Abstract
Background
18F-florbetapir uptake by brain tissue measured by positron emission tomography (PET) is accepted by regulatory agencies like the Food and Drug Administration (FDA) and the European Medicine Agencies (EMA) for assessing amyloid load in people with dementia. Its added value is mainly demonstrated by excluding Alzheimer’s pathology in an established dementia diagnosis. However, the National Institute on Aging and Alzheimer’s Association (NIA-AA) revised the diagnostic criteria for Alzheimer’s disease and confidence in the diagnosis of mild cognitive impairment (MCI) due to Alzheimer’s disease may be increased when using amyloid biomarkers tests like 18F-florbetapir. These tests, added to the MCI core clinical criteria, might increase the diagnostic test accuracy (DTA) of a testing strategy. However, the DTA of 18F-florbetapir to predict the progression from MCI to Alzheimer’s disease dementia (ADD) or other dementias has not yet been systematically evaluated.
Objectives
To determine the DTA of the 18F-florbetapir PET scan for detecting people with MCI at time of performing the test who will clinically progress to ADD, other forms of dementia (non-ADD), or any form of dementia at follow-up.
Search methods
This review is current to May 2017. We searched MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), BIOSIS Citation Index (Thomson Reuters Web of Science), Web of Science Core Collection, including the Science Citation Index (Thomson Reuters Web of Science) and the Conference Proceedings Citation Index (Thomson Reuters Web of Science), LILACS (BIREME), CINAHL (EBSCOhost), ClinicalTrials.gov (https://clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/search/en/). We also searched ALOIS, the Cochrane Dementia & Cognitive Improvement Group’s specialised register of dementia studies (http://www.medicine.ox.ac.uk/alois/). We checked the reference lists of any relevant studies and systematic reviews, and performed citation tracking using the Science Citation Index to identify any additional relevant studies. No language or date restrictions were applied to the electronic searches.
Selection criteria
We included studies that had prospectively defined cohorts with any accepted definition of MCI at time of performing the test and the use of18F-florbetapir scan to evaluate the DTA of the progression from MCI to ADD or other forms of dementia. In addition, we only selected studies that applied a reference standard for Alzheimer’s dementia diagnosis, for example, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) or Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria.
Data collection and analysis
We screened all titles and abstracts identified in electronic-database searches. Two review authors independently selected studies for inclusion and extracted data to create two-by-two tables, showing the binary test results cross-classified with the binary reference standard. We used these data to calculate sensitivities, specificities, and their 95% confidence intervals. Two independent assessors performed quality assessment using the QUADAS-2 tool plus some additional items to assess the methodological quality of the included studies.
Main results
We included three studies, two of which evaluated the progression from MCI to ADD, and one evaluated the progression from MCI to any form of dementia.
Progression from MCI to ADD was evaluated in 448 participants. The studies reported data on 401 participants with 1.6 years of follow-up and in 47 participants with three years of follow-up. Sixty-one (15.2%) participants converted at 1.6 years follow-up; nine (19.1%) participants converted at three years of follow-up.
Progression from MCI to any form of dementia was evaluated in five participants with 1.5 years of follow-up, with three (60%) participants converting to any form of dementia.
There were concerns regarding applicability in the reference standard in all three studies. Regarding the domain of flow and timing, two studies were considered at high risk of bias.
MCI to ADD;
Progression from MCI to ADD in those with a follow-up between two to less than four years had a sensitivity of 67% (95% CI 30 to 93) and a specificity of 71% (95% CI 54 to 85) by visual assessment (n = 47, 1 study).
Progression from MCI to ADD in those with a follow-up between one to less than two years had a sensitivity of 89% (95% CI 78 to 95) and a specificity of 58% (95% CI 53 to 64) by visual assessment, and a sensitivity of 87% (95% CI 76 to 94) and a specificity of 51% (95% CI 45 to 56) by quantitative assessment by the standardised uptake value ratio (SUVR)(n = 401, 1 study).
MCI to any form of dementia;
Progression from MCI to any form of dementia in those with a follow-up between one to less than two years had a sensitivity of 67% (95% CI 9 to 99) and a specificity of 50% (95% CI 1 to 99) by visual assessment (n = 5, 1 study).
MCI to any other forms of dementia (non-ADD);
There was no information regarding the progression from MCI to any other form of dementia (non-ADD).
Authors’ conclusions
Although sensitivity was good in one included study, considering the poor specificity and the limited data available in the literature, we cannot recommend routine use of 18F-florbetapir PET in clinical practice to predict the progression from MCI to ADD.
Because of the poor sensitivity and specificity, limited number of included participants, and the limited data available in the literature, we cannot recommend its routine use in clinical practice to predict the progression from MCI to any form of dementia.
Because of the high financial costs of 18F-florbetapir, clearly demonstrating the DTA and standardising the process of this modality are important prior to its wider use.
Plain language summary
18F-florbetapir PET scan for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment
Review question: In people with mild cognitive impairment (MCI), does using a 18F PET scan with florbetapir predict the progression to Alzheimer’s disease dementia (ADD) and other dementias?
Background
Due to global ageing, the number of people with dementia is expected to increase dramatically in the next few decades. Diagnosing dementia at an early stage is desirable, but there is no widespread agreement on the best approach. A range of simple pen and paper tests used by healthcare professionals can assess people with poor memory or cognitive impairment. Whether or not using special PET scans that detect amyloid —one of the hallmarks of Alzheimer’s disease— improves our ability to predict the progression from MCI to ADD or other forms of dementia remains unclear. Since these tests are expensive, it is important that they provide additional benefits.
Aim
We aimed to evaluate the accuracy of the 18F-florbetapir PET scan in identifying those people with MCI who clinically progress to ADD, other types of dementia, or any form of dementia over a period of time.
Study characteristics
The evidence is current to May 2017. We found three studies including 453 participants with MCI. Two studies evaluated the progression from MCI to ADD and one study evaluated the progression from MCI to any form of dementia.
Regarding the two studies that evaluated the progression from MCI to ADD, one study had 401 participants with a follow-up of 1.6 years and the mean age was 72 years. The other study had 47 participants with a follow-up of three years, and the mean age was 72 years.
The other study that looked at any form of dementia included 5 participants over 90 years old.
Two of the studies were funded by the test manufacturer.
Quality of the evidence
The main limitation of this review was that our findings were based on only three studies, with insufficient detail on how the people were selected, whether the information from the scan was assessed separately from the final diagnosis. The studies were considered to be at high risk of bias due to potential conflicts of interest detected.
Key findings
In this review, we found the following results based on the three studies.
At a follow-up of 1.6 years, using visual assessment, the scan correctly classified 89% of the participants who progressed to ADD but only 58% of the participants who did not progress to ADD. This means that in a group of 100 people with MCI, 15% of whom will develop ADD, we would expect 13 of 15 people to have a positive result and the other 2 participants to be falsely negative. Also 49 people who will not develop ADD would have a negative result, but 36 people who will not develop ADD would have a positive result (false positives).
In the study that followed up people for three years and used visual assessment, the scan correctly classified 67% of people who progressed to ADD and 71% who did not progress to ADD. This means that in a group of 100 people with MCI, 19 of whom will develop ADD, we would expect 13 people to have a positive result of the scan and 6 people to have a falsely negative result. In addition, 58 of 81 participants who will not progress to ADD would have a negative result, but 23 people who will not develop ADD would have a positive result (false positives). The small number of participants evaluated at three years lowered our confidence on these estimates of accuracy.
Regarding progression to any form of dementia, the extremely small number of participants meant that we were unable to provide meaningful estimates of accuracy.
We conclude that 18F-florbetapir PET scans cannot be recommended for routine use in clinical practice to predict the progression from MCI to ADD or any form of dementia based on the currently available data. More studies are needed to demonstrate its usefulness.
