PET imaging of garbage protein in Alzheimer’s disease: does it require reappraisal of brain PET analysis?

Excerpt

At the recent Alzheimer’s Disease Summit: The Path to 2025, held in November 2013, the societal and economic threat posed by Alzheimer’s disease (AD) to our civilization was acknowledged. By 2050 the condition will affect 135 million people worldwide, and it will incur an annual cost of $1 trillion, just in the US. To win the fight against the disease, the summit identified the investment in new biomarkers of the disease as a priority. A recent article by Villemagne et al. in the European Journal of Nuclear Medicine and Molecular Imaging is in line with this prioritization [1]. The article describes initial results obtained with a new marker of tau protein deposits in the brain, ¹⁸ F-THK523. Tau is involved in a pathophysiological process considered pivotal in Alzheimer’s disease and other dementing conditions grouped under the tauopathy denomination. The development of tracers targeting tau deposition is at the forefront in the search for valid biomarkers of dementing conditions. This research field was opened with the invention of the “PiB compound”, the PET tracer of beta-amyloid (Aß) deposits [2]. The various works now dedicated to tau protein detection raise a basic question: why do we need a marker of tau protein deposits since we now have access to multiple Aß tracers which are reported to be supreme diagnostic tools in AD? One reason is that Aß accumulation seems less directly related to neuronal death than the tau metabolic disturbances leading to the well-defined neurofibrillary degeneration. Also, the early enthusiasm generated by the Aß tracers has been attenuated by the remembrance of some basic facts established several decades ago. Among these facts are the well-established presence of Aß plaques in the brain of subjects in good cognitive health and the poor correspondence of Aß distribution with the cognitive manifestations of AD. Since the distribution of neurofibrillary degeneration is better correlated with the typology of cognitive deficits, tau might be a better choice in the search for valid AD biomarkers. The initial attraction for Aß PET tracers also declined after the deceiving results of clinical studies aiming at amyloid clearance from AD patients’ brain. These results have questioned the simplistic reasoning that equates disappearance of a single pathological feature with therapeutic benefit [3]. New questions have, therefore, been formulated such as, for instance, whether available amyloid PET tracers inform us about amyloid species that are the actual toxic actors in the pathophysiological process. The plea for a refined development of AD biomarkers has fuelled the search for PET tracers directed to tau deposits. This new effort is further encouraged by very recent and preliminary evaluations of therapeutic monoclonal antibodies that might reduce tau-related neurodegeneration [4]. Indeed, such new anti-AD strategies will require tools to assess the evolution of tau deposits in vivo. Such new tau tracers have been recently described [5, 6]. Data obtained with the [¹¹C] PBB3 PET tracer are particularly promising since the uptake distribution in AD patients and in a patient with a corticobasal syndrome — a classic non-AD tauopathy— paralleled the distribution of tau deposits in these disorders. …