Melatonin
DHA
300 mg
300 mg
Co-Q10
Vitamin E
Vitamin C
100 mg
400 IU
500 mg
100mg
Alpha lipoic acid
200 mg
N-acety-cysteine
400 mg
500 mg
400 mg
Supplements Regimen for Alzheimer’s Patients
Phosphatidylserine
100 mg
Acety-L-carnitine
400 mg
Ginkgo biloba
60 mg
Vitamin D
400 IU
Vinpocetine
5 mg
Vitamin B-complex supplement
B1 (thiamine)
50 mg
B3 (niacin as niacinamide 50 mg
B6 (pyridoxine)
50 mg
Folic acid
400 mcg
B12 (cobalamin)
500 mcg
100 mg
400 mg
5 mg
400 mcg
500 mcg
A Broad Spectrum of Potential
Etiologic Factors
• Role of Aging
• Heritability and Genetic
Susceptibilities
• Environmental Contributors,
Especially Toxins
Genetically determined differences in Xenobiotic
metabolism as a risk factor in Parkinson’s disease
Fundam appl Toxicol, 1996 (30)

Patients with inherited CYP2D6 ,Noninducible genetic polymorphism (10%
poor metabolizers) , cytochrome P450
enzyme deficiency had 2.4 X increased
risk for Parkinson’s disease
Xenobiotic metabolism in Parkinson’s
disease
Neurology, July, 1989


Severe deficiency of sulfate
conjugation in 70 % of PD subjects
PD may be unusually susceptible to
exogenous or even endogenous toxins
長期暴露農藥中
患巴金森氏症風險增加
記者江志雄╱羅東報導
巴金森氏症是老人常見腦神經退化疾病之一，
國內一項針對一百二十五名老年巴金森氏症患
者進行之研究發現，長期大量暴露在農藥中，
可能與罹患巴金森氏症有關，且暴露時間越長，
罹病風險越高。
過去香港也有研究指出，有長期農藥暴露史者，
罹病風險將提高三點六倍，德國也曾有類似報
告。
自由時報九十四年七月二十二日
Apoptosis
Xenobiotics
Drugs
Oxidant stress
and mitochondrial Alcohol
damage
ApoE, cytokines
GI permeability
Immune
Cells
“dysbiosis”
NO/alteration of
detoxification
Airborne
pollutants
Complex Problems,
Simple Solutions
Food is the best medicine
• There is no substitute for a healthy, well-balanced
diet. Supplements can help enhance the health
benefits of food, but they cannot do the Job.
• Many of the important phytochemicals are in the
pigments of plants.
• Fresh whole fruits and vegetables are your best
option.
• There is no magic bullet. Different phytochemicals
work together to achieve their effects.
• Limit fat consumption to around 30 percent of
your daily calories. raw, unhydrogenated oils,
such as canola oil, olive oil, flaxseed oil, and
peanut oil are the healthiest.
Morning
Counts as
Counts as
1
1
3/4 cup
medium-size
Mid-day
Counts as
Counts as
2
1
2 cups
medium-size
Evening
Counts as
Counts as
Counts as
2
1
1
1 cup
1/2
1/2 cup
飲食
遺傳
生活型態
生活型態
壓力
心理
Holistic Medicine
Mind, Body, and Spirit
Thank for your attention !