Alzheimer's disease

I. What every physician needs to know.

Alzheimer’s disease (AD), also called senile dementia of the Alzheimer type, or simply Alzheimer’s, is the most common form of dementia accounting for 60-80% of cases of dementia. The development of multiple cognitive deficits is manifested by both memory impairment and one or more of the following cognitive disturbances: aphasia (language disturbance), apraxia (inability to carry out motor activities), agnosia (failure to recognize or identify objects), and disturbance in executive functioning.

Definite risk factors include increasing age, being female, increased apolipoprotein E ε4 allele load, and family history of AD, dementia or Down syndrome. Some possible protective factors include higher educational achievement, increased apolipoprotein E ε2 allele load, use of estrogens in postmenopausal women, use of cholesterol-lowering statin medications, rheumatoid arthritis, and taking non-steroidal antiinflammatory drugs for longer than 2 years.

II. Diagnostic Confirmation: Are you sure your patient has Alzheimer's disease?

AD is characterized 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 and parietal lobes and parts of the frontal cortex and cingulate gyrus. Studies using neuroimaging have documented reductions in the size of specific brain regions in patients as they progressed from mild cognitive impairment to AD. Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those affected by AD.

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AD is also considered a tautopathy due to abnormal aggregation of the tau protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton. Levels of the neurotransmitters acetylcholine, serotonin, norepinephrine, and somatostatin are often reduced while glutamate levels are usually elevated.

A. History Part I: Pattern Recognition:

The pattern of memory impairment in AD is distinctive where the declarative memory for facts and events is profoundly affected while procedural memory and motor learning are relatively spared until late in the disease. The memory for recent events is prominently impaired early in AD while immediate memory is spared early on as are memories that are consolidated for long period of time.

A state of circumscribed anterograde long-term memory impairment with preserved general cognitive and social functioning is known as amnestic mild cognitive impairment (MCI) which is recognized as an early-stage of AD with conversion rate to dementia at about 10 to 15% per year. Language function and visuospatial skills tend to be affected relatively early, while deficits in executive function and behavioral symptoms often manifest later in the disease course.

Dyspraxia, or difficulty performing learned motor tasks, usually occurs later in the disease after deficit in memory and language are apparent. Apathy, social disengagement and disinhibition manifest in the middle and late course of the disease and sometimes superimpose with ongoing depression.

B. History Part 2: Prevalence:

Prevalence estimates suggest that AD affects about 10% of persons over the age of 65, making it one of the most common chronic diseases of the elderly. The number of Americans with AD is increasing every year because of the steady growth of the older population and will escalate rapidly in the coming years as the “baby boomer” generation ages.

Currently in the United States (US), 5.4 million people have an Alzheimer’s diagnosis. By 2050, that number is expected to more than triple. Women are more likely than men to develop AD or other dementias possibly due to the fact that they live longer than men to develop these conditions. Although there are dramatic increases in AD across the elderly age groups, an especially significant impact is expected to occur in the 85 and older age group which currently comprises nearly 50% of individuals with AD .

C. History Part 3: Competing diagnoses that can mimic Alzheimer's disease.

Different types of dementia have been associated with distinct symptom patterns and distinguishing microscopic brain abnormalities. The symptoms of different types ferent types of dementiaof dementia also overlap and can be further complicated by coexisting medical conditions.

Other types of dementias include vascular dementia, dementia with Lewy bodies, Parkinson’s disease with dementia, frontotemporal dementia, alcohol induced dementia, and other reversible dementias.

Vascular dementia is associated with impairment in one or more cognitive domains within a few months after a stroke, sometimes termed “post-stroke dementia”. Dementia with Lewy bodies is associated with visual hallucinations and such Parkinsonian symptoms as “mask-like” face, rigidity, stiffness, shuffling gait, and problems with balance.

Frontotemporal dementia patients show behavioral and personality changes that may include uncharacteristic impulsiveness and lack of inhibition, poor financial judgment and inappropriate social conduct. Other types of dementia characteristics are discussed in the dementia chapter.

D. Physical Examination Findings.

The general physical examination is usually normal in AD. There are no specific physical findings that can be looked for to diagnose AD; however, a detailed neurologic exam is very important and should include checking reflexes, testing for proprioception and cerebellar function, gait, and mental status. Look for signs of abuse or neglect and screen for impairments in hearing and vision.

E. What diagnostic tests should be performed?

Mental status examination or neuropsychological testing profiles a patient’s cognitive functioning and should be done in every suspected AD case. It is the most sensitive tool we have for early diagnosis. The mini-mental state examination (MMSE) is widely used to evaluate the cognitive impairments needed for diagnosis. The clock draw test & three-item recall have been made to create brief, focused screening tools that are less time consuming than the MMSE.

There are different neuropsychiatric testing tools that are used by the neuropsychologist or by the researchers in dementia but are complicated and hard to use by the general physician. In general, the neuropsychological testing has limited utility for differentiating among causes of dementia, as there is substantial overlap in test performance.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Lab tests are used to rule out other dementia types or other mimicking diseases. Vitamin B12 deficiency and hypothyroidism are common in the elderly and can affect cognitive functioning. Most clinicians will also perform complete blood count, electrolytes, creatinine, glucose, calcium, and liver function tests. One should screen for latent syphilis or neurosyphilis by ordering the rapid plasma reagin (RPR) test and a human immunodeficiency virus (HIV) test if there is a high index of suspicion for these conditions.

Genetic markers for known chromosomal mutations and apolipiprotein E genotyping are only useful for early onset dementia or significant family history. The E ε4 allele is a risk factor for AD, while the E ε2 allele appears to be protective. A role of these measurements in clinical practice has not been established.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Computed tomography (CT) or magnetic resonance imaging (MRI) scans of the brain show atrophy in AD and can rule out other cerebral pathology or subtypes of dementia. MRI volumetric measurement of hippocampus and entorhinal cortex atrophy is 95% sensitive but only 40% specific for AD. Functional imaging using single photon emission computed tomography (SPECT) and positron emission tomography (PET) may be helpful for early diagnosis and typically shows bilateral temporal and parietal hypoperfusion and hypometabolism respectively.

Functional MRI (fMRI) shows increased activation during memory tasks in individuals at high risk for AD but is not routinely recommended at this time. While imaging may add value to the clinical assessment, these technologies are not universally available and are not part of the routine assessment of patients with AD. The amyloid ligand Pittsburgh B and fluorodeoxyglucose (FDG) have both been shown to accurately discriminate between AD and frontotemporal lobar degeneration in positron emission tomography (PET) scans of the brain researchers found. Pittsburgh B had a higher sensitivity for AD than FGD.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Routine brain imaging in the diagnostic evaluation of a patient with cognitive impairment or dementia is controversial. Genetic testing, including apolipoprotein E (APOE) genotyping, is not indicated for clinical use.

III. Default Management.

There are many areas in which intervention can improve quality of life for both the patient and the caregiver. Successful intervention requires that the physician works effectively with providers of many other medical and non-medical services. In general, five issues should be discussed with the family: (a) community resources, (b) advocacy, (c) pharmacotherapy, (d) behavior management, and (e) experimental therapies and procedures.

AD patients underreport symptoms of coincidental illness, infection, dehydration, and pain that cause increased disability if not discovered and treated. It is imperative that adverse drug effects and drug interactions are minimized and anticholinergic and benzodiazepine medications are avoided.

Adequate supervision for medication compliance, proper nutritional intake and accident prevention is needed. Sensory deprivation can be minimized by social stimulation and vision and hearing care; a watch should be kept for overstimulation that may cause agitation.

A. Immediate management.

Currently available treatments for AD are symptomatic, providing only limited effect on the disease’s pathophysiology and progression. Four medications are currently approved by the US Food and Drug Administration (FDA) to treat the cognitive manifestations of AD: three are acetylcholinesterase inhibitors (AChEIs) like donepezil, galantamine and rivastigmine and the other is memantine, an n-methyl-d-aspartate (NMDA) receptor antagonist. Only donepezil is approved for treatment of advanced AD dementia.

In a systematic review of 29 trials in mild-to-moderate probable AD, AChEIs demonstrated a modest impact on neuropsychiatric and functional outcomes. Memantine has been shown to be moderately efficacious in the treatment of moderate to severe AD. The combination of memantine and donepezil has been shown to be of statistical significance but has clinically marginal effectiveness.

B. Physical Examination Tips to Guide Management.

No specific physical finding can give feedback on the success of therapy. Repeat MMSE testing can help follow up on the stability of cognitive impairment. MMSE will decline 3 points per year on the average in untreated mild to moderate patients. It is advised to measure cognitive status and ask about behavioral and functional abilities every 6 months.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

No specific lab tests need to be monitored in AD; however, routine complete blood count (CBC) and chemistry including thyroid-stimulating hormone (TSH) could be justified. There is no need to check urine unless warranted by an acute change in cognition with or without urinary symptoms.

D. Long-term management.

Acetylcholinesterase (also known as cholinesterase) inhibitors provide only modest benefit for 1–2 years, after which decline continues at a somewhat lesser rate than placebo. Antipsychotic drugs are modestly useful in reducing aggression and psychosis in Alzheimer’s patients with behavioral problems, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine use. The use of the AChEIs in MCI has not shown any effect in a delay of the onset of AD.

The appropriate length of treatment with AChEIs is still unknown, but some experts recommend that therapy be continued indefinitely if improvement or stabilization is noted. Clinicians and caregivers may notice a decline in function if AChEIs are discontinued.

Stimulation-oriented treatments help and include art, music and pet therapies, exercise, and any other kind of recreational activity. Both vitamin E and ginkgo are being investigated in large trials for the prevention of AD. Mood stabilizers such as carbamazepine and valproic acid have shown benefit in small trials. However, because of side effects, drug-drug interactions and necessary blood test monitoring, these agents are not recommended as first-line treatments.

E. Common Pitfalls and Side-Effects of Management

  • Avoid benzodiazepines, which may produce paradoxical excitation or daytime drowsiness.

  • Optimize treatment of associated comorbidities.

  • Avoid medications with anticholinergic effects including: antihistamines, which can cause urinary retention, and certain psychotropics.

  • Atypical antipsychotics may lower seizure threshold; watch for orthostatic hypotension.

The most common side effects of cholinesterase inhibitors which affect 12-20% of users are nausea and vomiting, both of which are linked to cholinergic excess. Use donepezil with caution with anticholinergic medication or in patients with sick sinus syndrome or a history of peptic ulcers. Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache, and fatigue.

Drug treatment for Alzheimer's disease
  • Donepezil: 5 mg/day for 6 weeks, then 10 mg/day.

  • Galantamine: 4 mg twice daily for 4 weeks, then 8 mg twice daily for 4 weeks, then 12 mg twice daily.

  • Rivastigmine: 1.5 mg twice daily for 4 weeks, then 3 mg twice daily for 4 weeks, then 4.5 mg twice daily for 4 weeks, then 6 mg twice daily.

  • Memantine: start 5 mg/day, increase by 5 mg/day at weekly intervals to max 20 mg/day. Doses greater than 5 mg/day should be divided twice daily.

IV. Management with Co-Morbidities

Agitation and psychosis are common in dementia, especially as the disease progresses. Any new behavioral symptoms should be evaluated before being attributed solely to the dementia. Precipitating causes of new agitation may include delirium, untreated pain, fecal impaction, urinary retention, new medications, sensory impairment, and environmental causes (e.g., new environment, excessive stimulation).

Selective serotonin reuptake inhibitors (SSRIs) are recommended for the treatment of depression in AD. Citalopram is often used because of its possible additional benefits for neuropsychiatric symptoms. Sertraline is a well-studied alternative to citalopram. A trial of trazodone may be considered to treat psychotic symptoms, especially when they interfere with sleep.

Antipsychotic agents have limited efficacy and are associated with increased mortality in patients with dementia. It is suggested to use low doses of olanzapine or quetiapine in patients with severe, disabling symptoms after informing families of the mortality risk.

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

Cognitive impairment subsequent to coronary artery bypass graft (CABG) surgery has been reported in up to 80% of patients, and older age significantly increases the risk for development of such complications. Postoperative cognitive function stabilizes or even improves after 12 months, but some are at high risk for continued cognitive deterioration 5 years post surgery.

Hypertension is well associated with cognitive impairment independent of secondary disease or organ damage, particularly in older patients.

E. Diabetes or other Endocrine issues

Patients with Type 2 diabetes mellitus show pronounced impairment in attention and verbal memory, with accelerated cognitive decline over time. It has been found that insulin resistance independent of hyperglycemia may have a negative consequence on brain systems mediating memory and attention.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

Oxygen deprivation disorders like chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea (OSA) are commonly associated with cognitive decline. These changes are caused by hypoxemia, and studies have indicated that oxygen therapy may result in modest improvement in cognition.

I. Gastrointestinal or Nutrition Issues

Older adults are at a considerable risk for nutritional deficiencies as a consequence of poor diet and malabsorption syndromes. Reduced folate levels may be associated with lower cognitive function and increased risk of AD; however, the accumulated evidence does not support a similar relationship for vitamin B6 and B12.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Behavioral and psychological symptoms of dementia are associated with poor outcomes. Delirium is very common in hospitalized AD patients and is usually worse with dehydration, sleep deprivation and use of psychoactive medications. It is associated with increased morbidity, mortality, functional decline, and immobility and its attendant complications, including aspiration pneumonia, pressure ulcers, deep venous thrombosis, pulmonary emboli, and urinary tract infections.

It is very important to identify and treat the underlying medical cause by reviewing contributing medications, evaluating drug interactions, assessing liver and kidney status, and evaluating for occult infection.

B. Anticipated Length of Stay.

Delirium related to cognitive impairment and Alzheimer’s dementia is independently associated with adverse hospital and long-term outcomes, including poor long-term functioning, mortality, increased length of stay, increased need for formal home health care and rehabilitation services, new institutionalization, and increased costs of care.

C. When is the Patient Ready for Discharge?

Ideally, patients should be discharged when clinically stable. Special care should be emphasized about the functional decline and deconditioning that could have developed secondary to a long hospital stay.

D. Arranging for Clinic Follow-up

Follow-up with a primary care physician should be arranged and is advised to be scheduled within 2 weeks of discharge. Home health services should be started as soon as possible to ensure good supervision of care and medical condition.

E. Placement Considerations.

When AD patients are admitted, the majority lose some ability to perform activities of daily living (ADL) and usually require some home health services and sometimes even subacute rehabilitation. Some very advanced AD cases may require skilled nursing facility (SNF) or nursing home (NH) placement due to the burn out of the caregiver and inability to care further for their loved one. Social work consultation early during admission is helpful to give a variety of options to the caregiver.

F. Prognosis and Patient Counseling.

The prognosis is generally poor for patients with more advanced AD, with average survival about 4-6 years. Discussing advance directives and selecting the proper code status for the patient is very important. Some patients may benefit from palliative or even hospice care consultation.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

Fall precautions, establishing advance directives, home and driving safety, and concerns about wandering and getting lost are very important to be considered before discharging AD patients. The rate of falls is higher in hospital and immediate post hospital settings, compared to a general community setting. It is important to assess the physical and functional ability as well as the balance of the dementia patient.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients with complex or atypical presentations or challenging management issues should be referred to a specialist with expertise in dementia. Family education and support may help reduce the need for SNF, and reduce caregiver stress, depression and burnout.

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