Imaging neuroinflammation in Mild Cognitive Impairment using a novel Translocator Protein 18kDA (TSPO) PET radioligand: [18F]-FEPPA
Centre for Additction and Mental Health
A characteristic of Alzheimer’s disease (AD) is the presence of dense deposits of amyloid protein, known as plaques, throughout the brains of afflicted patients. We and others believe that these plaques lead to an inflammatory response in the brain. The plaques begin accumulating even before people start experiencing memory problems or at the stage of mild cognitive impairment. Up to 50% of patients with mild cognitive impairment (MCI) develop AD within 1-3 years. The patients who later develop AD have higher levels of plaques compared to those who do not progress into AD. At this time, it is unknown whether increased neuroinflammation can be detected in MCI patients. We have developed a method to image and measure neuroinflammation, in tandem with the currently available technique for measuring plaques in living human brains, using radioactive dyes that can produce signals that are detectable by a positron emission tomography (PET) scanner. The main objective of our project is to investigate whether neuroinflammation is detectable in the brains of MCI patients. Furthermore, we will examine whether increased inflammation is found in brain areas where higher levels of plaques are found. If successful, this method will allow us to detect and treat AD earlier.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
The benefit of a disease-modifying therapy will be maximized when it is applied in the early stage of AD. The evidence of increased neuroinflammation in patients with MCI will also give us further support to develop a new therapeutic target. Our imaging biomarker for neuroinflammation can be used as a surrogate marker to test the effect of novel anti-inflammatory therapies.
From this project, we expect to establish whether an increase in neuroinflammation can be detected early in the disease process. If neuroinflammation is shown to have important role in early stage AD, we will have the first evidence to support the use of neuroinflammation imaging as both a diagnostic and disease-tracking tool. Furthermore, we may learn how neuroinflammation is related to increased plaques in the brain.
Amnestic mild cognitive impairment (aMCI) is defined as a transitional, clinical state between normal aging and Alzheimer’s disease (AD). The underlying neuropathology is very similar in aMCI and AD, with one common feature being the accumulation of amyloid (Aβ) plaques. Another important pathological feature of AD is neuroinflammation, however the course of development of neuroinflammation during disease is largely unknown. In order to gain a better understanding of the transitional state of aMCI, we sought to investigate neuroinflammation and amyloid accumulation with the use of positron emission tomography (PET). The main aim of our study was to investigate the degree of neuroinflammation, as reflected by [18F]-FEPPA uptake, in aMCI patients compared to age-matched healthy volunteers (HV). Furthermore, we explored if neuroinflammation was related to the amount of Aβ burden, as reflected by [11C]-PIB retention, in aMCI patients.
Of the 302 people that were initially contacted, 83 individuals were interested and were screened. Thirty-five individuals were not able to continue with the study due to reasons including, but not limited to, claustrophobia, concerns around radiation and arterial sampling, presence of metal implants not compatible with the 3T MRI, and neurological problems such as strokes, seizures, and Parkinson ’s disease. A total of 48 participants were eligible following the telephone screen and were invited for the consent and genetic screening visit. Individuals that were high-affinity binders (HABs) were invited for 4 subsequent visits: i) baseline, ii) [18F]-FEPPA scan, iii) [11C]-PIB scan and iv) MRI scan.
From the 10 aMCI and 14 HV completers, we did not observe any significant differences in [18F]-FEPPA binding between aMCI and healthy volunteers. In contrast, aMCI patients had significantly more amyloid in the prefrontal, temporal, inferior parietal and occipital cortices compared to HV. The largest Aβ accumulation was observed in the prefrontal cortex. From our exploratory correlations in aMCI patients, neuroinflammation in the prefrontal cortex, temporal cortex and hippocampus appeared to be positively associated with the amount of amyloid. After correcting for multiple comparisons, the spatial relationship remained only in the hippocampus. Additionally we explored whether neuroinflammation or amyloid were related to performance on neuropsychological assessments.
In conclusion, from our preliminary results, we did not find an increase in neuroinflammation in individuals with aMCI compared to healthy volunteers. Amyloid pathology, however, is evident in this transitional stage. Neuroinflammation may be related to amyloid in-vivo, however a larger sample size is required to confirm these exploratory correlations.