functional approaches to neurodegenerative disorders

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A Functional Medicine Approach to Neurology

2012

David Perlmutter, MD, FACN ABIHM

DrPerlmutter.com

Telephone: (239) 649-7400e-mail: [email protected]

copyright © 2012, David Perlmutter, MD

Saturday, April 14, 12

mailto:[email protected]





Lancet 358; August 11,2001: 461- 467




February 23, 2004




• Inflammation

• Oxidative stress




Risk of Alzheimer’s disease and duration of NSAID use

Stewart, W.F., et al., Neurology, March, 1997

• 1,686 patients taking NSAIDs, aspirin, or

acetaminophen for 2 or more years• RR NSAIDs 0.40

• RR aspirin 0.74

• RR acetaminophen 1.35




Cagnin, A., et al., Lancet 358; August 11, 2001: 461- 467

Alzheimer’s patient – 75 y/o male

MRI Activated microglia PET




Nonsteroidal Anti-inflammatory Drugs andthe Risk of Parkinson’s Disease

Chen, H., et al., Archives of Neurology 60: 1059-1064; August, 2003

• N= 140,000 14-18 years

• 45% reduction in incidence of PD in regular users of NSAIDs or aspirin




Nonsteroidal anti-inflammatory drugs may protect

against Parkinson’s disease

Wahner, A.D., et al., Neurology 69 ;1836-42: November 6, 2007

•

Comparison of 293 PD patients and 296 controlsevaluated over 5 year period

• Risk of PD was reduced by 48 % in users of NSAIDs 2 pills per week for 2 years




Increased Density of Glial Cells ExpressingCytokines in the Substantia Nigra of PD Patients

0

24

6

8

1012

14

16

IL-1B TNF-alpha

ControlParkinson's

Hirsch, E.C., et al., Ann Neurol 44(Suppl 1): S115-S120, 1998Saturday, April 14, 12


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?




β-amyloid




inflammatory cytokines




Visualizing amyloid burden using Pittsburgh Compound B

From: Imaging Technology for Neurodegenerative DiseasesChester Mathis PhD, et al., Arch Neurol 62; February, 2005: 196-200




Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, et al. (2010)

Recent studies have shown that while the adaptive immunesystem has limited access to the brain, the CNS can still mount a

robust response to invading pathogens via antimicrobial peptides

and the innate immune system.




antimicrobial peptides (AMPs)

AMPs, also called “host defense peptides” function in the brain’s

innate immune system. They are potent, broad-spectrum antibiotics

that target Gram-negative and Gram-positive bacteria,mycobacteria, enveloped viruses, fungi, protozoans and in some

cases, transformed or cancerous host cells. AMPs are also potent

immunomodulators that mediate cytokine release.




Organism

MIC (ɰg/ml)

Aβ42

Candida albicans 0.78

Escherichia coli 1.56

Staphlyococcusepidermidis

3.13

Streptococcus pneumonia

6.25

Soscia, S.J., et al

Antimicrobial activity of Aβ42





From: Imaging Technology for Neurodegenerative Diseases

Chester Mathis PhD, et al., Arch Neurol 62; February, 2005: 196-200





AD brain homogenates have increased

antimicrobial activity against C. albicans .

Text

Brain homogenates inoculated with log-phase C. albicans .





A large body of data supports a central role for neuroinflammation in AD neuropathology A

number of studies have proposed Ab as the source of AD-associated inflammation. However, a

re-evaluation of the role of Ab in inflammation may now be warranted in view of these data

suggesting that the peptide functions as an AMP in tissues. Inflammatory response in the

immunologically privileged CNS is mediated by the innate immune system. Rather than Ab actingas a sole independent initiator of neuroinflammation, our data raise the possibility that the peptide

may be part of a response mounted by the innate immune system.

If the normal function of Ab is to function as an AMP, then an

absence of the peptide may result in increased vulnerability to

infection.




Semagacestat is an oral agent designed to reduce the body's

production of amyloid beta plaques, which scientists believeplay an important role in causing Alzheimer's disease.

Patients treated with semagacestat worsened to a statisticallysignificantly greater degree than those treated with placebo.




antimicrobial peptides (AMPs)

cathelicidin

(CAMP)




Vol.19, July, 2005; 1067-1077




In this study, we show that 1,25-dihydroxyvitamin D3 andthree of its analogs induced expression of the humancathelicidin antimicrobial peptide (CAMP) gene.

Our findings reveal a novel activity of 1,25-dihydroxyvitaminD3 in regulation of primate innate immunity.




toll-like receptor

phagosome

vitamin D receptor

cathelicidin

microglia

CYP27B1

mRNA VDR

we’re introuble now !!




toll-like receptor

microglia




200

350

500

650

800

20 40 60 80

c a t h e l i c i d

i n ( n g / m l )

1,25 (OH)2 D (pg/ml)

J Immunol . April 1, 2009: 182(7) 4289-95




Vitamin D and the Brain

• membrane-bound antioxidant

• enhances neurotrophins

• increases hippocampal density (rodent)• supresses expression if inflammatory cytokines





• antimicrobial





A large body of data supports a central role for neuroinflammation in AD neuropathology A

number of studies have proposed Ab as the source of AD-associated inflammation. However, a

re-evaluation of the role of Ab in inflammation may now be warranted in view of these data

suggesting that the peptide functions as an AMP in tissues. Inflammatory response in the

immunologically privileged CNS is mediated by the innate immune system. Rather than Ab actingas a sole independent initiator of neuroinflammation, our data raise the possibility that the peptide

may be part of a response mounted by the innate immune system.

If the normal function of Ab is to function as an AMP, then an

absence of the peptide may result in increased vulnerability to

infection.




Microglia monitor the CNS environment with TLR patternrecognition receptors. TLR recognize pathogen-associated

molecular patterns from bacteria, fungi, parasites, viruses andcontribute to the innate immune response. Microglia express awide range of neurotoxic factors such as cytokines ⁄ chemokines, excitatory aminoacids, reactive oxygen species (ROS) and proteases.




?

Alzheimer’s disease




1 November 2008 Volume 3 (11) e3637

Methods: Cox proportional hazard models were used

to study the risk of developing AD according to thepresence or not of anti-HSV IgG and IgM antibodies,

assessed in the sera of 512 elderly initially free ofdementia followed for 14 years.


http://www.plosone.org/






0

5

10

15

20

Anti-HSV IgM positive (%)

non-demented Alzheimer’s







Cumulative Alzheimer’s disease rate according to anti-HSV IgM status.






Anti-HSV IgM status 2.55Female gender 1.48High educational level 0.87 APOE-ɛ4 allele 2.00

Hazard ratio of developing Alzheimer’s diseaseaccording to anti-HSV IgM status





“ Reactivation of HSV seropositivity is highly correlated with incident AD. HSVchronic infection may therefore be contributive to the progressive braindamage characteristic of AD.

As AD pathology begins many years before the dementia stage, the recurrentreactivation of HSV might act as a potent stimulus to the brain microglia,increasing the level of cytokines and initiating a positive feedback cycle thatgives rise to an increasing accumulation of pathological changes.”






• During acute HSV1 infection, same brainregions involved as in AD

• Long-term survivors of acute HSV1 brain infectionexhibit severe memory loss




• HSV1 infects 90% of adults - a necessary

characteristic in light of the high prevalence of AD

• HSV1 can remain latent throughout life. Canreactivate in the peripheral nervous system after earlylife infection




• HSV1 DNA by PCR is present in high proportion of

elderly, including AD patients. Found in frontal and temporalcortex, not occipital.

• HSV1 antibodies by ELISA found in CSF of elderly with or without AD indicating ongoing replication. Not found in

younger patients




• HSV1 present in 90% of adults, but only 20-40%

afflicted with cold sores

• So, what is the host factor ?




• APOE-ɛ4 is neither necessary nor sufficient for thedisease, i.e., it must act in conjunction with another factor

• Very few HSV1 infected controls carry the APOE-ɛ4 allele

• “ Intriguingly and consistently, we also found that APOE-ɛ4is a risk for cold sores.”

APOE-ɛ4




Our demonstration of this intrathecal immune response in AD andelderly normals subjects not only confirms that HSV1 is present in

human brain but it also reveals that the virus has replicated there,causing an acute, perhaps recurrent, infection.

Younger people were found to lack this HSV1-specific intrathecalimmune response. We used in situ PCR to confirm that the brains of AD patients and age-matched controls contain HSV1 DNA and thevirus is present in neurons.




APOE-ɛ4 associated with greater risk of HSV1virus spread to the brain and viral latency(rodent)

Both acute and chronic HSV1 infection lead toinflammation and oxidative neuronal damage

The virus competed better against apoE ε4- than

against apoE ε3-enriched lipoprotein particles for binding to the cell receptor and intracellular internalisation.




β-amyloid




β-secretase

ɣ-secretase

amyloid-β proteinprecursor




“It is concluded that there is strong evidence thatHSV1 virus is indeed a major factor in

Alzheimer’s disease and therefore there is astrong case for appropriate treatment, andpossibly for prevention in the future.”




Co-localization of HSV1 DNA and amyloid plaques. PCR detectsHSV1 DNA in specimens of brain tissue from Alzheimer’s patient. Inthe same tissue specimens, amyloid plaque were visualized usingthioflavin S staining.

HSV1 DNA

amyloid plaque




These results demonstrate that HSV1 is presentin almost all amyloid plaques of both AD sufferers andaged normals, and suggest that the virus might be acause of plaque formation. In AD, 72% of viral DNA was plaque-associated; thus itslocalization within amyloid plaques reflects a specificassociation, not a background, random distribution.These results support the deduction that HSV1 is a major

cause of plaque formation.




HSV1 is responsible for herpes simplexencephalitis, a severe but rare brain disorder whichafflicts the brain regions most affected in

Alzheimer’s disease.

This similarity in brain region involved, together withthe very high prevalence of HSV1 infection and theability of the virus to remain latent lifelong in the

body, suggest an HSV1 involvement in AD.




Our present data suggest that this virus is a major

cause of amyloid plaques and hence probably asignificant aetiological factor in Alzheimer’sdisease. They point to the usage of antiviral agentsto treat the disease and possibly of vaccination toprevent it.




0

7.5

15

22.5

30

< 400 IU 400-600 IU > 600 IU

Dementia % Alzheimer’s %

Buell, J.S., et al., Neurology ® 2010;74:18–26

Dietary 25(OH) D intake - daily




?





0

20

40

60

80

non-Alzheimer’s Alzheimer’s %

P C R

( + ) C h l a m y d i a p n e u m o n i a e




Culture of the organism from brain tissue homogenate from one ADpatient demonstrated that the organisms were viable andmetabolically active in those samples. Immunohistochemicalanalyses showed that astrocytes, microglia, and neurons all servedas host cells for C. pneumoniae in the AD brain, and that infectedcells were found in close proximity to both neuritic senile plaques andneurofibrillary tangles.




Evidence of successful culture of Chlamydia pneumoniae from anAD brain-tissue. Staining using a monoclonal antibodyspecifically targetting the C. pneumoniae major outer membraneprotein.




monoclonal antibodystaining of Chlamydia

pneumoniae

astrocytes

microglia

neurons




Multiple Sclerosis




?

multiple sclerosis




Lancet Neurol 2005; 4: 195–202

• The findings of many epidemiological

studies and a discordance of MS in

monozygotic twins suggest that the disorderis acquired.

• The most likely cause is infectious

because more than 90% of patients with

MS have high concentrations of IgG,manifest as oligoclonal bands, in the brain

and CSF.

• Most chronic inflammatory CNS disordersare infectious.




In virtually all infections of the CNS in whicholigoclonal bands represent intrathecal antibody

synthesis, the antigenic specificity of theimmune response is directed against theinfectious pathogen.




C pneumoniae adsorption in non-MS patients




C pneumoniae adsorption in MS patients




Our results demonstrate that the development of an intrathecalimmune response to C pneumoniae antigens is a common

occurrence in the population of patients with MS that we haveexamined. Epidemiologic studies have shown the presence of antibody titers in serum to C pneumoniae in over 50% of individualsover 40 years of age. However, the elevated levels in the CSF of patients with MS compared with control subjects with other neurological diseases strongly suggests a compartmentalization of

the elevated antibody response within the CNS. This thereforeargues for a persistent infection with C pneumoniae in the CNS of patients with MS.





Antibody in brain and CSFThe most important evidence to support infection as the cause of MS is that the brain and

CSF of more than 90% of patients with the disorder have high concentrationsof IgG,manifest as oligoclonal bands Few other CNS diseases are characterised by highconcentrations of IgG and oligoclonal bands . All those diseases that have high IgGconcentrations are inflammatory and most are infectious. Furthermore, when the specificityof the high concentrations of IgG and oligoclonal bands in those diseases was studied, IgGwas found to be antibody directed against thedisease cause. For example, the oligoclonal IgG found in subacute sclerosing

panencephalitis brains and CSF is directed against measles virus,10 not herpes simplexvirus or mumps virus, and in cryptococcal meningitis, the IgG is directed againstcryptococcus11 and not another fungus such as candida. These findings providea rationale for the hypothesis that the oligoclonal IgG in MS brain and CSF is antibodydirected against thecause of MS.


Human IgG staining of plaque - periplaque white matter




junction





• antimicrobial




Mean annual and winter UVB irradiationvalues were systematically compared to MSprevalence rates from previously published

data on 2,667 MS cases in correspondingregions of France. Linear regression wasused to test for interaction of annual andwinter UVB with male versus female sex inpredicting MS prevalence.




Multiple sclerosis prevalence rates (per 100,000) for each Mutualité Sociale Agricole




male

female




The most attractive explanation is UVBinduced synthesis of cutaneous vitamin D,which is the principal source of this metabolite.

Recent findings show regulation of HLA-DRB1*1501, the most significantly associatedMS gene, via vitamin D–responsiveelement in its promoter region.




June 8, 2010




• 25 treatment / 24 control MS patients

• 52 weeks• 28 wks up to 40,000 IU/day, 12 wks 10,000 IU/day,12 wks downtitrated to 0 IU/day

Neurology ®2010;74:1852–1859

Neurology ® 2010;74:1852–1859




Neurology ® 2010;74:1852–1859




Neurology ® 2010;74:1852–1859

0

12.5

25

37.5

50

annualized relapse rate

Control Treatment

( - 41% treatment group vs. control )




Neurology ® 2010;74:1852–1859

-0.3

-0.15

0

0.15

0.3

Change in Expanded Disability Status Scale

Control Treatment





0

5

10

15

20

Anti-HSV IgM positive (%)

non-demented Alzheimer’s






“I have suggested that the primary

environmental trigger in autism is notvaccinations, toxins, or infections, butgestational and early childhood vitamin Ddeficiency.”




• Swedish report - 117 psychiatric

patients, 10 patients with autismhad the lowest levels of vitamin D

• Higher incidence in affluent Americans - more sun avoidance

• Higher incidence in black children

•Reduction in carpal bone thickness

• Higher incidence in cloudy areas• Lower in mothers with higher

seafood consumption• Higher incidence in city children

(tall buildings)

• Correlated with higher incidence of viral infections




• Serum frozen from 3,173 Finnish participants1978-80

• 25-hydroxyvitamin D vs Parkinson’s disease

• 50 participants developed PD (assessed in 2007)


Serum Vitamin D and the Risk of Parkinson Disease



0

0.25

0.5

0.75

1

quartile 1 quartile 2 quartile 3 quartile 4

relative risk for Parkinson’s

serum 25-Hydroxyvitamin D level




January 5, 2010




Obesity




August 23, 2004





Central Obesity and the Aging Brain



Jagust. W., et al., Arch Neurol 62: 1545-48; October, 2005

• 112 older Latinos• Waist to Hip Ratio

• Volumetric MRI of hippocampus


Plot of waist-hip ratio vs age-adjusted hippocampal volume



Jagust, W. et al. Arch Neurol 2005; 62:1545-1548


NEUROLOGY



NEUROLOGYREVIEWS

July, 2006


Presentation at 58th Annual Meeting of the AmericanAcademy of Neurology 2006



Academy of Neurology - 2006 Dr. Rachel Whitmer

• 8,776 men and women aged 40-45 years, between1964 and 1973

• Triceps skin fold measurement

• Average follow up 27 years later • Risk of Alzheimer’s comparing lowest to highest

quintile increased 293%




Am J Clin Nutr 2000;72:690–3.

0

10

20

30

40

50

control obese

before UV-B radiation 24 hr after UV-B radiation

serum

vitam

inD

3(nmol/L

)


nonobese obese



Am J Clin Nutr 2000;72:690–3.

0

15

30

45

60

75

90

0 5 10 15 20 25

Time (hours)

S e r u m 2

5 ( O H ) D

( n m

o l / L )

serum 25-hydroxyvitamin D in the control ( ) and obese ( ) groups 0–24 h

after oral intake of vitamin D2 , 50 000 IU




Cytokines

TNF -α

Systemic infection ➔


Antiviral Agents in Alzheimer's Disease: Hope for the Future?



Matthew A. Wozniak, BSc; Ruth F. Itzhaki, BSc, MSc, PhD, MA


Systemic inflammation and disease progression in



Alzheimer disease

C. Holmes,et al., Neurology, September 2009;73;768-774

• 300 subjects, mild to severe Alzheimer’s

• cognitive assessment, TNF-α 2, 4 and 6 months



Al h i di



Alzheimer disease




Al h i di



Alzheimer disease


• Results: Acute systemic inflammatory events, found in around half of all

subjects, were associated with an increase in the serum levels of

proinflammatory cytokine TNF-α and a 2-fold increase in the rate of cognitive

decline over a 6-month period. High baseline levels of TNF-α were

associated with a 4-fold increase in the rate of cognitive decline. Subjects

who had low levels of serum TNF-α throughout the study showed no

cognitive decline over the 6-month period.

• Conclusions: Both acute and chronic systemic inflammation, associated with

increases in serum TNF- α , is associated with an increase in cognitivedecline in Alzheimer disease.


Antiviral Agents in Alzheimer's Disease: Hope for the Future?

M tth A W i k BS R th F It h ki BS MS PhD MA



Matthew A. Wozniak, BSc; Ruth F. Itzhaki, BSc, MSc, PhD, MA

E v i d e n c e ?




tIn summary, we propose that during events suchas stress and peripheral infection, latent HSV1reactivates (as in the PNS) and causes an acutebut localised infection, perhaps a “mild”, varianttype of encephalitis, causing greater damage –both direct, and indirect via inflammatoryprocesses – in APOE-ε4 carriers, and eventually, AD.




t

“At present, treatment of AD is palliative at best;our data provide a strong rationale for acompletely different approach, namely, antiviraltherapy, and perhaps in the future, vaccinationagainst HSV1 early in life.”





exacerbations



NEUROLOGY 2006;67:652–659

0

10

20

30

-2 -1 0 1 2 3 4 5


at risk period* no at risk period



NEUROLOGY 2006;67:652–659

weeks

0

1

2

3

4

5

0 2 12

n u m b e r o

f G d + l e s i o n s

*at risk period - 2 wks prior to 5 wks after infection




NEUROLOGY 2006;67:652–659

Text

MSMS

ARP - at risk period




microglialactivation

inflammatorycytokines

oxidativestress

mitochondrialfailure

neuronaldeath

decreasedacetylcholine

cholinesterase

inhibitors

Alzheimer’s Disease - Functional Medicine Model




Control(n=43) ADHD(n=53)

Stevens, L.J., et al., Am J Clin Nutr 62: 761-8; 1995

Breast fed (%) 81.4 45.3

Months breast-fed 6.5 2.5


“There’s a worm in the wheati t idit t t”



… in stupidity street”

- Ralph Hodgson


Range of neurologic disorders in patients with celiac disease



Zelnick, N., et al., Pediatrics 113(6): 1672-6; June, 2004

• ADHD present in 66-70% of children with untreated

celiac disease – it resolves on a gluten-free diet andreturns with gluten challenge


Case Report: S.H.



• 4 y/o male child, Dx “attention deficit disorder”

• “shakes uncontrollably” when frustrated• “cannot stay on task”

• “anger outbursts”


Case Report: S.H.

Past Medical History



• “Lots of ear infections” multiple courses of antibiotics –6 month course of “prophylactic antibiotics”

• Joint pain in lower extremities treated with multiplecourses of Naprosyn®

Past Medical History


Case Report: S.H.

Physical and Neurological Examinations



• Mouth breather

• Nonfocal – child clearly unable to remain

seated or composed

Physical and Neurological Examinations


Case Report: S.H.

Lab Studies



• all normal, except:

• antigliadin Ab IgG (+)

Lab Studies


Case Report: S.H.

Interventions



• Lactobaccilus acidophilus

• DHA

• Gluten free diet

Interventions


News

May 15, 2007



Omega-3 Enriched Phospholopids Show Promise For Pediatric

ADHD Patients

ISRAEL – Pediatric ADHD patients may benefit from omega-3 LC-PUFA

conjugated to phospholipids (PL-Omega3) according to a study presented

during the 2007 Annual Meeting of the Pediatric Academic Societies

(PAS), in Toronto. The study, conducted by Prof. Nachum Vaisman from theSourasky Tel Aviv Medical Center, Tel-Aviv, Israel, involved over sixty children,divided into three groups and randomized in a three month, double blind,placebo-controlled study. One group received PL-Omega3 (250 mg/d EPA+DHA and 300 mg/d PS), another received fish oil (250 mg/d EPA+DHA), whilethe control group received canola. Sustained visual attention and discriminationwere objectively measured using the Test of Variables of Attention (TOVA).

Omega-3 LC-PUFA incorporation into blood compartments also was analyzed.

Providing DHA to these children had apronounced impact on their Test of Variables of

Attention (TOVA) scores, inasmuch as 60% of

them presented asymptomatic total TOVA scoreat the end of the intervention."


Case Report: S.H.

Follow Up



• 2 wks – teacher indicates child vastly improved sincestarting medication

• Parents note patient calm, more interactive, sleepingbetter

Follow Up


Case Report: S.H.

Follow Up



• 2½ years – “ We have been able to start him in school as theyoungest student in the class. He has been able to excel inreading and math and we do not anticipate any further problems with him being hyperactive. He has been growingso fast that he is one of the tallest kids in his class.”

Follow Up




FunctionalConventional

ADHD

RDS(RitalinⓇ Deficiency

Syndrome)

ADHD

Gluten Sensitivity

DHA deficiency

Dysbiosis


Archives of Neurology

October, 2006




Cognitive Impairment in Celiac Disease



Hu, W.T., et al., Archives of Neurology 63: 1440-1446; October, 2006

• 13 patients with exacerbation of known celiac diseaseand onset of dementia of undetermined cause


Cognitive Impairment in Celiac Disease



Hu, W.T., et al., Archives of Neurology 63: 1440-1446; October, 2006

Magnetic resonance imaging (MRI) findings of patientswith celiac disease and cognitive impairment.


Celiac disease, brain atrophy, anddementia



dementia

Collin, P., et al., Neurology41: 372-375; March, 1991

• Report of 5 patients who developed dementia beforeage 60 yrs

• Celiac disease confirmed by jejunal biopsy and serumantigliadin antibodies

• “Conspicuously, gastrointestinal symptoms weremild…there may be an association of CD anddementia especially in the patients developing

intellectual deterioration at a relatively young age.”




December, 2006


Celiac disease



Celiac disease

• Present in 1.2% of population

• 23 million American children aged < 5 years(276,000 children)

• Another 23 million children 6-11years (276,000children)


Range of neurologic disorders in patientswith celiac disease



Zelnick, N., et al., Pediatrics 113(6): 1672-6; June, 2004

• ADHD present in 66-70% of children with untreatedceliac disease – it resolves on a gluten-free diet andreturns with gluten challenge


Breast-feeding protects against celiac diseaseIvarsson A et al Am J Clin Nutr 75(5): 014 21; May 2002



Ivarsson, A., et al., Am J Clin Nutr 75(5): 014-21; May 2002

• Evaluation of 627 Swedish children with celiacdisease

• Time in relation to breast-feeding that gluten was

introduced


Breast-feeding protects against celiac diseaseIvarsson A et al Am J Clin Nutr 75(5): 014 21; May 2002



Ivarsson, A., et al., Am J Clin Nutr 75(5): 014-21; May 2002

• Risk of celiac disease if children < 2 years wereintroduced to gluten while being breast-fed wasreduced by 41%

• If breast-feeding was continued after glutenintroduced, risk was reduced by 64%




17 year old female, CCs (x 9 months):

• night sweats• abdominal cramping, bloating after eating• carbohydrate craving• poor concentration

• OCD (picks fingers)• depression




PMHx:

• multiple ear childhood ear infections (AB Tx)• not breastfed• endometriosis with proven ovarian mass




Lab workup:

• gliadin antibody IgA 5 (<11)• gliadin antibody IgG 78 (<11)• Candida antibody IgG 11 (<10)• Candida antibody IgM 15 (<10)




Treatment:

• gluten-free diet• fluconazoleⓇ 100mg daily x 21 days




Follow-up at one month: • night sweats• abdominal cramping, bloating after eating• carbohydrate craving• poor concentration

• OCD (picks fingers)• depression r

e s o l v

e d




33 y/o woman, CC: • 3 yr. history involuntary jerking of arms• poor sleep• anxiety




Lab workup: • ANA 1:2560• Thyroid antibodies (+)• MRI brain - negative




Lab workup: • DYT1 alleles 1 and 2 mutation (-)




Lab workup: • gliadin antibody IgA 19 (<11)• gliadin antibody IgA 49 (<11)




Treatment: • gluten-free diet




Follow-up at one month: • sleep problems and anxiety resolved• dystonia “90% better”





microglialactivation inflammatorycytokines oxidativestress mitochondrialfailure neuronaldeath decreasedacetylcholine




• Inflammation

• Oxidative stress




?




Arch Neurol. 2007;64(7):954-956;July, 2007


Damage to Lipids, Proteins, DNA, and RNA in MildCognitive Impairment



Markesbery, W., Arch Neurol. 64(7):954-956; July, 2007

“These studies establish oxidative damage as an early event in the pathogenesis of Alzheimer disease that canserve as a therapeutic target to slow the progression or perhaps the onset of the disease.”


Damage to Lipids, Proteins, DNA, and RNA in MildCognitive Impairment



“Better antioxidants and agents used in combination to up-regulate defense mechanisms against oxidation will be

required to neutralize the oxidative component of thepathogenesis of AD. It is most likely that to optimize theseneuroprotective agents, they will have to be used in thepresymptomatic phase of the disease.”

Markesbery, W., Arch Neurol. 64(7):954-956; July, 2007


TBARS in temporal lobe cortex of Alzheimer’s brains

TBARS ( l/ t i )



0

2.5

5.0

7.5

10.0

Alzheimer's Control

TBARS (nmol/mg protein)

Tamoaka, A., et al., Neurology 54: 2319-2321;June, 2000


Alzheimer'sControl



0

15

30

45

60

Vitamin C Vitamin E Vitamin A

Mecocci, P., et al., Arch Neurol 59: 794-798; May, 2002


Reduced Risk of Alzheimer’s Disease inUsers of Antioxidant Vitamin Supplements

Zandi P P et al Archives of Neurology 61: 82-88; January



Zandi, P.P., et al., Archives of Neurology 61: 82-88; January,

2004

• Use of Vitamins C and E – reducedprevalence of Alzheimer’s by 78%


Idiopathic Parkinson’s disease: A disorder due to



nigral glutathione deficiency. Perry, T.L., et al., Neuroscience Letter, 33: 1986

• Profound decrease of reduced glutathione(GSH) in the substantia nigra of Parkinson’s patients


Randomized, double-blind, pilot evaluation of intravenousglutathione in Parkinson's disease

Hauser RA, Lyons KE, McClain T, Carter S, Perlmutter D.



Mov Disord. 2009 Feb 1 (online)

• 4 week, double-blinded, placebo-controlled

• PD patients - 11 treatment, 10 control

• IV GSH 1400mg TIW


Randomized, double-blind, pilot evaluation of intravenousglutathione in Parkinson's disease





• Well tolerated, no adverse events either group

• Assessment of ADL and motor components of UPDRS


2

3

4

+ 3.5



-3

-2

-1

0

1

0 4 weeks 8 weeks

change in UPDRS



- 2.8

glutathione stopped





Food is information



Arch Neurol 62; July, 2005:,1067- 72


Insulin Resistance and Cognitive ImpairmentThe InCHIANTI Study

G ldi C t l A h N l 62 J l 2005 1067 72



Geroldi, C., et al., Arch Neurol 62; July, 2005:,1067- 72

• Early in type 2 DM:

progressive insulin resistance

high fasting blood insulin levelsnormal fasting glucose

The IR

syndrome


Insulin Resistance and Cognitive ImpairmentThe InCHIANTI Study




y

• 523 participants 70-90 years of age

• MMSE

• Fasting plasma insulin, insulin resistanceindex, insulin sensitivity index


50

ce(%

)




0

25

normal cognitive impairment

Prev

alence

ofinsul in

resis

tanc


Glucose tolerance status and risk of dementia in the communityThe Hisayama Study

Ohara, T., et al., Neurology September 20, 2011 vol. 77 no. 12 1126-1134



• 15 year study

• 1017 dementia-free subjects 60 years• comparison of risk of dementia versusnormal, abnormal GTT, or DM


Glucose tolerance status and risk of dementia in the communityThe Hisayama Study

Ohara, T., et al., Neurology September 20, 2011 vol. 77 no. 12 1126-1134



0

0.5

1

1.5

2

all cause dementia Alzheimer’s disease vascular dementia

normal impaired gtt diabetes




Alzheimer’s disease diabetes


Diabetes mellitus and the risk of dementia – The Rotterdam Study

Ott A et al Neurology 53:1937-42 December 1999



Ott, A., et al., Neurology 53:1937-42, December, 1999

• 6,370 patients

• RR of Alzheimer’s with diabetes – 1.9X• RR dementia if using insulin – 4.3X


Diabetes mellitus and the risk of dementia – The Rotterdam Study

Ott A et al Neurology 53:1937-42 December 1999



Ott, A., et al., Neurology 53:1937 42, December, 1999

• Insulin use – 4.3X risk

More severe diabetesLonger history

Direct effects

More frequent hypoglycemic events


Diabetes and Alzheimer’s disease



• Vascular disease

• Glycation of proteins

• Amyloid


Glyco-Oxidation



• Advanced Glycosylation End Products(AGE) – Posttranslational modifications of

proteins – amino group of protein reactswith monosaccharide


Advanced glycation end productlevel, diabetes, and acceleratedcognitive aging

, MD, et al., Neurology October 4, 2011 77:1351-56

http://www.neurology.org/search?author1=K.+Yaffe&sortspec=date&submit=Submit




• 920 elders without dementia, mean 74 yrs

• 495 with diabetes, 425 with normal glucose

• Modified Mini-Mental Status Exam (3ME)• Compared to AGEs (urine pentisidine)

• 9 years


0 no diabetes diabetes

e



-8

-6

-4

-2

Low Medium High

Tertile of Pentosidine AGEs

, MD, et al., Neurology October 4, 2011 77:1351-56

M e a n 9 - y

e a r 3 M S c h a n

g e


Alzheimer’s Disease – Synergistic Effects of GlucoseDeficit, Oxidative Stress and Advanced GlycosylationEnd Products





MÜnch. G., et al.,Journal of Neural Transmission 105 (4-5): 439-461; July, 1998

AGEs are more than just markers of aging since they

can exert adverse biological effects on tissues andcells including the activation of intracellular signaltransduction pathways, leading to the upregulation of cytokine and free radical production (oxidative stress)


0

% annual brain volume change



-0.500

-0.375

-0.250

-0.125

4.4-5.2 5.3-5.5 5.6-5.8 5.9-9.0

HbA1c (%)

Enzinger, C., et al., Neurology 64: 1704-11; May 24, 2005


0




-0.500

-0.375

-0.250

-0.125

absent present

APOEε4 alleleEnzinger, C., et al., Neurology 64: 1704-11; May 24, 2005


0




-0.500

-0.375

-0.250

-0.125

4.4-5.2 5.3-5.5 5.6-5.8 5.9-9.0

HbA1c (%)

Enzinger, C., et al., Neurology 64: 1704-11; May 24, 2005


β-amyloid




From: Imaging Technology for Neurodegenerative DiseasesChester Mathis PhD, et al., Arch Neurol 62; February, 2005: 196-200


AGE modulated ß-Amyloid



• Generates ROS• Activates NFĸB

• Activates microglia

• Enhances production of superoxideradical and nitric oxide


AGEs oxidative stress



COX-2

upregulation


Arachidonic acid



COX-2

2 series prostaglandins( proinflammatory )




Investigations on Oxidative Stress and Therapeutic

Implications in Dementia


Investigations on Oxidative Stress and TherapeuticalImplications in Dementia Durany, N., et al., European Archives of Psychiatry and Clinical

Neuroscience 249(3): S68-S73; December, 1999

http://images.amazon.com/images/P/B00007LN22.01.LZZZZZZZ.jpg






• Glycated proteins produce nearly 50 fold more radicalsthan non-glycated ones

• “… pharmacologoical approaches which break the

vicious cycle of oxidative stress andneurodegeneration offer new opportunities for thetreatment of AD. These approaches include AGE-inhibitors, antioxidants, and anti-inflammatory

substances which prevent radical production.”


cholinesteraseinhibitors



microglialactivation

inflammatorycytokines

oxidativestress

mitochondrialfailure

neuronaldeath

decreasedacetylcholine

inhibitors

Alzheimer’s Disease - Functional Medicine Model

AGEs


Advanced Glycosylated End Products

Nutritional Therapy -



• benfotiamine• alpha-lipoic acid

• taurine• resveratrol• N-acetyl cysteine• aspirin• carnosine

• DHA• low carbohydrate diet

• resveratrol


Neurobiol Aging. 2011 Oct 7.

Low-dose pterostilbene, but not resveratrol, is a potent

neuromodulator in aging and Alzheimer's disease.Chang J, Rimando A, Pallas M, Camins A, Porquet D, Reeves J, Shukitt-Hale B, Smith MA, Joseph JA, Casadesus G.

Source

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Casadesus%20G%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Casadesus%20G%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Joseph%20JA%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Joseph%20JA%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Smith%20MA%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Smith%20MA%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Shukitt-Hale%20B%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Shukitt-Hale%20B%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Reeves%20J%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Reeves%20J%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Porquet%20D%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Porquet%20D%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Camins%20A%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Camins%20A%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Pallas%20M%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Pallas%20M%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Rimando%20A%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Rimando%20A%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chang%20J%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chang%20J%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed/21982274?dopt=AbstractPlus#

http://www.ncbi.nlm.nih.gov/pubmed/21982274?dopt=AbstractPlus#



Department of Neuroscience, Case Western Reserve University, Cleveland, OH, USA.

Abstract

Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer's disease (AD). However, the

mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of

this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of p terostilbene at improving functional deficits and AD pathology in the

SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of

action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD. Two months of pterostilbene

diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1

(SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by

pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression. Taken together our findings indicate

that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome

proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene.

Copyright © 2011. Published by Elsevier Inc.

• Importantly, markers of cellular stress, inflammation, and AD pathologywere positively modulated by pterostilbene but not resveratrol.

• Taken together our findings indicate that at equivalent and diet-achievabledoses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol.


Advanced Glycosylated End Products

Nutritional Therapy -



• benfotiamine• alpha-lipoic acid

• taurine• resveratrol• N-acetyl cysteine• aspirin• carnosine

• DHA• low carbohydrate diet

• alpha-lipoic acid




Preventable Risk Factors Account for

Nearly Half of All Alzheimer’s Disease Cases







Published report: Lancet Neurology, July 18, 2011

“ A 25% reduction in seven risk factors could potentiallyprevent as many as three million cases of Alzheimer’sdisease worldwide.”

• quitting smoking

• increasing physical activity

• increasing mental activity

• controlling blood pressure

• controlling diabetes• managing obesity

• managing depression







These risk factors directly contribute to 2.9million cases of Alzheimer’s disease in

America and 17.2 million cases worldwide.





• 161,808 women, aged 50-79 years

• Followed for 5 years

• Compared risk of type 2 DM in usersversus nonusers of statin drugs


Epigenetics



•reducing inflammation

•increasing antioxidant protection

•enhancing neurogenesis•enhancing neuroplasticity


reduce inflammationincrease antioxidant function



Nrf2 activationepigenetic

factorsquinolinic acid




The Nrf2 pathway is the guardian of antioxidant function

Enhancing Nrf2 activation may be useful in the treatment of braindegeneration


• Oxidative stress• Caloric restriction• Curcumin• Green tea extract• Resveratrol• Broccoli



curcumin

Broccoli

• Garlic (allicin)• DHA




Turmeric (Curcuma longa)






Curry Spice May Fight Alzheimer's DiseaseEarly Studies Show Curry Reduces Plaque Buildup in Brain Linked to Disease



WebMD Medical News

• Curry is a dietary staple in India, a country where the rate of Alzheimer's disease is among the world's lowest.

• No side effects were seen in patients taking as much as 2,000to 8,000 mg per day.

• “ The prospect of finding a safe and effective new approach toboth prevention and treatment of Alzheimer's disease is

tremendously exciting," said Gregory Cole, MD, a professor of medicine and neurology at UCLA.


reduces inflammationincreases antioxidant function



Nrf2 activationCurcuminquinolinic acid





140.0

Curcumin – oxidative damage



70.0

87.5

105.0

122.5

Tg +

UntreatedCurcumin

Lim, G.P., et al., J. Neurscience21(21): 8370-77; Nov.1. 2001


Nrf2 activation

• Oxidative stress • Catalase



• Caloric restriction• Curcumin• Green tea extract• Pterostilbene

• Sulforaphane• Garlic (allicin)• DHA

• Glutathione• SOD• GST (Phase II detox)• Inhibits NF-kB

• Inhibits microglialactivation




The Nrf2-signaling pathway mediates multiple avenues of cytoprotectionby activating the transcription of more than 200 genes that are crucial in

the metabolism of drugs and toxins, protection against oxidative stressand inflammation ... We hypothesize that this signaling pathway plays acritical role in the determination of species longevity and that thispathway may indeed be the master regulator of the aging process.


Resveratrol

Organic Resveratrol




KEAP



gene activation




Mol. Nutr. Food Res. 2010, 54 , 1–13

Nrf2 activation by various dietary plant extracts


Epigenetics



•reducing inflammation

•increasing antioxidant protection

•enhancing neurogenesis•enhancing neuroplasticity


Brain Anatomy 101



- The Hippocampus





Memory and MRI-based hippocampalvolumes in aging and Alzheimer’s disease Petersen, R.C., et al., Neurology 54: 581-587; February, 2000



• Hippocampal volume accurately predicts memoryfunction


Hippocampus



• Stress damages it• This is where neurogenesis occurs


Hippocampus

S



• Stress damages it


Sustained stress



hippocampal destruction





Hippocampal neuronsof control monkey …



compared to chronicallystressed, subordinate,ulcerated monkey

Uno et al., J Neurosci 9, 1989; 1705


Cortisol levels as a function of hippocampal atrophy

20 000

Cortisol (micrograms / dl)



3.750

7.813

11.875

15.938

20.000

0 1 2 3

From: de Leon, et al., Abnormal cortisol response in Alzheimer’sdisease linked to hippocampal atrophy. Lancet 2, 391-92;1988

Hippocampal lesion size




Stress No Stress


Marital status and the risk of Alzheimer’sdisease Helmer, C., et al., Neurology 53:1953-1958; 1999



• 3,675 non-demented individuals –

married, divorced, widowed, never married (at outset of study)• Followed up at 1, 3, and 5 years


Incidence of Alzheimer’s disease according tomarital status (per 100 person years) Helmer, C., et al., Neurology 53:1953-1958; 1999



Age (years)





“… the sisters expressing negative emotions did notlive as long as the sisters conveying more positiveones (happiness, love, hope, gratitude and

contentment) emotional states ma pla a role in



contentment)…emotional states may play a role indetermining cognitive function.”

Dr. David Snowden

University of Kentucky




Stress No Stress




Stress No Stress Love


The greatest thing



The greatest thingyou’ll ever learn

is just to love,

and be loved, in return


Hippocampus

• Stress damages it



• Stress damages it• This is where neurogenesis occurs


Hippocampus



• This is where neurogenesis occurs





Issue 1 Fall 2005



What this study adds

Recommendations for the use of cholinesteraseinhibitors do not seem to be evidence based

_____________________

Benefits measured on rating scales wereminimal _____________________

The methodological quality of the availabletrials was poor





Alzheimer’s Disease Prevention








Published report: Lancet Neurology July 18 2011

Preventable Risk Factors Account for Nearly Half of All Alzheimer’s Disease Cases




These risk factors directly contribute to 2.9million cases of Alzheimer’s disease in Americaand 17.2 million cases worldwide.





ArchivesofNeurologyApril,2011




Review of ... “all clinical trials of memantine vs placebo that

included patients with mild AD.”



p

In the United States, nearly half of the patients with mild Alzheimer’s Disease and a substantial proportion of patientswith mild cognitive impairment are receiving memantine despite

a lack of evidence that the drug is helpful and some evidencethat it is not.

Conclusions: Despite its frequent off-label use, evidence

is lacking for a benefit of memantine in mild AD, and there is

meager evidence for its efficacy in moderate AD.


Despite its frequent off-label use evidence is



Despite its frequent off-label use, evidence islacking for a benefit of memantine in mild AD,and there is meager evidence for its efficacyin moderate AD. Prospective trials are neededto further assess the potential for efficacy ofmemantine either alone or added to

cholinesterase inhibitors in mild and moderateAD.


New England Journal of Medicine, March 8, 2012



“There were no significant benefits of the

combination of donepezil and memantine

over donepezil alone.”





Functional Enhancement



274




Increasing tissue oxygen levels produces several

important long term therapeutic benefits including

enhanced growth of new blood vessels, increasedability of white blood cells to destroy bacteria and

remove toxins, increase growth of fibroblasts (cells

involved in wound healing), and enhanced

metabolic activity of previously marginallyfunctioning cells including brain neurons. Patients

receiving hyperbaric oxygen therapy enter a 1-

person clear acrylic chamber where they breathe

100% oxygen delivered to the chamber


17 year old female, age 15 years “flu”.Progressive decline in neurological function.



Exam: Feeding tube, produces grunting sounds,no words, poor coordination

Saturday April 14 12




Treatment:• Hyperbaric oxygen

• Glutathione



280




name deleted




282




Functional Enhancement

calorie restriction




Caloric restriction

Physical exerciseDHAMental exercise BDNF


Brain-Derived Neurotrophic Factor BDNF

• A neurotrophin crucial to the structural integrity of d lt



p g yadult neurons

• Neuroplasticity, learning

• Neurogenesis



• A neurotrophin crucial to the structural integrity of d lt



p g yadult neurons


• Neurogenesis


Neurogenesis in the adult human hippocampus

Eriksson, P.S., et al., Nature Medicine 4(11); 1998: 1313-17



• Human brain tissue was obtainedpostmortem from patients treated with BrdU,

a thymidine analog that labels DNA during Sphase


BrdU-labeled nuclei (arrows) in thedentate granule cell layer (GCL)



Eriksson, P.S., et al., Nature Medicine 4(11); 1998 : 1313-17


Neurogenesis in the adult human hippocampus

Eriksson, P.S., et al., Nature Medicine 4(11); 1998: 1313-17



• “Our study demonstrates that cell genesisoccurs in human brains and that the human

brain retains the potential for self-renewalthroughout life.”


granule



BrdU (mitosis)

TUJ-1 (neuronal differentiation)

granulecelllayer

Tim Bliss, PhD, The Hippocampus Book, Oxford University Press


Neurotrophic Factors

• Nerve Growth Factor (NGF)



(NGF)

• Brain DerivedNeurotrophic Factor (BDNF)

• Basic FibroblastGrowth Factor

(bFGF)



• A neurotrophin crucial to the structural integrity of adult neurons



adult neurons


• Neurogenesis




Caloric restriction

Physical exerciseDHAMental exercise BDNF


BDNF

Neurogenesis



BDNFNeuroplasticity

Neuronal Repair





Mechanisms underlying the neuroprotective effects of calorie restriction.

•Reduces ROS formation

• Reduces inflammation



Marwan Maalouf , Jong M. Rho, Mark P. Mattson

Apoptotic pathways are depicted in black and neuroprotective pathways are shown inred. Dark arrows indicate excitatory effects whereas inverted arrows are inhibitory

• Inhibits apoptosis

• Enhances mitochondrial replication



↓ ROS ↑ ATP







• Reduces ROS formation






• Enhances mitochondrial replication




Caloric restrictionPhysical exerciseDHAMental exercise BDNF


BDNF

Neurogenesis

N l ti it



Neuroplasticity

Neuronal Repair




calorie restriction → neurogenesis




Mark Mattson, Ph.DSenior Investigator, Chief, Cellular and Molecular Neurosciences Sectionand Chief, Laboratory of

Neurosciences, National Institutes of Health, Bethesda, Maryland


115

120

125

130

Unrestricted Diet restricted



Jaewon Lee, et al.

90

95

100

105

110

115

BDNF levels in hippocampus




Our data are the first evidence that diet can affect the process of neurogenesi

as well as the first evidence that diet can affect neurotrophic factor production

These findings provide insight into the mechanisms whereby diet impacts on

brain plasticity, aging, and neurodegenerative disorders.


100

125

150

Unrestricted Diet restricted

%

ofrestricted)



Jaewon Lee, et al.

0

25

50

75

cortex hippocampus

BDNFm

RNA

leve

l(%


Unrestricted Restricted diet



Jaewon Lee, et al.

Dentate gyrus stained for BrdU after 3 months




Jaewon Lee, et al.

BDNF localization and expression after 3 months

dentate gyrus





Jaewon Lee, et al.

BDNF localization and expression after 3 months

cortex




What about humans?




• Evaluation of BDNF levels in 17 healthy obese oroverweight subjects, 24-48 years, at baseline and

after 3 months of 25% calorie reduction

• Diet: calories 55% carbohydrate, 20% protein, 25%

fat


3 5

5.25

7

Basal Final

F

( n g / m

l )



A. Veronica Araya, Ximena Orellana, Jaime Espinoza

0

1.75

3.5

Basal and final serum BDNF level in 17 overweight or

obese subjects - calorie restricted

S

e r u

m

B D N F


“Dietary factors play major roles in determining whether the brain ages

successfully or experiences a neurodegenerative disease.”

“High calorie diets increase the risk for Alzheimer’s disease and

Parkinson’s disease ”



Parkinson’s disease.”

“Dietary factors may interact with disease-causing or predisposing genes in

molecular cascades that either promote or prevent the degeneration ofneurons.”


PNAS January 27, 2009 vol. 106 no. 4 1255–1260



• Assessment of memoryfunction in 50 healthy tooverweight subjects.

• Memory assessment at onsetand after 3 months

• Comparison of 30% calorierestriction vs control


120

130

control calorie restricted

memory



PNAS January 27, 2009 vol. 106 no. 4 1255–1260

90

100

110

baseline 3 months

yscore (%)


Neuroprotective mechanisms of calorie restriction

Improved mitochondrial function

• reduced ROS• increased energy output (mitochondrial biogenesis)



Regulation of gene expression

• decreased pro-apoptotic factors• decreased inlammatory factors• increased neuroprotective trophins• increased molecular chaperones





glucose



ketones


muscleamino acidsglycogen

glucose

CO2Overnight fast



fat

liverfatty acids

CO2

ketones


muscleamino acidsglycogen

glucose

CO2Prolonged fast



fat

liverfatty acids

CO2

ketones


4.5

6

β-Hydroxybutyrate Glucose

s / l i t e r



0

1.5

3

0 2.5 10 20 30 40

days of fasting

m M o l e s

GEORGE F. CAHILL, JR. and RICHARD L. VEECH




Upavasa





Mechanisms underlying the neuroprotective effects of ketogenic diet.



• Twenty participants - likely AD or MCI, mean age 74 yrs• Double-blinded, isocaloric MCT or LCT

•APOE 4 status stratified

• β-OHB measured• Neuropsychiatric eval - ADAS-COG, paragraph recall





Mechanisms underlying the neuroprotective effects of ketogenic diet.





↑ BDNF




ketogenic standard

fat

carbohydrate

protein

60% 10%

20% 70%

20% 20%


Ketones are a “superfuel” for the brain



Upavasa


Enhancing Ketones

• fasting



• coconut oil

• avocado• carbohydrate restriction





Epigenetic Factors



Caloric restrictionPhysical exerciseDHA BDNF





Exercise enhances the proliferation of neural stem cells of middle-aged mice



Chih-Wei Wu, et al., J Appl Physiol 105: 1585–1594, 2008.




Nicola T. Lautenschlager; Kay L. Cox; Leon Flicker; et al.JAMA, September 3, 2008—Vol 300, No. 9

JAMA


• 138 participants

• complained of mild memory dysfunction• intervention - 24 weeks of exercise, average 142

minutes more each week




• assessment of ADAS-cog scale over 18 months


-0.6

0.3

Change in ADAS-cog




-1.5time 0 18 months

control intervention


-0 85

0.30

control intervention




-2.00

0.85

change in ADAS-cog


In summary, the results of this randomizedtrial indicate that a physical activityprogram of an additional 142 minutesof exercise per week on average

modestly improved cognition relative tocontrols in older adults with subjectiveand objective memory impairment.





Neurology ReviewsJanuary, 2011




• The hippocampus shrinks in late adulthood, leading toimpaired memory and increased risk for dementia.



• Randomized controlled trial,120 older adults, 1 year,

stretching vs. aerobic exercise.

• Measurement of hippocampal volume, BDNF andmemory function at baseline, 6 months and 1 year





“ These results clearly indicate that aerobicexercise is neuroprotective and that starting an



exercise regimen later in life is not futile for either enhancing cognition or augmenting brainvolume.”





Physical Activity, Including Walking, and CognitiveFunction in Older Women Weuve, J., et al., JAMA 292; September, 2004: 1454-61

• Nurses Health Study, 18,766 women aged 70-81years,underwent cognitive testing twice over 2



years ( 1995 - 2001) compared to exercise from1986 until baseline cognitive assessment



• Physical activity is strongly associated with higher levels of cognitive function and less cognitivedecline The cognitive benefits of greater physical



decline. The cognitive benefits of greater physicalactivity were similar in extent to being about 3 years

younger in age and were associated with a 20%lower risk of cognitive impairment.





September, 2011




CONCLUSION

These data suggest that aerobic exercise is associated with

d d i k f iti i i t d d ti it

CONCLUSION

These data suggest that aerobic exercise is associated with

d d i k f iti i i t d d ti it



a reduced risk of cognitive impairment and dementia; itmay slow dementing illness. This may occur via facilitation of

neuroprotective neurotrophic factors and neuroplasticity. Thus,ongoing, moderate-intensity physical exercise should beconsidered as a prescription for lowering cognitive risks and

slowing cognitive decline across the age spectrum.

a reduced risk of cognitive impairment and dementia; itmay slow dementing illness. This may occur via facilitation of

neuroprotective neurotrophic factors and neuroplasticity. Thus,ongoing, moderate-intensity physical exercise should beconsidered as a prescription for lowering cognitive risks and

slowing cognitive decline across the age spectrum.



• “In this large, prospective study of older women,higher levels of long-term regular physical activitywere strongly associated with higher levels of



were strongly associated with higher levels of cognitive function and less cognitive decline.

Specifically, the apparent cognitive benefits of greater physical activity were similar in extent tobeing about 3 years younger in age and wereassociated with a 20% lower risk of cognitive

impairment.”




367





Caloric restriction



Caloric restrictionPhysical exercise

DHA BDNF


Docosahexaenoic acid (DHA)( 22:6ω3)



OH

||O


Dietary Omega-3 Fatty Acids Normalize BDNF Levels,Reduce Oxidative Damage, and Counteract LearningDisability after Traumatic Brain Injury

Wu, A., Journal of Neurotrauma 21(10): 1457-1467; October, 2004



DHA

• Signal transduction and gene expression


0.6

0.8

1.0

relative risk of Alzheimer's disease



0.2

0.4

1 2 3 4 5quintiles of intake - DHA

Morris, M.C., et al., Arch Neurol 60: 940-946; July, 2003


Fatty acid analysis of blood plasma of patientswith Alzheimer’s disease, other types of dementia,and cognitive impairment



“ Interestingly, a decreased level of plasma DHA

was not limited to the AD patients but appears tobe common in cognitive impairment in aging.”


November, 2006




Plasma Phosphatidylcholine Docosahexaenoic Acid Content and Risk of Dementiaand Alzheimer Disease

The Framingham Heart Study Schaefer, E., et al., Archives of Neurology 63: 1545-1550; November, 2006

• Prospective follow up study of 899 men and women



• Prospective follow-up study of 899 men and womenfree of dementia mean 9.1 years.

• Measurement of plasma phosphatidylcholinedocosahexaenoic acid at baseline.


Plasma Phosphatidylcholine Docosahexaenoic Acid Content and Risk of Dementiaand Alzheimer Disease

The Framingham Heart Study Schaefer, E., et al., Archives of Neurology 63: 1545-1550; November, 2006

T til f l PC DHA h d 47%



• Top quartile of plasma PC DHA showed a 47%

reduced risk of developing dementia of all causes inthe Framingham Heart Study




Crude cumulative incidence of dementia in subjects with baselineplasma phosphatidylcholine docosahexaenoic acid (PC DHA)levels in the upper quartile compared with those with levels in thelower 3 quartiles.


DHA

Sources

Fish and fish oils



Microalgae





Omega-3 DHA boosts memory for healthyadults13-Jul-2009

Related topics: Omega-3, Research, Nutritional lipids and oils, Cardiovascular health, Cognitive andmental function

Daily supplements with the omega-3 fatty acid docosahexaenoic acid (DHA) may improve both memoryfunction and heart health in healthy older adults, according to a new study from Martek.

The results, specific to people with a decline in cognitive function that occurs naturally with age, were presented at

the Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD 2009) in Vienna.

Almost 500 people took part in the randomised, double-blind, placebo-controlled, multi-center, six month study,which also recorded improvements in the heart rate of people receiving the DHA supplement. The study was funded

b k i i

http://www.nutraingredients.com/content/search?SearchText=Martek

http://www.nutraingredients.com/content/search?SearchText=DHA

http://www.nutraingredients.com/content/search?SearchText=DHA

http://www.nutraingredients.com/content/search?SearchText=Alzheimer%27s


http://www.nutraingredients.com/Health-condition-categories/Cognitive-and-mental-function




http://www.nutraingredients.com/Health-condition-categories/Cardiovascular-health

http://www.nutraingredients.com/Health-condition-categories/Cardiovascular-health

http://www.nutraingredients.com/Product-Categories/Nutritional-lipids-and-oils

http://www.nutraingredients.com/Product-Categories/Nutritional-lipids-and-oils

http://www.nutraingredients.com/Research

http://www.nutraingredients.com/Research

http://www.nutraingredients.com/On-your-radar/Omega-3

http://www.nutraingredients.com/On-your-radar/Omega-3



by Martek Biosciences.

“In our study, healthy people with memory complaints who took algal DHA capsules for six months had almost

double the reduction in errors on a test that measures learning and memory performance versus those who took a

placebo,” said Yurko-Mauro, PhD, associate director of clinical research at Martek and lead researcher of the study.

“The benefit is r oughly equivalent to having the learning and memory skills of someone three years younger.”

“Results of the M IDAS Trial: Effects of Docosahexaenoic Acid on Physiological and Safety Parameters in Age-Related

Cognitive Decline”

Authors: K. Yurko-Mauro, D. McCarthy, E. Bailey-Hall, E.B. Nelson, A. Blackwell, MIDAS Investigators


Neuronal Cyclooxygenase 2 Expression in the HippocampalFormation as a Function of the Clinical Progression of Alzheimer’s Disease Ho, L., et al., Arch Neurol 58: 487-492; March, 2001

200







0

100

0 0.5 1 2 5

Clinical dementia rating

Cox-2

stainingIntensityin CA3


0.6

0.8

1.0

relative risk of Alzheimer's disease



0.2

0.4

1 2 3 4 5quintiles of intake - DHA

Morris, M.C., et al., Arch Neurol 60: 940-946; July, 2003Saturday, April 14, 12

Essential fatty acids and the brain:possible health implications Youdim, K., et al., International Journal of Developmental

Neuroscience: 383-399; July 1, 2000

DHA plays a pivotal role in :



• Mitochondrial and neuronal membrane fluidity• Signal transduction

• Neurogenesis

• Gliogenesis

• Synaptogenesis






• A neurotrophin crucial to the structural integrity of adult neurons


N i



• Neurogenesis


Neuroplasticity

The ability of neurons and their networks to



Neuroplasticitychange based upon experience




Donald Olding Hebb, Ph.D, 1904 – 1985


Donald Olding Hebb, Ph.D

“When an axon of cell A is

near enough to excite cell B

and repeatedly or persistently

takes part in firing it, some

growth process or metabolicchange takes place in one or

both cells such that A's

efficiency, as one of the cells

firing B, is increased.”

The Organization of Behaviour, 1949



"Neurons that fire together wire together." Hebb's Law


Donald Olding Hebb, Ph.D

“When an axon of cell A is

near enough to excite cell B

and repeatedly or persistently

takes part in firing it, some

growth process or metabolicchange takes place in one or

both cells such that A's

efficiency, as one of the cells

firing B, is increased.”

The Organization of Behaviour, 1949



"Neurons that fire together wire together." Hebb's Law




Michael Merzenich, Ph.D





“Experience coupled with attention leads tophysical changes and future functioning of the

nervous system... moment by moment we chooseand sculpt our ever-changing minds, we choosewho we will be the next moment in a very realsense, and these choices are left embossed in



physical form on our material selves.”

- Michael Merzenich,in, Train Your Mind, Change Your Brain,

by Sharon Begley


“The brain we develop reflects the life welead.”

- The Dalai Lama




“We are the product of what we think.What we think, we become.”

- Mohandas Gandhi




conscious mind




unconscious mind




A B C D E F G H I J K L M N O P Q R S T U V W X Y Z




A man and a woman kissing



Alvaro Pascual-Leone, MD, PhD





“Mental practice alone may be sufficient to promotethe plastic modulation of neural circuits.”

- Alvaro Pascual-Leone, MD, PhDin, Train Your Mind, Change Your Brain,

by Sharon Begley




“The mind is everything. What you thinkyou become.”

- Buddha




Neuroplasticity

The ability of neurons and their networks tochange based upon experience



Neuroplasticitychange based upon experience

This experience can be intrinsic and self directed




Andrew Newberg, MD




Andrew Newberg, MD

Franciscan nuns in “centering prayer” focusing on a particular phrase or

prayer from the bible.




“We think this is part of what is associated with somebody losing that

sense of self. They feel at one with God, at one with their spiritual

mantra, whatever it is they are looking at. This was a group of Tibetan

Buddhist meditators.”

Andrew Newberg, MD


Anterior cingulate




• empathy

• compassion

• social awareness

Strengthened by spiritualityAnterior cingulate




• intuition

• connects limbic system

to frontal lobe


• connects limbic system

to frontal lobe

Limbic system - processes wide range

of feelings and emotions



Frontal lobes - initiates thoughts andbehavior, planning for the

future, abstract conceptualization




David Perlmutter and Albert L. Rhoton, MD, Microsurgical Anatomy of theDistal Anterior Cerebral Artery, Journal of Neurosurgery, 49 (2): 204-228;August 1978




David Perlmutter and Albert L. Rhoton, MD, Microsurgical Anatomy of theDistal Anterior Cerebral Artery, Journal of Neurosurgery, 49 (2): 204-228;August 1978


Anterior cingulate




Amygdala




Amygdala

• fight or flight• response to fear,

real or imagined

• instantaneous

Inhibited by spirituality



instantaneous

response


Anterior cingulate

h

Amygdala

fi h fl h



• empathy

• compassion


• intuition

• measured response

• fight or flight

• response to fear,real or imagined

• instantaneous,

unrestrained response


Anterior cingulate

h

Amygdala

fi h fli h



• empathy

• compassion


• intuition

• measured response

• fight or flight

• response to fear,real or imagined

• instantaneous,

unrestrained response





Anterior cingulate

• empathy

• compassion


Amygdala

• fight or flight

• response to fear,

real or imagined



• intuition• measured response

g

• instantaneous,unrestrained response


meditation - prayer

calorie restrictionDHA



physical exercise fasting





“But let us not forget that knowledge and skills alone



But let us not forget that knowledge and skills alone

cannot lead humanity to a happy and dignified life.

What humanity owes to personalities like Buddha,

Moses, and Jesus ranks for me higher than all theachievements of the inquiring and constructive mind.”

Albert Einstein, The Human Side


Alzheimer’s disease protocol

Evaluation

• History - stepwise or slowly progressive? Head traumaremote or recent? Associated issues - gait disorder, urinary

incontinence, sleep disorder

• Family history

• Medications

C biditi di b t l di b it



• Comorbidities - diabetes, vascular disease, obesity

• Physical exam• Neurological exam - including cognitive function



Treatment

• Nutritional - Mediterranean diet, low carbohydrate, higher fat calories, higher lysine/arginine ratio, allow coffee, green

tea, (follow ketones - ketostix)

• Medications - Parenteral methyl B12 - 5000mcg BIW,

valacyclovir 500mg BID

H b i d di d f



• Hyperbaric oxygen - depending on degree of

cerebrovascular disease



Treatment

• Supplements - MCT oil - 1 TBSP BID, L-lysine - 1500mg/day, turmeric, sulforaphane, green tea extract, resveratrol,

(Nrf2 Activator™) coenzyme Q10 100 mg/day (CoQMax

CF™), DHA - 1200mg /day, NAC, alpha-lipoic acid,

phoshatidylserine, acetyl L-carnitine, (BrainSustain

NeuroActives™)(treat labs - vitamin D, homocysteine



NeuroActives )(treat labs vitamin D, homocysteine

(MethylProtect™), red cell studies, metals, glucose)



Treatment

• Lifestyle - exercise - 20 min. aerobic / day, sunshine,

verifiable cognitive activities, creativity, sleep (L-tryptophan)




Multiple sclerosis protocol

Evaluation

• History - stepwise or slowly progressive? early life health -

breast fed, place of birth, antibiotics?

• Family history

• Medications

• Comorbidities - candidiasis, hypothyroidism



, yp y

• Physical exam• Neurological exam - including cognitive function



Treatment

• Nutritional - Mediterranean diet, low carbohydrate, higher

fat calories, allow coffee, green tea, (follow ketones -

ketostix)

• Hyperbaric oxygen - 20 treatments, 60 minutes, 1.8 ATA,

followed by one treatment monthly



followed by one treatment monthly



Treatment

• Medications - minocycline - 100mg BID x 3 weeks (may

extend), methyl B12 - 5000mcg IM BIW, IV glutathione for

exacerbations - 3000mg /day for 4-5 days, treat labs (IV

magnesium sulphate 2000mg BIW, fluconazole, Armour

thyroid)



y )



Treatment

• Lifestyle - exercise (aerobic - 20 minutes daily, avoid

overheating, motion program - yoga, pilates), meditation,

sleep





Treatment

• Supplements - MCT oil - 1 TBSP BID, turmeric,

sulforaphane, green tea extract, resveratrol, (Nrf2

Activator™) DHA 1200mg /day Coenzyme Q10 NAC

functional approaches to neurodegenerative disorders

Documents