The goal of clinically relevant detection of neuropathological hallmarks may be in sight.
Clinically relevant detection of the neuropathological hallmarks of early-stage Alzheimer disease (AD) in living patients has been an ongoing challenge. Recent findings suggest that while challenges stubbornly persist, a glimmer of a finish line is in sight. \
Although a recent study showed that the plasma concentration of free amyloid-beta (AÎ²) is not a biomarker of AD,1 results of a phase 3 clinical trial of [18F]flutemetamol positron emission tomography (PET) demonstrate high specificity and sensitivity for detection of AÎ² pathology and potential clinical use in evaluation of neuritic plaque burden.2
Free amyloid-beta plasma concentration
The study that investigated plasma levels of free AÎ² was conducted by researchers from Umea University in Sweden.1 They analyzed plasma samples, taken an average of 9.4 years before AD diagnosis, from 339 preclinical AD cases and 339 dementia-free age- and sex-matched controls.
The aim was to determine concentrations of free plasma AÎ²40 and AÎ²42; however, the investigators found no difference in AÎ² concentrations between preclinical AD cases and dementia-free controls or difference in concentrations before and after diagnosis among subjects for whom longitudinal data were available. Thus, the researchers concluded that free plasma AÎ² was not a viable diagnostic biomarker of AD.
The phase 3 clinical trial, conducted by a multinational investigative team, furthered ongoing research on the potential value of [18F]flutemetamol PET imaging in the analysis of neuritic plaques and the prospect of early AD diagnosis and intervention.2 The researchers noted that earlier studies demonstrated a good association between [18F]flutemetamol PET tracer retention and the presence of AÎ² plaques in brain biopsy and autopsy samples. The data, however, were often gleaned from end-of-life subjects with advanced disease.
Building a Better Older Brain
More relevant to diagnostic research and drug testing would be study in patients with incipient disease development. The team noted that subjects with a limited life expectancy unrelated to cognitive status-such as elderly cancer patients who may or may not have moderate AD pathology-would be a useful study population. The current trial did just that; it comparatively examined a broad spectrum of AÎ² pathology in subjects with AD as well as those with other dementing and nondementing illnesses.
The study analyzed a total of 106 brains of subjects who had a life expectancy of 12 months or less and had cognitive statuses ranging from normal to advanced dementia. Using a range of CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) standards, in vivo PET findings were compared with post-mortem histopathology to demonstrate the ability of [18F]flutemetamol PET to identify fibrillar AÎ².
Of the 106 brains, 76 (72%) were determined to be abnormal, and, of these, a neuropathic diagnosis of AD was made in 66, although only half of this population had “pure” AD not admixed with other dementia-related illnesses. The tracer technology showed 91% sensitivity and 90% specificity for detection of moderate or frequent neuritic plaques. The probability of an abnormal PET scan correlated with the degree of neocortical plaque density and AD diagnosis, and all non–AD-associated dementia cases as well as cases lacking histopathological signs of AÎ² deposits were [18F]flutemetamol-negative.
The bottom line
The findings confirmed that [18F]flutemetamol has high specificity and sensitivity for AÎ² pathology and detection of neuritic plaque burden and that an AD diagnosis could be distinguished from other dementing illnesses in the large majority of cases examined. The study authors noted that the utility of the technology would largely be to rule out AD and perhaps provide a more sensitive assessment of AD progression.
1. LÃ¶vheim H, Elgh F, Johansson A, et al. Plasma concentrations of free amyloid Î² cannot predict the development of Alzheimer’s disease. Alzheimers Dement. 2016 Sep 28. [Epub ahead of print] doi: 10.1016/j.jalz.2016.12.004.
2. Ikonomovic MD, Buckley CJ, Heurling K, et al. Post-mortem histopathology underlying Î²-amyloid PET imaging following flutemetamol F 18 injection. Acta Neuropathol Commun. 2016;4:130.