ALZHEIMER’S DISEASE

ALZHEIMER’S DISEASE

Current Diagnosis

• Routine screening for cognitive impairment is controversial but may be beneficial for early diagnosis and identifying treatable causes.

• Combining the Mini-Cog screening test with screening questions on the informant-based AD8 provides a rapid, sensitive, validated screening assessment.

• A comprehensive dementia evaluation includes a battery of cognitive tests, a laboratory panel for treatable causes, a neurologic examination, a brain MRI, and other testing (e.g., depression screen), as indicated.

• The diagnosis of Alzheimer’s disease (AD) continues to rest on having a presentation and course of dementia that is consistent with the disease, and ruling out other identifiable etiologies.

• AD often coexists with cerebrovascular disease; atypical and non- AD dementias generally merit a consultation with a neurology or geriatric specialist.

Current Therapy

• Patient and family education and support are the cornerstones of effective care.

• Preventive measures with the strongest supporting evidence include hypertension control; head injury prevention; physical, cognitive, and social activity; and a Mediterranean diet.

• Cholinesterase inhibitors and memantine (Namenda) alone or jointly have a modest effect on improving or slowing cognitive decline.

•   The primary approach to managing behavioral symptoms is person-centered care using dementia-focused communication skills.

• First-line drug agents that may help control behavioral symptoms include cholinesterase inhibitors and mood stabilizers; antipsychotics may be helpful for moderate to severe agitation.

Alzheimer’s disease (AD) and related disorders of cognitive function are a common and growing issue for all clinicians who provide care to older adults. In discussing this condition, several related but distinctly different terms are used:

•   Cognitive impairment refers to the presence of one or more measurable deficits in cerebral function when compared with normal persons of the same age.

•   Neurocognitive disorder generally refers to a clinical syndrome involving cognitive decline from a previous level of functioning, most commonly associated with Alzheimer’s disease. Each neurocognitive disorder is divided into mild and major forms, with the latter distinguished by multiple cognitive domains affected and clinically significant functional disability. Within this new DSM-V framework, mild cognitive impairment is now referred to as mild neurocognitive disorder, and dementia is now referred to as major neurocognitive disorder.

•   AD is the most common cause of dementia; it has a characteristic pathophysiology and clinical presentation.

Lack of a simple, reliable diagnostic test makes it difficult to know with certainty how many persons in the United States currently have AD, but estimates place the number between 5 and 8 million. Onset can occur when people are in their 40’s or 50’s, but it is largely a disease of older persons, with the prevalence approximately doubling every 5 years after age 65. By age 85 to 90, up to 50% of individuals will meet criteria for dementia, often with mixed features of AD and cerebrovascular disease.

Risk Factors

Numerous risk factors have been associated with AD (Table 1); however, the strongest ones—age and a positive family history— cannot be modified. Of the modifiable risk factors, current emphasis is being placed on reduction of risk factors for atherosclerotic disease (especially hypertension) and traumatic brain injury, particularly sports-related concussions.

Table 1

Major Risk Factors for Alzheimer’s Disease and Evidence of Ability to Modify Risk

*  A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion. For information about the SORT evidence rating system, see http://www.aafp.org/afpsort.xml.

AD is associated with the pathological hallmarks of extracellular amyloid plaques and intracellular neurofibrillary tangles that are composed of hyper-phosphorylated tau protein. How these two protein markers of AD lead to the gradual loss of neuronal cell connections and eventually cell death remains poorly understood. New brain imaging techniques have shown that amyloid deposits may begin decades before the onset of clinical signs, whereas the presence of neurofibrillary tangles composed of abnormal tau protein is much more strongly correlated with disease severity. Genetic mutations that cause AD and the strongest known AD genetic risk factor, the epsilon 4 allele of the apolipoprotein E locus, have led to a primary focus on abnormal amyloid protein processing, but amyloid- based therapeutics to date have been ineffective.

Despite intensive research efforts, the precise mechanisms and interrelationships between extracellular amyloid plaque and intracellular neurofibrillary tangle deposition remains elusive.

Prevention

With the disappointing lack of progress in developing safe, effective new medications to treat AD, increased emphasis is being placed on prevention through (a) modification of vascular risk factors, prevention of neural injury, and buildup of neuronal reserves (see Table 1). Among the preventive measures that can be recommended to persons with a family history of AD or other risk factors for the disease include:

•   Control of hypertension, with the goal of a blood pressure of 130 to 140 or 80 to 90. Lower blood pressures are not generally advocated, especially in older persons, because of concern that more aggressive blood pressure reduction in persons with existing vascular disease may reduce cerebral perfusion, leading to ischemic damage.

•   Reduction in other cardiovascular risk factors by not smoking and by treating hyperlipidemia and diabetes.

•   Avoidance of and/or treatment of anything else that causes injury to brain cells, including head trauma, alcoholism, and obstructive sleep apnea.

•   Maintenance of good general health by engaging in regular physical activity, being socially active, and adhering to healthy dietary principles, such as the Mediterranean diet.

•   Promotion of brain use and activity through such activities as learning a language and doing puzzles.

Clinical Features

Diagnostic criteria for dementia include a chronic, progressive disease characterized by (a) memory impairment; (b) impairment of one or more other aspects of neurologic function, such as executive function, visuospatial function, aphasia, apraxia, and/or agnosia; and (c) significant reduction in social or occupational function from the person’s previous level of performance, which is not explained by another psychiatric or neurologic disorder. Diagnostic criteria for AD include meeting all criteria for dementia and ruling out delirium and the other dementias (see next section). Over time, these criteria may change: In 2011 the Alzheimer’s Association and the National Institute on Aging defined AD to include a preclinical stage and mild cognitive impairment (MCI); however, at present, these definitions are for research purposes only.

The cardinal feature of AD is short-term memory loss or difficulty learning new information, which is often accompanied by a lack of awareness or concern of the memory problem. Word-finding difficulties, loss of time orientation, getting lost or misplacing things, and impaired judgment and planning are other common features. On average, the person with AD lives 6 to 10 years after the diagnosis and progresses through several stages. Over time, progressive cognitive disturbances become more pervasive, leading to impairment in instrumental activities of daily living (IADLs) and later even basic activities of daily living (ADLs). Ultimately, if the person does not die from some other cause, they will progress to being unable to express themself verbally and will be relatively immobile, with contractures, swallowing problems, cachexia, weight loss, and eventually death.

Differential Diagnosis

The most important considerations in the differential diagnosis of AD are the following:

•   Vascular dementia (VaD). There are two general types: (a) cortical—resulting from multiple infarcts in the cerebral cortex, and (b) subcortical—resulting from small-vessel disease with multiple lacunar infarcts. Presentation is highly variable; however, memory deficits are typically less prominent than in AD.

•   Frontotemporal dementia (FTD). This diagnosis is relatively uncommon but accounts for about half of all cases before age 65. The clinical presentation is highly variable, depending on the lateral distribution of pathological changes. Language disturbances involving expression or comprehension, or prominent changes in behavior and personality (e.g., apathy, disinhibition, repetitive motor behaviors, loss of empathy) are the two main clinical subtypes (left and right side predominant, respectively). Clinical diagnosis can be aided by MRI brain imaging showing severe focal atrophy in the frontal and/or temporal lobes.

•   Lewy body dementia (LBD) and Parkinson’s disease dementia (PDD). Characteristics include parkinsonian motor signs (bradykinesia, rigidity, and tremor), prominent visual hallucinations, and sleep-wake disturbances (e.g., fluctuating arousal, daytime somnolence, acting out dreams). LBD is used to describe the syndrome when cognitive symptoms predominate; PDD refers to late-occurring dementia in a patient with Parkinson’s disease.

•   Rare but distinctive forms of dementia. These include progressive supranuclear palsy, normal pressure hydrocephalus, Creutzfeldt- Jakob disease, postanoxic dementia, posttraumatic brain injury, chronic subdural hematoma(s), and Huntington’s disease.

•   MCI. This is a condition in which the person is able to carry out his or her normal activities but has deficits in certain areas of higher function such as short-term memory, judgment, and planning. There are two kinds of MCI, amnestic, which is characterized by isolated short-term memory loss, and nonamnestic, in which one or more other cognitive domains are affected. Amnestic MCI is particularly likely to progress to AD and in such cases reflects a prodromal stage of the disease.

•   Delirium. In contrast to the dementias, delirium tends to be subacute or acute in onset and to be completely or partially reversible. Key characteristics include fluctuating consciousness, confusion, and hallucinations or delusions. The cause is usually identifiable and is most often because of medication, stress (such as infection or surgery), or a metabolic disturbance. Delirium often coexists with dementia as one of its biggest risk factors is cognitive impairment.

•   Depression. Decades ago, depression was at times mistaken for dementia and termed “pseudodementia,” because people with depression often say “I don’t know” in response to cognitive status questions. Improved interviewing techniques and routine use of depression screening tests as part of dementia evaluations have largely eliminated this confusion. However, depression remains an important consideration in the dementia evaluation because it frequently coexists with dementia, particularly in early stages of the illness.

Screening for Cognitive Impairment

Whether to screen for AD is highly controversial. Advantages of early diagnosis include offering earlier treatment and research participation, allowing the person an opportunity to make life- planning decisions at a point where his or her residual cognitive function is at its best, helping family understand what is happening and learn how best to provide support, providing guidance to patient and family about managing finances wisely and avoiding scams, and providing time for decision making about such things as durable power of attorney and advance-care planning. Medicare currently requires cognitive screening as part of the welcome-to-Medicare visit; in addition, we recommend screening anyone age 75 and older and anyone for whom a memory lapse or vagueness noted in an interview or an error in judgment (e.g., causing an auto accident) raises suspicion of cognitive impairment.

Primary care physicians can conduct expedient, reliable screening for dementia by simultaneously administering the Mini-Cog and the AD8. Both can be administered by a nurse or medical assistant, and each takes less than 3 minutes.

•   The Mini-Cog is administered directly to the person being screened. It consists of asking the person to remember three items; to draw a clock face, putting in the numbers and placing the hands at “10 after 11”; and then to recall the three items. A positive screen occurs if the person cannot recall any of the items (regardless of the clock drawing), or if they recall one to two items and the clock is drawn incorrectly.

•   The AD8 requires the person being screened to be accompanied by a spouse, child, or other person who knows him or her well. It inquires about whether the person has had a change over the past several years in eight areas: judgment, interest in hobbies/activities, repeating things, learning, orientation, financial management, remembering appointments, and other memory. A change in two or more items is a positive screen.

Downloadable, printable copies of both instruments with instructions are available at http://www.ncalzheimers.org/.

Diagnostic Evaluation

There are five general steps in a diagnostic evaluation for AD: (1) history; (2) cognitive assessment; (3) physical examination, with a focus on the neurologic evaluation; (4) laboratory testing; and (5) establishment of a working diagnosis (including consideration of and attempts to rule out other depression, delirium, and non-Alzheimer’s dementias). Each of these is discussed below.

History

Patients suspected of having AD typically present either because a family member reports changes in their behavior and function, or because of a positive screening evaluation. Judgment and decision making can be impaired early in the disease, which may lead to an incident that draws attention to the problem. Examples include auto accidents, an uncharacteristic purchase, problems managing a household budget, or being victimized by a scam. Increased awareness of early warning signs and the Medicare requirement for cognitive screening should help identify a higher proportion of patients with mild, as opposed to major, neurocognitive disorder.

The person with the illness rarely gives a reliable history, so the primary source of historical information about functional change needs to be a family member close to the individual. Such a history typically includes gradual decrease in function in multiple domains including memory, plus unusual behaviors such as repeating oneself, getting lost while driving, having trouble managing a checkbook, saying things that the person normally wouldn’t have said, and difficulty making decisions.

An important element of the history should be questions aimed at identifying other potential causes of cognitive impairment, such as alcoholism, illicit drug use, and prescription medications.

In addition, inquiry as to the person’s psychiatric history should be undertaken as well as screening for anxiety and depression. A formal screening tool, such as the Geriatric Depression Scale or the Patient Health Questionnaire nine-item depression screen (PHQ-9) is recommended.

Cognitive Status Examination

The cognitive status examination should include a standardized cognitive status battery, both for comparison with other patients and to provide a numerical result that can be followed over time. We recommend either the St. Louis University Mental Status Examination (SLUMS) or the Montreal Cognitive Assessment examination (MOCA), both of which cover a wide range of cognitive domains, detect cognitive impairment earlier than older tests (such as the Mini- Mental State Examination), have been validated in many populations, and are freely available in the public domain (i.e., available for download from the Internet).

The standardized examination should be supplemented by several other components to help round out the evaluation, identify behavioral issues, and screen for non-Alzheimer’s dementias.

Supplementary examination components that are useful include

•   Verbal fluency testing—naming as many objects, such as animals, as they can in 1 minute (category fluency) and as many words beginning with a single letter such as “F” as they can in 1 minute (letter fluency). These not only tap into early loss cognitive areas but also help differentiate between AD (where category fluency tends to be more impaired) and other dementias where impairment is similar (e.g., VaD) or letter fluency tends to be more impaired (e.g., FTD and LBD).

•   Trails B test—this is a timed paper-and-pencil test; it is a particularly sensitive test for early cognitive changes in nonmemory domains (visuospatial and executive).

•   Psychological and behavioral symptom evaluation—this is best obtained from a family member using a questionnaire tool such as the Neuropsychiatric Inventory (NPI).

Physical Examination

The physical examination should focus on neurologic function, looking for signs that suggest a diagnosis other than AD. In particular, the examination should look for asymmetry in strength and/or motor function (suggesting one or more prior strokes), tremor and bradykinesia (suggesting parkinsonism or LBD), abnormalities of eye movement—especially inability to gaze downward (suggesting primary supranuclear palsy), peripheral neuropathy (suggesting the possibility of vitamin B12 deficiency, hypothyroidism, alcoholism, or neurosyphilis [although diabetes is more often the cause]). In addition, a screening examination for cardiovascular and pulmonary function should be conducted.

Laboratory Testing and Neuroimaging

If the cognitive status examination confirms dysfunction, then a laboratory battery should be conducted largely to help identify remediable causes of cognitive impairment. Basic testing should include a complete blood count, blood glucose, electrolytes, renal function (BUN/creatinine), thyroid function, liver function tests, vitamin B12 level, and, if appropriate, a serologic test for syphilis.

Although research advances in brain imaging offer promise for more early and definitive diagnosis, a routine brain MRI remains the standard of practice. It can identify cerebrovascular disease as discrete old infarcts (usually cortical) or as greater-than-normal deep white- matter changes (leukoariosis; suggests subcortical vascular disease).

The MRI is also useful in ruling out tumor or normal pressure hydrocephalus and in identifying focal cortical atrophy consistent with FTD.

Recently, positive emission tomography (PET) scanning for brain amyloid (florbetapir F 18 or Amyvid) has become commercially available, but is currently reimbursed by Medicare only if done as part of a research protocol. A large multicenter study is currently underway to evaluate the potential impact of amyloid brain PET imaging on clinical care for AD patients. Future therapeutic advances in MCI and early AD will likely usher in the selective, if not routine use of amyloid brain imaging in clinical care. At present, however, the only clinical indication for routine metabolic brain PET reimbursed by Medicare is to distinguish FTD from AD.

Establishment of a Working Diagnosis

Because no gold-standard clinical test exists for diagnosing AD, the evaluation usually results in a working diagnosis. If the evaluation raises suspicions that a non-AD dementia may be involved (Table 2), then consultation with a specialist in neurology or geriatric medicine is advised. General principles of management apply to all dementias; however, different dementias respond differently to certain medications discussed later in this chapter, and so consultation may help direct appropriate therapeutic interventions in addition to clarifying diagnosis

Table 2

Differential Diagnosis of Alzheimer’s Disease

Treatment

In managing AD, the physician needs to treat at least two individuals: the person with the disease and the person (or persons) who serve as the primary caregiver. A common thread in this dualistic approach is to promote safety and quality of life for all involved. While cognitive function is the key to diagnosis, behavioral symptoms are often the most important to address in management. Table 3 reviews the main therapeutic targets and interventions.

Table 3

Alzheimer’s Disease Management Strategies

* A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion. For information about the SORT evidence rating system, see http://www.aafp.org/afpsort.xml.

1  Not FDA approved for this indication.

Counseling and Caregiver Support

The patient and caregiver should be counseled about the disease course, about increased safety risks from such things as operating machinery and driving a motor vehicle, about the desirability of establishing a durable power of attorney for health care decisions, and about the value of having conversations early on about desires for end-of-life care, including completion of advance directives. As the disease progresses, regular meetings with the patient and family are important, so as to anticipate and address key decision points.

AD leads to progressive dependency; maintaining the health and well-being of the caregiver(s) is a critical component of care. Make sure the caregiver has a physician and is under treatment for any medical problems he or she may have. In addition, the caregiver should be advised about community resources that can provide assistance, such as the local chapter of the Alzheimer’s Association, programs for persons with early-stage dementia, support programs for caregivers, local adult day care centers, and respite programs. In addition, because the majority of persons with AD spend their final days in a nursing home or assisted living community, health care providers should be prepared to provide support for that decision when appropriate.

Management of Cognitive Symptoms

The lack of novel therapeutic approaches during the past 10 years, in spite of very active research, has been a major disappointment. The cholinesterase inhibitors and memantine (Namenda) remain mainstays of treatment. Key points in using these drugs include the following (see Table 4):

Table 4

Drug Therapy for Cognitive Symptoms in Alzheimer’s Disease

*  Extended release formulations qd.

†  Transdermal patch (oral dosing with high incidence of GI side effects not  listed).

•   There is no demonstrated value to withholding drugs for later, when the patient gets worse.

•   The overall benefit of treatment may be difficult to assess clinically; “real-world” changes noted by caregivers may be more important than cognitive test scores.

•   Side effects are largely gastrointestinal (pain, bloating, nausea). Treatment should involve reducing the dose or switching to another agent. Donepezil (Aricept), while generally given at bedtime, may cause leg cramps, insomnia, or vivid bizarre dreams that often abate by switching to morning dosing.

•   Studies indicate that combining a cholinesterase inhibitor with memantine (Namenda) produces a modest additive benefit.

•   Long-term treatment effects involve symptom reduction and are not cumulative; if the efficacy of one or more drug treatments is in question, it is reasonable to pursue a sequential trial taper and withdrawal (resuming the previous dose or medication if acute decline is noted by informants).

•   Ensuring adequate sleep, activity, and nutrition is important for optimizing the patient’s functional abilities.

Management of Behavioral Symptoms

A wide variety of behavioral symptoms can develop. Among the more common are (a) early in the disease—repetitive questions, wandering, and refusing assistance; (b) in the mid-stage of the disease—resistance to care, agitation or pacing, verbal and physical agitation and aggression, and antisocial behaviors such as inappropriate sexual remarks; (c) late in the disease—resistance to care and repetitive vocalizations such as moaning and screaming.

The key to managing most behavioral symptoms rests on nonpharmacologic approaches involving good dementia communication skills. Key elements include making eye contact before speaking; using simple language; speaking slowly, clearly, and in a low-pitched voice; communicating caring through such actions as smiling and giving a hug; asking only one question at a time and allowing the patient adequate time to respond; breaking instructions into small steps and presenting one at a time; and backing off and trying later if the person becomes agitated or refuses. If the person doesn’t seem to understand a statement, repeat the statement using the same wording; if this does not work, rephrase and allow time for processing. When a specific problem develops, such as resistance to care or unwanted exiting, caregivers should use a structured problem- solving approach that defines the symptom, tries to identify reasons (including emotions and delusions) behind the symptom, and develops a management strategy to try and evaluate, using a quality improvement approach.

At times, however, families or facility caregivers report aggressive, frightening, or socially unacceptable behaviors that do not remit even in spite of excellent psychosocial, personalized care. In these situations, medical providers are often asked for a prescription.

Sometimes all that is needed is time, as aberrant behaviors tend to moderate over time. If a medication is needed, the first step should be a cholinesterase inhibitor, which has been shown to have potential benefits on apathy, delusions, and purposeless motor behaviors. If that is unsuccessful, then an antipsychotic or anticonvulsant should be considered, starting at a low dose and increasing until improvement is seen or intolerable side effects occur. Patients who demonstrate, or later develop, prominent behavioral features (e.g., visual hallucinations, disinhibition) should be referred to an appropriate specialist in neurology, geriatrics, or psychiatry. Caution is particularly warranted in managing psychotic symptoms in patients with Lewy body dementias, including Parkinson’s disease with dementia. Eliminating anticholinergic or reducing dopaminergic medications should be the first line of treatment.

Monitoring

Patients and caregivers should be reevaluated every 3 to 6 months. If the person with AD resists going to the doctor (a common feature early in the disease), then some of these check-in evaluations can be handled by telephone. Indeed, telephone consultation is highly valued by caregivers, for whom a trip to the doctor can be costly and disruptive. To help provide readily available consultation, primary care practices are encouraged to designate a nurse, nurse practitioner, or physician assistant to focus on dementia treatment and care. This focus would include coordinating dementia screening in the practice, knowing each of the patients and families with dementia, coordinating a support group (if the practice chooses to have one), and responding to questions from caregivers. Caution is particularly warranted in managing psychotic symptoms in patients with Lewy body dementias, including Parkinson’s disease with dementia.

Eliminating anticholinergic or reducing dopaminergic medications should be the first line of treatment.

References

1.     Jack Jr. C.R., Albert M.S., Knopman D.S., et al. Introduction to the recommendations from the National Institute on Aging— Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:257–262.

2.    Galvin J.E., Sadowski C.H. Practical guidelines for the recognition and diagnosis of dementia. J Am Board Fam Med. 2012;25:367–382.

3.     Odenheimer G., Borson S., Sanders A.E., et al. Quality improvement in neurology: Dementia management quality measures. Neurology. 2013;81:1545–1549.

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