Knowing Amyloid Status Has Clinical Utility in AD

Pauline Anderson

November 11, 2016

Amyloid positron emission tomography (PET) increases physicians' diagnostic confidence and has clinical utility in patients suspected of having Alzheimer's disease (AD), a new open-label clinical trial suggests.

The study showed that knowing results of amyloid PET led to a change in diagnosis in patients with a prescan diagnosis of AD but an amyloid-negative scan, as well as in those diagnosed with a non-AD-related dementia but who had an amyloid-positive scan.

The study results "provide a realistic estimate of the incremental value of the examination in routine clinical settings," the study authors, led by Marina Boccardi, PhD, LANVIE-Laboratory of Neuroimaging of Aging, University of Geneva, Switzerland, and Laboratory of Alzheimer's Neuroimaging and Epidemiology, Brescia, Italy, conclude.

"This kind of study is key to the assessment of the clinical utility of amyloid PET as an AD biomarker," they note.

The study was published online October 31 in JAMA Neurology.

It's clear that amyloid PET plays a useful role in research, but because of its imperfect ability to predict disease or influence treatment, there has been significant debate about whether it has much clinical utility. The Centers for Medicare & Medicaid Services (CMS) has decided to withhold coverage of this test, and insurance companies typically follow CMS decisions.

The new Incremental Diagnostic Value of Amyloid PET with [18F]-Florbetapir (INDIA-FBP) study included 228 cognitively impaired adults, mean age 70.5 years, who were referred to largely nonacademic AD evaluation units in Italy. The study's aim, the authors write, was to "quantify the effect of amyloid PET on the routine clinical diagnostic assessment" of patients evaluated for cognitive impairment in a "naturalistic setting."

Patients underwent routine diagnostic workup and examinations. Tests included MRI, computed tomography (CT), 18F-fludeoxyglucose-PET/CT, cerebrospinal fluid collection, and clinical and neuropsychological assessment but did not include amyloid PET.

From these results, dementia experts formulated their diagnoses, rated their confidence that cognitive impairment was due to AD, and prescribed treatment.

On the basis of the prescan information, 165 patients were deemed to have AD and 63 to have another type of dementia. Of the 63 without AD, 37 were diagnosed with frontotemporal lobar degeneration (FTLD) and 26 with subcortical diseases, including cerebrovascular disease, dementia with Lewy bodies, corticobasal degeneration, Parkinson's disease dementia, multiple-system atrophy, progression supranuclear palsy, and normal pressure hydrocephalus.

Diagnostic Revisions

Before drug treatments were prescribed, the patients underwent amyloid PET. After learning of these results, the experts were asked to revise their diagnoses, diagnostic confidence and treatment plan.

Experts changed their diagnosis for 79% of patients who had a previous diagnosis of AD and an amyloid-negative scan (P < .001) and in 53% of persons with non-AD diagnoses and an amyloid-positive scan (P < .001). That the diagnosis was changed in so many patients presumed to have AD but whose scans were negative confirms the important negative predictive value of amyloid imaging, commented the authors.

Among those diagnosed with non-AD disorders, amyloid PET more often helped in the diagnosis of patients with FTLD than in patients with subcortical diseases.

Overall, 89.8% of patients with amyloid-positive results received a final diagnosis of AD, and 86.8% of those with amyloid-negative results received a final diagnosis of non-AD.

Diagnostic confidence in an AD diagnosis increased by 15.2% in amyloid-positive (P < .001) scans and decreased by 29.9% in amyloid-negative (P < .001) scans.

The experts introduced cognition-specific medications (acetylcholinesterase inhibitors, memantine) in 65.6% of patients with positive scans and discontinued these drugs in 33.3% of patients with negative scans (P < .001).

Even without disease-modifying drugs, knowing the amyloid status of a patient can affect patient management, noted Dr Boccardi. "We can be much prompter in delivering what we have available as a treatment."

When prescribing a therapy that is not appropriate for AD pathophysiology, "we are giving elderly patients an additional drug that may have an impact on their metabolism" or may be contraindicated with other therapies they're taking, she said.

If physicians are more confident in an AD diagnosis, they may be more apt to recommend cognitive rehabilitation or lifestyle changes, according to Dr Boccardi. "If they're uncertain about the diagnosis, they may wait, tell the patient to come back later, and only after that patient progresses or doesn't progress, decide what to do."

Knowing amyloid status may be particularly important for patients with mild cognitive impairment (MCI). "The sooner we do something, the longer we can keep the patient in a phase where they have less symptoms," said Dr Boccardi. "As long as patients are MCI, they still have a good degree of autonomy, are not yet institutionalized, and so they cost less to society."

Amyloid PET may become even more valuable in future when effective AD-specific therapies are available, said Dr Boccardi.

She stressed that amyloid PET examinations "are not sufficient to make a diagnosis of AD" and that physicians "need the entire clinical picture" to do so. "Positivity does not just equal Alzheimer's disease."

Dr Boccardi pointed out that some "normal" persons and those with a subjective cognitive symptom "may have a positive scan but this does not necessarily mean that they are going to convert to clinical AD."

Treatable Mimics

In the absence of disease-modifying therapy for AD, the most important goal of a diagnostic evaluation is to identify treatable mimics or otherwise modifiable comorbid factors, according to an accompanying editorial.

For example, write Richard J. Caselli, MD, and Bryan K. Woodruff, MD, Department of Neurology, Mayo Clinic Arizona, Phoenix, a chronic autoimmune encephalopathy may have the superficial appearance of AD but can be entirely reversible.

"Similarly, fungal meningitis, polypharmacy-induced toxic encephalopathy, chronic subdural hematoma, and many other conditions that affect cognition may resemble AD to the unwary clinician but must be identified and treated."

Unlike MRI, which can disclose a wealth of pathologic conditions, Dr Caselli and Dr Woodruff say amyloid PET answers a single question: Is it positive or negative? "Or, restated, is it more or less likely this patient has AD?"

The editorial writers outlined patient populations that could benefit from amyloid PET, in addition to the elderly with cognitive issues. One such group includes patients with early-onset dementia who are still working and need proof that they are not a malingerer in order to get disability coverage.

Other patients who might benefit are those with normal pressure hydrocephalus, in whom a positive amyloid PET scan might prevent unnecessary and ineffective surgery, and those with cerebral amyloid angiopathy who develop tumor-like accumulations, in whom the scans might eliminate the need for brain biopsy for diagnosis.

"These potential clinical applications for amyloid PET have been left out of the current debate that instead focuses on enhancing diagnostic confidence in a typical older patient with dementia so as to distinguish one currently irreversible degenerative disease from another."

The debate will change with the arrival of disease-modifying therapies, they write. "Then, the clinical necessity of molecular imaging to identify the therapeutic target — be it amyloid PET for amyloid-targeted therapies or tau PET for tau-targeted therapies — will be unquestioned" and studies such as the current one "will no longer be needed."

The editorial authors stressed that amyloid PET is expensive —– about $4000 in the United States. "Does the ability to modestly increase diagnostic confidence in distinguishing between several equally degenerative diseases and, in turn, jockey marginally effective symptomatic medications justify this added cost to an already expensive disease?"

Although there may be room for argument about cost, the current findings "provide important insight into the real-world utility of amyloid PET," the editorial writers concluded.

This study was sponsored by Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro San Giovanni di Dio Fatebenefratelli and Avid Radiopharmaceuticals Inc. The study was conducted at IRCCS San Giovanni di Dio Fatebenefratelli; Avid Radiopharmaceuticals Inc provided [18F]-florbetapir at no cost. Dr Boccardi has received research grants from Piramal and served as a paid member of advisory boards for Eli Lilly. Dr Castelli reported receiving research funding from Merck. Dr Woodruff reported receiving funding from Genentech and Avid Pharmaceuticals.

JAMA Neurol. Published online October 31, 2016. Abstract, Editorial

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