Researchers are making strides toward discovering which individuals have an increased risk of Alzheimer's disease thanks to two novel PET radiotracers that show increased uptake in key regions of the brain, according to two studies published online May 14 in JAMA Neurology.
In the first study, a group from South Korea used PET with the tracer F-18 AV-1451, also known as flortaucipir. The tracer is designed to bind to amyloid and tau-based neurofibrillary tangles, which influence the decline of Alzheimer's patients who have memory loss or physical deficiencies from the disease. Flortaucipir is currently being developed by Avid Radiopharmaceuticals for the early detection of neurodegeneration associated with Alzheimer's disease.
In a second study, researchers from the University of Pennsylvania and other institutions used PET with flutemetamol to predict which patients might progress to Alzheimer's disease in the short term. If subjects had positive PET scans as well as positive MRI scans and poor cognitive tests, they were nearly nine times more likely to develop Alzheimer's disease, the group found.
Progressing to Alzheimer's
Previous research has shown that the accumulation of beta-amyloid protein, neurofibrillary tangles, and cerebral small vessel disease can lead to various degrees of cognitive impairment and potentially progress to Alzheimer's disease.
Tau protein has also been associated with beta-amyloid deposition and cerebral small vessel disease, and it is evident in patients with subcortical vascular cognitive impairment. To date, however, it's unknown whether tau has a direct influence relative to underlying cognitive impairment.
To further investigate a possible link, researchers led by Dr. Hee Jin Kim, PhD, from Samsung Medical Center in Seoul studied 61 patients with subcortical vascular cognitive impairment, 27 patients with Alzheimer's disease cognitive impairment, and 19 healthy controls.
All patients underwent a series of imaging procedures. Flortaucipir was used to measure tau, while florbetaben (NeuraCeq, Piramal Imaging) was used to measure beta amyloid. In addition, subjects underwent brain scans with a 3-tesla MRI scanner (Achieva, Philips Healthcare) to detect cerebral small vessel disease based on the volume of white-matter hyperintensities, the number of lacunes, and microbleeds.
Flortaucipir uptake
In reviewing the results, the researchers found greater flortaucipir uptake in the inferior temporal and medial temporal regions of the brain in patients with subcortical vascular cognitive impairment than in normal controls. The locations are particularly noteworthy because the patients with higher uptake also had worse language skills and general cognitive function.
In addition, the presence of beta amyloid and cerebral small vessel disease was each independently associated with increased flortaucipir uptake in the medial temporal and inferior temporal regions, respectively.
"Our findings suggest that in subcortical vascular cognitive impairment, both beta amyloid and cerebral small vessel disease were independently associated with increased tau accumulation," Kim and colleagues wrote. "Furthermore, tau burden played a pivotal role because it was the final common pathway for the cognitive impairment in patients with subcortical vascular cognitive impairment."
Flutemetamol-PET
In the second study, a group led by Dr. David Wolk of the University of Pennsylvania used beta-amyloid results from PET with F-18 flutemetamol (Vizamyl, GE Healthcare) to determine which individuals were at high risk of progressing from amnestic mild cognitive impairment (MCI) to probable Alzheimer's within three years.
Patients with amnestic MCI can be challenging to diagnose. While they may progress to Alzheimer disease, they can also remain stable or revert to normal behavior.
The multicenter study included 232 patients who were recruited from 28 clinical centers in Europe and the U.S. between November 2009 and January 2014. All subjects had amnestic MCI and underwent flutemetamol-PET scans at baseline, followed by as many as six clinical assessments every six months for up to three years.
The PET images were interpreted by five readers who were blinded to the patients' conditions and clinical status. Physicians were also unaware of the PET results and had to depend on the subjects' clinical evaluations.
Increased risk
The baseline flutemetamol-PET scans showed positive beta-amyloid results for 98 patients (42%); 134 (58%) were negative. At the end of the study, three years later, 81 subjects (36%) received a diagnosis of probable Alzheimer's disease. Among patients with positive baseline PET scans, 52 (54%) received the diagnosis of probable Alzheimer's, while 29 (23%) with negative initial PET scans had a similar progression to probable Alzheimer's.
Based on the results, Wolk and colleagues concluded that patents with positive beta-amyloid findings on flutemetamol-PET scans were at 2.5 times (or 70%) greater risk of progressing to probable Alzheimer's within three years, compared with subjects who had negative PET images (26% risk).
Adding additional risk markers to the analysis increased its predictive power even more. If a patient had a positive flutemetamol-PET scan and low hippocampal volume on MRI, he or she was 5.6 times more likely to progress to Alzheimer's; that increased to 8.5 times if the first two markers were present and the patient also had poor cognitive status.
"The study results support using beta-amyloid PET to identify patients with amnestic MCI who are at increased risk for relatively near-term progression to dementia," Wolk and colleagues wrote. "Furthermore, when used with MRI (routinely performed for these patients) and a standard psychometric measure of memory, more precision in the likelihood of progression may be achieved for a significant proportion of patients."
