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.

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DIATHESIS & ANTECEDENTS

TRIGGERS

MEDIATORS

SIGNSSYMPTOMS

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)

PhenotypeVSGenotype

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 Oxidative stress

Detoxification

Neuro-Endocrine

GI Function

Structural

Mind － Body

XenobioticsDrugsAlcohol

GI permeability

“dysbiosis”

Airbornepollutants

NO/alteration of detoxification

ImmuneCells

ApoptosisOxidant stressand mitochondrialdamage

ApoE, cytokines

Alzheimer’s disease

Alzheimer’s disease prevalence

0

1

2

3

4

5

6

7

8

9

1930 1950 1970 1990 2010 2030

affectedindividuals(millions)

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 -amyloid

echanisms 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 Treatmentof 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 2, 3, and 4 .

• Familial late-onset AD, the 4 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 4 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 studiesBMJ. 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 b- pleated 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 P.M

GLA 300 mg

Melatonin 3-9 mg at bed time

DHA 300 mg 300 mg

Co-Q10 100 mg 100mg

Vitamin E 400 IU

Vitamin C 500 mg 500 mg

Alpha lipoic acid 200 mg

N-acety-cysteine 400 mg 400 mg

Supplements Regimen for Alzheimer’s Patients

Phosphatidylserine 100 mg 100 mg

Acety-L-carnitine 400 mg 400 mg

Ginkgo biloba 60 mg

Vitamin D 400 IU

Vinpocetine 5 mg 5 mg

Vitamin B-complex supplement

B1 (thiamine) 50 mg

B3 (niacin as niacinamide 50 mg

B6 (pyridoxine) 50 mg

Folic acid 400 mcg 400 mcg

B12 (cobalamin) 500 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 ,Non-

inducible 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

XenobioticsDrugsAlcohol

GI permeability

“dysbiosis”

Airbornepollutants

NO/alteration of detoxification

ImmuneCells

ApoptosisOxidant stressand mitochondrialdamage

ApoE, cytokines

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

13/4 cup                      

             Counts as

1medium-size

Mid-day

                                         

          Counts as

22 cups

                

          Counts as

1medium-size

Evening

                      

     

     

Counts as

21 cup

                                

  

     

Counts as

11/2

                     

    

     

Counts as

11/2 cup

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Holistic Medicine Mind, Body, and Spirit

Thank for your attention !