18F PET with flutemetamol 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 flutemetamol 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-flutemetamol 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 two studies evaluating the progression from MCI to ADD. The studies included 252 MCI eligible participants, with 243 participants that had follow-up. Of these, 127 were women. The average age in one study with two years of follow-up was 72.7 + 7.09 years. In the other study with three years of follow-up, the average age was 71.1 + 8.62 years. The setting in one study was memory clinics.

Study funding sources: both 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 two studies, with not enough details on how the people were selected, how the interpretation of the PET scan was made in one study, how the clinical diagnosis of dementia was established in the other study. 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 that the 18F-flutemetamol PET scan, as a single test, in one study with 19 participants included with 2 years of follow-up, had a sensitivity of 89% and a specificity of 80%. This means that in a cohort with 100 participants with MCI and a proportion of progression in this study of 47%, we would expect 42 of 47 MCI participants with a positive result for 18F-flutemetamol scan to progress to ADD, and 5 participants to be falsely positive. In addition, we would expect 42 of 53 participants who will not progress to ADD to have a negative result for 18F-flutemetamol, and 11 to be falsely negative.

In the other study with 224 participants included in the analysis with 3 years follow-up, the sensitivity was 64% and the specificity was 69%. This means that in a cohort with 100 participants with MCI and a proportion of progression in this study of 36%, we would expect 23 of 36 MCI participants with a positive result for 18F-flutemetamol to progress to ADD, and 13 participants to be falsely positive. In addition, we would expect 44 of 64 participants who will not progress to ADD to have a negative result for 18F-flutemetamol, and 20 to be falsely negative.

There was no information regarding the progression from MCI to other forms of dementia and progression to any form of dementia at follow-up.

We conclude that 18F-flutemetamol PET imaging cannot be recommended for routine use in clinical practice to predict the progression from MCI to ADD based on the currently available data. More studies are needed to clearly demonstrate its usefulness.

Authors' conclusions: 

Due to the varying sensitivity and specificity for predicting the progression from MCI to ADD and the limited data available, we cannot recommend routine use of 18F-flutemetamol in clinical practice. 18F-flutemetamol has high financial costs; therefore, clearly demonstrating its DTA and standardising the process of the 18F-flutemetamol modality is important prior to its wider use.

Read the full abstract...
Background: 

18F-flutemetamol 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 the confidence in the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease may be increased when using some amyloid biomarkers tests like 18F-flutemetamol. 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-flutemetamol 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-flutemetamol 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 strategy: 

The most recent search for this review was performed in 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 of 18F-flutemetamol 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: 

Progression from MCI to ADD was evaluated in 243 participants from two studies. The studies reported data on 19 participants with two years of follow-up and on 224 participants with three years of follow-up. Nine (47.4%) participants converted at two years follow-up and 81 (36.2%) converted at three years of follow-up.

There were concerns about participant selection and sampling in both studies. The index test domain in one study was considered unclear and in the second study it was considered at low risk of bias. For the reference standard domain, one study was considered at low risk and the second study was considered to have an unclear risk of bias. Regarding the domains of flow and timing, both studies were considered at high risk of bias.

MCI to ADD;

Progression from MCI to ADD at two years of follow-up had a sensitivity of 89% (95% CI 52 to 100) and a specificity of 80% (95% CI 44 to 97) by quantitative assessment by SUVR (n = 19, 1 study).

Progression from MCI to ADD at three years of follow-up had a sensitivity of 64% (95% CI 53 to 75) and a specificity of 69% (95% CI 60 to 76) by visual assessment (n = 224, 1 study).

There was no information regarding the other two objectives in this systematic review (SR): progression from MCI to other forms of dementia and progression to any form of dementia at follow-up.

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