Radialis PET Imager for the Assessment of Neuritic Amyloid Plaque Burden

Background Information and Scientific Rationale

It is estimated that more 1.3 million people in Canada live with mild cognitive impairment, and more than a quarter of a million people in Canada live with mild dementia. The most common form of dementia is Alzheimer's disease, implicated in approximately two-thirds of cases (1, 2). The proportion of the population living with dementia is expected to increase in the coming decades, due to the increase in life span, aging of the population, and the prevalence of dementia in those over age 75. By 2050, the incidence of dementia may triple, impacting millions of Canadians, their families, the health care system and the economy (3).

Current consensus guidelines recommend cholinesterase inhibitors for the symptomatic treatment of dementia caused by Alzheimer's disease, which may slightly delay cognitive decline, and memantine for the symptomatic treatment of moderate-to-severe cases (4). On July 6, 2023, the FDA granted full approval for lecanemab, the first disease-modifying drug for Alzheimer's disease. Lecanemab is a human monoclonal antibody that targets amyloid-β soluble protofibrils and oligomers with high affinity and has low affinity against amyloid-β monomers and insoluble fibrils. According to the amyloid hypothesis, soluble and insoluble amyloid-β peptides trigger a cascade that impairs neurons and synapses in the brain, leading to cognitive decline (5). In the Clarity AD randomized phase III trial, patients aged 50-90 with clinical and biomarker evidence of mild cognitive impairment caused by Alzheimer's disease, including PET or CSF analysis demonstrating amyloid burden and MR brain excluding alternative causes, those receiving lecanemab had statistically significantly greater reductions in brain amyloid burden than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6) and lower rates of cognitive decline on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) and other measures of cognition. Amyloid-related imaging abnormalities with edema or effusions (ARIA-E) were reported in 12.6% of those receiving the drug (6).

Enabling access to disease-modifying medications for Alzheimer's disease in Canada poses multiple challenges to provincial and territorial healthcare systems. To determine eligibility for therapy, and to assess efficacy, patients would need to undergo PET to assess neuritic amyloid plaque burden. Across many jurisdictions, including in Canada, there is limited PET/CT scanner capacity. With competitive and expanding indications in oncology, the introduction of new oncology tracers (PSMA, SSTR-peptide tracers) and high-volume non-oncology indications such as PET myocardial perfusion imaging (82Rb PET), there is little capacity to perform amyloid PET imaging (7). Furthermore, tracer availability is currently limited. Without an increase in scanner and tracer availability, these may result in a significant barrier to the clinical rollout of disease-modifying drugs in Canada.

Organ-based PET technology, such as positron emission mammography, has been evaluated for a few decades. Recently, an organ-targeted Radialis PET Imager (RPI), using two planar detector heads mounted on a movable gantry was developed using hardware improvements to increase sensitivity and noise equivalent count rate (NECR) performance across a clinically useful activity range, down to low-dose activities at 1/10th of a standard dose (8, 9). The RPI system has undergone extensive validation in laboratory settings, utilizing a comprehensive set of standardized experiments outlined in the National Electrical Manufacturers Association (NEMA) NU-4 standards. These experiments serve to objectively compare the performance of the RPI with that of other organ-targeted PET and whole-body (WB) PET/CT systems available on the market or in clinical trials. NEMA tests have demonstrated an in-plane spatial resolution of 2.3 ± 0.1 mm, which is comparable to the best-in-class organ-targeted PET scanners. Additionally, the RPI system achieves a peak sensitivity of 3.5% and an average system sensitivity of 2.4%, surpassing the sensitivity of all available PET scanners. In terms of NECR, the peak NECR of 5,400 cps/MBq of the RPI is much larger than that of any WB or organ-targeted systems. The detectability of small objects was demonstrated using Micro hotspot phantom images, where micro hotspot phantom sources were visualized down to 1.35 mm diameter rods, simulating the detectability of very small objects and lesions.