Neuro-Imaging: Assisting 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.
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
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. Life Molecular 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.
Beta-amyloid imaging has been incorporated into major AD therapeutic trials. There are several compounds currently investigated that have shown beta-amyloid reduction after treatment using beta-amyloid PET imaging. For a comprehensive overview, please see the following article (https://www.alzforum.org/news/conference-coverage/four-immunotherapies-now-banish-amyloid-brain). The effect on cognition of removing beta-amyloid from the brain is to be determined.
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. Neuraceq was first approved in the EEA via a centralized procedure on 20 Feb 2014. It was subsequently approved in the United States on 19 Mar 2014, in South Korea on 19 Dec 2014, in Japan on 25 Oct 2016, in Canada on 22 Feb 2017 and Switzerland on 23 Aug 2017. A marketing authorization application has been granted in Taiwan in 2019.
Selected recent publications florbetaben:
- de Wilde et al. (2018) Association of Amyloid Positron Emission Tomography With Changes in Diagnosis and Patient Treatment in an Unselected Memory Clinic Cohort: The ABIDE Project. JAMA Neurol. 2018 Jun 11. doi: 10.1001/jamaneurol.2018.1346. https://www.ncbi.nlm.nih.gov/pubmed/29889941
- Ceccaldi et al. (2018) Added value of 18F-florbetaben amyloid PET in the diagnostic workup of most complex patients with dementia in France: A naturalistic study. Alzheimers & Dementia, Mar;14(3):293-305. doi: 10.1016/j.jalz.2017.09.009. https://www.ncbi.nlm.nih.gov/pubmed/29107051
- Rowe et al. (2017) 18F-Florbetaben PET beta-amyloid binding expressed in Centiloids. Europen Journal of Nuclear Medicine and Molecular Imaging, Nov;44(12):2053-2059. doi: 10.1007/s00259-017-3749-6. https://www.ncbi.nlm.nih.gov/pubmed/28643043
- Bullich et al. (2017) Optimal Reference Region to Measure Longitudinal Amyloid-β Change with 18F-Florbetaben PET. Journal of Nuclear Medicine, Aug;58(8):1300-1306. doi: 10.2967/jnumed.116.187351. https://www.ncbi.nlm.nih.gov/pubmed/28183994
- 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
- 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
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.
Selected recent publications about PI-2620
- Mueller et al. (2019) Tau PET imaging with 18F-PI-2620 in patients with Alzheimer’s disease and healthy controls: a first-in-human study. JNM (ahead of print). 10.2967/jnumed.119.236224
- Bullich et al. (2019) Evaluation of dosimetry, quantitative methods and test-retest variability of 18F-PI-2620 PET for the assessment of tau deposits in the human brain. JNM (ahead of print). doi:10.2967/jnumed.119.236240
- Kroth et al. (2019) Discovery and preclinical characterization of [18F]PI-2620, a next-generation tau PET tracer for the assessment of tau pathology in Alzheimer’s disease and other tauopathies. EJNMMI (in press). PDF file open-access: click here
Initial clinical results have been presented at recent scientific conferences. For more detailed information see also the following reports:
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.