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Alzheimer disease (AD) is an irreversible neurodegenerative disorder characterized by a decline in a patient’s activities of daily living (ADL) and cognitive abilities, as well as changes in behavior.

There are many hypotheses about the causes of dementia, including deposits of amyloid plaques; tau proteins that self-replicate, contributing to neurofibrillary tangles; loss of cells that produce the neurotransmitter acetylcholine; and, more recently, genetic variants and inflammatory conditions.1-7

Although the cause of AD is not clear, recent research advances have furthered the understanding of AD. It now is known that pathophysiologic changes begin years before the disease manifests clinically and that the AD spectrum spans from clinically asymptomatic to severely impaired.8 In addition,  biomarkers have been identified and are beginning to be used to aid in diagnosis, instead of diagnosis being based solely on its clinical presentation as has been done historically. 

Recognizing the concept of AD as a physiologic continuum is essential in the development of diagnostic tools, management strategies, and disease-modifying therapies (DMTs).8.9 


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Alzheimer Dementia Redefined

In 2011, the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association revised the 1984 criteria for AD,10 incorporating scientific advances in the field.11,12 The following clinical dementia rating (CDR) from the new criteria describes clinical disease progression11:

  • Preclinical (initial stage): brain changes may already be in progress, but clinical symptoms are not yet apparent.
  • Mild cognitive impairment (MCI): marked by symptoms of memory and/or other thinking problems that are greater than normal for a person’s age and education but do not interfere with his or her independence.
  • Alzheimer’s dementia (final stage): symptoms such as memory loss, word-finding difficulties, and visual/spatial problems are severe enough to impact the ability to function independently.

The main objective of the revised criteria was to be flexible enough to be used by clinicians without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid analysis and by researchers with access to these tools.9 The modified criteria have been reliable for the diagnosis of probable AD, with a sensitivity of 81% and specificity of 70% across more than a dozen clinical pathological studies.12 

The modified diagnostic criteria are intended to incorporate the spectrum of severity, ranging from the mildest to the most severe stages of dementia.12 Diagnosis of a cognitive impairment should include a patient history obtained directly from the patient and a knowledgeable source (caretaker, relative) in combination with objective cognitive assessment with either a “bedside” mental status examination or neuropsychological testing.12  When the diagnosis is still unclear, neuropsychological testing should be conducted.  In addition, the documented deficit must involve at least 2 of the following 5 areas12:

  1. Impaired ability to acquire and remember new information: repetitive questions or conversations, misplacing personal belongings, forgetting events or appointments, getting lost on a familiar route.
  2. Impaired reasoning and handling of complex tasks, poor judgment: poor understanding of safety risks, an inability to manage finances, poor decision-making ability, and an inability to plan complex or sequential activities.
  3. Impaired visuospatial abilities: an inability to recognize faces or common objects or to find objects in direct view despite good acuity, an inability to operate simple implements, and difficulty in orienting clothing to the body.
  4. Impaired language functions (speaking, reading, writing):  difficulty thinking of common words while speaking, hesitations, and errors in speech, spelling, and writing.
  5. Changes in personality, behavior, or comportment: uncharacteristic mood fluctuations, such as agitation, impaired motivation and initiative, apathy, loss of drive, social withdrawal, decreased interest in previous activities, loss of empathy, compulsive or obsessive behaviors, and socially unacceptable behaviors.

It is important to note that differentiating between dementia and MCI depends on whether or not there is disruption in the ability to perform normal daily activities.11