Alzheimers Disease

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Alzheimers Disease

• 18 Nov 2004
• Dr.pitiporn rattanataweeboon

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Alzheimers disease

• progressive and fatal neurodegenerative disorder
• Prevalence in 2000 in the United States was 4.5
  million.
• the number of symptomatic cases in the United
  States is predicted to rise to 13.2 million by
  2050.

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clinical syndrome of AD

• memory defecit with difficulty learning and
• recalling new information
• progressive language disorder beginning
• with anomia and progressing to fluent aphasia
• disturbances of visuospatial skills
• environmental disorientation , difficulty copying
• figures in MMSE
• deficits in executive function (planning,insight,
• judgment)
• the patient is unaware of memory or
• cognitive compromise.

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• Neuropsychiatric symptoms
• - Apathy early
• - Diminished interest
• - Agitation becomes increasingly
• - Depressive symptoms 50 of patients
• - Delusions 25 of patients

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• Motor systems abnormalities are absent in AD
  until the final few years of the disease
• Survival 7 to 10 years after onset of symptoms
  and typically die from bronchitis or pneumonia.

JAMA .Vol. 287 No. 18, May 8, 2002
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• 15 each year of patients with mild cognitive
  impairment progress to dementia, usually
  Alzheimers disease
• Mini-Mental State Examination specificity 96 ,
  sensitivity 63
• (standard cutoff score 24 )
• substantial proportion of cases of early dementia
  undetected.

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RISK FACTORS

• Age
• Family history
• apolipoprotein 4 (APOE 4) allele
• Others head injury, low serum levels of folate
  and vitamin B12 , elevated plasma homocysteine

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pathophysiology
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Oligomerization of the -amyloid peptide
initiates oxidative injury, plaque formation
(following -amyloid aggregation), and possibly
tangle formation (dashed line). Oxidative injury
and inflammation contribute to membrane
disruption, degeneration of the neuronal axon,
and loss of synapses. Neurodegeneration ensues
leading to cell death and neurotransmitter
deficits
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Diagnosis

• Based on the criteria National Institute of
  Neurologic and Communicative Disorders and
  StrokeAlzheimer's Disease and Related Disorders
  Association (NINCDSADRDA)
• excluding other common causes of dementia
• in the elderly.
• Screening for thyroid dysfunction and vitamin
• B12 deficiency
• syphilis in typical clinical circumstances
• Neuroimaging should be obtained (identify
• vascular dementia ,other intracranial pathology)

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In Panel A, a magnetic resonance image shows
cortical atrophy and ventricular enlargement. In
Panel B, a positron-emission tomographic scan
shows reduced glucose metabolism in the parietal
lobes bilaterally (blue-green) as compared with
more normal metabolism in other cortical areas
(yellow).
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Treatment
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Antiamyloid Therapies

• No antiamyloid therapies are currently available.
• Immunization reduces pathological signs of
• Alzheimer's disease in transgenic mice that
• have the amyloid precursor protein mutation.
• - This clinical trial was interrupted when
• encephalitis developed in 6 of the patients.
• Statins metabolism of cholesterol involved
• in the generation of beta-amyloid peptide
• - preliminary evidence suggests that statins
• may be beneficial in reducing the accumulation
• of beta-amyloid peptide

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Neuroprotective Agent

• Antioxidants alpha-tocopherol
  (vitamin E )
• A randomized, placebo-controlled trial
• compared the effect of vitamin E, selegiline, the
• two drugs together, and placebo
• results significant delay in the primary
• outcomes ( time to death, placement in a
• nursing home, development of severe
• dementia, or a defined severity of impairment of
• Activities of daily living ) in the
  selegiline,vitamin
• E , and combination-therapy groups, as
• compared with the placebo group.

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• vitamin E 230 days
• selegiline 215 days
• 145 days for those receiving both agents.
• No differences in cognitive function in the
• four groups.
• No statistically significant differences in vital
• signs, weight change, laboratory values,
• adverse events
• On the basis of this study, many practitioners
• have added high-dose vitamin E supplements
• (2000 IU daily) to their standard treatment
• regimen for Alzheimer's disease.

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• Memantine
• an N-methyl-D-aspartate antagonist
• interfere glutamatergic excitotoxicity
• improvement on the function on hippocampal
• neurons
• A double-blind, placebo-controlled trial of
• memantine in patients with moderate-to-severe
• Alzheimer's disease showed the superiority of
• memantine over placebo as indicated by both
• the Activities of Daily Living Inventory and the
• Severe neuropsychological test for patients
• with severe dementia), but not on the Global
• Deterioration Scale

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• memantine with cholinesterase inhibitor in
  patients with moderate-to-severe Alzheimer's
  disease reduced decline in activities of daily
  living, and a reduced frequency of new behavioral
  symptoms as compared with those receiving placebo.

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Antiinflammatory Agents

• brains of patients with Alzheimer's disease have
  microscopic evidence of inflammation
• evidence is insufficient to support treatment
  with antiinflammatory agents
• Primary-prevention trials have not yet explored
  the possible value

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Hormone-Replacement Therapy

• randomized, placebo-controlled trials of
  estrogen-replacement therapy in such women showed
  no benefit

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Cholinesterase Inhibitors

• Standard of care for patients with Alzheimer's
  disease
• Treatment of mild-to-moderate patients
• significant difference between patients receiving
  the drug and placebo in terms of the scores for
  cognitive function and global assessment scales

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• The ADAS-Cog shows a typical rate of increase of
  seven points annually in untreated populations.
• A four-point decrease in the ADAS-Cog in the
  course of a clinical trial is equivalent to
  reversing the symptoms of the disease by
  approximately six months, and a seven-point
  decrement is equivalent to reversing the symptoms
  by approximately one year.

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cholinesterase inhibitors have similar efficacy
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Side effects
Cummings JL. Use of cholinesterase inhibitors in
clinical practice evidence-based
recommendations. Am J Geriatr Psychiatry 2003
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• Othersweight loss, insomnia, abnormal dreams,
  muscle cramps, bradycardia, syncope, and fatigue.
  
• Adverse effects occur during the initiation of
  treatment reduced with slower rates of drug
  titration
• introducing cholinesterase inhibitors at low
  doses, increasing the dose gradually, and
  administering the medication with meals may limit
  gastrointestinal side effects

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• The optimal duration of treatment with
  cholinesterase inhibitors is uncertain.
• The duration of most blinded trials six months.
• Trials lasting one year have also shown a
  difference between patients receiving the active
  drug and patients receiving a placebo.
• Patients continue to derive benefit from therapy
  for two to three years

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• Specific strategies for switching agents not
  tested in adequate numbers of patients
• Concurrent administration of more than one
  cholinesterase inhibitor has not been studied and
  is not advised.
• Cholinesterase inhibitors are commonly
  administered with vitamin E and memantine

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Other Treatments for Cognitive Deterioration

• ginkgo biloba had small but statistically
  significant effects as compared with placebo in
  patients with Alzheimer's disease.
• A primary-prevention trial to determine whether
  ginkgo biloba reduces the rate of development of
  Alzheimer's disease is currently in progress.
• Huperzine A is a cholinesterase inhibitor, and
  preliminary clinical trials have shown it to be
  of benefit in Alzheimer's disease

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Management of Neuropsychiatric Symptoms and
Behavioral Disturbances

• Safety issues
• - Driving
• - Cooking
• - Wandering
• - Falls

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Treatment of behavioral symptoms

• wandering, hoarding or hiding objects,
  withdrawal, and socially inappropriate behavior
  are often more responsive to behavioral therapy
• Other problems, such as agitation, aggression,
  delusions, and hallucinations, may be more
  responsive to medications

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Health Maintenance and General Medical Treatment

• Exercise
• Control hypertension and other medical
  conditions
• Annual immunization against influenza
• Dental hygiene
• Use of eyeglasses and hearing aids
• Nutrition, hydration, and skin care.

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Reference

• Devid S. Geldmacher and Peter J. Whitehouse .
  Evaluation of Dementia. NEJM.Aug 1996 330-335
• Jeffrey L Cummings .Alzheimer Disease .JAMA ,May
  8 ,2002 2335-2338
• Claudia H . Kawas. Early Alzheimers Disease .
  NEJM.Sep 11,2003 1056-1062
• Jeffrey L Cummings ,Drug Therapy Alzheimers
  Disease . NEJM, July 1,200456-65