Neuroimaging: assisting with the diagnosis of dementia
In 2015, an estimated 46.8 million people worldwide were living with dementia. Alzheimer’s disease (AD) is the most common cause of dementia representing 60 to 70% of all cases of dementia worldwide. The neuropathological hallmarks of AD are: the presence of extracellular deposits of ß-amyloid peptides, intra-neuronal neurofibrillary tangles, and the predominance of neocortical neuronal degeneration.
Accurate diagnosis and early identification of cognitive and functional impairment due to AD and other etiologies are critical for optimization of patient care and initiation of appropriate therapies. Piramal Imaging’s focus on AD is driven by the limitations of conventional diagnostic modalities. Although history-taking, neuropsychological tests and structural brain imaging are considered a mainstay of clinical diagnosis in patients with evidence of cognitive decline, these tests cannot diagnose AD with very high certainty particularly at an early stage, nor can they sufficiently rule out AD as the underlying etiology of cognitive decline.
Better detection methods of the neuropathological hallmarks of AD are therefore needed to reduce the frequency of misdiagnosis. Fortunately, radiotracers applied with modern imaging technologies are now available to accurately detect these protein depositions. When used in conjunction with other clinical tests, in vivo imaging technologies and molecular imaging in particular can assist in the diagnosis of AD by detecting the presence or absence of ß-amyloid plaques.
An overview of misfolded protein depositions with their associated histopathology and clinical manifestation is shown in the figure below which was published recently along with an overview of approaches to visualize them.
Source: Jovalekic et al. (2017) New protein deposition tracers in the pipeline. EJNMMI Radiopharmacy and Chemistry, January 2017, 1:11. http://link.springer.com/article/10.1186/s41181-016-0015-3
Florbetaben, an 18F-labeled stilbene derivative, trade name NeuraCeqTM (florbetaben F18 injection), is a diagnostic radiopharmaceutical developed to visualize ß-amyloid plaques in the brain. The tracer successfully completed a global multicenter phase 0–III development program and obtained approval in Europe, US and South Korea in 2014.
A research program is running to develop an 18F-labeled compound targeting Tau, a potential biomarker for diagnosing non-AD dementias as well as for monitoring neurodegeneration in AD-related dementia. Tau tangles are an important measure of neuronal death and correlate strongly with cognitive decline. Detection of Tau may therefore contribute to advanced monitoring of cognitive performance in patients with dementia. With PI-2620 a suitable lead compound has been identified, that is currently being further investigated in clinical studies. First results have been presented at scientific conferences in 2017. For more detailed information see also the AD/PD 2017 conference report from Alzforum about Tau tracers in development.
Illustrative example for visualization of Tau deposition in an AD case (upper row) using PI-2620. Brain areas colored in yellow-red show increased binding of the tracer and indicate Tau deposition whereas no cortical tracer accumulation was found in the non-demented control (lower row).
Another CNS product candidate is an 18F-labeled deuterated monoamine oxidase B (MAO-B) ligand specifically targeting activated astrocytes during neuroinflammation. An early component of neuroinflammation, astrogliosis is involved in neurodegenerative disorders including AD, multiple sclerosis, amyotrophic lateral sclerosis and Parkinson’s disease. PET imaging of activated astrocytes during neuroinflammation would enhance characterization and monitoring of disease progression and therapy. A Phase I study is currently planned to further investigate this 18F-MAO-B ligand.
Selected publications florbetaben:
Selected ongoing clinical trials involving florbetaben