Research & Development
Research & Development

Neuroimaging

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.

Neuroimaging

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

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.

Neuroimaging

PI-2620

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).


MAO-B

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:

  • Tiepolt et al. (2016) Early [(18)F]florbetaben and [(11)C]PiB PET images are a surrogate biomarker of neuronal injury in Alzheimer's disease. European Journal of Nuclear Medicine and Molecular Imaging. Aug;43(9):1700-9. https://www.ncbi.nlm.nih.gov/pubmed/27026271
  • Daerr et al. (2016) Evaluation of early-phase [18F]-florbetaben PET acquisition in clinical routine cases. NeuroImage: Clinical. Available online first. http://www.sciencedirect.com/science/article/pii/S2213158216301863
  • Catafau et al. (2016) Cerebellar Amyloid-ß Plaques: How Frequent Are They, and Do They Influence 18F-Florbetaben SUV Ratios? Journal of Nuclear Medicine. Nov;57(11):1740-1745. https://www.ncbi.nlm.nih.gov/pubmed/27363836
  • Law et al. (2016) Cardiac Amyloid Imaging with 18F-Florbetaben PET: A Pilot Study. Journal of Nuclear Medicine. Nov;57(11):1733-1739. https://www.ncbi.nlm.nih.gov/pubmed/27307344.
    SNMMI press release
  • Seibyl et al. (2016) Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study. Journal of Nuclear Medicine, Jun;57(6):900-6. doi: 10.2967/jnumed.115.161927. http://www.ncbi.nlm.nih.gov/pubmed/26823561
  • Sabri et al. (2015) Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer's disease: phase 3 study. Alzheimer’s and Dementia, Aug;11(8):964-74. doi: 10.1016/j.jalz.2015.02.004. http://www.ncbi.nlm.nih.gov/pubmed/25824567
  • Syed and Deeks (2015) [(18)F]Florbetaben: a review in ß-amyloid PET imaging in cognitive impairment. CNS Drugs, Jul;29(7):605-13. doi: 10.1007/s40263-015-0258-7. http://www.ncbi.nlm.nih.gov/pubmed/26175116
  • Ong et al. (2015) Aß imaging with 18F-florbetaben in prodromal Alzheimer's disease: a prospective outcome study. Journal of Neurology, Neurosurgery & Psychiatry, Apr;86(4):431-6. doi: 10.1136/jnnp-2014-308094. http://www.ncbi.nlm.nih.gov/pubmed/24970906
  • Oh et al. (2016) ß-Amyloid Deposition Is Associated with Decreased Right Prefrontal Activation during Task Switching among Cognitively Normal Elderly. Journal of Neuroscience, Feb 10;36(6):1962-70. doi: 10.1523/JNEUROSCI.3266-15.2016. http://www.ncbi.nlm.nih.gov/pubmed/26865619
  • Brendel et al. (2015) Amyloid-PET predicts inhibition of de novo plaque formation upon chronic ?-secretase modulator treatment. Molecular Psychiatry, Oct;20(10):1179-87. doi: 10.1038/mp.2015.74. http://www.ncbi.nlm.nih.gov/pubmed/26055427

Selected ongoing clinical trials involving florbetaben

  • Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) Study (NCT02420756)
    Ideas
    For more information click here
  • Impact of FBB PET Amyloid Imaging in Change of Diagnosis in Patients With AD (NCT02681172)
  • 18F-Florbetaben PET Amyloid Imaging in Case of Intermediate CSF Biology for the Diagnosis of Alzheimer's Disease : a Pilot Study (MAF) (NCT02556502)
  • Study of Genetic Alzheimer's Disease Mutation Carriers in Preclinical Stages of the Disease: 18F-Florbetaben Positron Emission Tomography Study (NCT02362880)
  • Measuring Brain Amyloid Plaque Load in Older Adults Using BAY 94-9172 (NCT01222351)
  • Imaging of Cognition, Learning, and Memory in Aging (NCT01297114)