Alzheimer's Disease & Dementia Xử trí

Pharmacological therapy

In initiating pharmacological therapy, it is important to explain to both the patient and the family that medications will not cure dementia and may not work for everyone. Symptomatic treatment, even with improvement of symptoms, will stop disease progression and cognitive decline will continue even with therapy. It is important to note that response to medications should be monitored to assess cognitive, behavioral and functional benefits. If necessary, dose titration and change of medication should be done. Lastly, severity of the disease should be assessed prior to starting medications.

Pharmacological Therapy for Cognitive Symptoms

Cholinesterase Inhibitors

This group of drugs should be considered in patients in all stages of AD. All inhibit the enzyme cholinesterase in the synaptic cleft, thereby enhancing central cholinergic function. Donepezil inhibits acetylcholinesterase, Galantamine inhibits acetylcholinesterase while providing allosteric modulation of nicotinic receptors, and Rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase. Cholinesterase inhibitors improve cognition, behavioral and functional measures in AD. These drugs may also be given in patients with DLB. Both Donepezil and Galantamine have shown modest efficacy in treating cognitive impairment in patients with vascular dementia or mixed dementia. However, they should be used with caution. Cholinesterase inhibitors are generally well tolerated but a common side effect is gastrointestinal (GI) disturbances like nausea, vomiting, and diarrhea. These drugs are not recommended for the treatment of FTD and MCI.

Donepezil

This drug showed significant effects in cognitive function as evaluated by cognitive subscale of the AD assessment scale. Studies have shown the efficacy of Donepezil in reducing a few behavioral problems and psychotic symptoms in patients with mild to moderate dementia. It is used for the treatment of mild to moderate AD and has been approved for the use in more severe forms of AD and DLB.

Galantamine

Galantamine has been shown to improve functional ability and may also provide significant effects on behavior in patients with AD. It is used in patients with mild to moderate DLB that cannot tolerate Donepezil and Rivastigmine. Higher doses are more efficacious than lower doses, but doses >24 mg/day have showed no additional benefit. Slow dose escalation of Galantamine appears to improve tolerability. It is important to note that there is evidence of some benefit in cognition in patients with mixed AD and cerebrovascular disease.

Rivastigmine

This drug showed significant effects in cognitive and global function in patients with mild to moderately severe AD. Meta-analysis results show that Rivastigmine may provide benefit in AD patients experiencing rapid symptom progression compared to those with slow progression. It has also been found to be effective in managing cognitive decline among patients with DLB. Additionally, a transdermal patch preparation has been shown to have the advantage of causing less GI side effects, better 24-hour drug profile, and the ease of administration in patients. This transdermal patch has been approved for treatment in all stages of AD. Rivastigmine is also used in patients with mild to moderate dementia associated with Parkinson’s disease and severe DLB.

“Please see Parkinson’s Disease and Parkinson’s Disease Dementia disease management chart for further information.”

Aducanumab and Lecanumab

These are amyloid β- directed antibodies for the treatment of AD with confirmed amyloid pathology. Studies have shown significant dose- and time-dependent reduction of amyloid β plaques compared to placebo. They are approved under accelerated approval by the United States Food and Drug Administration (US FDA) to be initiated in patients with mild cognitive impairment or mild dementia stage of AD. However, there is no safety or effectiveness data yet on initiating treatment at earlier or later stages of the disease. 

Memantine

Memantine is a noncompetitive NMDA-receptor antagonist given in patients with moderate to severe AD. This drug may be given to patients with mild to moderate AD as a monotherapy if cholinesterase inhibitor is contraindicated, not tolerated or in cases of disease progression despite an adequate trial of cholinesterase inhibitors. Current available data on this drug suggest that combination with cholinesterase inhibitor increases the likelihood of delaying symptom progression compared to cholinesterase inhibitor alone in moderate to severe cases of established AD. Studies suggest that there is improvement of cognition at all levels of AD severity, but effects on behavior, ADL, and global outcome were more significant for moderate to severe AD.

Other Agents Used to Treat Cognitive Symptoms

Cerebrolysin

Cerebrolysin is a no-otropic agent composed of 25% low molecular weight peptides and free amino acids produced by the biotechnologocally standardized enzymatic breakdown of purified porcine brain proteins. Studies have shown that Cerebrolysin preparation is well-tolerated. It is a useful addition to current treatment options for dementia based on current available clinical data.

Ginkgo biloba (EGb 761)

It is a botanical product derived from maidenhair tree that has clinical trials supporting the efficacy in AD and vascular dementia. The potential mechanisms of action include antiplatelet activity, vasoactive effects, increasing neuron tolerance to anoxia, and prevention of membrane damage caused by free radicals. The majority of studies confirm Ginkgo biloba is safe with few side effects.

Selegiline

Selegiline is a selective monoamine oxidase-B (MAO-B) inhibitor that is postulated to act as an antioxidant or neuroprotective agent in AD patients. However, there is minimal evidence for its efficacy in the treatment of AD.

Vitamin E

Vitamin E is generally not recommended for the 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 opt to give doses of ≤400 IU/day. It has been shown that doses >400 IU/day resulted in statistically significant increases in mortality. There are new safety concerns including dose-dependent mortality and increased heart failure rate in patients with diabetes mellitus (DM) and cardiovascular disease. It has also been associated with worsening of coagulation defects among vitamin K-deficient patients.

Pharmacological Therapy for Neuropsychiatric Symptoms

Treatments for Psychosis and Agitation

These drugs are indicated when nonpharmacological options (eg identification and treatment of causes, psychotherapy, education, and collaboration among health care providers, patients and family, etc) fail or when the behavior requires urgent attention such as in the case of dangerous aggression. The aim of the treatment is to minimize psychotic symptoms (eg paranoia, hallucinations, etc) and the associated or independent symptoms (eg screaming, violence). This, in turn, will help increase comfort and safety of patients and families. The intervention used should be directed by the level of agitation experienced by the patient and the risk to caregivers and patients themselves. It should be noted that violent behavior usually needs to be treated by pharmacological therapy. The cause of agitation should be investigated. If agitation continues repeatedly, psychosocial measures should be used as first-line therapy. Pharmacological therapy is then warranted if these measures are unsuccessful or if agitation is thought to be dangerous to the patient or caregiver.

Antidementia Agents

Donepezil may be used to treat negative symptoms such as aberrant motor behavior, apathy, anxiety, and depression. While Memantine is used to treat positive symptoms such as agitation, aggression, irritability, hallucination, and delusion. Lastly, Rivastigmine may be used to treat behavioral and psychological symptoms of DLB.

Antipsychotics

Before initiating antipsychotics, it is crucial to conduct an assessment exploring possible reasons of distress and check for and address clinical or environmental causes (eg delirium, neglect, pain) of distress. These drugs are the primary treatment available for psychotic symptoms of dementia who are at risk of inflicting harm to self and others, and in those patients in severe distress experiencing agitation, delusions or hallucinations. The dose and the need for the medication must be constantly reviewed, and the risk of stroke and myocardial infarction (MI) should be considered. The lowest effective dose should be used at the shortest period needed. Side effects should first be treated by decreasing the dose. The American Psychiatric Society recommends tapering the dose within 16 weeks of initiation. It is important to remember that treatment of elderly patients with dementia-related psychosis using antipsychotics may be associated with increased risk of cerebrovascular and cardiovascular events including deaths. Reassess every 6 weeks, at least. Antipsychotics are also considered in severe behavioral and psychological symptoms unresponsive to other treatments. However, these drugs are not routinely recommended in patients with dementia with aggression and psychosis. Atypical antipsychotics may be better tolerated. The choice of agent will be based on the side effect profile that is most suited to the patient. Antipsychotics are commonly administered in the evening to help sleep and to treat sundowning. Oral route of administration is preferred. Medications for AD and vascular dementia (eg Memantine, cholinesterase inhibitors) should first be optimized and given at the appropriate doses, having provided good behavioral control. The drug Brexpiprazole has been approved by the US FDA for the treatment of agitation symptoms associated with dementia due to AD.

Benzodiazepines

This class of drugs is sued for agitation, where anxiety is a prominent feature. They are useful as start doses for occasional agitation or when sedation is needed (eg dental procedures). These drugs are generally not used in dementia unless in cases when they are necessary. With benzodiazepines, there is a risk of disinhibition, over sedation, falls, and delirium. Short-acting agents and agents that do not require metabolism are preferred. When initiating benzodiazepines, start with low doses first. Increase the dose carefully and cautiously. The elderly are more sensitive to the side effects of benzodiazepines. 

Treatment for Depression and Apathy

Antidepressants

Tricyclic antidepressants (TCAs), MAO inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs) may be used to treat depression. Among the three, SSRIs are the preferred agents. It has been shown that on some occasions, cognitive deficits may partially improve with treatment of depression. The choice of agent depends on drug interactions, side effects, and desired action. For example, TCAs have significant cardiovascular effects and anticholinergic properties. On the other hand, SSRIs have better side effect profile. Dietary restrictions (eg high tyramine containing foods), drug interactions, and side effects tend to limit the usefulness of MAOIs. Just as with benzodiazepines, start the antidepressant in low doses; increase dose carefully and cautiously. The elderly are also more sensitive to the side effects of antidepressants. These drugs are not effective for behavioral and psychological symptoms of dementia in patients with FTD.

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Nonpharmacological

Supportive Measures

In managing dementia, psychosocial intervention is tailored to the individual’s needs with the goals of maintaining cognitive function and being able to do activities that promote independence. This would consist of supportive measures and psychotherapy.

Patient, Caregiver, and Healthcare Workers Education

Good communication needs to be established between the clinician, the patient and the family. Intensive long-term education and support services given to the caregivers may delay the time to nursing home placement. It is vital to educate both the patient and caregivers about the illness and the available treatments. Physicians must address the concerns about behavioral symptoms which may be associated with the loss of status, dignity, and the need for increased caregiver support. Reassure both that these things are part of the illness, due to direct damage to the brain, and are usually controllable with treatment. Emphasis on the importance of continuous treatment for dementia and routine follow-up for evaluation is needed. Teaching the patient, the family, and other caregivers to recognize symptoms and to anticipate future manifestations is important. It may be helpful to educate the caregivers concerning the basic principles of care. Educating nursing home staff may reduce use of physical restraints and unnecessary antipsychotics.  

Keep note of the following:

• Keep requests relatively simple; avoid giving the patient complex tasks which may lead to frustration
• Avoid confrontation and defer requests if the patient becomes angered
• Be consistent and avoid unnecessary change
• Provide frequent reminders, explanations, and orientation cues
• Recognize decline in capacity and adjust expectations
• Seek professional attention during sudden decline in function or when new symptoms emerge

Caregiver Support

It is important to support or assist caregivers as this will reduce the risk of substandard care, neglect, or abuse. For this, one may refer caregivers to support group networks or psychoeducational workshops that are available. Respite care (eg visiting nurses, day care programs, brief nursing home stays, etc.), if available, should be utilized to provide periods of rest for the caregivers. Furthermore, these allow caregivers to continue to work or fulfill other responsibilities and to help them relieve the stress and mood disturbances that are associated with long-term care.

Financial and Legal Issues

Patients with dementia often lose their ability to make medical, legal, and financial decisions as the disorder progresses. Caregivers can seek the patient’s guidance regarding long-term care while the latter is still able to participate. Patients may wish to pass authority for legal and financial decision-making to a trusted family member or friend. This will then help avoid the difficulty and expense of petitioning to the court for guardianship or conservatorship later. Discussions with regards to the preference about medical treatment (eg nursing home placement, artificial life support, etc) can be made during the early part of the illness so that the patient may make their own wishes known. It is important to educate the patient and caregivers about the importance of financial planning for future treatment and nursing care. Finally, advise the patients to complete or update their wills, establish appropriate trusts and transfer of assets during the early part of the illness when mental competence for such decisions is still maintained.

Psychotherapy or Functional Training

Psychotherapy may be beneficial to some dementia patients. This aims to improve the quality of life and to maximize function in view of their existing deficits, while promoting cognition, independence and wellbeing. The choice of therapy should be based on the patient's characteristics, preference, availability, and cost. The treatment must be tailored to the cognitive abilities and tolerance of each patient as adverse emotional effects have been reported. Therapy is offered regularly as most do not have a lasting effect. 

Behavioral Therapy

Behavioral therapy is based on the principles of conditioning and leaning theory. The objective is aimed at eliminating or suppressing behavioral and psychological symptoms. However, the efficacy of behavioral therapy in dementia has only been shown in a few studies only.

Cognitive-behavioral Therapy

Cognitive-behavioral therapy has been shown in one clinical trial to have favorable results in the early stages of AD. This aims to address the disabilities resulting from the impact of cognitive impairment on the ADL. With cognitive-behavioral therapy, there is emphasis on improving or maintaining functions of daily living, strength building, compensating impairments, and promoting independence. Cognitive stimulation lets the patient engage in a range of activities and discussions. Lastly, cognitive training is tailored for each patient’s level of activity to reflect particular cognitive functions.

Functional Training

This focuses on optimizing function and ADL. Functional training includes activities such as skill training or activity planning, exercise, assistive technology and rehabilitation programs (eg occupational therapy, physiotherapy) which promote independence.

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Prevention

Modifiable Risk Factors Which Prevent Dementia By:

Reducing neuropathological damage (amyloid or tai mediated, vascular or inflammatory)

• Avoid or stop smoking
• Manage to control DM
• Prevent head injury
• Reduce air pollution
• Reduce midlife obesity
• Treat hypertension and dyslipidemia
• Nutritional interventions (eg Mediterranean-like diet, high-level consumption of mono- and polyunsaturated fatty acids)

• Attain high level of education
• Maintain frequent social contact
• Treat hearing and visual impairment

• Avoid excessive alcohol intake
• Maintain frequent exercise or physical activity
  • Moderate intensity aerobic physical activity for at least 150 minutes per week or 75 minutes per week of vigorous intensity aerobic physical activity is recommended in adults aged ≥65 years
• Reduce occurrence of depression