Power Point2

How a change in antioxidant therapy with antiangiogenetic properties in relation to the

prevention and prevalence of Alzheimer's disease will affect the

biosphere in 50 years

Sammy Howard, Jamie May, Cailean Parker, Caymen Rexrode, Jennifer

Roach

Retrieved from http://www.zmescience.com/tag/alzheimer/

Introduction

• Characteristics• Cause• Pathophysiology• Diagnosis• Prevention/Management

Methods

• Mathematical model

Results

Discussion and Conclusion

Introduction: Characteristics

• Pre-dementia: short-term memory loss• Begins with ageing or stress (Waldemar, et.

al. 2007). • Effects the hippocampal complex which is

involved in the encoding, storage and retrieval (Backman, Jones, Berger, Laukka, & Small, 2004). • Impaired semantic memory

• Apathy, depression – mild cognitive impairment (Alzheimer’s Association).

Retrieved from http://drjockers.com/natural-solutions-to-beat-alzheimers-disease/


• Early: memory problems• New facts and memories impacted more • Language problems – smaller vocabulary and decreased fluency

(Frances, Palmer, Snape, & Wilcock, 1999). • Difficulties with executive functions, perception, and performing

movements (Waldemar, et. al. 2007). • Decreased blood flow in the brain (Waldemar, et. al. 2007).


• Moderate: unable to perform most common activities of living• Long-term memory is impaired• Behavioral and neuropsychiatric changes• Inability to perform daily tasks, remember words, read and write,

and coordinate movements.• Deposits of amyloid plaques in temporal and frontal cortexes

(Brookmeyer, Gray, & Kawas, 1998).

Introduction: Characteristics• Advanced: completely dependent on

caregivers • Language is reduced to simple words and

phrases• Extreme amount of apathy and exhaustion leads

to muscle mass and mobility deterioration• AD is normally not the cause of death, but

rather side-effects from the disease such as pressure ulcers and pneumonia are fatal (Brookmeyer, Gray, & Kawas, 1998).Retrieved from

http://imgbuddy.com/simple-human-brain-drawing.asp

Retrieved from http://usatoday30.usatoday.com/news/health/2008-10-02-q-and-a-doraiswamy_N.htm

Introduction: Cause - Genetics• The exact cause of AD is not known, although genetics have been attributed

to the most likely cause (Buckner, et. al., 2005). • Genetic heritability accounts for up to 79% of AD cases (Wilson, et. al., 2001). • Mutated amyloid precursor proteins and presenilins 1 and 2 increase

production of amyloid-beta plaque – main component of senile plaques (Waring, & Rosenberg, 2008).

• Late-onset AD is mainly attributed to apoplipoprotein E gene specifically the E4 allele.• ApoE plays a fundamental role in maintenance and repair of neurons (Frances, Palmer,

Snape, & Wilcock, 1999).

Introduction: Cause - Genetics

• ApoE4 may increase amyloid-beta deposition in plaques and impair its clearance (Strittmatter, et. al., 1992).

• Non-plaque amyloid-beta oligomers bind to surface receptors on neurons and change the synapse structure• Disrupts neuronal communication (Lacor, et. al., 2003).

• Inhibition of neurite extension by apoE4 appears to be related to alterations in the cytoskeleton, especially an effect on microtubule stability (Polvikoski, et. al., 2005).

Introduction: Cause – Amyloid Hypothesis

• Extracellular amyloid-beta deposits are the fundamental cause of the disease

• Toxic non-plaque amyloid-beta oligomers bind to a surface receptor on neurons and change the structure of the synapse

• The location of the gene for the amyloid precursor protein is on chromosome 21 – same as people with Down Syndrome (Nistor, et. al., 2012).

• Apoe4 – cannot break down amyloid-beta which leads to excess buildup in the brain (Jonsson, et. al., 2013).

Introduction: Cause – Tau Hypothesis

• Tau protein initiates the disease cascade• Hyperphosphorylated tau pairs with other tau threads

• Loss of tau function of promoting assembly and stabilizing microtubules• Gain in toxic function (Iqbal, et. al., 2005).

• This eventually forms neurofibrillary tangles inside nerve cell bodies (Goedert & Spillantini, 2006).

• Microtubules disintegrate• Destroys the cell’s cytoskeleton which collapses the neuron’s transport system

• Results in communication malfunction between neurons and later in the death of cells (Iqbal, et. al., 2005).

Retrieved from https://sites.google.com/site/bme365ralzheimers/pathophysiology

Introduction: Cause – Other Hypotheses

• Air pollution• Can lead to chronic oxidative stress

• Results from a redox imbalance from a production of reactive oxygen species

• Exceeds the capacity of antioxidant defense mechanisms

• Associated with respiratory and cardiovascular pathology• The brain is poor in antioxidant defense mechanisms (Moulton &

Yang, 2012).

Retrieved from http://www.nrdc.org/air/

Introduction: Pathophysiology• Neuropathology: loss of neurons and synapses in brain

• Atrophy in brainstem nuclei and temporal and parietal lobes (Moulton & Yang, 2012).

• Biochemistry: protein mis-folding disease• Plaque accumulation of amyloid-beta and tau protein in brain

(Cataldo, Prochaska, & Glantz, 2010).

• Disease mechanism: aggregated amyloid fibrils• Toxic form of protein that disrupts calcium ion homeostasis• Amyloid-beta increases in mitochondria and inhibits enzymes

and neurons (Kivipelto, et. al., 2001).

Retrieved from http://scicurious.scientopia.org/2011/05/04/science-101-the-neuron/

Introduction: Diagnosis • Alzheimer’s is a widespread disease that often goes undiagnosed

until it has progressed to its latest stages • Cognitive impairment as a result of dementia is failed to be

diagnosed over 50 percent of the time in its earliest stages – mild to moderate

• Family members and caregivers are often oblivious to the signs• Early detection is vital because medical, behavioral, and social

interventions exist that can dramatically slow disease pathogenesis if caught in time (Kerwin, 2009)

Introduction: Diagnosis

Factors that will make early detection a majority:• Employing proper screening tools to expose indicators of

decline on a patient to patient basis• Establishing a known high-risk population • “Vulnerable elderly” – individuals of 65 years of age or

older who are at a high risk of death or functional decline in the next 2 years (Kerwin, 2009)

Introduction: Mini-Mental State Exam (MMSE)

• Referred to as the “gold standard” – most widely used screening tool

• Tracks cognitive decline over time• Results based on the performance of tasks such as

counting backwards from 100 by 7s and a 3-stage command

• Globally implemented and translated into over 50 different languages (Kerwin, 2009)

Introduction: Mini-Cog

• Referred to and the “quick and easy” alternative to the MMSE

• Evaluates cognitive ability based on the performance of a clock drawing and word recall activity in only 3 minutes time

• Particularly effective – not effected by level of education and has a high degree of accuracy (Kerwin, 2009)

Introduction: Montreal Cognitive Assessment

• Takes significantly longer• Designed specifically to detect mild dementia • Evaluated based on performance of activities such as

drawing lines connecting letters and numbers and explaining abstract similarities between 2 objects (oranges and bananas)

• Second most widely translated test – over 20 different languages (Kerwin, 2009)

Introduction: AD 8 Dementia Screening Interview

• Designed primarily as an informing agent for physicians • Detects early changes in memory• Takes only 3 minutes and can either be self-administered

or administered by a professional (Kerwin, 2009)

Introduction: 7-Minute Neurocognitive Screen

• Highly sensitive to separating cognitive impairment as a result of normal aging from cognitive impairment as a result of Alzheimer’s

• Patient is evaluated through the administration of 4 brief tests analyzing orientation, recall, clock-drawing, and verbal fluency (Kerwin, 2009)

Introduction: Depression

• Self-reported memory problems are more often indicative of depression than dementia

• Depression occurs in 25 percent of dementia patients • This is an issue due to symptoms that depression causes

independently of cognitive decline (Kerwin, 2009)

Introduction: Prevention and Management

• Prevention in terms of Alzheimer’s treatment does not follow the traditional meaning of the word

• The onset of Alzheimer’s is inevitable, so prevention is focused on slowing the disease’s progress

• Current emphasis of Alzheimer’s preventative research is discovering reliable early warning signs for two reasons: profound brain alterations occur well before dementia is revealed therapeutic interventions directed only at mild to moderate stages

are often too late to reduce symptom severity (Selkoe, 2012)


Possible Treatments• Amyloid plaque clearing antibodies• Pharmaceuticals • Lifestyle factors• Diet (Selkoe, 2012)

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Antibodies: reduce presence of amyloid plaque burden in cerebrospinal fluid (Selkoe, 2012)Pharmaceuticals• No miracle drug to remedy all Alzheimer’s aliments;

Cholinesterase inhibitors: most commonly class of drug used for symptomatic treatment (cognitive, global, functional, and behavioral)

• Memantines: new approach that blocks the chronic hyper-activation of the receptors that heavily contribute to symptom magnification (Bansal, Walker, & Walker, 2013)

Introduction: Prevention and ManagementLifestyle Factors• Physical activity: decreases the accumulation of

amyloid plaque modifies the biology of Alzheimer’s for the patient’s benefit

• Learning: lifelong intellectual stimulation, higher levels of education, and novelty lessen risk of onset or alter disease progression

• Human interaction: consistent social engagement and ultimately nonexistence of isolation (Selkoe, 2012)

Retrieved from http://lozilu.com/5-simple-tips-to-learn-to-love-running/


Diet• Antioxidants: vitamins E and C have been found to

significantly delay or at least slow the progression of Alzheimer’s

• A diet with a heightened focus on supplementation with fruits and vegetables (mainly blueberries, strawberries, and spinach) rich in antioxidants reduces the probability that a patient’s symptoms will mandate institutionalization (Waldemar, et al. 2007)

Retrieved from http://uppermerionfarmersmarket.org/umfm/tag/strawberries/

Methods

• To estimate the percentage of the US population living with the disease, first find the age-specific disease incidence rate.

• This is represented by the following equation:(1) Incidence (% per year) = 0.117e 0.127 (t-60) (Brookmeyer,

Johnson, Ziegler-Graham, & Arrighi, 2007)

Methods• Limitations:

• This model only applies to US populations.• Based on the model, incidence continues to rise at the oldest ages, but it can be

inferred that the model is not sensitive to assumptions about incidence after age 95.

• Age-specific prevalence rates are the proportion of people living with Alzheimer’s disease at a certain age in a given year.

• This equation is dependent upon age-specific incidence rates of the disease and the mortality rate of individuals with and without the disease.

Methods

• The value of r j, y is the age-specific disease incidence, divided by 100.

• The value of d j, y is the US mortality rate at age j in year y, all divided by 100,000 (see Figure 1).

• λ represents the relative risk of death of Alzheimer’s disease patients relative to individuals of the same age and sex without the disease (λ = 1.44).

• The percentage of people living with Alzheimer’s disease at age t in year y can be found using P t, y (D) / [P t, y (D) + P

t, y ()].

Methods• The probability that a person born in year y – t is alive at age t with and

without the disease:

(2)

and

(3)

• The equations are according to Brookmeyer, Gray, and Kawas (1998).

Methods

• In this stimulation, the interventions began at year 2020 and ended at year 2060.

• Reductions in age-specific incidence rates of 5%, 10%, 25%, and 50% were considered.

• Age-specific incidence rates were multiplied by the relative risks of intervention to find new probabilities (Brookmeyer, Gray, & Kawas, 1998).

Methods

Figure 1. Mortality rates in the US.1900-1997 1998-2065

Rate Age 1-4 y = -504LN(x) + 2343.1 y = -2.928LOG(x+17) + 35.265Rate 5-14 y = -126.3LN(x) + 598.87 y = -1.793LOG(x+17) + 19.573Rate 15-24 y = -137.6LN(x) + 789.12 y = -0.177LOG(x+17) +81.363Rate 25-34 y = -199.3LN(x) + 1116.2 y = -1.894LOG(x+17) + 107.86Rate 35-44 y = -230.7LN(x) + 1407.9 y = -5.863LOG(x+17) + 204.86Rate 45-54 y = -277LN(x) + 2011.8 y = -1.239LOG(x+17) + 430.45Rate 55-64 y = -440.3LN(x) + 3609.2 y = -342.7LOG(x+17) + 1517.5Rate 65-74 y = -852.2LN(x) + 7435.6 y = -216.8LOG(x+17) + 2554.1Rate 75-84 y = -1690LN(x) + 15643 y = -331.2LOG(x+17) + 5882.6Rate 85+ y = -2842LN(x) + 31763 y = -1165LOG(x+17) + 16007

Methods

• The age specific mortality rates from 1900 to 1945 were obtained directly from Historical Statistics of the United States

• The age specific mortality rates from 2000 to 2008 were obtained from the CDC records archive

• Performing a regression on this data produced equations for estimating the mortality rates for specific age groups back to 1900

Results

• 5 graphs (Figures 2-6): Estimated Percent of People Living with Alzheimer’s Disease at Certain Ages

• Show change in percent of people living with Alzheimer’s in certain age groups over 50 years (2015-2061)

• Capable of depicting change in percentages resulting from introduction of intervention of some predetermined efficiency

Results

• Depicts ages 55, 65, 85, and 95• 55: first age at which Alzheimer’s begins to appear frequently

enough as to be visible on the graph• 65: considered to be first age in which the disease become truly

prevalent• 85: first age in the last age group in regard to mortality rates• 95: considered the maximum age at which the equation for

incidence rate holds accuracy.

Results

• No intervention represented as an intervention with efficiency of 0

• Percent of people afflicted gradually increases with every subsequent year, becoming more pronounced as the age too increases

(Figure 2: 0% Efficiency Intervention)

Results

• Any intervention assumed to be introduced in 2020, 5 years after the start of the model

• Phased in at a constant rate over the next 40 years• Reaches full efficiency in 2060

Results• 5% efficiency intervention• Does not necessarily decrease the

instances of Alzheimer’s• Delays not prevents growth of

curve• Once intervention reaches full

efficiency, curve continues to grow at the same rate as before, but from a lower percent

• Applies to all other interventions


Results

• 10% efficiency intervention• Slightly decrease the overall

instance in all age groups except 55


Results

• 25% efficiency intervention• Exhibits a much more drastic

decrease in percentages in all age groups


Results

• 50% efficiency intervention• Causes greatest decrease in

instances of Alzheimer’s disease in all age groups (obviously)



• Greater efficacy of treatment decreases the prevalence rate of Alzheimer’s

• Without continued treatment the rates slowly begin to increase

(Figure 6: 50% Efficiency of Intervention)

Discussion and Conclusion• More effective treatments seem to have a

correlation to antioxidant effects• The capacity of Vitamin E to improve cognitive

functions has been related to its antioxidant properties (Vina, Lloret, Oris & Alonso, 2004).

• Vitamin E and C as a combined treatment have been shown to be associated with decreased prevalence and incidence rates (Salloway, Mintzer, Weiner & Cummings, 2008). Retrieved from

http://youreananimal.com/vitamin-e-fat-friendly/


• A treatment that has both antioxidant and anti-inflammatory properties can allow an individual to maintain cognitive function and possibly prevent neuronal degeneration (Allison, Cacabelos, Lombardi, Alvarez & Vigo, 2001).

• It is imperative to study and identify the most effective treatments

• Treatment must be maintained in order to retain the lowest possible prevalence rates

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