Alzheimer

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Alzheimers Disease and its Treatment
Presented by Kirmal Masih Medicinal
Chemistry March 25th
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What is Alzheimers ?

• Alzheimer's disease (AD), also known as Senile
  Dementia of the Alzheimer Type (SDAT) or simply
  Alzheimers is the most common form of dementia.
  This incurable, degenerative, terminal disease
  was first described by a German psychiatrist and
  neuropathologist Alois Alzheimer in 1906 and was
  named after him.
• Alzheimer's disease (AD) is a slowly progressive
  disease of the brain that is characterized by
  impairment of memory and eventually by
  disturbances in reasoning, planning, language,
  and perception.
• Many scientists believe that Alzheimer's disease
  results from an increase in the production or
  accumulation of a specific protein (beta-amyloid
  protein) in the brain that leads to nerve cell
  death.

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Statistics of Alzheimers disease

• Generally, it is diagnosed in people over
  65 years of age, although the less-prevalent
  early onset of Alzheimers can occur much
  earlier.
• In 2006, there were 26.6 million sufferers
  worldwide.
• Alzheimers is predicted to affect 1 in 85 people
  globally by 2050.

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Stages of Alzheimers Disease
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Symptoms of Developing A.D

• 1) Early Stage
• This is considered as a mild/early stage and the
  duration period is 2-4 years.
• Frequent recent memory loss, particularly of
  recent conversations and events.
• Repeated questions, some problems expressing and
  understanding language.
• Writing and using objects become difficult and
  depression and apathy can occur.
• Drastic personality changes may accompany
  functional decline.
• Need reminders for daily activities and
  difficulties with sequencing impact driving early
  in this stage.

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• 2) Second stage
• This is considered as a middle/moderate stage and
  the duration is 2-10 years.
• Can no longer cover up problems. 
• Pervasive and persistent memory loss impacts life
  across settings.
• Rambling speech, unusual reasoning, confusion
  about current events, time, and place. 
• Potential to become lost in familiar settings,
  sleep disturbances, and mood or behavioral
  symptoms accelerate.
• Nearly 80 of patients exhibit emotional and
  behavioral problems which are aggravated by
  stress and change.
• Slowness, rigidity, tremors, and gait problems
  impact mobility and coordination. 
• Need structure, reminders, and assistance with
  activities of daily living.

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• 3) Moderate stage
• Increased memory loss and confusion.
• Problems recognizing family and friends.
• Inability to learn new things.
• Difficulty carrying out tasks that involve
  multiple steps (such as getting dressed).
• Problems coping with new situations.
• Delusions and paranoia.
• Impulsive behavior.
• In moderate AD, damage occurs in areas of the
  brain that control language, reasoning,
  sensory processing, and conscious thought

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• 4) Last stage
• This is considered as the severe stage and the
  duration is 1-3 years.
• Confused about past and present. Loss of
  recognition of familiar people and places
• Generally incapacitated with severe to total loss
  of verbal skills.
• Unable to care for self.  Falls possible and
  immobility likely.
• Problems with swallowing, incontinence, and
  illness.
• Extreme problems with mood, behavioral problems,
  hallucinations, and delirium.
• Patients need total support and care, and often
  die from infections or pneumonia

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Diagnosis of Alzheimers Disease

• Alzheimer's disease is usually diagnosed
  clinically from the patient history, collateral
  history from relatives, and clinical
  observations, based on the presence of
  characteristic neurological and
  neuropsychological features and the absence of
  alternative conditions.
• Advanced medical imaging with computed tomography
  (CT) or magnetic resonance imaging (MRI), and
  with single photon emission computer tomography
  (SPECT) or positron emission tomography (PET) can
  be used to help exclude other cerebral pathology
  or subtypes of dementia.
• The diagnosis can be confirmed with very high
  accuracy post-mortem when brain material is
  available and can be examined histologically.

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PET scan of the brain of a person with AD showing
a loss of function in the temporal lobe.
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Diagnostic Tools

• Neuropsychological tests such as the mini-mental
  state examination (MMSE) are widely used to
  evaluate the cognitive impairments needed for
  diagnosis. More comprehensive test arrays are
  necessary for high reliability of results,
  particularly in the earliest stages of the
  disease.
• Psychological tests for depression are employed,
  since depression can either be concurrent with
  AD, an early sign of cognitive impairment, or
  even the cause.
• When available as a diagnostic tool, SPECT and
  PET neuroimaging are used to confirm a diagnosis
  of Alzheimer's in conjunction with evaluations
  involving mental status examination. In a person
  already having dementia, SPECT appears to be
  superior in differentiating Alzheimer's disease
  from other possible causes, compared with the
  usual attempts employing mental testing and
  medical history analysis.

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Causes of Alzheimers Disease

• Scientists dont yet fully understand what causes
  AD, but it is clear that it develops because of a
  complex series of events that take place in the
  brain over a long period of time. It is likely
  that the causes include genetic, environmental,
  and lifestyle factors.
• Some drug therapies propose that AD is caused by
  reduced synthesis of the neurotransmitter
  acetylcholine.
• Other cholinergic effects have also been
  proposed, for example, initiation of large-scale
  aggregation of amyloid leading to generalized
  neuroinflammation.
• Alzheimer's disease is characterized by a
  build-up of proteins in the brain. Though this
  cannot be measured in a living person, extensive
  autopsy studies have revealed this phenomenon.
  The build-up manifests in two ways
• Plaques deposits of the protein beta-amyloid
  that accumulate in the spaces between nerve cells
  
• Tangles deposits of the protein tau that
  accumulate inside of nerve cells

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Microscopy image of a neurofibrillary tangle,
conformed by hyperphosphorylated tau protein.
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Neuropathology

• Alzheimer's disease is characterised by loss of
  neurons and synapses in the cerebral cortex and
  certain subcortical regions. This loss results in
  gross atrophy of the affected regions, including
  degeneration in the temporal lobe and parietal
  lobe, and parts of the frontal cortex and
  cingulate gyrus.
• Both amyloid plaques and neurofibrillary tangles
  are clearly visible by microscopy in brains of
  those afflicted by AD.
• Plaques are dense, mostly insoluble deposits of
  amyloid beta peptides and cellular material
  outside and around neurons.
• Tangles (neurofibrillary tangles) are aggregates
  of the microtubule-associated protein tau which
  has become hyperphosphorylated and accumulate
  inside the cells themselves.
• Although many older individuals develop some
  plaques and tangles as a consequence of ageing,
  the brains of AD patients have a greater number
  of them in specific brain regions such as the
  temporal lobe.

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Amyloid Precursor Protein

• Alzheimer's disease has been identified as a
  protein misfolding disease (proteopathy), caused
  by accumulation of abnormally folded A-beta and
  tau proteins in the brain. Plaques are made up of
  small peptides, 3943 amino acids in length,
  called beta-amyloid (also written as A-beta or
  Aß).
• Beta-amyloid is a fragment from a larger protein
  called amyloid precursor protein (APP), a
  transmembrane protein that penetrates through the
  neuron's membrane.
• APP is critical to neuron growth, survival and
  post-injury repair. In Alzheimer's disease, an
  unknown process causes APP to be divided into
  smaller fragments by enzymes through proteolysis.
  
• One of these fragments gives rise to fibrils of
  beta-amyloid, which form clumps that deposit
  outside neurons in dense formations known as
  senile plaques.
• AD is also considered a tauopathy due to abnormal
  aggregation of the tau protein. Every neuron has
  a cytoskeleton, an internal support structure
  partly made up of structures called microtubules.
  
• These microtubules act like tracks, guiding
  nutrients and molecules from the body of the cell
  to the ends of the axon and back. A protein
  called tau stabilizes the microtubules when
  phosphorylated, and is therefore called a
  microtubule-associated protein.
• In AD, tau undergoes chemical changes, becoming
  hyperphosphorylated it then begins to pair with
  other threads, creating neurofibrillary tangles
  and disintegrating the neuron's transport system.

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Enzymes act on the APP (amyloid precursor
protein) and cut it into fragments. The
beta-amyloid fragment is crucial in the formation
of senile plaques in AD.
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Mechanism

• Exactly how disturbances of production and
  aggregation of the beta amyloid peptide gives
  rise to the pathology of AD is not known. The
  amyloid hypothesis traditionally points to the
  accumulation of beta amyloid peptides as the
  central event triggering neuron degeneration.
  Accumulation of aggregated amyloid fibrils, which
  are believed to be the toxic form of the protein
  responsible for disrupting the cell's calcium ion
  homeostasis, induces programmed cell death
  (apoptosis). It is also known that Aß selectively
  builds up in the mitochondria in the cells of
  Alzheimer's-affected brains, and it also inhibits
  certain enzyme functions and the utilization of
  glucose by neurons.
• Various inflammatory processes and cytokines may
  also have a role in the pathology of Alzheimer's
  disease. Inflammation is a general marker of
  tissue damage in any disease, and may be either
  secondary to tissue damage in AD or a marker of
  an immunological response.
• Alterations in the distribution of different
  neurotrophic factors and in the expression of
  their receptors such as the brain derived
  neurotrophic factor (BDNF) have been described in
  AD

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Apolipoprotein E

• Apolipoprotein E (APOE) found on chromosome 19
  appears to be a predisposing genetic risk factor
  for the late on-set of AD the most typical AD.
• APOE helps carry cholesterol in the bloodstream.
• APOE comes in several different forms, or
  alleles.
• Three formsAPOE e2, APOE e3, and APOE e4occur
  most frequently.

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Medicines used to treat A.D and its Symptoms

• Aricept Used to
  delay or slow the symptoms of ADDonepezil
  Loses its effect over
  time
  Used for mild, moderate and severe AD
  Does not
  prevent or cure AD
• CelexaCitalopram
  Used to reduce depression and anxiety
  May take 4 to 6
  weeks to work
  Sometimes used to help people get to
  sleep
• Depakote Used to
  treat severe aggressionSodium Valproate
  Also used to treat depression and
  anxiety
• Exelon Used to
  delay or slow the symptoms of AD Rivastigmine
  Loses its effect over time
  Used
  for mild to moderate AD
  Can get in pill form or as a
  skin patch
  Does not prevent or cure AD

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• Namenda
  Used to delay or slow the symptoms
  of ADMemantine
  Loses its effect over time
  
  Used for moderate to severe
  AD
  Sometimes given with
  Aricept, Exelon
  Does
  not prevent or cure AD
• Razadyne
  Used to prevent or slow the symptoms
  of AD Galantamine
  Loses its effect over time
  
  Used for mild to moderate
  AD
  Can get in pill form
  or as a skin patch
  Does
  not prevent or cure AD
• Zoloft
  Used to reduce depression and
  anxiety Sertraline
  May take 4 to 6 weeks
  to work
  Sometimes used to
  help people get to sleep
• Trileptal
  Used to treat severe aggression
  Oxcarbazepine
  Also used to treat depression and
  anxiety
• Tegretol
  Used to treat severe aggression
  Carbamazepine
  Also used to treat depression and
  anxiety
• Remeron
  Used to reduce depression and
  anxiety Mirtazepine
  May take 4 to 6 weeks to
  work
  Sometimes used to help
  people get to sleep

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Treatment

• Although there is currently no way to cure
  Alzheimer's disease or stop its progression,
  researchers are making encouraging advances in
  Alzheimer's treatment, including medications and
  non-drug approaches to improve symptom
  management.
• Mild/Moderate AD
• Cholinesterase inhibitors increase the levels
  of acetylcholine in the brain, which plays a key
  role in memory and learning. This kind of drug
  postpones the worsening of symptoms for 6 to 12
  months in about half of the people who take it.
  Cholinesterase inhibitors most commonly
  prescribed for mild to moderate Alzheimer's
  disease include Aricept (donezepil HCL), Exelon
  (rivastigmine), and Razadyne (galantamine).

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• Moderate/Severe AD
• Namenda (memantine) regulates glutamate in the
  brain, which plays a key role in processing
  information. This drug is used to treat moderate
  to severe Alzheimer's disease and may delay the
  worsening of symptoms in some people. It may
  allow patients to maintain certain daily
  functions a little longer than they would without
  the medication.

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Drugs for Alzheimers

• Razadyne
• Razadyne (galantamine HBr) is FDA-approved for
  mild and moderate stages of the disease.
• Razadyne is a cholinesterase inhibitor that
  prevents the breakdown of acetylcholine in the
  brain. Acetylcholine plays a key role in memory
  and learning higher levels in the brain help
  nerve cells communicate more efficiently.
  Razadyne also stimulates nicotinic receptors to
  release more acetylcholine in the brain.

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• Razadyne delays the worsening of Alzheimer's
  symptoms for 6 to 12 months in about half of the
  people who take it.
• Razadyne is available in tablet and capsule form,
  and is commonly started at 4 mg twice a day. If
  it's well tolerated after 4 weeks, the dosage may
  be increased to 8 mg twice a day.
• Razadyne also comes in an extended release,
  once-a-day tablet.
• Razadyne is available in generic form
  (galantamine HBr).

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• Exelon (Rivastigmine)
• Exelon is FDA approved for mild and moderate
  stages of the disease it is also approved for
  the treatment of mild to moderate dementia due to
  Parkinson's disease.
• Exelon is available as a capsule, liquid, and
  patch.

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• Exelon is a cholinesterase inhibitor that
  prevents the breakdown of acetylcholine and
  butyrylcholine in the brain by blocking the
  activity of two different enzymes. Acetylcholine
  and butyrylcholine play a key role in memory and
  learning.
• When given orally, bioavailability is about 40
  in the 3 mg dose. The compound can cross the
  blood-brain barrier.

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• Aricept (Donepizel)
• One of the most widely used drugs to treat the
  symptoms of Alzheimer's disease. Aricept is
  FDA-approved for mild, moderate, and severe
  stages of the disease.

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Continued

• Aricept is available in tablet form or an orally
  disintegrating tablet form, and is commonly
  started at 5 mg a day.
• Can cross the blood-brain barrier.

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• Namenda (Memantine)
• Namenda is an N-methyl D-aspartate (NMDA)
  antagonist that regulates the activity of
  glutamate in the brain. Glutamate plays a key
  role in memory and learning, but excess glutamate
  can lead to the disruption of nerve cell
  communication or nerve cell death.

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Continued

• Studies involving Namenda have shown that the
  drug can slow the rate of decline in thinking and
  the ability to perform daily activities in
  individuals who have moderate to severe
  Alzheimer's disease
• A dysfunction of glutamatergic neurotransmission
  is thought to be involved in the etiology of AD.
• Namenda is available in generic form (memantine
  HCL).

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New Treatments for A.D

• A molecule designed by a Purdue University
  researcher to stop the debilitating symptoms of
  Alzheimer's disease has been shown in its first
  phase of clinical trials to be safe and to reduce
  biomarkers for the disease.
• The molecule, called a beta-secretase inhibitor,
  prevents the first step in a chain of events that
  leads to amyloid plaque formation in the brain.
  This plaque formation creates fibrous clumps of
  toxic proteins that are believed to cause the
  devastating symptoms of Alzheimer's.
• Researchers at Mount Sinai School of Medicine
  have found that a compound called NIC5-15, might
  be a safe and effective treatment to stabilize
  cognitive performance in patients with mild to
  moderate Alzheimer's disease. The two
  investigators, Giulio Maria Pasinetti, M.D.,
  Ph.D. , and Hillel Grossman, M.D., presented
  Phase IIA preliminary clinical findings at the
  Alzheimer's Association 2009 International
  Conference on Alzheimer's Disease (ICAD) in
  Vienna on July 12.

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Continued

• NIC5-15's potential to preserve cognitive
  performance will be further evaluated in a Phase
  IIB clinical trial. Early evidence suggests that
  NIC5-15 is a safe and tolerable natural compound
  that may reduce the progression of Alzheimer's
  disease-related dementia by preventing the
  formation of beta-amyloid plaque, a waxy
  substance that accumulates between brain cells
  and impacts cognitive function.

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References

• http//www.sciencedaily.com/releases/2008/01/08012
  3101629.htm
• http//www.sciencedaily.com/releases/2009/07/09071
  2145228.htm
• http//www.nia.nih.gov/Alzheimers/Publications/Car
  ingAD/other/medicines.htm
• http//en.wikipedia.org/wiki/Rivastigmine
• http//en.wikipedia.org/wiki/Galantamine
• http//en.wikipedia.org/wiki/Donepezil
• http//en.wikipedia.org/wiki/Mementine
• Newsweek 06/15/98, Vol. 131 Issue 24, p52, 2p, 

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Continued

• Harvard Mental Health Letter Apr2010, Vol. 26
  Issue 10, p7-7, 1/2p
• Asian Journal of Animal Veterinary Advances
  2010, Vol. 5 Issue 1, p13-23, 11p, 1 Chart, 2
  Graphs
• Medical Device Daily 2/16/2010, Vol. 14 Issue
  30, p1-6, 2p

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Assigned Reading

• An Introduction to Medicinal Chemistry by Graham
  L. Patrick, pp. 589-590.
• Abbott, Alison. Neuroscience The plaque plan.
  Nature (London, United Kingdom) (2008),
  456(7219), 161-164.
• Bolognesi, Maria L. Matera, Riccardo Minarini,
  Anna Rosini, Michela Melchiorre, Carlo.
  Alzheimer's disease new approaches to drug
  discovery. Current Opinion in Chemical Biology
  (2009), 13(3), 303-308.

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Questions

• What are the three stages of Alzheimers Disease?
• What are some of the diagnostic tools of
  diagnosing Alzheimers Disease?
• What drugs are used to treat mild/moderate
  Alzheimers Disease?
• Which drug is most commonly used to treat
  Alzheimers Disease?
• Have current pharmaceutical agents been
  successful in slowing the progress of Alzheimers
  Disease?
• Why is it important to develop biomarkers for
  Alzheimers Disease?