Functional Approaches To Neurodegenerative Disorders

A Functional Medicine Approach to Neurology 2012
David Perlmutter, MD, FACN ABIHM DrPerlmutter.com Telephone: (239) 649-7400 e-mail: patientinformation@perlhealth.com
copyright 2012, David Perlmutter, MD
Saturday, April 14, 12
Lancet 358; August 11, 2001: 461- 467
February 23, 2004
Neurodegenerative diseases
Inflammation
Oxidative stress
Risk of Alzheimers 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
Alzheimers patient 75 y/o male
MRI
Activated microglia PET
Cagnin, A., et al., Lancet 358; August 11, 2001: 461- 467
Nonsteroidal Anti-inflammatory Drugs and the Risk of Parkinsons 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 Parkinsons disease

Wahner, A.D., et al., Neurology 69 ;1836-42: November 6, 2007
Comparison of 293 PD patients and 296 controls

evaluated 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 Expressing Cytokines in the Substantia Nigra of PD Patients
16 14 12 Control Parkinson's 10 8 6 4 2 0
IL-1B
Hirsch, E.C., et al., Ann Neurol 44(Suppl 1): S115-S120, 1998
TNF-alpha
-amyloid
inflammatory cytokines
Visualizing amyloid burden using Pittsburgh Compound B

From: Imaging Technology for Neurodegenerative Diseases
Chester Mathis PhD, et al., Arch Neurol 62; February, 2005: 196-200
Recent studies have shown that while the adaptive immune system 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.
Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, et al. (2010)
antimicrobial peptides (AMPs)
AMPs, also called host defense peptides function in the brains 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.
Antimicrobial activity of A42
Organism Candida albicans Escherichia coli Staphlyococcus epidermidis Streptococcus pneumonia
MIC (g/ml) A42 0.78 1.56 3.13 6.25
Soscia, S.J., et al

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 neuroinammation in AD neuropathology A number of studies have proposed Ab as the source of AD-associated inammation. However, a re-evaluation of the role of Ab in inammation may now be warranted in view of these data suggesting that the peptide functions as an AMP in tissues. Inammatory response in the immunologically privileged CNS is mediated by the innate immune system. Rather than Ab acting as a sole independent initiator of neuroinammation, 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 believe play an important role in causing Alzheimer's disease. Patients treated with semagacestat worsened to a statistically signicantly 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 and three of its analogs induced expression of the human cathelicidin antimicrobial peptide (CAMP) gene. Our ndings reveal a novel activity of 1,25-dihydroxyvitamin D3 in regulation of primate innate immunity.
toll-like receptor were in trouble now !!
D
cathelicidin
CYP27B1
mRNA VDR vitamin D receptor
phagosome
microglia Toll-like receptor
toll-like receptor
microglia Toll-like receptor
800
cathelicidin (ng/ml)
650
500
350
200
20
40
60
80
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 neuroinammation in AD neuropathology A number of studies have proposed Ab as the source of AD-associated inammation. However, a re-evaluation of the role of Ab in inammation may now be warranted in view of these data suggesting that the peptide functions as an AMP in tissues. Inammatory response in the immunologically privileged CNS is mediated by the innate immune system. Rather than Ab acting as a sole independent initiator of neuroinammation, 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 pattern recognition receptors. TLR recognize pathogen-associated molecular patterns from bacteria, fungi, parasites, viruses and contribute to the innate immune response. Microglia express a wide range of neurotoxic factors such as cytokines chemokines, excitatory amino acids, reactive oxygen species (ROS) and proteases.
Alzheimers disease
Methods: Cox proportional hazard models were used to study the risk of developing AD according to the presence or not of anti-HSV IgG and IgM antibodies, assessed in the sera of 512 elderly initially free of dementia followed for 14 years.
www.plosone.org 1 November 2008 Volume 3 (11) e3637
non-demented
20
Alzheimers
15
10
5 0 Anti-HSV IgM positive (%)
Cumulative Alzheimers disease rate according to anti-HSV IgM status.
Hazard ratio of developing Alzheimers disease according to anti-HSV IgM status
HR Anti-HSV IgM status Female gender High educational level APOE-4 allele 2.55 1.48 0.87 2.00
Reactivation of HSV seropositivity is highly correlated with incident AD. HSV chronic infection may therefore be contributive to the progressive brain damage characteristic of AD. As AD pathology begins many years before the dementia stage, the recurrent reactivation of HSV might act as a potent stimulus to the brain microglia, increasing the level of cytokines and initiating a positive feedback cycle that gives rise to an increasing accumulation of pathological changes.
During acute HSV1 infection, same brain regions involved as in AD Long-term survivors of acute HSV1 brain infection exhibit 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. Can reactivate in the peripheral nervous system after early life infection
HSV1 DNA by PCR is present in high proportion of elderly, including AD patients. Found in frontal and temporal cortex, 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-4

APOE-4 is neither necessary nor sufficient for the disease, i.e., it must act in conjunction with another factor Very few HSV1 infected controls carry the APOE-4 allele
Intriguingly and consistently, we also found that APOE-4

is a risk for cold sores.
Our demonstration of this intrathecal immune response in AD and elderly normals subjects not only conrms 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-specic intrathecal immune response. We used in situ PCR to conrm that the brains of AD patients and age-matched controls contain HSV1 DNA and the virus is present in neurons.
APOE-4 associated with greater risk of HSV1 virus spread to the brain and viral latency (rodent) Both acute and chronic HSV1 infection lead to inflammation and oxidative neuronal damage The virus competed better against apoE 4- than against apoE 3-enriched lipoprotein particles for binding to the cell receptor and intracellular internalisation.
-amyloid
-secretase amyloid- protein precursor -secretase
It is concluded that there is strong evidence that HSV1 virus is indeed a major factor in Alzheimers disease and therefore there is a strong case for appropriate treatment, and possibly for prevention in the future.
HSV1 DNA amyloid plaque
Co-localization of HSV1 DNA and amyloid plaques. PCR detects HSV1 DNA in specimens of brain tissue from Alzheimers patient. In the same tissue specimens, amyloid plaque were visualized using thioavin S staining.
HSV1 DNA amyloid plaque
Co-localization of HSV1 DNA and amyloid plaques. PCR detects HSV1 DNA in specimens of brain tissue from Alzheimers patient. In the same tissue specimens, amyloid plaque were visualized using thioavin S staining.
These results demonstrate that HSV1 is present in almost all amyloid plaques of both AD sufferers and aged normals, and suggest that the virus might be a cause of plaque formation. In AD, 72% of viral DNA was plaque-associated; thus its localization within amyloid plaques reects a specic association, not a background, random distribution. These results support the deduction that HSV1 is a major cause of plaque formation.
HSV1 is responsible for herpes simplex encephalitis, a severe but rare brain disorder which aficts the brain regions most affected in Alzheimers disease. This similarity in brain region involved, together with the very high prevalence of HSV1 infection and the ability 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 a signicant aetiological factor in Alzheimers disease. They point to the usage of antiviral agents to treat the disease and possibly of vaccination to prevent it.
Our present data suggest that this virus is a major cause of amyloid plaques and hence probably a signicant aetiological factor in Alzheimers disease. They point to the usage of antiviral agents to treat the disease and possibly of vaccination to prevent it.
Dementia %
Alzheimers %
30
22.5
15
7.5
0 < 400 IU 400-600 IU > 600 IU
Dietary 25(OH) D intake - daily

Buell, J.S., et al., Neurology 2010;74:1826
Alzheimers disease
% PCR (+) Chlamydia pneumoniae
80
60
40
20
non-Alzheimers
Alzheimers
Culture of the organism from brain tissue homogenate from one AD patient demonstrated that the organisms were viable and metabolically active in those samples. Immunohistochemical analyses showed that astrocytes, microglia, and neurons all served as host cells for C. pneumoniae in the AD brain, and that infected cells were found in close proximity to both neuritic senile plaques and neurobrillary tangles.
Evidence of successful culture of Chlamydia pneumoniae from an AD brain-tissue. Staining using a monoclonal antibody specically targetting the C. pneumoniae major outer membrane protein.
astrocytes monoclonal antibody staining of Chlamydia pneumoniae microglia
neurons
Multiple Sclerosis
multiple sclerosis
The ndings of many epidemiological studies and a discordance of MS in monozygotic twins suggest that the disorder is 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 inammatory CNS disorders

are infectious.
Lancet Neurol 2005; 4: 195202

In virtually all infections of the CNS in which oligoclonal bands represent intrathecal antibody synthesis, the antigenic specificity of the immune response is directed against the infectious pathogen.

C pneumoniae adsorption in non-MS patients
C pneumoniae adsorption in MS patients
Our results demonstrate that the development of an intrathecal immune response to C pneumoniae antigens is a common occurrence in the population of patients with MS that we have examined. Epidemiologic studies have shown the presence of antibody titers in serum to C pneumoniae in over 50% of individuals over 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 therefore argues for a persistent infection with C pneumoniae in the CNS of patients with MS.
Antibody in brain and CSF The 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 high concentrations of IgG and oligoclonal bands . All those diseases that have high IgG concentrations are inammatory and most are infectious. Furthermore, when the specicity of the high concentrations of IgG and oligoclonal bands in those diseases was studied, IgG was found to be antibody directed against the disease cause. For example, the oligoclonal IgG found in subacute sclerosing panencephalitis brains and CSF is directed against measles virus,10 not herpes simplex virus or mumps virus, and in cryptococcal meningitis, the IgG is directed against cryptococcus11 and not another fungus such as candida. These ndings provide a rationale for the hypothesis that the oligoclonal IgG in MS brain and CSF is antibody directed against the cause of MS.

Human IgG staining of plaque - periplaque white matter junction

antimicrobial
Mean annual and winter UVB irradiation values were systematically compared to MS prevalence rates from previously published data on 2,667 MS cases in corresponding regions of France. Linear regression was used to test for interaction of annual and winter UVB with male versus female sex in predicting MS prevalence.
Multiple sclerosis prevalence rates (per 100,000) for each Mutualit Sociale Agricole
male
female
The most attractive explanation is UVB induced synthesis of cutaneous vitamin D, which is the principal source of this metabolite. Recent findings show regulation of HLADRB1*1501, the most significantly associated MS gene, via vitamin Dresponsive element 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;74:18521859
Neurology 2010;74:18521859
Neurology 2010;74:18521859
Control
Treatment
50
37.5
25
12.5
annualized relapse rate ( - 41% treatment group vs. control )

Neurology 2010;74:18521859
Control
Treatment
0.3
0.15
-0.15
-0.3
Change in Expanded Disability Status Scale
Neurology 2010;74:18521859
non-demented
20
Alzheimers
15
10
5 0 Anti-HSV IgM positive (%)
I have suggested that the primary environmental trigger in autism is not vaccinations, toxins, or infections, but gestational and early childhood vitamin D deficiency.
Swedish report - 117 psychiatric
patients, 10 patients with autism had 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 participants 1978-80 25-hydroxyvitamin D vs Parkinsons disease 50 participants developed PD (assessed in 2007)
Serum Vitamin D and the Risk of Parkinson Disease
relative risk for Parkinsons

1
0.75
0.5
0.25
0 quartile 1 quartile 2 quartile 3 quartile 4
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 R
EVIEWS
July, 2006
Presentation at 58th Annual Meeting of the American Academy of Neurology - 2006

Dr. Rachel Whitmer
8,776 men and women aged 40-45 years, between 1964 and 1973 Triceps skin fold measurement Average follow up 27 years later Risk of Alzheimers comparing lowest to highest quintile increased 293%
before UV-B radiation
24 hr after UV-B radiation
serum vitamin D3 (nmol/L)
50
40 30 20 10 0 control obese
Am J Clin Nutr 2000;72:6903.

nonobese
Serum 25(OH)D (nmol/L)
90 75 60 45 30 15 0
obese
10
15
20
25
Time (hours)
serum 25-hydroxyvitamin D in the control ( ) and obese ( ) groups 024 h after oral intake of vitamin D2 , 50 000 IU
Am J Clin Nutr 2000;72:6903.
Cytokines TNF -
Systemic infection
Antiviral Agents in Alzheimer's Disease: Hope for the Future? (... Antiviral Agents in Alzheimer's Disease: Hope for the Future?
Matthew A. Wozniak, BSc; Ruth F. Itzhaki, BSc, MSc, PhD, MA
http://www.medscape.com/viewarticle/729391_print
Systemic inammation and disease progression in Alzheimer disease

C. Holmes,et al., Neurology, September 2009;73;768-774
300 subjects, mild to severe Alzheimers cognitive assessment, TNF- 2, 4 and 6 months




Results: Acute systemic inammatory events, found in around half of all subjects, were associated with an increase in the serum levels of proinammatory cytokine TNF- and a 2-fold increase in the rate of cognitive decline over a 6-month period. High baseline levels of TNF- were associated with a 4-fold increase in the rate of cognitive decline. Subjects who had low levels of serum TNF- throughout the study showed no cognitive decline over the 6-month period. Conclusions: Both acute and chronic systemic inammation, associated with increases in serum TNF- , is associated with an increase in cognitive decline in Alzheimer disease.
Antiviral Agents in Alzheimer's Disease: Hope for the Future? (... Antiviral Agents in Alzheimer's Disease: Hope for the Future?
Matthew A. Wozniak, BSc; Ruth F. Itzhaki, BSc, MSc, PhD, MA
http://www.medscape.com/viewarticle/729391_print
nce ? vide E
In summary, we propose that during events such as stress and peripheral infection, latent HSV1 reactivates (as in the PNS) and causes an acute but localised infection, perhaps a mild, variant type of encephalitis, causing greater damage both direct, and indirect via inammatory processes in APOE-4 carriers, and eventually, AD.
t
At present, treatment of AD is palliative at best; our data provide a strong rationale for a completely different approach, namely, antiviral therapy, and perhaps in the future, vaccination against HSV1 early in life.
exacerbations
30
20
10
0 -2 -1 0 1 2 3 4 5
weeks of the at risk period
NEUROLOGY 2006;67:652659
at risk period*
no at risk period
number of Gd+ lesions
5 4 3 2 1 0 0 2 12
weeks
*at risk period - 2 wks prior to 5 wks after infection
NEUROLOGY 2006;67:652659
MS MS
Text
ARP - at risk period

NEUROLOGY 2006;67:652659
cholinesterase inhibitors
microglial activation
inflammatory oxidative cytokines stress
mitochondrial neuronal failure death
decreased acetylcholine
Alzheimers Disease - Functional Medicine Model
Control (n=43) Breast fed (%) 81.4 Months breast-fed 6.5
ADHD (n=53) 45.3 2.5
Stevens, L.J., et al., Am J Clin Nutr 62: 761-8; 1995
Theres a worm in the wheat 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 and returns 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 multiple courses of Naprosyn
Case Report: S.H.
Physical and Neurological Examinations

Mouth breather Nonfocal child clearly unable to remain seated or composed
Case Report: S.H.
Lab Studies
all normal, except: antigliadin Ab IgG (+)
Case Report: S.H.
Interventions
Lactobaccilus acidophilus DHA Gluten free diet
News
May 15, 2007
Omega-3 Enriched Phospholopids Show Promise For Pediatric ADHD Patients
Providing ADHD patients may benefit had a ISRAEL PediatricDHA to these childrenfrom omega-3 LC-PUFA conjugated to phospholipids (PL-Omega3) according to a study presented pronounced impact on their Test of Variables of during the 2007 Annual Meeting of the inasmuch as 60% of Attention (TOVA) scores, Pediatric Academic Societies (PAS), in Toronto. The study, conducted by Prof. Nachum Vaisman from the them presented asymptomatic involved over sixty children, Sourasky Tel Aviv Medical Center, Tel-Aviv, Israel,total TOVA score divided into three groupsthe intervention." at the end of 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), while the control group received canola. Sustained visual attention and discrimination were objectively measured using the Test of Variables of Attention (TOVA). Omega-3 LC-PUFA incorporation into blood compartments also was analyzed.
Case Report: S.H.
Follow Up
2 wks teacher indicates child vastly improved since starting medication Parents note patient calm, more interactive, sleeping better
Case Report: S.H.
Follow Up
2 years We have been able to start him in school as the
youngest student in the class. He has been able to excel in reading and math and we do not anticipate any further problems with him being hyperactive. He has been growing so fast that he is one of the tallest kids in his class.
Conventional
Functional
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 disease and 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 patients with celiac disease and cognitive impairment.
Celiac disease, brain atrophy, and dementia

Collin, P., et al., Neurology41: 372-375; March, 1991
Report of 5 patients who developed dementia before age 60 yrs Celiac disease confirmed by jejunal biopsy and serum antigliadin antibodies Conspicuously, gastrointestinal symptoms were mildthere may be an association of CD and dementia especially in the patients developing intellectual deterioration at a relatively young age.
December, 2006
Celiac disease
Present in 1.2% of population 23 million American children aged < 5 years (276,000 children) Another 23 million children 6-11years (276,000 children)
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 and returns with gluten challenge
Breast-feeding protects against celiac disease

Ivarsson, A., et al., Am J Clin Nutr 75(5): 014-21; May 2002
Evaluation of 627 Swedish children with celiac disease Time in relation to breast-feeding that gluten was introduced
Breast-feeding protects against celiac disease

Ivarsson, A., et al., Am J Clin Nutr 75(5): 014-21; May 2002
Risk of celiac disease if children < 2 years were introduced to gluten while being breast-fed was reduced by 41% If breast-feeding was continued after gluten introduced, 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: (<11) gliadin antibody IgA 5 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
s re
lv o
d e
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 gliadin antibody IgA
19 49
(<11) (<11)
Treatment:
gluten-free diet
Follow-up at one month:
sleep problems and anxiety resolved dystonia 90% better
Alzheimers disease
Neurodegenerative diseases
Inflammation
Oxidative stress
Arch Neurol. 2007;64(7):954-956; July, 2007
Damage to Lipids, Proteins, DNA, and RNA in Mild Cognitive 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 can serve as a therapeutic target to slow the progression or perhaps the onset of the disease.
Damage to Lipids, Proteins, DNA, and RNA in Mild Cognitive Impairment

Markesbery, W., Arch Neurol. 64(7):954-956; July, 2007
Better antioxidants and agents used in combination to upregulate defense mechanisms against oxidation will be required to neutralize the oxidative component of the pathogenesis of AD. It is most likely that to optimize these neuroprotective agents, they will have to be used in the presymptomatic phase of the disease.
TBARS in temporal lobe cortex of Alzheimers brains

TBARS (nmol/mg protein)
10.0
7.5
5.0 2.5 0 Alzheimer's

Tamoaka, A., et al., Neurology 54: 2319-2321;June, 2000
Control
Alzheimer's Control 60 45 30 15 0 Vitamin C Vitamin E Vitamin A
Mecocci, P., et al., Arch Neurol 59: 794-798; May, 2002

Reduced Risk of Alzheimers Disease in Users of Antioxidant Vitamin Supplements

Zandi, P.P., et al., Archives of Neurology 61: 82-88; January, 2004
Use of both Vitamins C and E reduced prevalence of Alzheimers by 78%
Idiopathic Parkinsons 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 Parkinsons patients
Randomized, double-blind, pilot evaluation of intravenous glutathione 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 intravenous glutathione in Parkinson's disease

Well tolerated, no adverse events either group Assessment of ADL and motor components of UPDRS
4 3 2 1
+ 3.5
change in UPDRS
0 -1 -2
- 2.8
-3 0 4 weeks 8 weeks
glutathione stopped
Food is information
Arch Neurol 62; July, 2005:,1067- 72
Insulin Resistance and Cognitive Impairment

The InCHIANTI Study Geroldi, C., et al., Arch Neurol 62; July, 2005:,1067- 72
Early in type 2 DM: progressive insulin resistance high fasting blood insulin levels normal fasting glucose
The IR syndrome
Insulin Resistance and Cognitive Impairment

The InCHIANTI Study Geroldi, C., et al., Arch Neurol 62; July, 2005:,1067- 72
523 participants 70-90 years of age MMSE Fasting plasma insulin, insulin resistance index, insulin sensitivity index
Prevalence of insulin resistance (%)
50
25
normal
cognitive impairment
Geroldi, C., et al., Arch Neurol 62; July, 2005:,1067- 72

Glucose tolerance status and risk of dementia in the community

The 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 versus
normal, abnormal GTT, or DM
Glucose tolerance status and risk of dementia in the community

The Hisayama Study
Ohara, T., et al., Neurology September
20, 2011 vol. 77 no. 12 1126-1134
normal
2 1.5 1 0.5 0 all cause dementia
impaired gtt
diabetes
Alzheimers disease
vascular dementia
Alzheimers disease
diabetes
Diabetes mellitus and the risk of dementia The Rotterdam Study

Ott, A., et al., Neurology 53:1937-42, December, 1999
6,370 patients RR of Alzheimers 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
Insulin use 4.3X risk More severe diabetes Longer history Direct effects More frequent hypoglycemic events
Diabetes and Alzheimers disease
Vascular disease Glycation of proteins Amyloid
Glyco-Oxidation
Advanced Glycosylation End Products (AGE) Posttranslational modifications of proteins amino group of protein reacts with monosaccharide
Advanced glycation end product level, diabetes, and accelerated cognitive aging
K. Yaffe, MD, et al., Neurology October 4, 2011 77:1351-56
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
no diabetes
diabetes
Mean 9-year 3MS change
-2
-4
-6
-8
Low
Medium
Tertile of Pentosidine AGEs
High
K. Yaffe, MD, et al., Neurology October 4, 2011 77:1351-56

Alzheimers Disease Synergistic Effects of Glucose Deficit, Oxidative Stress and Advanced Glycosylation End Products
Mnch. G., et al.,Journal of Neural Transmission 105 (4-5): 439461; July, 1998
AGEs are more than just markers of aging since they can exert adverse biological effects on tissues and cells including the activation of intracellular signal transduction pathways, leading to the upregulation of cytokine and free radical production (oxidative stress)
% annual brain volume change 0 -0.125 -0.250 -0.375 -0.500 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
% annual brain volume change 0 -0.125 -0.250 -0.375 -0.500 absent

present
APOE4 allele
% annual brain volume change 0 -0.125 -0.250 -0.375 -0.500 4.4-5.2 5.3-5.5 5.6-5.8 5.9-9.0 HbA1c (%)
-amyloid

AGE modulated -Amyloid Generates ROS Activates NFB Activates microglia Enhances production of superoxide radical and nitric oxide
AGEs
oxidative stress
COX-2
upregulation
Arachidonic acid
COX-2
2 series prostaglandins ( proinflammatory )
Investigations on Oxidative Stress and Therapeutica Implications in Dementia
Investigations on Oxidative Stress and Therapeutical Implications in Dementia

Durany, N., et al., European Archives of Psychiatry and Clinical Neuroscience 249(3): S68-S73; December, 1999
Glycated proteins produce nearly 50 fold more radicals than non-glycated ones pharmacologoical approaches which break the vicious cycle of oxidative stress and neurodegeneration offer new opportunities for the treatment of AD. These approaches include AGEinhibitors, antioxidants, and anti-inflammatory substances which prevent radical production.
cholinesterase inhibitors
AGEs
Alzheimers Disease - Functional Medicine Model
Advanced Glycosylated End Products Nutritional Therapy -
benfotiamine alpha-lipoic acid taurine resveratrol N-acetyl cysteine aspirin carnosine DHA low carbohydrate diet
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
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 pterostilbene at improving functional decits 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, inammation, and pathology markers known to be altered in AD. Two months of pterostilbene diet but not resveratrol signicantly 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, inammation, 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 ndings 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 pathology were positively modulated by pterostilbene but not resveratrol.
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.
Advanced Glycosylated End Products Nutritional Therapy -
benfotiamine alpha-lipoic acid taurine resveratrol N-acetyl cysteine aspirin carnosine DHA low carbohydrate diet
Preventable Risk Factors Account for Nearly Half of All Alzheimers Disease Cases
Published report: Lancet Neurology, July 18, 2011
A 25% reduction in seven risk factors could potentially prevent as many as three million cases of Alzheimers disease worldwide.
quitting smoking increasing physical activity increasing mental activity controlling blood pressure controlling diabetes managing obesity managing depression
These risk factors directly contribute to 2.9 million cases of Alzheimers 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 users
versus nonusers of statin drugs
Epigenetics
reducing inflammation increasing antioxidant protection enhancing neurogenesis enhancing neuroplasticity
reduce inflammation increase antioxidant function
epigenetic factors
Nrf2 activation
quinolinic acid
The Nrf2 pathway is the guardian of antioxidant function Enhancing Nrf2 activation may be useful in the treatment of brain degeneration
Oxidative stress Caloric restriction Curcumin Green tea extract Resveratrol Broccoli Garlic (allicin) DHA curcumin
Turmeric (Curcuma longa)



Curry Spice May Fight Alzheimer's Disease

Early 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 2,000 to 8,000 mg per day. The prospect of finding a safe and effective new approach to both prevention and treatment of Alzheimer's disease is tremendously exciting," said Gregory Cole, MD, a professor of medicine and neurology at UCLA.
reduces inflammation increases antioxidant function
Curcumin
Nrf2 activation
quinolinic acid
Curcumin oxidative damage

140.0
122.5 Untreated Curcumin
105.0 87.5 70.0 Tg +
Lim, G.P., et al., J. Neurscience 21(21): 8370-77; Nov.1. 2001
Nrf2 activation
Oxidative stress Caloric restriction Curcumin Green tea extract Pterostilbene Sulforaphane Garlic (allicin) DHA
Catalase Glutathione SOD GST (Phase II detox) Inhibits NF-kB Inhibits microglial
activation
The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating the transcription of more than 200 genes that are crucial in the metabolism of drugs and toxins, protection against oxidative stress and inammation ... We hypothesize that this signaling pathway plays a critical role in the determination of species longevity and that this pathway may indeed be the master regulator of the aging process.
Resveratrol
Organic Resveratrol
KEAP
Nrf2
gene activation
Nrf2 activation by various dietary plant extracts

Mol. Nutr. Food Res. 2010, 54, 113 Saturday, April 14, 12
Epigenetics
reducing inflammation increasing antioxidant protection enhancing neurogenesis enhancing neuroplasticity
Brain Anatomy 101
- The Hippocampus
Memory and MRI-based hippocampal volumes in aging and Alzheimers disease

Petersen, R.C., et al., Neurology 54: 581-587; February, 2000
Hippocampal volume accurately predicts memory function
Hippocampus
Stress damages it This is where neurogenesis occurs
Hippocampus
Stress damages it
Sustained stress
hippocampal destruction
Hippocampal neurons of control monkey
compared to chronically stressed, subordinate, ulcerated monkey
Uno et al., J Neurosci 9, 1989; 1705

Cortisol levels as a function of hippocampal atrophy

Cortisol (micrograms / dl) 20.000 15.938 11.875 7.813 3.750 0 1 2 3
Hippocampal lesion size

From: de Leon, et al., Abnormal cortisol response in Alzheimers disease linked to hippocampal atrophy. Lancet 2, 391-92;1988
Stress
No Stress
Marital status and the risk of Alzheimers disease

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 Alzheimers disease according to marital status (per 100 person years)
Helmer, C., et al., Neurology 53:1953-1958; 1999
Age (years)
the sisters expressing negative emotions did not live as long as the sisters conveying more positive ones (happiness, love, hope, gratitude and contentment)emotional states may play a role in determining cognitive function.
Dr. David Snowden University of Kentucky
Stress
No Stress
Stress
No Stress
Love
The greatest thing youll ever learn is just to love, and be loved, in return
Hippocampus
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 cholinesterase inhibitors do not seem to be evidence based _____________________ Benefits measured on rating scales were minimal _____________________ The methodological quality of the available trials was poor
Alzheimers Disease Prevention
These risk factors directly contribute to 2.9 million cases of Alzheimers disease in America and 17.2 million cases worldwide.
Archives of Neurology April, 2011
Review of ... all clinical trials of memantine vs placebo that included patients with mild AD. Conclusions: Despite its frequent off-label use, evidence is lacking for a benet of memantine in mild AD, and there is meager evidence for its efcacy in moderate AD. In the United States, nearly half of the patients with mild Alzheimers Disease and a substantial proportion of patients with mild cognitive impairment are receiving memantine despite a lack of evidence that the drug is helpful and some evidence that it is not.
Despite its frequent off-label use, evidence is lacking for a benet of memantine in mild AD, and there is meager evidence for its efcacy in moderate AD. Prospective trials are needed to further assess the potential for efcacy of memantine either alone or added to cholinesterase inhibitors in mild and moderate AD.
New England Journal of Medicine, March 8, 2012
There were no signicant benets 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, increased ability 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 marginally functioning cells including brain neurons. Patients receiving hyperbaric oxygen therapy enter a 1person 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
Treatment: Hyperbaric oxygen Glutathione
280
name deleted
282
Functional Enhancement calorie restriction
Brain Regeneration - Neurogenesis
Caloric restriction Physical exercise DHA Mental exercise
BDNF
Brain-Derived Neurotrophic Factor BDNF

A neurotrophin crucial to the structural integrity of adult neurons Neuroplasticity, learning Neurogenesis

Neurogenesis in the adult human hippocampus

Eriksson, P.S., et al., Nature Medicine 4(11); 1998: 1313-17
Human brain tissue was obtained postmortem from patients treated with BrdU, a thymidine analog that labels DNA during S phase
BrdU-labeled nuclei (arrows) in the dentate 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 genesis occurs in human brains and that the human brain retains the potential for self-renewal throughout life.
granule cell layer
BrdU (mitosis) TUJ-1 (neuronal differentiation)

Tim Bliss, PhD, The Hippocampus Book, Oxford University Press
Neurotrophic Factors
Nerve Growth Factor
(NGF)
Brain Derived Neurotrophic Factor
(BDNF)
Basic Fibroblast Growth Factor
(bFGF)

BDNF
BDNF
Neurogenesis Neuroplasticity Neuronal Repair
Mechanisms underlying the neuroprotective effects of calorie restriction.
Reduces ROS formation Reduces inammation Inhibits apoptosis Enhances mitochondrial replication
Apoptotic pathways are depicted in black and neuroprotective pathways are shown in red. Dark arrows indicate excitatory effects whereas inverted arrows are inhibitory
Marwan Maalouf , Jong M. Rho, Mark P. Mattson
ROS
ATP
Reduces ROS formation
Reduces ROS formation Reduces inammation
Reduces ROS formation Reduces inammation Inhibits apoptosis
Reduces ROS formation Reduces inammation Inhibits apoptosis Enhances mitochondrial replication
BDNF
BDNF
Neurogenesis Neuroplasticity Neuronal Repair
calorie restriction
neurogenesis
Mark Mattson, Ph.D

Senior Investigator, Chief, Cellular and Molecular Neurosciences Section and Chief, Laboratory of Neurosciences, National Institutes of Health, Bethesda, Maryland
Unrestricted
Diet restricted
130 125 120 115 110 105 100 95 90
BDNF levels in hippocampus

Jaewon Lee, et al.
Our data are the rst evidence that diet can affect the process of neurogenesis as well as the rst evidence that diet can affect neurotrophic factor production. These ndings provide insight into the mechanisms whereby diet impacts on brain plasticity, aging, and neurodegenerative disorders.
Unrestricted
BDNF mRNA level (% of restricted)
Diet restricted
150 125 100 75 50 25 0
cortex
hippocampus
Jaewon Lee, et al.

Unrestricted
Restricted diet
Dentate gyrus stained for BrdU after 3 months
Jaewon Lee, et al.

Unrestricted
Restricted diet
dentate gyrus
BDNF localization and expression after 3 months
Jaewon Lee, et al.

Unrestricted
Restricted diet
cortex
BDNF localization and expression after 3 months
Jaewon Lee, et al.

What about humans?
Evaluation of BDNF levels in 17 healthy obese or overweight subjects, 24-48 years, at baseline and after 3 months of 25% calorie reduction Diet: calories 55% carbohydrate, 20% protein, 25% fat
Basal
Final
7
Serum BDNF (ng/ml)
5.25
3.5 1.75 0
Basal and nal serum BDNF level in 17 overweight or obese subjects - calorie restricted
A. Veronica Araya, Ximena Orellana, Jaime Espinoza
Dietary factors play major roles in determining whether the brain ages successfully or experiences a neurodegenerative disease. High calorie diets increase the risk for Alzheimers disease and Parkinsons disease. Dietary factors may interact with disease-causing or predisposing genes in molecular cascades that either promote or prevent the degeneration of neurons.
PNAS January 27, 2009 vol. 106 no. 4 12551260
Assessment of memory
function in 50 healthy to overweight subjects. and after 3 months
Memory assessment at onset Comparison of 30% calorie

restriction vs control
control
calorie restricted
130
memory score (%)
120
110 100 90 baseline 3 months
PNAS January 27, 2009 vol. 106 no. 4 12551260

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
Calorie Reduction / Fasting
Gene expression
BDNF
Mitochondrial Function Neurogenesis
glucose
ketones
Overnight fast
CO2 glucose
glycogen ketones
amino acids
muscle
liver
fatty acids
CO2
fat
Prolonged fast
CO2 glucose
glycogen ketones
amino acids
muscle
liver
fatty acids
CO2
fat
-Hydroxybutyrate
6
Glucose
mMoles/liter
4.5
1.5
2.5
10
20
30
40
days of fasting
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 -OHB measured Neuropsychiatric eval - ADAS-COG, paragraph recall
Mechanisms underlying the neuroprotective effects of ketogenic diet.
BDNF
ketogenic fat carbohydrate protein 60% 20% 20%
standard 10% 70% 20%
Ketones are a superfuel for the brain
Upavasa
Enhancing Ketones
fasting coconut oil avocado carbohydrate restriction
Epigenetic Factors
Caloric restriction Physical exercise DHA
BDNF
Exercise enhances the proliferation of neural stem cells of middle-aged mice
Chih-Wei Wu, et al., J Appl Physiol 105: 15851594, 2008.
JAMA
Nicola T. Lautenschlager; Kay L. Cox; Leon Flicker; et al. JAMA, September 3, 2008Vol 300, No. 9
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
Change in ADAS-cog
0.3
-0.6
-1.5 time 0
18 months
control
intervention
control
intervention
0.30
-0.85
-2.00
change in ADAS-cog
In summary, the results of this randomized trial indicate that a physical activity program of an additional 142 minutes of exercise per week on average modestly improved cognition relative to controls in older adults with subjective and objective memory impairment.
Neurology Reviews January, 2011
Healthy study needed 6 miles/week to maintain 20 year adults 426 adults - 299 healthy, 127 cognitively impaired cognitive function and brain volume, cognitively impaired required 5 miles/week walking 5 mile weekly MMSE declined 5volume in non-exercising MMSE and brain points MRI
cognitively impaired, 1 point in exercisers
The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Randomized controlled trial,120 older adults, 1 year, stretching vs. aerobic exercise. Measurement of hippocampal volume, BDNF and memory function at baseline, 6 months and 1 year
These results clearly indicate that aerobic exercise is neuroprotective and that starting an exercise regimen later in life is not futile for either enhancing cognition or augmenting brain volume.
Physical Activity, Including Walking, and Cognitive Function in Older Women

Weuve, J., et al., JAMA 292; September, 2004: 1454-61
Nurses Health Study, 18,766 women aged 70-81 years,underwent cognitive testing twice over 2 years ( 1995 - 2001) compared to exercise from 1986 until baseline cognitive assessment

Physical activity is strongly associated with higher levels of cognitive function and less cognitive decline. The cognitive benefits of greater physical activity 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 a reduced risk of cognitive impairment and dementia; it may slow dementing illness. This may occur via facilitation of neuroprotective neurotrophic factors and neuroplasticity. Thus, ongoing, moderate-intensity physical exercise should be considered 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 activity 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 to being about 3 years younger in age and were associated with a 20% lower risk of cognitive impairment.
367
Caloric restriction Physical exercise DHA
BDNF
Docosahexaenoic acid (DHA) ( 22:63)
v=v=v=v=v=v=v=vv
OH
||
Dietary Omega-3 Fatty Acids Normalize BDNF Levels, Reduce Oxidative Damage, and Counteract Learning Disability after Traumatic Brain Injury
Wu, A., Journal of Neurotrauma 21(10): 1457-1467; October, 2004
DHA
Signal transduction and gene expression
relative risk of Alzheimer's disease 1.0 0.8 0.6 0.4 0.2 1 2 3 4 5

quintiles of intake - DHA
Morris, M.C., et al., Arch Neurol 60: 940-946; July, 2003
Fatty acid analysis of blood plasma of patients with Alzheimers disease, other types of dementia, and cognitive impairment
Interestingly, a decreased level of plasma DHA was not limited to the AD patients but appears to be common in cognitive impairment in aging.
November, 2006
Plasma Phosphatidylcholine Docosahexaenoic Acid Content and Risk of Dementia and 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 free of dementia mean 9.1 years. Measurement of plasma phosphatidylcholine docosahexaenoic acid at baseline.
Plasma Phosphatidylcholine Docosahexaenoic Acid Content and Risk of Dementia and Alzheimer Disease The Framingham Heart Study
Schaefer, E., et al., Archives of Neurology 63: 1545-1550; November, 2006
Top quartile of plasma PC DHA showed a 47% reduced risk of developing dementia of all causes in the Framingham Heart Study
Crude cumulative incidence of dementia in subjects with baseline plasma phosphatidylcholine docosahexaenoic acid (PC DHA) levels in the upper quartile compared with those with levels in the lower 3 quartiles.
Sources
Fish and fish oils DHA Microalgae
Omega-3 DHA boosts memory for healthy adults

13-Jul-2009 Related topics: Omega-3, Research, Nutritional lipids and oils, Cardiovascular health, Cognitive and mental function
Daily supplements with the omega-3 fatty acid docosahexaenoic acid (DHA) may improve both memory function 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 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 roughly equivalent to having the learning and memory skills of someone three years younger.
Results of the MIDAS 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 Hippocampal Formation as a Function of the Clinical Progression of Alzheimers Disease
Ho, L., et al., Arch Neurol 58: 487-492; March, 2001
200
Cox-2 staining Intensity in CA3
100
0 0 0.5 1 2 5 Clinical dementia rating

relative risk of Alzheimer's disease 1.0 0.8 0.6 0.4 0.2 1 2 3 4 5
quintiles of intake - DHA

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

Neuroplasticity
The ability of neurons and their networks to change based upon experience
Donald Olding Hebb, Ph.D,

1904 1985
The Organization of Behaviour, 1949 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 ring it, some growth process or metabolic change takes place in one or both cells such that A's efciency, as one of the cells ring B, is increased.
"Neurons that re together wire together."
Hebb's Law
The Organization of Behaviour, 1949 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 ring it, some growth process or metabolic change takes place in one or both cells such that A's efciency, as one of the cells ring B, is increased.
"Neurons that re together wire together."
Hebb's Law
Michael Merzenich, Ph.D
Experience coupled with attention leads to physical changes and future functioning of the nervous system... moment by moment we choose and sculpt our ever-changing minds, we choose who we will be the next moment in a very real sense, 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 we lead. - 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 ST UVW XY Z
A man and a woman kissing
Alvaro Pascual-Leone, MD, PhD
Mental practice alone may be sufficient to promote the plastic modulation of neural circuits. - Alvaro Pascual-Leone, MD, PhD
in, Train Your Mind, Change Your Brain, by Sharon Begley
The mind is everything. What you think you become. - Buddha
Neuroplasticity
The ability of neurons and their networks to change based upon experience This experience can be intrinsic and self directed
Andrew Newberg, MD
Franciscan nuns in centering prayer focusing on a particular phrase or prayer from the bible.
Andrew Newberg, MD
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
Anterior cingulate Strengthened by spirituality
empathy compassion social awareness 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 and behavior, planning for the future, abstract conceptualization
David Perlmutter and Albert L. Rhoton, MD, Microsurgical Anatomy of the Distal Anterior Cerebral Artery, Journal of Neurosurgery, 49 (2): 204-228; August 1978
David Perlmutter and Albert L. Rhoton, MD, Microsurgical Anatomy of the Distal Anterior Cerebral Artery, Journal of Neurosurgery, 49 (2): 204-228; August 1978
Anterior cingulate
Amygdala
Amygdala Inhibited by spirituality
ght or ight response to fear,

real or imagined instantaneous response
Amygdala
Anterior cingulate
real or imagined instantaneous, unrestrained response
empathy compassion social awareness intuition measured response
Amygdala
Anterior cingulate
Amygdala
Anterior cingulate
meditation - prayer
DHA
calorie restriction
physical exercise
fasting
But let us not forget that knowledge and skills alone cannot lead humanity to a happy and dignied life. What humanity owes to personalities like Buddha, Moses, and Jesus ranks for me higher than all the achievements of the inquiring and constructive mind. Albert Einstein, The Human Side
Alzheimers disease protocol Evaluation

History - stepwise or slowly progressive? Head trauma remote or recent? Associated issues - gait disorder, urinary incontinence, sleep disorder Family history Medications Comorbidities - diabetes, vascular disease, obesity Physical exam Neurological exam - including cognitive function
Alzheimers disease protocol 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 Hyperbaric oxygen - depending on degree of cerebrovascular disease
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 (MethylProtect), red cell studies, metals, glucose)
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 Physical exam Neurological exam - including cognitive function
Multiple sclerosis protocol 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
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)
Lifestyle - exercise (aerobic - 20 minutes daily, avoid overheating, motion program - yoga, pilates), meditation, sleep
Supplements - MCT oil - 1 TBSP BID, turmeric, sulforaphane, green tea extract, resveratrol, (Nrf2 Activator) , DHA - 1200mg /day, Coenzyme Q10, NAC, alpha-lipoic acid, phoshatidylserine, acetyl L-carnitine, (BrainSustain NeuroActives) probiotics (ProBio Defense), (treat labs - vitamin D, homocysteine, (MethylProtect) red cell studies, dysbiosis)

Functional Approaches To Neurodegenerative Disorders

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A Functional Medicine Approach to Neurology 2012

Saturday, April 14, 12

Lancet 358; August 11, 2001: 461- 467

Saturday, April 14, 12

February 23, 2004

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Saturday, April 14, 12

Risk of Alzheimers disease and duration of NSAID use

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Alzheimers patient 75 y/o male

Activated microglia PET

Nonsteroidal Anti-inflammatory Drugs and the Risk of Parkinsons Disease

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Nonsteroidal anti-inflammatory drugs may protect against Parkinsons disease

Comparison of 293 PD patients and 296 controls

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Visualizing amyloid burden using Pittsburgh Compound B

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antimicrobial peptides (AMPs)

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Antimicrobial activity of A42

Organism Candida albicans Escherichia coli Staphlyococcus epidermidis Streptococcus pneumonia

MIC (g/ml) A42 0.78 1.56 3.13 6.25

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Visualizing amyloid burden using Pittsburgh Compound B

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AD brain homogenates have increased antimicrobial activity against C. albicans.

Brain homogenates inoculated with log-phase C. albicans.

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antimicrobial peptides (AMPs)

Saturday, April 14, 12

Vol.19, July, 2005; 1067-1077

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toll-like receptor were in trouble now !!

mRNA VDR vitamin D receptor

microglia Toll-like receptor

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microglia Toll-like receptor

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

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

Vitamin D and the Brain

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Vitamin D and the Brain

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