By Gloria Chia-Yi Chiang, MD

Assistant Professor of Radiology, Weill Cornell Medical College

Dr. Chiang reports no financial relationships relevant to this field of study.

SYNOPSIS: The use of amyloid PET scanning to assist in accurate diagnosis of patients with symptoms of cognitive impairment as well as frank dementia results in a change of diagnosis in at least 25% of patients.

SOURCE: de Wilde A, van der Flier WM, Pelkmans W, et al. Association of amyloid positron emission tomography with changes in diagnosis and patient treatment in an unselected memory clinic cohort: The ABIDE Project. JAMA Neurol 2018; Jun aa. doi:10.1001/jamaneurol.2018.1346. [Epub ahead of print].

A new research framework has been proposed for classifying dementia, integrating the underlying molecular profile (i.e., beta-amyloid and tau pathology) and the cognitive stage, either unimpaired, mild cognitive impairment (MCI), or frank dementia.1 Although the framework seeks to provide more precise diagnoses for interventional clinical trials, the movement toward defining neurodegenerative diseases based on their underlying molecular pathology is evident.

In this study, de Wilde et al sought to bridge the gap between research and clinical settings by assessing the value of amyloid PET, using fluoride-18 florbetaben, in patients evaluated at the memory clinic at VU University Medical Center (Netherlands). Over a two-year period, 866 patients who visited this memory clinic were offered an amyloid PET as part of their dementia workup. More than half the patients (476) consented to undergo PET imaging and were enrolled in this prospective study. An additional 31 patients with known MCI from the University Medical Center Utrecht memory clinic were included to enrich the sample. In the final cohort, 46% had dementia, with more than two-thirds due to Alzheimer’s disease (AD); 23% had MCI; and 31% had subjective cognitive decline. Almost half the patients were found to have positive amyloid PET studies. In 25% of patients, the pre-PET diagnosis changed after imaging. This occurred most frequently in older patients and with a negative amyloid PET study. In other words, the absence of detectable brain amyloidosis on PET identified the need to pursue non-AD causes of dementia. In 24% of patients, there was a change in the treatment plan. In patients with dementia, this often entailed referral to clinical trials or the start of cholinesterase inhibitors. In patients with subjective cognitive impairment, a negative amyloid PET study could lead the clinician to pursue genetic testing, a psychiatry referral, or referral for other imaging, including dopamine transporter or fluorodeoxyglucose PET imaging.

In our era of patient-centered medicine, the authors further included an assessment of the physical and emotional burden of an amyloid PET scan from the patients’ point of view. Eighty percent of patients reported that the PET scan was not burdensome and that the results decreased uncertainty regarding their diagnosis, without a significant increase in anxiety. The main complaints related to the PET scan were the duration of the scan, claustrophobia, needing IV access for radiotracer administration, and fear of adverse effects related to the scan. Patients reported their motivations for undergoing an amyloid PET scan were to learn about their diagnosis and to contribute to science.

COMMENTARY

There were several strengths. First, this was a large prospective study in a clinical cohort comprised of multiple clinical stages, from subjective cognitive impairment to dementia, which differed from previously published, smaller research-based cohorts. To further the clinical relevance of the paper, the authors employed a fluoride-18-based PET tracer, which has a longer half-life than Pittsburgh Compound B, an amyloid tracer commonly used in research studies, and is more readily available to institutions without their own cyclotron. Finally, the authors used a dichotomous visual assessment of the amyloid PET scans to determine positivity, which is more easily translatable into clinical practice than quantitative cutoffs that often require image processing pipelines. In the United States, the authors of the multicenter Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study tried to determine the clinical value of amyloid PET.2 The IDEAS researchers have reported that amyloid PET changes clinical management in two-thirds of patients with MCI and dementia. The authors of a published review pooling estimates from 12 studies similarly reported that amyloid PET changed treatment plans in 64% of patients.3 de Wilde et al found a lower percentage of patients whose treatment plans changed, possibly a result of inclusion of patients with subjective cognitive impairment and more lax selection criteria for enrollment. Subjects referred for the IDEAS study may be more likely to be clinical dilemmas, requiring the need for an amyloid PET scan for differential diagnosis, whereas de Wilde et al offered PET to all-comers in their memory clinic.

An interesting component to the study was the evaluation of patient-centered outcomes. A common argument against the use of imaging tests for AD is that the disease is untreatable. Confirming an AD diagnosis would only cause unnecessary anxiety and harm to the patient. This paper goes against this argument, since most patients believed that the amyloid PET result decreased the uncertainty surrounding their diagnosis and did not significantly increase their anxiety. In other words, patients want to know their diagnosis, even if the disease is untreatable. This is concordant with an international survey of the United States and five European countries, performed by Alzheimer Europe and the Harvard School of Public Health, in which two-thirds of respondents said they would get a medical test for AD even before they showed symptoms.4 The main limitation of the study was that pathological diagnoses were not available in this clinical cohort to confirm the accuracy of the amyloid PET scans. Also, there could have been a selection bias, since patients were given the option of undergoing an amyloid PET scan as part of their workup.

Currently, 20% of people with clinical diagnoses of AD exhibit no AD pathology on autopsy.5 With more widespread use of amyloid PET, the hope is that the field will move toward fewer misdiagnoses, better selection of patients for targeted clinical trials, and perhaps, one day, effective therapies.

REFERENCES

  1. Jack Jr CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018;14:535-562.
  2. Alzheimer’s Association. Clinical Impact of Brain Amyloid PET Scans – Interim Results from the IDEAS Study. Available at: https://bit.ly/2wRkOAq. Accessed July 5, 2018.
  3. Barthel H, Sabri O. Clinical use and utility of amyloid imaging. J Nucl Med 2017;58:1711-1717.
  4. Blendon RJ, Georges J, et al. Key findings from a five-country survey of public attitudes about Alzheimer’s disease. Poster presented at AAIC; July 2011.
  5. Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol 2012;71:266-273.