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ALZHEIMER'S DISEASE AND DEMENTIA
Dementia is a clinical syndrome characterized by impairment of multiple higher cortical functions that include memory, orientation, thinking, comprehension, calculation, capacity for learning, language, judgment,  executive function and visuo-spatial function. It is usually accompanied or preceded by deterioration in emotional control, social behavior or motivation.
Alzheimer's disease is the most common cause of dementia. Sporadic cases usually present after >60 year while familial types are rare and present in <60 year of age (early-onset dementia).
Short-term memory loss is the most common early symptom. Other spheres of cognitive impairment manifest after several years.

Principles of Therapy

Important to explain to patient and family prior to initiating therapy:

  • Medications will not cure dementia and may not work for everyone
  • Symptomatic treatment, even with improvement of symptoms, will not stop disease progression and cognitive decline will continue even with therapy
  • Medications may be discontinued if with no response after an adequate trial of 3-6 months

Treatments for Psychosis and Agitation

  • Aim of treatment is to minimize psychotic symptoms (eg paranoia, hallucinations, etc) and the associated or independent symptoms (eg screaming, violence)
    • This will help increase comfort and safety of patients and families
  • Intervention used should be directed by the level of agitation experienced by the patient and the risk to caregivers and patient
    • Violent behavior usually needs to be treated by pharmacological therapy
  • Agitation needs to be investigated further to reveal underlying causes
    • If agitation continues repeatedly, psychosocial measures should be used as 1st-line therapy
  • If psychosocial measures are unsuccessful or if agitation is thought to be dangerous to patient/caregiver then pharmacological therapy is warranted

Pharmacotherapy

Pharmacological Therapy for Cognitive Symptoms

Cholinesterase Inhibitors (ChEI)

  • Should be considered in patients in all stages of Alzheimer's disease
  • All inhibit cholinesterase in the synaptic cleft, thereby enhancing central cholinergic function
    • Donepezil inhibits acetylcholinesterase
    • Galantamine inhibits acetylcholinesterase and provides allosteric modulation of nicotinic receptors
    • Rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase
  • Improve cognitive, behavioral and functional measures in Alzheimer's disease
  • May also be given in patients with dementia with Lewy bodies
  • Donepezil and Galantamine have shown modest efficacy in treating cognitive impairment in patients with vascular dementia or mixed dementia
  • Generally well tolerated, common side effect being GI disturbances (nausea, vomiting, diarrhea) which tend to be mild-moderate in severity

Donepezil

  • Showed significant effects in cognitive function as evaluated by cognitive subscale of the Alzheimer's disease Assessment Scale
  • Studies have shown efficacy of Donepezil in reducing a number of behavioral problems and psychotic symptoms in patients with mild-moderate dementia
  • Used for the treatment of mild-moderate Alzheimer's disease and has been approved for use in more severe forms of Alzheimer's disease

Galantamine

  • Improves functional ability and may also provide significant effects on behavior in patients with Alzheimer's disease
  • Used in patients with mild to moderate Alzheimer's disease in maintaining cognition
  • Higher doses are more efficacious than lower doses, but doses >24 mg/day showed no added benefit
  • Slow dose escalation appears to improve its tolerability
  • There is evidence of some benefit in cognition in patients with mixed Alzheimer's disease and cerebrovascular disease

Rivastigmine

  • Showed significant effects in cognitive and global function in patients with mild-moderately severe Alzheimer's disease
  • May provide benefit in Alzheimer's disease patients experiencing rapid symptom progression
  • Also found to be effective in managing cognitive decline among patients with dementia with Lewy bodies
  • Transdermal patch preparation has the advantage of causing less gastrointestinal side effects, better 24 hour drug profile and easier to administer in patients
    • Approved for treatment of all stages of Alzheimer's disease
  • Used in patients with mild-moderate dementia associated with Parkinson’s disease
  • *Please see Parkinson’s Disease and Parkinson’s Disease Dementia Management Chart for more details

Memantine

  • Noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist given in patients with moderate-severe Alzheimer's disease
  • May be given to patients with mild-moderate Alzheimer's disease if cholinesterase inhibitor is contraindicated
  • Current available data suggest that combination with cholinesterase inhibitor increases likelihood of delaying symptom progression compared to cholinesterase inhibitor alone
  • Studies suggest improvement of cognition at all levels of Alzheimer's disease severity but effects on behavior, activities of daily living and global outcome were more significant for moderate-severe Alzheimer's disease

Other Agents Used to Treat Cognitive Symptoms

Ginkgo biloba

  • A botanical product derived from maidenhair tree, it has clinical trials supporting its efficacy in Alzheimer's disease and vascular dementia
  • Potential mechanisms of action include antiplatelet activity, vasoactive effects, increasing neuron tolerance to anoxia and prevention of membrane damage caused by free radicals
  • Majority of studies confirm Ginkgo biloba is safe with few side effects

Cerebrolysin®

  • Nootropic agent composed of 25% low molecular weight peptides and free amino acids produced by enzymatic breakdown of purified porcine brain proteins
  • Studies showed Cerebrolysin® preparation is well-tolerated
  • Useful addition to current treatment options for dementia based on current available clinical data

Selegiline

  • A selective monoamine oxidase-B (MAO-B) inhibitor; postulated to act as an antioxidant or neuroprotective agent in Alzheimer's disease patients
  • Evidence for its efficacy in the treatment of Alzheimer's disease symptoms is minimal

Vitamin E

  • Generally not recommended for treatment of cognitive symptoms of dementia due to its limited evidence of efficacy and safety concerns
    • After weighing the potential benefits and risks of vitamin E, some physicians may still opt to give it at doses ≤ 400 IU/day
    • Doses >400 IU/day resulted in statistically significant increase in mortality
  • New safety concerns include increased dose-dependent mortality, increased heart failure rate in patients with diabetes mellitus and cardiovascular disease
  • Associated with worsening of coagulation defects among vitamin K-deficient patients

Pharmacological Therapy for Non-Cognitive Symptoms

Antipsychotics1

  • Primary treatment available for psychotic symptoms of dementia
  • Dose and the need for medication must be constantly reviewed and the risk of stroke should be considered
  • Lowest effective dose should be used at the shortest period needed and side effects should first be treated by decreasing the dose
    • Treatment of elderly patients with dementia-related psychosis with antipsychotics may be associated with increased risk of cerebrovascular events including fatalities
  • Conventional antipsychotics are effective in behavioral with psychological symptoms of dementia
  • Atypical agents may be better tolerated
  • Choice of agent will be based on side effect profile that is most suited to the patient
  • Commonly administered in the evening to help sleep and to treat ‘sundowning’
  • Oral route is usually preferred
  • Medications for Alzheimer's disease and vascular dementia eg acetycholinesterase inhibitors and/or Memantine should be optimized and given at the appropriate doses since these provide good behavioral control

Benzodiazepines1

  • For agitation, where anxiety is a prominent feature
  • Useful as start doses for occasional agitation or when sedation is needed eg dental procedure
  • Generally not used in dementia unless in cases that they are necessary
  • Risk of disinhibition, over sedation, falls and delirium
  • Short-acting agents and agents that do not require metabolism for activation are preferred
  • Start with low doses; increase dose carefully and cautiously
    • Elderly are more sensitive to the side effects of benzodiazepines

Treatment for Depression and Apathy

Antidepressants1

  • Tricyclic antidepressants (TCA), MAOI and selective serotonin reuptake inhibitors (SSRIs) may be used to treat depression
    • SSRIs are the preferred agents
  • Occasionally, cognitive deficits may recover partially or fully with treatment of depression
  • Choice of agent depends on drug interactions, side effects and desired action
    • Tricyclic antidepressants have significant cardiovascular effects and anticholinergic properties
    • SSRI may have better side effect profile
  • Dietary restrictions (high tyramine food), drug interactions and side effects tend to limit the usefulness of MAOI
  • Start with low doses; increase dose carefully and cautiously
    • Elderly are more sensitive to the side effects of antidepressants

1Various antipsychotics, benzodiazepines and antidepressants are available. Specific prescribing information may be found in the latest MIMS.

Non-Pharmacological Therapy

Supportive Measures

  • Psychosocial intervention is tailored to individual’s needs with goals of maintaining cognitive function and doing activities that promotes independence
    • It consists of supportive measures and psychotherapy

Psychotherapy

  • May be beneficial to some patients 
  • Aims to improve quality of life and maximize function in view of existing deficits
  • Choice of therapy should be based on patient characteristics and preference, availability and cost
  • Treatment must be tailored to the cognitive abilities and tolerance of each patient as adverse emotional effects have been reported
  • Therapy must be offered regularly as most do not have a lasting effect

Behavioral Therapy

  • Based on the principles of conditioning and learning theory
  • Objective is aimed at eliminating or suppressing behavioral and psychological symptoms
  • Efficacy in dementia has been shown in few studies only

Reality Orientation

  • One of the most commonly used strategies
  • Helps patients with memory loss and disorientation to recall facts about themselves and their surroundings
  • Reorients patients by continuous stimulation and repetitive orientation to the environment (eg time, place and person)
  • Deals with regular use of orientation devices (eg signposts, notices, memory aids)
  • May slow decline in cognition and may help delay placement in nursing homes

Validation Therapy

  • Involves acknowledging, supporting the feelings and meanings hidden behind the patient’s behavior and speech
  • Promotes contentment resulting in less negative affect and behavioral disturbances

Reminiscence Therapy

  • Helps the patient by reliving the past positive and personally important experiences
  • Promotes restoration of self-worth, improvement in motivation, well-being, self-care, behavior and social interaction

Cognitive-behavioral Therapy

  • Shown in one clinical trial to have favorable results in the early stages of Alzheimer's disease

Interpersonal Therapy

  • Focuses on either interpersonal disputes, interpersonal/personality difficulties, bereavement and life events/ transitions

Alternative Therapies

  • Involves aromatherapy, art, activity (eg sport, drama, dance), light and music therapies
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Ginkgo biloba has been shown to improve cognitive as well as neuropsychiatric symptoms (NPS) in patients with Alzheimer’s disease (AD) and mixed dementia. During a Schwabe-sponsored symposium last 20 October 2014 held at the University of Malaya in Malaysia, Professor Serge Gauthier of the McGill Centre for Studies in Aging in Quebec, Canada, and Dr Robert Hoerr of the Dr Willmar Schwabe GmbH & Co. KG in Germany, discussed studies that support the safety and efficacy of Ginkgo biloba extract (EGb 761®) in patients with AD and dementia.
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