The Clinical Potential of CalorieRestricted and Ketogenic Diets in
the Treatment of Alzheimer’s
Disease in the Context of
Hyperinsulinemia
Robert Kachko, ND, LAc
Inner Source Natural Health
and Acupuncture
345 7th Avenue, New York, NY
Two Bold Promises…
How many of you feel comfortable treating
Alzheimer’s and other neurodegenerative
diseases?
1.By the end of this lecture you’ll
have enough tools to REVERSE
mild to moderate AD
2.You already know how!
A Continuum
Observable
pathology
(changeable)
• Degeneration doesn’t occur overnight (decades)
• Diseases of the brain are at their core systemic and
multi-factorial
• Neurogenesis is a part of normal brain processes
• If we don’t treat them this way, what we can
accomplish will be marginal
• At least half of the people who take only the available
pharmaceuticals don’t respond
Alzheimer’s, like every chronic disease, is first a systemic lifestyle
disease
“Humans live on one quarter of what
they eat; on the other three quarters
lives their doctor.”
- 3800 BCE inscription on Egyptian Pyramid
At the heart of naturopathic medicine
• In the context of our evolutionary biology…
• Human genome: “Stone age genes in a computer age world”
• A thrifty genome means we must respect our epigenome
• Bioenergetics and nutrient sensing play a crucial role in AD pathology
• Modern naturopathic medicine in the US rests on the shoulders of the
Hygienic Physicians
• The Motivational Triad:
1. Exert the least amount of energy
2. For the highest feasible reward
3. And increase our lifespan long enough to procreate
• But our physiology is being hijacked!
• Have you ever seen an obese animal in the wild?
• Our typical mechanisms of satiety can no longer be trusted ->
overeating has become the norm in our society
• So, CR is not starvation but rather finding a new appropriate intake
pattern aligned with our evolutionary biology
What is the
ideal set
point?
An Aging Global Population
Petsko GA. A seat at the table. Genome Biology. 2008;9(12):113.
The Plague of the Modern Brain
• More than 80% of elderly dementia cases
worldwide due to AD (1)
• If you’re not seeing it in your practice yet, you
will soon:
• 15% of individuals 70+ have dementia
• Number of 90 year olds to increase 5x by midcentury
• It is expected that by 2050, one new case of
AD is expected to develop every 33 seconds
(or nearly a million new cases per year)
• Total estimated prevalence: 13.8 million (2)
Monetary Costs of Dementia in
the United States
• Prevalence of dementia in U.S. Population over 70 yrs:
• 14.7%
• Yearly cost per person attributable to dementia:
• $41,689 - $56,290
• Total cost for care of :
1.
Dementia
$159 billion - $215 billion
2.
Heart disease $102 billion
3.
Cancer
$ 77 billion
AD is already the 3rd leading cause of death in the US
Reference (3)
Amyloid-β and Tau:
“The Trigger and Bullet in Alzheimer Disease Pathogenesis”
Reference (4)
Reference (5)
The Hippocampus:
Brain circuitries
modified by diet
Neuroendocrin
e factors and
ANS impact
nutrient
utilization and
insulin
secretion
Reference (6-8)
“Diabetes of the brain” :
AD and Hyperinsulinemia
• Current Estimated lifetime risk of DM: 38% (9)
• HbA1c correlates with lower cognitive capacity
and changes in hippocampal microstructure (10)
• Risk of AD attributed to hyperinsulinemia: 40%
• 50–100% increase in overall risk (11,12)
• T2DM and positive APOE e4: higher neuritic
plaques and neurofibrillary tangles in the cortex and
hippocampus (14)
• High glucose: Changes in cognitive capacity and
hippocampal microstructure even without DM2 (15)
• Autopsy studies: correlation between increased
pancreatic amyloid deposition and the progression of
AD (16)
The connection:
AD and Hyperinsulinemia
1. Glycogen Synthase Kinase 3
(GSK3)
2. Insulin Degrading Enzyme (IDE)
3. APP degradation (trophic vs antitrophic mechanisms)
4. AMPK/MTOR (disrupted
autophagy, activated by Abeta)
Insulin Resistance
AD
• Hallmark of pathology: impaired cerebral glucose utilization
• Impairments in brain insulin/IGF signaling lead to increased
expression of amyloid-β precursor protein (AβPP) and accumulation
of AβPP-Aβ.
• Mechanisms (17):
1. Activated kinases which phosphorylate tau
2. Higher APP expression
3. Oxidative and ER stress
4. Increased ROS and RNS = DNA, RNA, Lipid, Protein
damage
5. Direct mitochondrial dysfunction
6. Increased pro-inflammatory and apoptotic cascades
7. Dowregulation of genes which enhance cholinergic
homeostasis
GSK3: Increased amyloid formation
• GSK-3 could play a role in amyloid formation by enhancing bsecretase activity
• GSK3-beta inhibitors have been shown to reduce AD
pathology (19)
• Impaired insulin signaling: weakened inhibition of
glycogen synthase kinase 3 (18)
• Cyclical: Amyloid accumulation can induce further
GSK-3 activation through the mechanisms of oxidative
stress and inflammation.
1. GSK-3: implicated in modulating the
hyperphosphorylation of tau proteins and
neurofibrillary tangles
2. It is possible that GSK-3 disrupts Ach activity and
accelerates axonal degeneration (20)
IDE: Decreased amyloid removal
• Main extracellular route of amyloid removal
1. Insulin competes for IDE degradation with beta
amyloid (21)
2. Elevated levels of serum insulin in response to
administered glucose in patients with AD are due
to defects in insulin clearance via IDE rather than
to overproduction of endogenous insulin
• Thus, either a primary genetic defect or competitive
inhibition from chronic hyperinsulinemia can both be
responsible for the accumulation of Aβ in the
pathogenesis of AD (22)
Trophic vs Anti-Trophic Factors and Prionic Loops
Inhibited APP Degradation
• Amyloid beta precursor protein (APP) cleaved by beta-secretase,
gamma-secretase and other protein complexes
• In vitro study: Under normal conditions, majority of APP protein is
cleaved by alpha-secretase within the Ab domain, generating a
secreted N-terminal fragment (sAPPa) and a membrane-bound Cterminal fragment of 83 amino acids (C83) which excludes Ab
generation (protective)
• Elevated plasma glucose impacts protein degradation
• but not APP gene transcription (NfkB related promotion)
1.
2.
Proteasome and lysosome pathways impacted by high sugar
Post-translational modification impacted through
glycosylation, phosphorylation and ubiquitination
• APP half life increased from 25 to 60 minutes (23)
Mechanisms
Overall Calorie Restricted (CR) and
Intermittent Fasting (IF) Diets
AKA “Show me a drug that does all of this…”
The Physiology Of Fasting
Sources of Fuel through the 3 stages of Fasting
(Textbook of Natural Medicine, Figure 50-1)
CR Whole-Body Mechanisms
• Nutrient Sensing (Insulin), Insulin Signaling (IGF-1) and
mTOR Pathways
• CR suppresses these pathways (24)
• Oxidative damage
• CR has been shown to inhibit oxidative damage to lipids,
DNA and proteins (25-30)
• Mice on 30-40% CR had reductions in oxidative stress as
measured by levels of protein carbonyls (protein damage)
and thiobarbituric acid reactive substances (lipids)
compared to ad libitum fed mice (non-reversible) (31)
• Enhanced genomic stability
• CR Induces NER, BER, and double-strand break repair
(32)
CR Whole-Body Mechanisms
• Inflammation
• Mitigates the damage of neurological and cardiac
ischemia/reperfusion injury, ozone induced lung inflammation,
and resolution of foot-pad edema after carrageenan injection in
rats and mice
• Reactive reductions of TNFalpha, Interleukin-1beta, Interleukin-6,
and several other pro-inflammatory prostaglandins (33)
• Inhibits NfK-B which modulates APP gene expression (34)
• Mitochondrial biogenesis
• CR and CREX (CR plus exercise) induce mitochondrial
biogenesis without changing the activity of key enzymes involved
in the TCA cycle, lipid beta-oxidation, or the ETC
• CR up-regulates SIRT1 which induces mitochondrial regeneration
and mitophagy (75)
Hormesis
“Intermittent stressors” induce
3 main mechanisms:
1. Increased synaptic activity and release of
neurotrophic factors (ie BDNF)
2. Activation of adaptive cellular responses
against oxidative stress, inflammation,
metabolic damage
3. Increase in peripherally produced nervous
system modulators such as ketone bodies
• Stay tuned…
Cognition specific effects:
Brain Derived Neurotrophic Factor (BDNF)
1. Orchestrates oxidative and metabolic stress response
2. Modifies synaptic plasticity: making new connections
• Human studies: compromised levels of BDNF in the
preclinical stages of the disease and at postmortem
(37)
• Shown to increase neurogenesis most in hippocampus
(35)
• Adult hippocampal neurogenesis – stem cells –Highly
open to the environment via blood vessels - and thus
systemic changes (36)
• CR consistently increases BDNF production
Cognition-specific effects: PGC1α
• PGC-1α expression is decreased in the brains of persons with
AD as a function of dementia severity
• Experimental hyperglycemic conditions in cortico hippocampal
neuron cultures derived from Tg2576 embryos show inhibited
PGC-1α expression (and thus inhibited α-secretase)
• PGC1 participates in hippocampal synapse formation and
plasticity (38)
• PGC1 and thus mitogenesis upregulated by CR in brains of
mice, through induced nitric oxide synthase (39,40)
Cognition-specific effects:
Nrf2
• Decreased Nrf2 levels were detected in
the nucleus of hippocampal neurons of
human AD brains (41)
• ROS increase Nrf2 activation
• Nrf2 elevation delayed AD in APP/PS1 mice
• CR improves Nrf2 status
Outcomes
AKA: “Just consider the potential here…”
Types of Calorie Restriction /
Intermittent Fasting
• What to consider in choosing the right type?
• Compliance
• Comorbidities
• Limited human data distinguishing which is best
• Key: macronutrient levels and micronutrient levels are still sufficient
and optimized for each individual
1. Daily calorie restriction (20-50% of total calories)
2. ADF – alternate day fasting
• 600 calories men / 500 women - every other day
3.
Daily Intermittent Fasting
• Daily up to 16-18 hours
4.
5:2 diet
• 5 days normal eating, 2 days 600 calories per day
5.
6.
7.
5 days out of the month
24-36 hours / 1 day per week
Ketogenic Diet (similar effects)
Insulin control: Clinical Outcomes
• Body Weight and Visceral Fat Loss
• 3%–8% reductions in body weight after 3–24 weeks of treatment
• Along with 4-7% reductions in visceral fat
• On average, ADF (3-4 fast days per week) appears to produce a
0.75 kg weekly reduction in body weight, whereas IF (1-3 fast
days per week) produces a 0.25 kg weekly weight loss.
• *Insulin sensitivity via HOMA-IR correlates with weight loss in
most studies (best study: 8% weight loss leads to 33% reduction)
• Total CR tends to reduce resistance more than IF or ADF
• Glucose/Insulin levels
• Insulin: In studies of IF/ADF on pre-diabetic individuals, decreases
in fasting insulin ranged from 20% to 31% after 8–12 weeks of
treatment
• Glucose: Consistent but minor 3-6% decrease in fasting glucose in
IF/ADF (with almost no change in CR studies)
Reference (42)
Cognition-specific outcomes
• Animals:
• Dozens of rat studies show impact on surrogate markers discussed and
memory outcomes
• Specifically in transgenic mice bread for AD
• Rats maintained on IF produce less amyloid-beta and seem to be more
resistant to amyloid-beta impairment of synaptic function (43)
• Improved recovery from spinal cord injury (45)
• 50% reduction in lesion size and improve growth of new nerve cells
• Improved recovery from TBI
• Fasting for 24 hours after moderate TBI confers neuroprotection,
maintains cognitive function, and improves mitochondrial function.
• Systemic neurodegeneration
• IF has been shown to be effective in animal models of Huntington’s
Disease, Parkinson’s Disease, and stroke (44)
•
Cognition-specific outcomes
• Epidemiological studies (humans):
• Higher intake of calories and fat in 980 elderly individuals studied
over 4 years associated with 2.3x higher AD risk, but only in
APOE4+ (46)
• In an 18 year study, those who habitually consumed fewer
calories had lower AD rates. For every 1.0 increase in BMI at age
70 years, AD risk increased by 36% (47)
• In a population-based case-control study 1072 cognitively healthy
individuals age 70-92, high caloric intake was associated with a
nearly two-fold increased odds of having Mild Cognitive
Impairment (48)
Cognition-specific outcomes
• Intervention Studies (Humans - more to come):
• 3–4 months CR improved cognitive function
(verbal memory) in overweight women and in
elderly subjects (76)
• In parallel with reducing fasting insulin and
CRP
• 1 month on a low glycemic diet
• Improved delayed visual memory,
cerebrospinal fluid biomarkers of Aβ
metabolism and brain bioenergetics (78)
Cognition-specific outcomes
• Adherence to a daily 30% CR regimen in a cohort of 50
healthy elderly subjects (mean age: 60.5 years; mean
BMI: 28) improved performance on memory tests
versus both a group with increased intake of PUFAs
and the control AL group (77)
• Verbal memory scores improved with a mean
increase of 20% after 3 months of intervention in
the CR group
• 32 aged Malaysian men (avg. age: 59.7 ; BMI: 27) 25% CR diet in conjunction with two days/week of
religious fasting (76)
• Marked reductions in scores on tests of tension,
anger, confusion, and depression
SIMILAR OUTCOMES, HIGHER COMPLIANCE?
THE KETOGENIC DIET
Ketogenic Diet (KD)
• Defined: less than 40g of carbohydrate per day
• moderate in protein and high in quality fat
• Varies, one example: max 30 g carbohydrate, 1 g/kg body
weight protein, 20% saturated fat, and 80%
polyunsaturated and monounsaturated fat
• Biochemistry review:
• Preferred energy substrate of the brain is actually ketone
bodies (acetone, acetoacetic acid, and betahydroxybutyrate) rather than glucose.
• The AD brain tends to utilize glucose poorly anyway
• The brain uses 16% of the body’s total O2 consumed but
accounts for only 2% of total body mass.
• The average human brain metabolizes 110-145 g/day of
glucose for ATP production, and during severe
restriction the available glucose from body stores of
glycogen can supply only 33g /day.
Ketogenic Diet (KD)
• In acute states, glycogen stores of the brain
provide enough glucose for only 5 minutes of
normal function.
• In the nourished state, Carnitine
palmitoyltransferase - I is inhibited by insulin
signaling and few KB are produced
• this is the rate limiting step for FFA transfer into
mitochondria.
• The typical western diet is rich in carbohydrates
and leads to very little ketone production.
• Alzheimer's disease patients frequently
undergo changes in food preference toward
more calories and sweet, carbohydrate-rich
foods (49)
This is not ketoacidosis…
• Under normal conditions the concentration of KBs is usually
very low (< 0.3mmol/L) compared to glucose (approx.
4mmol/L)
• During physiological ketosis (fast or very low calorie KD)
ketonemia reaches maximum levels of 7/8mmol/L with no
changes in pH
• In uncontrolled diabetic ketoacidosis this can exceed
20mmol/L with a concomitant lowering of blood pH
• Blood levels of KBs in healthy people do not exceed
8mmol/L because the central nervous system (CNS)
efficiently uses these molecules as energy supply in place of
glucose
• KB improve glucose homeostasis and insulin resistance
• In considering extended fasts for increasing production of KB,
intermittent daily fasting has been shown to be more effective
than overall calorie restriction (50)
Ketogenic Diet Mechanisms
1.
2.
3.
4.
5.
6.
7.
Mitochondria produced lower amounts of ROS in animals fed ketogenic
diets compared to those who were not (51)
Glutathione and glutathione peroxidase was higher in the hippocampus
when fed KD (51)
Increases in cerebral ATP and Phosphocreatine concentrations
Anti-apoptotic mechanisms including decreased effects of clusterin and
Caspase-3 and increased activity of calbindin
Decrease in seizure-induced neuronal hyperexcitability (KD have been
used to treat seizures successfully since the 1920s), along with increased
production of neuro-inhibitory neurotransmitters such as GABA and
decreased production of neuro-stimulatory ones such as glutamate (52)
Increased rates of chaperone-mediated autophagy, possibly by increased
oxidation of cellular components by BHB (52)
Increase in NADH and the mitochondrial pool of acetyl CoA and
Succinate (52)
Bypassing inefficient
insulin / glucose
dependent neuronal
bioenergetics:
“The hippocampus is especially vulnerable to
glucose insufficiency and in AD, cerebral
glucose metabolism is reduced by 20–40%. In
addition, the reduction in glucose metabolism
rate correlates with senile plaque density. The
hypometabolism seen in AD has recently
attracted attention as a possible target for
intervention in the disease process.
Much of the benefit of KB can be attributed to
their ability to increase mitochondrial
efficiency.” (53)
Medium Chain Triglycerides
• The consumption of MCT leads directly to an increase in plasma KB
regardless of the actual macronutrients consumed in addition to this
1.
A single 40g dose of MCT induced a significant elevation in betahydroxybutyrate 2 hours after consumption.
• Improvement was rapid (90 min post-prandial) and significant, and was
reproducible when extended to dosing over 90 days Interestingly, the
effect was most notable in APOE E4(-) subjects. (54)
2.
3.
AC-1202 is a medium chain triglyceride composed of glycerin and caprylic
acid:
• Significant cognitive improvements in APOE4- but not + individuals,
but effects were not sustained beyond 2 week washout period
(continued therapy, larger studies needed) (74)
E4(-) subjects may have higher fasting insulin levels than in E4 (+) subjects
(55)
• KB do not cross the BBB alone and are transported via
Monocarboxylate transporters (MCTs), which have been shown to be
elevated in patients with insulin resistance (55). Thus, those with
insulin resistance are more susceptible to the benefits of Medium
Chain Triglycerides.
• Dose: 2 tablespoons coconut oil = potentially therapeutic dose of 20g MCTs
Who shouldn’t fast
• Cautions
•
•
•
•
•
•
•
•
•
Anyone with disordered eating patterns
Diabetics
Thyroid: T4 to T3
Adrenal insufficiency, chronic stress, cortisol dysregulation
Cancer
Pregnant
Children
Undernourished
Female hormonal issues
A COMPREHENSIVE
NATUROPATHIC
APPROACH
Appendix - AKA: “Here’s where
it all comes together…”
A Comprehensive Naturopathic
Approach
• Diet
• Anti-oxidants
• Nutrient cofactors
• CR Mimetics (Resveratrol)
•
•
•
•
•
•
•
•
Exercise
Sleep
GI Health
Stress Reduction / Positive mental outlook
Community building/Social Engagement
Cognitive Exercises
Addressing Environmental Toxicity
Acupuncture
Reversal of cognitive decline: A novel therapeutic program
AGING, September 2014, Vol. 6 No.9
Reversal of cognitive decline: A novel therapeutic program
AGING, September 2014, Vol. 6 No.9
Cognitive impairment reversed
Diet
• MIND Diet Study - February 2015 (56)
• Mediterranean + DASH + Cognition-specific additions
• No recommendation for fruit except positive score for
berries
• Only one fish meal per week vs 6 per week in MD
• 10 brain healthy food groups (green leafy vegetables, other
vegetables, nuts, berries, beans, whole grains, fish, poultry,
olive oil, and wine) and
• 5 unhealthy food groups (red meats, butter and stick
margarine, cheese, pastries and sweets, and fried/fast
food).
• 53% reduction in the rate of AD in the highest tertile
• 35% reduction for middle tertile
• Consider factoring in: Low Glycemic Load
Reference (57)
Vitamin E
• “Among patients with mild to moderate AD, 2000 IU/d of alpha
tocopherol compared with placebo resulted in slower functional
decline. There were no significant differences in the groups receiving
memantine alone or memantine plus alpha tocopherol.”
• -> Delay in clinical progression of 19% per year compared with
placebo (6.2 months over the follow up period)
• Mixed tocopherols and tocotrienols provide a better alternative
• PreADViSe trial: SELECT trial evolved into a trial studying effects of
Selenium+Vitamin E on AD (in progress)
Vitamin D
• 1,25OH-vitamin D3 regulates neurotrophin expression:
• nerve growth factor, neurotrophin 3, and glial-derived
neurotrophic factor
• Reduces amyloid-induced cytotoxicity and apoptosis in
primary cortical neurons.
• Study: 1,658 elderly adults free from dementia, cardiovascular
disease, and stroke (58)
• 5.6 year follow-up:
• Deficient (25-50 nmol/L): 51% increased risk of all-cause
dementia
• Severely deficient (<25 nmol/L): 122% increased risk
• Note: No benefit for dementia risk found beyond 50 nmol/L
Resveratrol
• Calorie restriction-mimetic properties
• Resveratrol enhances clearance of amyloid-beta peptide,
promotes cleavage of amyloid precursor protein, and overall
reduces neuronal damage (59)
• Improves insulin sensitivity via AMPK and SIRT1 (PPAR-1alpha)
and reduces ROS production, TNF-alpha and CRP (60)
• Need large trials in humans. A recent Sept 2015 study did note
that resveratrol was safe and well-tolerated in AD patients, but
clinical conclusions could not be made (61)
Nutrient Precursors: DHA
• Randomized, double-blind, placebo-controlled clinical study of
485 healthy subjects over 55 with mild memory complaints
given 900mg DHA/d or placebo
• Primary outcome: CANTAB Paired Associate Learning (PAL), a
visuospatial learning and episodic memory test
• -> 2-fold reduction in the number of visuospatial learning and
episodic memory errors
• -> 7-year improvement in PAL test performance versus a 3.6-year
improvement with placebo
Exercise
• Synergism between minor stressors of exercise and CR in
raising BDNF levels
• MRI scans administered at baseline and at an 18-month
follow-up in 97 healthy, cognitively intact older adults
• Leisure time physical activity associated with sustained
hippocampal volume (specifically) in those at high genetic APOE4
risk (but not in others) (62)
• MANY large cross-sectional and longitudinal studies available
Molecular Psychiatry (2013) 18, 864–874
Sleep
• Sleep–wake and circadian disruption often occur early in the course of
the disease (63)
• Sleep deprivation exacerbates Aβ plaque pathology
• Poor sleep also promotes tau phosphorylation and neuronal injury
• REM and Slow-Wave Sleep diminished in AD (64)
• Prolonged-release melatonin (65):
• 6 month randomized double blind trial 80 patients, average age
75.3 years [range, 52–85 years]) diagnosed with mild to moderate
AD
1. Improvements in cognition including self-care and ADL
• Improvement in MMSE scores after 24 weeks of 1.5 points,
while the placebo group scores deteriorated by 2.8 points
2. Improvements in sleep
• Though other studies have shown no effect of melatonin on
sleep specifically in the AD population
Environmental
toxicity
Ref (66)
Cognitive Exercise
• Community-dwelling adults aged 65 and older (N = 487)
without a diagnosis of clinically significant cognitive
impairment (67)
•
1 hour per day, 5 days per week, for 8 weeks
• Outcomes:
• RBANS Auditory Memory/Attention improvement was
significantly greater in the experimental group (3.9 points) than in
the control group (1.8 points)
• Other improvements:
• Word list total score, word list delayed recall, digits backwards,
letter–number sequencing
• Several patient-friendly programs commercially available
Social Engagement
• Meta-analysis: 148 studies, involving 308,849:
• Decreased mortality is associated with increased
social engagement (68)
• Higher “Social Network Index” to greater quality of
life, lower rates of dementia and of overall mortality
(69)
• Rate of global cognitive decline was reduced by an
average of 70% in persons who were frequently
socially active (90th percentile) as compared to
persons who were infrequently socially active (70)
• Especially important beyond the age of 70
Acupuncture
• Systematic Review and Meta-Analysis of 10 RCTs
included a total of 585 patients, age 46 to 81,
treatment range from 4 to 24 weeks
• Acupuncture superior to drugs in improving MMSE
• statistically significant difference between
acupuncture plus donepezil and donepezil alone in
improving the MMSE score
Limited evidence
• Trehalose
• Differentially inhibits aggregation and neurotoxicity of betaamyloid 40 and 42 (71)
• No human studies to date
• Zinc
•
•
•
•
Shown to inhibit glutamate induced neuro-toxicity
AD patients tend to be zinc deficient (72)
Small double blind study showed benefit over 6 months (73)
Zinc:copper ratio key
• Botanicals
• Curcuma longa, Bacopa monnieri, and Withania somnifera have
limited study evidence and cannot be currently recommended as
standalone therapies for AD
A Call To Action
Naturopathic Medicine Week 2015
• Who better than NDs to lead the charge in
advancements in neurodegenerative disease?
• Human studies are lacking -> precisely why the work
needs to be done
• To reach our potential, forged by our collective ambition,
we need:
• Increased awareness of Naturopathic Medicine
• Improved data on clinical and cost effectiveness
•
“Human progress is neither automatic nor inevitable... Every
step toward the goal of justice requires sacrifice, suffering,
and struggle; the tireless exertions and passionate concern
of dedicated individuals.”
Martin Luther King, Jr.
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