Q&A: Tracing the Role of Inflammation in Alzheimer’s Disease

Much of the field of Alzheimer’s disease research is focused on looking for amyloid plaques and tau tangles, but inflammation may also play a crucial role in the disease’s progression. Tarun Singhal, MD, MBBS, a neurologist and nuclear medicine physician in the Brigham’s Ann Romney Center for Neurologic Diseases, is developing better ways to visualize inflammation in the brain to improve understanding and clinical care for neurological disorders using novel Positron Emission Tomography (PET) ligands. Singhal leads a research team that has used a radioactive label to identify inflammation in the brain in several neurologic diseases such as multiple sclerosis and multiple system atrophy and has recently applied this to help better understand Alzheimer’s disease. In a publication in the “Interesting Image” section of Clinical Nuclear Medicine, Singhal and his team identified increased activation of microglia, a type of brain cell, in the brain of a 69-year-old patient with Alzheimer’s disease. In this Q&A, he discusses why visualizing inflammation may be so important for understanding Alzheimer’s disease and the potential for the PET ligand in other neurological and neuropsychiatric conditions.

Q: What inspired this research? How does being a practicing clinician inform your work?

 There is clearly a need to identify novel targets for diagnosing and treating neurodegenerative diseases, particularly Alzheimer’s disease, which pose a significant disease burden on humanity. Conventional structural imaging does not always explain or keep up with how a patient with Alzheimer’s disease is progressing, which puts patients and their family under a lot of stress. In recent years, neuroinflammation has emerged as a key diagnostic and therapeutic target that has the potential to transform the care of these individuals. However, this needs to be studied directly in humans in an effective and reliable fashion. PET imaging can play an important role in this process. Patients need better treatment and this tracer, known as [F-18] PBR06-PET, can be used to identify inflammation and study the progression of the disease in AD.

Being a clinical neurologist and a nuclear medicine physician, my goal has always been to develop techniques that are clinically useful. [F-18]PBR06 is a novel PET imaging tracer that targets neuroinflammation and has a significantly higher chance of being ultimately clinically useful because of its longer half-life, improved imaging characteristics and better logistics. For example, such [F-18] labeled compounds can be synthesized in a central radiopharmacy and transported to multiple medical centers for multicentric studies and potential clinical use, without the necessity of each center having its own cyclotron and radiopharmaceutical synthesis laboratory.

Our hope is that our work will inspire more studies in Alzheimer’s disease that use this type of compound to identify inflammation to better understand the pathogenesis of Alzheimer’s and for informing and expediting novel drug development.

Q: How does the inflammation hypothesis fit with more traditional methods of understanding and diagnosing Alzheimer’s with amyloid and tau proteins?

Along with amyloid and tau proteins accumulation in the brain in Alzheimer’s disease, there is evidence that a concomitant inflammatory signal in an individual means the person has a higher chance of disease progression. Immune cells in the brain, such as microglia, influence and interact with the abnormal protein deposition process, and may ultimately contribute to neuronal injury leading to disease progression.

Q:  Can you tell us more about the image you’ve published? What does it show us? Who is the patient behind the image?

The patient was a 69-year-old woman who was having memory and word-finding difficulties and was relatively early in her course of Alzheimer’s disease. What we see in the scan is the accumulation of the radiotracer in certain regions of the brain that are known to be affected early in Alzheimer’s disease, i.e. regions that are known to show a greater amyloid accumulation and decreased glucose uptake. Most previous studies have used [C-11] labeled PET compounds that have a much shorter half-life (approximately 20 minutes). However, their use is not feasible in the clinical setting and it is very difficult to perform multicentric trials using such tracers. While [F-18]PBR06 has been previously studied in animal models of Alzheimer’s disease, to the best of our knowledge, this is the first report of [F-18]PBR06 in an Alzheimer’s patient.

Q: Are there certain steps that you or your team are taking to try to make the tool more accessible or more affordable, so that it can be used widely?

From a PET imaging standpoint, compounds like [F-18]PBR06 can potentially transform research and ultimately, hopefully, clinical care. However, there is a need for generating more data and for the education of  stakeholders including clinicians, funding agencies and drug developers about the current state-of-the-art knowledge and future prospects of this technology.  Imaging research like ours can be expensive, but can be highly cost-effective in the longer term by improving our understanding of disease pathogenesis and aiding novel drug development. This has potentially huge practical implications for patients and their families. We are doing everything we can to expedite our research in this area, share our work with the community, exchange knowledge and eagerly look forward to building collaborations towards these goals.

Q: What are other areas of research in your lab?

We are using [F-18]PBR06 to study other neurological and neuropsychiatric conditions because neuroinflammation is a common mechanism that occurs across brain diseases. There is a great interest in the neurological research community to understand neuroinflammation from a mechanistic standpoint and also as a therapeutic target. We’ve been applying this tool to understand the interaction between neurochemistry, neurodegeneration and neuroinflammation in patients with multiple sclerosis (MS) and the role of that interaction in some of the hidden symptoms of MS, like fatigue and depression. In the PET Imaging Program in Neurologic Diseases, we are also studying cutting-edge and clinically relevant PET approaches using [F-18]PBR06, [F-18]SynVesT-1 and other novel PET radioligands to evaluate the effects of treatments and to aid novel therapeutic drug development in MS, parkinsonian disorders and various other neurologic and neuropsychiatric diseases. We are committed to methodological innovation and translational work using brain PET to improve the lives of persons with brain diseases, worldwide.


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One Response to “Q&A: Tracing the Role of Inflammation in Alzheimer’s Disease”

  1. Dr Ravi K gupta

    Excellent, very informative and useful.

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