Alzheimers Disease AD: A general overview of the disease and its current and potential treatments

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Alzheimers Disease (AD) A general overview of
the disease and its current and potential
treatments
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Prevalence rate for AD

• Named for Alois Alzheimer (1st to ID plaques
  tangles)
• AD accounts for 50 of reported cases of dementia
• 7 over age 65 50 over age 85
• 4 million Americans currently diagnosed with AD
• 14 million diagnoses by 2050
• In U.S., 67 million/year spent on treatment
• Fourth leading cause of death in adults after
  cancer, heart disease, and stroke

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DSM-IV diagnosis of Dementia

• Gradual and persistent decline in multiple
  cognitive areas manifested by both
• Memory impairment
• Impairment in one of the following areas
• Language
• Visuospatial skills
• Executive dysfunction
• Cognitive decline represents decline from
  previous functioning
• Deficits cannot be accounted for by delirium,
  other CNS condition, systemic condition, or
  substance-induced
• Cognitive deficits are not better characterized
  by another Axis I disorder

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Risk Factors for AD

• Age (1 risk factor)
• Family History
• Gender
• Head Injury
• Low Education

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Neuropathological hallmarks of AD

• Senile Plaques
• Contain insoluable ß-amyloid
• Degenerating neurites with reactive microglia
  astrocytes

• Neurofibrillary Changes
• Abnormally phosphorylated tau occurring in the
  nerve cell body

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Stages of AD (Braak Braak 1993)

• Amyloid Deposition
• 3 stages
• Stage A- a few ill-defined patches in lingual and
  fusiform gyri
• Stage B- increased deposition in neocortex and
  allocortical areas
• Stage C- Plaques in neocortical and upper
  portions of cortex

• Neurofibrillary Changes
• 6 stages
• Stage I-II- single layer of transentorhinal area
• Stage III-IV- involvement of transentorhinal and
  entorhinal area (Limbic)
• Stage V-VI- spread of isocortical destruction

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Behavioral Symptoms of AD

• Cognitive
• Misorientation to place and time
• Memory decline
• Aphasia
• Apraxia
• Distorted attention and visual perception
• Reduced problem solving skills
• Decline in activities of daily living
• Non-cognitive
• Depression
• Insomnia
• Incontinence
• Delusions
• Illusions
• Hallucinations
• Aggressive verbal, emotional, or physical
  outbursts
• Sexual disorders and weight loss

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Some current and potential treatments of AD

• Anticholinesterases
• Nerve growth factor
• MAO-B inhibitors
• Antioxidants and anti-inflammatories
• Estrogen therapy

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Anticholinesterases

• Cholinergic hypothesis
• Cholinergic neurons of basal forebrain that
  innervate cortex and hippocampus degenerate in AD
• Degree of destruction of cholinergic neurons
  correlates with cognitive dysfunction, learning
  disabilities, and severity of dementia
• Scopolamine (a muscarinic antagonist) resulted in
  decreased attention and short-term memory
• Cognitive changes were reversed by an
  anticholinesterase (Bartus, 1985)

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Anticholinesterase Therapy

• Results led to first AD treatment with an
  anticholineterase
• Tetrahydroaminoacedrine (THA)
• First USA approved anti-AD drug
• Davis 1992, showed improved cognitive symptoms in
  40 of patients
• Side effects hepatotoxicity and gastrointestinal
  upset
• Positive effects spurred development of current
  anticholinesterases donezepil, galantamine, and
  rivastigmine

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Therapies to slow progression MAO-B inhibitors

• L-deprenyl (an MAO-B inhibitor) has shown a
  beneficial effect in AD (Thomas, 2000)
• MAO-B is increased in AD brains
• This results in an increased monoamine breakdown
• L-deprenyl aids in eliminating the breakdown of
  neurotransmitters that are also affected by AD

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Nerve Growth Factor (NGF)

• A neurotrophic factor
• Receptors for NGF found in rat basal forebrain
  (Hefti Mash, 1989)
• Application of NGF to rat cholinergic neurons
  stimulated expression of ChAT
• Decline in NGF receptors in AD and aging brains
• NGF related mechanisms may be involved in
  pathogenesis of AD
• Results suggested need to focus on possible NGF
  therapies

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Antioxidant therapy

• Amyloid plaque deposition in AD is suggested to
  mediate oxidative and inflammatory damage to
  neurons
• Alpha-lipoic Acid is an antioxidant and
  anti-inflammatory
• Reported to attenuate free radicals and reduce
  inflammatory activities (Hager, Riederer,
  Munch, 2001)
• Hager et al., (2001) showed its ability to
  stabilize cognitive functions over 1 year

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Hypothesized benefits of Alpha-lipoic acid

• Inflammation triggered by glycation end-products
  found in senile plaques (Munch et al., 1997)
• Microglia and astroglia cannot degrade plaques
  and create free radical and proinflammatory
  cytokines (Hager et al, 2001)
• Use of alpha-lipoic acid could be used to
  counteract these processes due to its suggested
  neuroprotective properties
• More research necessary

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Estrogen Therapy

• Estrogen therapy associated with reduced risk of
  AD and protection against longitudinal declines
  in memory associated with aging (Maki Resnick,
  2000)
• Mechanisms of protection involve
• Increase in dendritic spine density (Gould et
  al., 1990)
• Increase in synaptic excitability in hippocampal
  neurons (Wong Moss, 1992)
• Enhancement of cholinergic neurotransmission
  (Honjo et al., 1992)

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Estrogen Therapy continued Einstein 2000

• Investigated effects on dendritic spine density
• In gonadectomized rats aged for 13 months
• Found significantly lower spine density in
  dentate granule cells of females relative to male
  and younger female counterparts
• Estrogen therapy effects were dimorphic
• Short-term estrogen therapy increased dendritic
  spines in females
• Decreased in males
• Einstein suggests further research in estrogen
  therapy, but also in gender differences in
  disease state and response to therapy

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Future of AD Therapies

• A definite need to consolidate information and
  generate interacting models
• A need to focus on halting disease progression
  rather than symptom amelioration
• A better understanding of AD etiology in order to
  aid vaccine development and gene therapies