Scientists at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital (MGH) have developed a novel PET scan imaging probe that evaluates the epigenetic regulatory pathways in the cells of a living human brain. This development is expected to revolutionize the diagnosis and treatment of neurological disorders which was previously not possible.
These experts have been working to develop this radiotracer, called Martinostat, for the last seven years. After achieving positive results in detecting epigenetic changes in rodents and other non-human primates, it is the first time when they have experimented with this probe in the living human brain. The findings of the study were published in the journal Science Translational Medicine on 10 August.
This breakthrough will now lead us to a better understanding of the underlying causes of a neurological disease. Often, neurological diseases have a deep-rooted link with the epigenetic changes that take place in the neural cells but due to our limited knowledge, not much can be precisely said about the disease-causing epigenetic changes.
Previous research has shown that enzymes, histone deacetylases (HDACs) which belong to a family of chromatin-modifying enzymes, are actively involved in the epigenetic machinery that influences the gene transcription in brain cells. Furthermore, HDACs have shown a pronounced role in neurological disorders such as schizophrenia and Alzheimer’s disease which elicit effects over time.
How Can This Imaging Probe Help?
In this imaging probe the changes in the structure and activity of these enzymes are visualized. While the expression of HDACs was carefully visualized by this probe, it was found that a healthy human brain has conserved regions of HDAC expression which are suggestive of tightly regulated epigenetic processes.
The working of this imaging probe is specific to visualizing the subtypes of HDAC, known as isoform 1,2 and 3 which are actively involved in the regulation of neuroplasticity, learning, memory, cognitive function and behavior.
Neuroplasticity means that the brain has an ability to reorganize and create new neural pathways to improve its cognitive and critical abilities. While a healthy brain has its neuroplasticity and cognitive function intact, people who suffer from neurological diseases have reduced neuroplasticity leading towards extinction of important neural pathways, consequently manifested by irreversible symptom manifestation of these diseases. This reduction in neural pathway proliferation has a link with HDAC expression.
Upon further investigation, the scientists were able to draw a clear distinction in HDAC activity in healthy brains and in the brains of people who have been diagnosed with a neurological disease. Interestingly, in healthy brains, HDAC expression was found to be higher in cortical gray matter than in white matter. In addition to this, the distribution pattern was conserved, apart from lowest HDAC expression recorded in the amygdala and hippocampus, while the highest levels were observed in the cerebellum and putamen. Upon rescans in each individual, to test the validity of the results, a variation of only 3% was found which further favored the result accuracy of this probe.
To become certain about the regional specificity of the probe, biochemical profiling was also carried out on postmortem brain tissues. Upon quantification of HDAC1, HDAC2, HDAC3 and HDAC6, with the use of western blotting, it was found that the HDAC expression remained constant in all gray matter region which included superior frontal gyrus, dorsolateral prefrontal cortex, hippocampus and anterior.
However, the researchers could not negate the result being influenced by the dead brain cells in this case.
Epigenetic changes refer to the modifications in the gene expression that are not the direct result of change in the DNA sequence. Moreover, these epigenetic changes include DNA methylation, histone protein modification non-coding RNA-associated gene silencing. These are often naturally occurring changes which in turn alter the gene expression which may also be triggered by an individual’s lifestyle, environmental conditions and age.
Martinostat probe is remarkable in its working mechanism, which is highly specific and reversible in its binding. With a decent affinity, the probe also demonstrates an excellent brain penetrance which has a crucial clinical implication of determining HDAC inhibitors across blood-brain barrier.
This probe was also able to interact with genes and alter their expression when human stem cell-derived neural progenitor cells were treated to study the impact of different probe dosages. The dose volumes showed a link with the acetylation levels of many genes which was responsible to encode proteins crucial for the brain cell function. These genes included BDNF, GRN and acetylation/methylation sites histone H3 lysine 9 and histone H4 lysine 12 which was directly involved in synaptic plasticity, neurodegeneration. This property can be very useful in specific disease diagnosis and treatment.
This probe has a potential to show high binding kinetics and binding specificity for further role in heart, pancreas, spleen and kidney related epigenetic PET scans.
Looking at the potential of this probe, these promising properties of this probe are surely expected to bring targeted therapeutic delivery from neurological diseases which are not easy to treat due to the complex brain anatomy.