ARTICLE IN BRIEF
More than 40 Alzheimer disease (AD) experts came together to develop new diagnostic criteria for AD, which now include descriptions of asymptomatic, preclinical phases of the disease.
The scientific advances over the last three decades have led to a new set of diagnostic guidelines that incorporate clinical and research criteria that should help clinicians better identify someone with Alzheimer disease (AD) and the earliest clinical stages of disease.
The proposed new diagnostic criteria and research agenda for AD were presented in four separate papers published online April 19 before the May print edition of the Alzheimer's Association journal Alzheimer's & Dementia. The authors included more than 40 AD experts who were brought together to re-write the guidelines by the National Institute on Aging and the Alzheimer's Association.
The new guidelines include an update of the 1984 diagnostic criteria for the dementia due to AD; a refinement of the criteria for the symptomatic, pre-dementia phase, referred to as mild cognitive impairment (MCI), due to AD; and criteria for the biomarkers that are available for clinical research and not for clinical diagnosis. These biomarkers may ultimately be used to diagnose the asymptomatic, preclinical phase of AD.
The 1984 guidelines only talked about the dementia phase of the disorder, said Guy McKhann, MD, director of the Mind/Brain Institute at Johns Hopkins University, who led the update of the clinical criteria. Now, clinicians understand there are many stages of AD that culminate with dementia.
“The biggest difference between then and now is we now think of this process as a continuum that started many years before we make the diagnosis of dementia,” he said. While the 1984 criteria has held up over its 27 years with a sensitivity of 81 percent and a specificity of 70 percent, it has become cwlear that the old guidelines did not distinguish other conditions that cause dementia and AD, he said.
The guidelines include descriptions of MCI that can help in the evaluation of patients complaining of changes in memory and other cognitive abilities. The work group on MCI, led by Marilyn Albert, PhD, professor of neurology at Johns Hopkins University School of Medicine, described a hypothetical framework for use of the biomarkers that measure amyloid-beta and tau to increase the level of diagnostic certainty.
“What is done in the clinician's office will essentially be the same,” said Dr. Albert. “Still, there was enormous consensus that we needed to talk about biomarkers.”
Similar to AD dementia, MCI due to AD cannot be currently diagnosed by a laboratory test, according to the guidelines, she said, “but requires the judgment of a clinician.”
Clinicians should assess whether a person's change in cognition (reported by the person, a family member or informant) has changed over time. The assessment includes a formal bedside exam looking for subtle impairment of cognition function. A patient with MCI still has preserved abilities to function in their environment. The clinician should rule out other causes of cognitive problems that can occur in the face of vascular, traumatic and other medical conditions.
The guidelines were developed to provide clinicians with criteria to diagnosis AD without access to neuropsychological testing, advanced brain imaging and CSF biomarkers, and a section on research criteria that includes the use of these technologies.
The diagnosis of AD should be made when there are cognitive or neuropsychiatric symptoms that interfere with the ability to function at work or at usual activities; and represent a decline from previous levels of functioning and performance. Other conditions that cause dementia should be ruled out, the guidelines state.
The assessment of cognitive impairment should include a history from the patient and a knowledgeable family member or informant and either a “bedside” mental status examination or neuropsychological testing.
Neuropsychological tests should be performed if the history and clinical examination of mental status are not enough for a diagnosis. Clinicians should look for a minimum of two cognitive or behavioral impairments, including problems acquiring or remembering new information — for example, repetitive questions or conversations, misplacing personal belongings, forgetting events or appointments, getting lost on a familiar route.
According to the guidelines, clinicians should also examine the patient's ability to handle complex tasks. This would include an assessment of whether the patient understands safety risks and can plan complex or sequential activities, such as knowing when there is a doctor's appointment and the steps leading up to getting there. Among questions: Can they manage household finances? Do they have impaired visuospatial abilities such as recognizing faces or common objects? Do they have impaired language functions, i.e. difficulty accessing common words while speaking, and speech, spelling, and writing mistakes? Are there uncharacteristic mood changes, including agitation, impaired motivation, initiative, apathy, loss of drive, social withdrawal, decreased interest in previous activities, loss of empathy, compulsive or obsessive behaviors and socially unacceptable behaviors?
CLASSIFICATIONS FOR AD
The work group proposed the classification of the disease to include individuals with dementia caused by AD:
- probable AD dementia marked by gradual symptom onset over months to years, clear-cut history of worsening of cognition by report or observation; deficits in learning and recall of recently learned information, objectagnosia, impaired face recognition, simultanagnosia, and alexia, deficits in executive function, and a patient who is a carrier of a causative AD mutation;
- possible AD dementia marked by an atypical course such as a sudden onset of cognitive impairment or not enough historical information or obvious decline in cognition on exam, or an etiologically mixed presentation with evidence of cerebrovascular disease or other neurological diseases;
- probable or possible AD dementia with evidence of the AD pathophysiological process.
The first two classifications are intended for use in all clinical settings. The third is currently intended for research purposes and CSF biomarkers of brain amyloid-beta (A-beta) protein deposition and tau, and PET amyloid imaging would be used to bolster the clinical diagnosis.
Reisa Sperling, MD, associate professor of neurology at Harvard Medical School's Brigham and Women's Hospital, led the work group entrusted with identifying the markers now under development to assess preclinical AD. They include biomarkers of amyloid-beta deposition; CSF A-beta 42, and PET amyloid imaging; and biomarkers of neuronal injury such as CSF tau/phosphorylated-tau; hippocampal volume or medial temporal atrophy by volumetric measures or visual rating, brain atrophy, FDG-PET imaging, SPECT perfusion imaging.
The guidelines also includes a staging system for preclinical assessment. This remains a research tool. The staging catagories for preclinical AD research include:
- stage 1, asymptomatic cerebral amyloidosis;
- stage 2, symptomatic amyloidosis, neurodegeneration; and
- stage 3, amyloidosis, neuronal injury, and subtle cognitive/behavioral decline.
The preclinical guidelines are for research purposes only, said Dr. Sperling. “We wanted to define AD on the basis of underlying brain changes and not just symptoms. We need to identify people at greatest risk for the disease and intervene early.”
The new guidelines are intended to increase our certainty that the underlying clinical picture is Alzheimer's,” said Ronald C. Petersen, MD, PhD, director of the Mayo Alzheimer's Disease Research Center, who coined the term MCI and led studies to confirm that many of these patients go on to develop AD. Dr. Petersen was among the three dozen experts called in to help with the guidelines.
There are many things that can cause memory and thinking problems, he said, including medication side effects, anxiety and depression, and successful treatment of the underlying cause can help alleviate the symptoms. But MCI is progressive with about 15 percent of patients converting to AD every year.
Ultimately, the biomarkers will help identify those patients who will go on to develop AD. “But we need a lot more work to sort this out,” said Dr. Petersen.
Oscar L. Lopez, MD, professor of neurology at University of Pittsburgh, agrees. “MCI is a clincal syndrome that constitutes a risk factor for the conversion to AD,” said Dr. Lopez, who was not involved with the guidelines. “However, not all MCI patients progress to AD. The use of biomarkers will help the field better identify those MCI patients who will progress to AD.”
But it is not ready to be moved out of the research section of the guidelines, he added. “We do not have a cure for AD and consequently there is no treatment to offer. Prevention trials with current dementia medications failed. And we do not know when a person with MCI will convert to AD. A person can remain in the MCI phase for years although the biomarkers indicate the presence of AD pathology.”
“The new guidelines push the field forward,” Dr. Lopez said. There are tools that the clinician can use to strengthen a diagnosis of AD, he said. “PET and SPECT scans can be ordered in the clinical setting.”
The Alzheimer's Association estimates that there are 5.4 million AD patients, and several of the authors of the new guidelines said that there may well be an equal number of people with MCI.