Course Authors

John E. Morley, M.D.

During the last three years, Dr. Morley has received grant/research support from Vivus, Merck & Co., Upjohn, B. Braun McGaw, Bayer Corp and Nestec, Ltd. He has also served on the Speakers' Bureau for LXN, Organon, Ross, Pharmacia & Upjohn, Glaxo Wellcome, Hoechst Marion Roussel, Searle, Merck & Co., Roche, Bristol-Myers Squibb, Novartis, Pratt, B. Braun McGaw, Pfizer and Parke-Davis.

This activity is made possible by an unrestricted educational grant from the Novartis Foundation for Gerontology.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 

Learning Objectives

Upon completion of this Cyberounds^®, you should be able to:

• Recognize the significance of benign cognitive dysfunction

• Discuss the possible role of homocysteine in dementia

• Manage the non-cognitive behavioral problems of dementia.

 

Cognitive dysfunction represents one of the most important causes of functional deterioration in the United States. Approximately 8% of persons in the United States over 65 years of age have dementia and, if persons with milder cognitive dysfunction are included, nearly 16%. By the age of 85 years, as high as 47% of the age group may have dementia. It has been estimated that dementia in the United States costs nearly $100 billion annually.(1) Alzheimer's disease is the most common cause of dementia, responsible for approximately 70% of all cases.

Benign (Mild) Cognitive Impairment (MCI)

A number of older persons have cognitive impairment that is worse than that expected for their age and educational level but do not meet the criteria for dementia. Persons with mild cognitive impairment have, primarily, a decline in memory function, as compared to patients with early Alzheimer's Disease, who tend to demonstrate impairments in multiple cognitive areas.(2) The rate of cognitive decline is more rapid in persons with mild cognitive impairment than age-matched controls but slower than in patients with mild Alzheimer's disease. Following a major event, such as a hip fracture, persons with mild cognitive impairment show less functional improvement than those with normal cognitive function. Mild cognitive impairment has also been demonstrated to be a predictor for increased mortality and of dementia.(3)

*Utilize paragraph recall of the Boston Naming Test

It is important to aggressively treat risk factors for dementia in this population, as it would appear that mild cognitive impairment is not benign! There is a need for controlled trials examining the utility of putative cognitive enhancers in this population.(4) This population may also improve from hormonal replacement therapy both in men and women. Positive controlled trials for testosterone replacement in men have been completed.(8)

Differential Diagnosis of Dementias

The gold standard for diagnosis of Alzheimer's disease during life is the National Institute of Neurological and Communicative Disorders and Alzheimer's Disease and Related Disorders Association Work Group.(5) The major criteria are objective testing, establishing dementia deficits in at least two areas of cognition (memory, language domain, praxis, agnosia, executive function), progressive worsening of cognitive function, no alteration in consciousness, onset between 50 and 90 years and absence of other possible causes. Sensitivity of this tool is 80 to 90% and specificity about 75%.

Family members have been shown to fail to recognize dementia in 21% of subjects.(6),(7) A number of studies have shown that physicians are extremely poor at recognizing and investigating cognitive dysfunction.(8)

The clinical features of the common dementias are outlined in the table below.

Approaches to the Pharmacological Management of Cognitive Disturbances in Alzheimer's Disease

Cholinesterase inhibitors

• Tacrine
• Donapezil
• Rivastigmene
• Galantamine

- Improvement in function in some individuals when given early in the disease.
- Can save costs by decreasing time to nursing home admission.

Cholinergic agonists

• Muscarine - Xanomelline
• Nicotinic

Monoamine oxidase B Inhibitors

• Deprenyl (Selegeline ^®)

- Positive results in a number of studies

Antioxidants

• Vitamin E

- May increase survival and delay nursing home admission

Hormones

• Estrogen
• Testosterone

- No intervention data as yet for estrogen and two placebo controlled studies in MCI for testosterone. Estrogen increases HDL; testosterone either has no effect or a beneficial effect on lipids in older persons, suggesting some protection from vascular dementia.

Variable epidemiological data

Anti-inflammatory agents

• Prednisone

- There is good evidence that corticosteroids are neurotoxic.(9) Indeed, the epidemiological data are clearly superior for NSAIDs than for steroids. Furthermore, steroids would enhance catabolic states.

• Nonsteroidal anti-inflammatory agents

- The dosage of NSAID is most likely crucial and must be high in order to be effective. It is possible that COX-2 inhibitors could offer some advantage.
- Some positive epidemiological studies
- No clinical intervention studies

Herbs

• Gingko Biloba

- Positive meta-analysis
- Some reports of excessive bleeding

Ergot alkaloids/nootropics

- Positive effects in large clinical trials - possibly better in vascular dementia

Propenofylline (xanthine derivative)

- Positive effects in four double-blind trials

Experimental

• Block tau protein phosphorylation
• Block b-amyloid
• Decrease APOE e4
• Alter brain membrane, e.g., Ganglioside GMI and Phosphatidylserine
• Nerve growth factor
• Presenilin and/or g secretase inhibitors

Homocysteine and Alzheimer's Disease

Four epidemiological studies have shown a relationship between elevated homocysteine levels and memory dysfunctions.(10),(11),(12),(13) In one of these studies, low vitamin B12 and folate levels were also associated with poorer cognitive dysfunction. Previous studies have strongly connected elevated homocysteine levels to atherosclerotic disease. Thus, these findings raise the possibility that vascular disease may act as a trigger for Alzheimer's disease. Intervention studies to lower homocysteine, utilizing vitamins B12, B6 and folate, need to be undertaken to confirm a role of elevated homocysteine in Alzheimer's disease. In the meantime, administration of a multivitamin preparation to persons with dementia would appear to be a prudent approach.

Non-Pharmacological Management of Patients with Dementia

This was covered in a previous Cyberounds^®.

Management of Non-Cognitive Behavioral Symptoms

Numerous behavioral symptoms have been reported in patients with dementia.(14) Depressive symptomatology is particularly common in patients with vascular dementia but also occur in patients with Alzheimer's disease. The Cornell Scale for Depression in Dementia may be helpful in recognizing depression in demented persons. Thoughts of death or suicidal ideation can occur in nearly a third of patients with dementia early in the course of the disease. Hallucinations, delusions and paranoic ideation occur in approximately a quarter of patients. Anxiety is often present. Other behaviors include agitation, irritability, wandering, restlessness, sleep disturbances, aggressiveness, screaming and inappropriate sexual behavior.

It should also be remembered that agitation or other behavioral symptoms may be caused by delirium. Demented patients are particularly vulnerable to develop delirium. Rapid treatment is important. Haloperidol has low anticholinergic potency.

There are minimal studies on anxiety and its treatment in persons with Alzheimer's disease. Anxiety may result from a fear of becoming a burden or a fear of being left alone. Anxiety is often associated with suspiciousness. Behavior modification, by producing a consistent environment and providing reassurance, is the best intervention. Short-acting benzodiazepines may be useful. We have found buspirone useful but it needs to be remembered that it takes four to six weeks before its effects are seen. Trazodone may be useful to help the anxious patient go to sleep.

Many of the behavioral symptoms seen in demented patients are related to phase shifting of the circadian rhythm. Patients with Alzheimer's disease often are phase-shifted, such as peak activity occurring around dinnertime. Use of high lux (2000 lux) lighting for two hours in the morning may reverse this problem. Melatonin has also been said to work in anecdotal cases.

In the case of agitation, the best interventions are behavioral ones.(15) These include:

1. Career support and education. The ability to deal with agitation is often more important than the agitation itself.
2. Psychotherapy. A variety of psychotherapeutic approaches have been utilized. These include Reality Orientation, Validation Therapy (accept the person's reality - better in late disease), Reminiscence and Music and other Creative Arts Therapies. Strong evidence for the use of many of these therapies is lacking.
3. Environmental Modification. These should include clear environmental distinctions and a restraint-free environment.
4. Special Care Units. While these have been heralded with enthusiasm by their adherents, controlled studies have demonstrated neither efficaciousness nor cost-effectiveness.
5. A hearing amplifier can be used to provide negative feedback to demented patients with continuous screaming.

When agitation first occurs, it is important to rule out an underlying medical cause. Delirium occurs, commonly, in persons with dementia. Pain is often a precipitant of disruptive behaviors and it needs to be carefully assessed in agitated patients.

A number of drugs can be utilized to regulate severe agitation. These include:

Typical Antipsychotics: A meta-analysis found these drugs were moderately superior to placebo in modifying psychotic and/or disruptive behavior in demented persons.(16)

Atypical Antipsychotics: Resperidone and olanzapine are less likely to produce pseudoparkinsonism. A small number of studies suggest that they are as effective as the typical antipsychotics.(17) In persons with Parkinson's of Lewy Body dementia, quetiapine fumarate (Seroquel^®) is the drug of choice.

Serotonin Selective Reuptake Inhibitors (SSRIs): Citalopram was better than placebo in decreasing irritability, fear, dysphoria, and restlessness in Alzheimer's patients.(*) Similar results were found with fluvoxamine but statistical significance was not reached.(*)

Cholinergic Drugs: There is evidence that drugs that enhance cholinergic function may cause a modest improvement in disruptive behaviors.(17)

Trazodone: This can be used to calm agitated behavior but only anecdotal studies exist.

b-blockers: These have been used in agitated patients with reported positive effects.

Divalproex sodium: Often used in the United States to treat agitation and psychotic behaviors with doses of 375 to 2000 mg/d. In uncontrolled trials, improvement was reported in 68% of patients.

Carbamazepine: Positive in one double blind trial.

Estrogens: These can be helpful in some males with aggressive sexual behavior. They should not be used until behavior modification, staff education and SSRIs have been used.

Conclusion

Table 3 is a simple algorithmic approach to the management of disruptive behaviors in demented patients.

Clinical Diagnosis of Probable Alzheimer Disease

Criteria Include

• Dementia established by clinical examination and cognitive test (Mini-Mental State Examination) and confirmed by neuropsychological tests.
• Deficits in > areas of cognition
• Progressive worsening of memory and other cognitive function
• No disturbance of consciousness
• Onset between ages 40 and 90 years
• Absence of systemic disorder or brain disease that could account for progressive
• cognitive deficits
• The diagnosis is supported by progressive deterioration of specific cognitive functions such as language (aphasia), motor skills (apraxia) and perception (agnosia)
• Impaired activities of daily living
• Altered behavior
• Family history of similar disorders
• Normal lumbar puncture, normal electroencephalogram or nonspecific changes,
• Progressive cerebral atrophy on computed tomography
• Features consistent with the diagnosis:
• Plateaus in the course of progression
• Associated symptoms including depression, insomnia, incontinence, delusions,
• illusions, hallucinations, catastrophic outbursts, sexual disorders or weight loss
• Neurologic signs, including increased muscle tone, myoclonus, or gait disorder
• Seizures (in advanced stage)
• Computed tomography normal for age
• Features that make the diagnosis uncertain or unlikely:
• Sudden, apoplectic onset
• Focal neurologic findings such as hemiparesis, sensory loss, visual field deficits,
• and incoordination (early in the course)
• Seizures or gait disturbance (at the onset or early in the course)

From the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group.