Research Article
Introduction
- Jeffrey L. Cummings
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- Published online by Cambridge University Press:
- 07 November 2014, pp. 4-5
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Alzheimer’s disease (AD) research is progressing rapidly and on multiple fronts. Advances are being made in early diagnosis, neuroimaging, and biomarkers; optimal care uses currently available medications and strategies; and new therapies are emerging. Early diagnosis is necessary for optimal patient management. Biomarkers are critical to early diagnosis, and biomarker development is dependent on better understanding of disease pathophysiology (Slide 1). The discussions in this supplement examine how progress in AD research can be translated into clinical care.
Primary care practitioners (PCPs) provide most of the care of patients with AD, and these clinicians are optimally poised to discover new cases emerging among elderly patients. Caregivers are most likely to voice concerns about declining memory in a family member to a PCP before seeking specialty evaluation. PCPs, however, have little time to devote to complex assessments and cannot have specialty-level expertise in all disorders. PCPs must have clinical tools that assist them in rapidly identifying potential problems and triaging them for further evaluation or specialty referral.
Short Clinical Assessments Applicable to Busy Practices
- Ziad Nasreddine
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- Published online by Cambridge University Press:
- 07 November 2014, pp. 6-9
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Because biomarkers to detect Alzheimer’s disease (AD) have not yet been validated, physicians must rely on clinical assessments. The Research Committee of the American Neuropsychiatric Association recommended that the ideal cognitive screening instrument have the following characteristics: First, it should take <15 minutes to administer by a clinician at any level of training. Second, it should sample all major cognitive domains, including memory, attention/concentration, executive function, visual-spatial skills, language, and orientation. Third, it should be reliable, having adequate test-retest and inter-rater validity. Finally, it should be able to detect cognitive disorders commonly encountered by neuropsychiatrists.
The American Academy of Neurology Practice Parameters from 1994 and 2001 and the Canadian Consensus Guidelines on Dementia from 2007 recommend that physicians screen subjects with suspected dementia or mild cognitive impairment (MCI), since these patients are at increased risk for AD. Currently, there are no data on the utility of screening subjects who are asymptomatic.
The most commonly used brief cognitive tests are the Mini-Mental State Examination (MMSE), according to a survey conducted by the International Psychogeriatric Association (IPA) in 2006, followed by the clock-drawing test, the delayed-word recall, the verbal fluency test, the similarities test, and the trail-making test. Clinicians appraised these assessments as the most effective and easiest to administer (Slide 1).
Neuropsychological Characterization of Dementia Patients
- Kathleen Welsh-Bohmer
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- Published online by Cambridge University Press:
- 07 November 2014, pp. 10-13
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Computerized Neuropsychological Assessments
- Ellen Woo
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- Published online by Cambridge University Press:
- 07 November 2014, pp. 14-17
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Computer-based measures to evaluate cognition have been used with growing frequency in recent years. These batteries are shown to be useful for identifying mild cognitive impairment (MCI) and dementia. There are few requirements to administer these tests. All that is typically needed is a computer, a response pad for patients to input their answers, and an examiner. In many cases, the examiner does not need to be a trained neuropsychologist. These computer-based assessments should yield a score report detailing the patient’s cognitive profile.
An important advantage of computerized assessments over standard paper-and-pencil testing is that they can provide precise measurement at the millisecond level. This can be a more sensitive measure of cognitive impairment, especially in high-functioning older adults and in patients with milder levels of cognitive deficit. Computer tests also have a shorter assessment time. Many batteries take <1 hour to administer, whereas many standard neuropsychological batteries require >4 hours to complete. The presentation of items in some batteries can be adapted to patients’ performance levels to avoid floor effects (the test restricts how low a patients’ scores can be) and ceiling effects (the test restricts how high scores can be). Computer tests have increased standardization; they are administered the same way every time. Scoring is automatic, meaning the results are available immediately and human scoring error is reduced. Examiner effects are reduced, which is an important advantage because clinicians may differ in how they administer standard tests, which may impact patients’ responses. In addition, the batteries are easily transported, and multiple tasks can be made available on a single computer.
Use of Magnetic Resonance Imaging to Identify Mild Cognitive Impairment: Who Should Be Imaged?
- Liana G. Apostolova
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- Published online by Cambridge University Press:
- 07 November 2014, pp. 18-20
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Problems with memory are a very common complaint in the elderly and are not synonymous with dementia. Some degree of cognitive decline, manifested as greater difficulty in learning and retrieving new information for instance, develops with normal aging. Thus many older patients do not perform at the same level they did when they were younger but they do perform well when compared to their peers. For many, cognitive change ends at this stage and they proceed to lead normal, healthy, dementia-free lives.
The cohort that has cognitive changes beyond what is expected in normal aging but does not yet meet criteria for dementia concerns clinicians greatly as many of these patients eventually become demented. These patients usually go through a latent stage in which neurodegenerative pathology silently spreads in the brain. Once there is enough pathological burden, cognitive decline beyond what is expected for normal aging can be detected by formal neuropsychological testing. Frequently such patients go through a state called mild cognitive impairment (MCI). In this state patients are still functionally intact and live independently, but show cognitive impairment relative to the age- and education-adjusted norms.
The MCI state in itself is a prominent risk factor for developing dementia. Most patients with amnestic MCI develop Alzheimer’s disease (AD) dementia over time. At six years, as many as 80% progress to AD. Thus, MCI is a very important topic of research and an increasingly important topic of clinical care.
FDG and Amyloid Positron Emission Tomography
- Mark A. Mintun
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- Published online by Cambridge University Press:
- 07 November 2014, pp. 21-24
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For over 20 years, researchers have used the tracer [18F]fluorodeoxyglucose (FDG) in positron emission tomography (PET) imaging. FDG PET imaging has been utilized to study the characteristic metabolic changes in Alzheimer’s disease (AD), and as more molecular imaging tracers become available for human research, PET will likely assume many new roles for investigating more specific abnormalities, such as amyloid deposition, in the future.
FDG is a glucose analog that images glucose metabolism and also illustrates neural firing. Different synapse activity, particularly excitatory activity from glutamate release, appears to change FDG uptake. AD will affect both brain infrastructure by decreasing the amount of cell bodies and synapses as well as decreasing synaptic activity, which are both changes that decrease the amount of FDG. AD is not a perfectly uniform process, and this is reflected by distinct progressive patterns of decreased FDG and decreased metabolism across different regions of the brain.
FDG enters the brain via blood flow, and then into brain tissue by both diffusion and facilitated transport. Once it enters the glia and neurons, FDG can be phosphorylated, a step that is essentially irreversible, but then cannot be processed further by the cells, effectively trapping the FDG in situ. The amount of trapping that occurs in the brain over the first 10–20 minutes is very high and constitutes over 80% of the uptake. Thus, after the first 10–20 minutes uptake phase, a pattern of FDG emerges that mirrors the distribution of glucose metabolism in all subcortical and cortical structures.
Cerebrospinal Fluid: When Is It Worthwhile to Do a Lumbar Puncture?
- Elaine R. Peskind
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- Published online by Cambridge University Press:
- 07 November 2014, pp. 25-27
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Clinicians should have an understanding of a lumbar puncture is indicated in the differential diagnosis of dementia and delirium. In most cases, this procedure is not commonly performed in outpatient practice for the differential diagnosis of dementia. However, in patients who have acute or subacute onset or a very rapid decline—such as in suspected Creutzfeldt-Jakob disease (CJD)—cerebrospinal fluid (CSF) 14-3-3, and tau proteins can be diagnostic for at least sporadic CJD. Practice parameters from the American Academy of Neurology (AAN) suggest performing a spinal tap on patients ≤55 years of age. However, that recommendation may not always be beneficial, particularly in a patient who has a prominent family history of either Alzheimer’s disease (AD) or frontotemporal dementia. Per the AAN practice parameter, lumbar puncture for CSF analysis is indicated in the diagnosis of central nervous system (CNS) infection, carcinomatous meningitis, or CNS vasculitis.
Beyond the clinically indicated lumbar puncture, there is utility of CSF biomarkers, including CSF Aβ42, total tau, and phospho-tau, which are the best studied. These biomarkers may be useful for cases involving atypical presentations of dementia, eg, when it is difficult to determine if the patient has AD versus frontotemporal dementia. They may be most useful for cases in which there is an atypical presentation of the fluorodeoxyglucose PET image or PET image features of both AD and frontotemporal dementia.
Integrating Symptomatic- and Disease-Modifying Treatments
- Jeffrey L. Cummings
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- Published online by Cambridge University Press:
- 07 November 2014, pp. 28-30
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Although treatments for Alzheimer’s disease (AD) currently focus on symptomatic therapies, we are entering into an era of disease-modifying therapies. Central to disease modification is early diagnosis; the disease should be slowed as early as possible, maximizing the preservation of cognitive integrity. Ideally, AD should be diagnosed before the onset of dementia, perhaps with the use of biomarkers.
Some therapies suggest that cholinesterase inhibitors and memantine have disease-modifying properties, though not all studies agree. Doody and colleagues have produced data suggesting that these agents may modify the course of AD, but it is not clear that they affect the underlying mechanisms that lead to cell death. Rather than being disease-modifying agents, cholinesterase inhibitors and memantine have potential as disease-course-modifying agents. Language precision will be extremely important in describing these therapies. One European consensus conference concluded that affecting disease course is not adequate for disease modification, but this has not been largely endorsed.
Symptomatic therapies are those affecting the course of the disease. Their benefits are multidimensional, improving cognition, global assessment, activities of daily living, behavior, and caregiver burden. Symptomatic therapies should defer decline. Clinical trials show that symptomatic therapies produce an initial improvement above baseline. However, some patients experience observable changes and some experience none. These therapies are believed to produce ~1 point improvement on the Mini-Mental State Examination (MMSE) average, and a decline that is otherwise parallel to a placebo group after a period of delayed progression (Slide 1).
Beyond Standard Anti-Dementia Therapies: Diet, Exercise, Socialization, and Supplements
- Gary W. Small
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- Published online by Cambridge University Press:
- 07 November 2014, pp. 31-33
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Several lines of evidence point to lifestyle choices that may improve brain health. Genetic factors are important to the process of aging, especially as it relates to vulnerability to Alzheimer’s disease (AD), but non-genetic factors clearly have a role as well. This paper highlights studies suggesting that diet, exercise, socialization, and supplements may protect the brain from age-related decline.
Observational evidence has indicated that several dietary practices can help maintain the health of one’s brain. The first such practice is to moderate one’s caloric intake. Illnesses related to obesity, such as diabetes, hypertension, and high cholesterol, are associated with poorer brain health. The second is to increase one’s intake of antioxidant foods, such as fresh fruits, and vegetables. The third is to increase intake of foods rich in omega-3 fatty acids, such as fish and olive oil. These fats in the diet may be associated with lower risk of dementia. Finally, consuming low glycemic-index carbohydrates instead of high glycemic-index carbohydrates, which spike blood sugar levels and are associated with higher risk of type 2 diabetes, may benefit the brain.
Many studies have been conducted on the connection between a lower risk for AD and healthy diet. While there are not much data from randomized-controlled trials, epidemiologic studies support the theory that diet can have an impact on vulnerability to AD.
Cholinesterase Inhibitors and Memantine: Best Practices
- Rachelle S. Doody
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- 07 November 2014, pp. 34-35
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Today’s therapies must be put in the context of both currently available treatments as well as treatment trials with exciting potential for use in the near future. Current clinical trial methodologies do not allow for clear separation of symptomatic treatments from disease-modifying therapies; it may be unproductive to maintain this distinction given the current range of treatments available. A more currently relevant focus is added value. Therapies should aim to provide added value through incremental benefits above and beyond existing treatments, as well as enduring benefits.
Alzheimer’s disease (AD) treatment guidelines are not used by physicians only. Healthcare payers often make use of these guidelines to delimit coverage. Cost concerns will also impact AD treatments after generic cholinesterase inhibitors are made available; it is widely believed that a great number of patients will switch to generics. Therefore, treatment guidelines must account for the possible adverse effects of switching therapies as well as the desirability of persistent treatment. There are many AD treatment guidelines, among them the American Academy of Neurology (AAN) Management of Dementia Guidelines, which are currently being revised. The Institute for the Study on Aging (ISOA) Management of Alzheimer’s Disease in Managed Care Guideline also presents a different approach for a different audience.
The first step to creating evidence-based best practices guidelines is to determine what is meant by “evidence.” A system of classification exists for examining forms of evidence: Class I evidence is provided by one or more well-designed, randomized, controlled clinical trials, including overviews or meta-analyses of such trials. Class II evidence is provided by well-designed observational studies with concurrent controls; for example, case-control studies that generate hypotheses about epidemiologic associations. Class III evidence is provided by expert opinion, case series, case reports, and studies with historical controls.
Amyloid-Based Therapeutics: Findings Translated into Novel Treatments
- Paul S. Aisen
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- 07 November 2014, pp. 36-38
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For decades following the 1906 identification of Alzheimer’s disease (AD), it was believed that the disorder was untreatable. Only in the late 1970s, with the introduction of the cholinergic hypothesis of the underlying mechanisms of AD, were treatment options considered possible. The first positive treatment study was conducted in 1985. In 1993, tacrine, a cholinesterase inhibitor, was approved for the treatment of AD; three similar drugs soon followed. Memantine, an NMDA receptor antagonist, was approved in 2003, representing a second therapeutic class for AD.
Cholinesterase inhibitors were the first therapeutic options successfully employed, and there is strong evidence these agents confer benefits. The addition of memantine to the standard course of therapy can be beneficial as well, particularly at the moderate stages of the disorder (Mini-Mental State Exam score of ≤14). For patients without cardiovascular disease, diabetes, or statin use, 1,000 IU vitamin E BID is a consideration to mitigate the effects of AD. However, there is presently concern over the risks involved in vitamin E therapy. Unfortunately, there are no established treatments for mild cognitive impairment (MCI). Vitamin E is ineffective in treating MCI, and cholinesterase inhibitors, while possibly risky, are only minimally effective. The need for effective treatment remains expansive. The benefits of the available agents are modest, and there are currently no treatments for individuals with memory impairment who do not yet meet the diagnostic criteria for AD.
Current State of Immunotherapy for Alzheimer’s Disease
- Norman R. Relkin
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- Published online by Cambridge University Press:
- 07 November 2014, pp. 39-41
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There are currently over two dozen agents targeting β-amyloid (Aβ) in human clinical trials. More than a dozen of these are forms of anti-amyloid immunotherapy. Although other anti-amyloid interventions are further along in the development process, thus far only immunotherapy has provided post-mortem evidence that it can alter elements of the underlying pathology of Alzheimer’s disease (AD) in actual patients.
In the past 30 years, there have been many attempts to develop treatments for AD. Early therapies were developed based on a limited understanding of the disease (Slide 1). Prior to the 1980s, a clear pathophysiologic mechanism for AD was not known; instead, symptomatic therapies targeted associated symptoms, such as agitation, insomnia, and psychosis. In the 1970s, several preclinical studies pointed toward synaptic transmission abnormalities, particularly neurochemical abnormalities, as the root cause of AD, and treatments with cholinesterase inhibitors grew out of that theory. Today, the cholinergic hypothesis has been largely discredited in the primary pathogenesis of AD. Another theory based on neurotransmitter abnormalities, the glutaminergic hypothesis, has also gone out of favor as a causal explanation for AD. This did not stop medications based on these mechanisms from finding a meaningful place in the clinical pharmacopeia for treatment of AD.
In the 1990s, many clinical trials followed up on epidemiologic studies suggesting systemic causes of AD. These clinical trials focused on anti-inflammatories, hormone replacement, and antioxidants. The trials performed have largely failed, with the possible exception of the trials of vitamin E, an antioxidant. None of these agents have proven useful as disease-modifying therapies for symptomatic AD.
Non-Amyloid Approaches to Neuroprotection
- Mary Sano
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- Published online by Cambridge University Press:
- 07 November 2014, pp. 42-44
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The introduction of the amyloid hypothesis, which identifies amyloid as the primary target for treating Alzheimer’s disease (AD), was a watershed in the field of AD research. Treatment approaches have since focused on how amyloid might be manipulated. In fact, there are challenges to amyloid manipulation. First, removal of amyloid has shown minimal clinical effects. Second, some data indicate that secretase modulation shows hints of stimulating feedback systems, which cause concern over how to effectively manipulate amyloid. Third, side-effect profiles of the direct manipulation of amyloid are not currently optimal. Finally, evidence suggests that cell and synapse loss may be better markers of dementia and its severity. Alternative approaches to direct manipulation of amyloid include antioxidant mechanisms for prevention, anti-inflammatory mechanisms for neuroprotection, manipulation of metabolic risks, modification of tau accumulation, and neuroregeneration.
These alternative mechanisms of action provide support for a wide range of potential agents for clinical trials. The exact connection between mechanism of action and clinical outcomes is not well defined, but typically trial designs using these mechanisms attempt to measure affects on disease progression, often with longer studies that include established clinical outcomes accompanied by putative biomarkers of disease. One trend that has provided much information has been to examine the effects of these drugs in subjects at risk for AD, thereby expanding the intervention to prevention of disease. These studies include both secondary prevention studies, for example deferring onset in those with prodromal disease such as mild cognitive impairment (MCI), and primary prevention directed at those with no specific signs or symptoms.
Food and Drug Administration Regulation
- Russell Katz
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- 07 November 2014, pp. 45-46
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As disease-modifying therapies near realization, there are concerns about the criteria by which these therapies will be judged. It is not yet clear what kind of evidence (clinical, biomarker, or otherwise) will be required to support a disease-modifying claim. When such a drug is approved, regulators must be certain that the claims in the label are factual and unambiguous, yet a definition for “disease modification” remains to be established. One strong potential definition is: “a therapy that affects the underlying pathology and structure of the disease”. However, this is only one possibility, and a consensus definition must be codified before criteria to evaluate it can be determined.
There is room for informed speculation, however. Criteria to evaluate disease-modifying effects have been proposed, and typically involve one of two approaches (neither of which has yet been endorsed by regulators). The first is a clinical approach, in which clinical designs are employed that would ideally force a conclusion that a drug has a disease-modifying effect. In one proposed design, patients would be randomized to drug or placebo for an appropriate duration. At the end of that period, and if a difference in outcome between drug and placebo on an appropriate clinical measure or measures has been achieved, patients originally randomized to drug would then be treated with placebo, while patients originally treated with placebo would remain on placebo.