A New Spectrum of Biomarkers Emerges for Alzheimer's Disease

Researchers reframing the processes that affect this disease and what radiologists see on imaging

Gloria Chia-Yi Chiang, MD

RSNA News highlights the research being done in brain imaging to support Alzheimer's disease and dementia diagnosis and treatment. This is part two in a series of stories on this topic. Read part one, part three and part four.

The framework for characterizing Alzheimer disease (AD) is expanding, and radiologists are at the epicenter of research on developing exciting new biomarkers.

Currently, neuroradiologists are guided by the National Institute on Aging-Alzheimer’s Association “ATN” framework for categorizing underlying AD pathology— amyloid, tau, and neurodegeneration.

However, research is reframing the model to incorporate vascular pathology, inflammation, alpha-synuclein accumulation, and what researchers are labeling, “X,” for the other contributing processes that are just now being identified.

Gloria Chia-Yi Chiang, MD, vice chair of clinical and translational research, director of the Brain Health Imaging Institute and associate professor of radiology at Weill Cornell Medicine and New York-Presbyterian Hospital, is researching the additional “VISX” elements.

VISX” Biomarkers Will Expand the Existing ATN Framework of Alzheimer's Disease

For comorbid vascular pathology, radiologists typically characterize chronic small vessel ischemia by grading white matter hyperintensities on a T2-FLAIR sequence.

“With susceptibility-weighted imaging, microhemorrhages and sulcal siderosis are now even more important to report, as many MRIs requested for dementia end up being baseline MRIs for lecanemab treatment,” Dr. Chiang said. Lecanemab is an antibody infusion therapy that targets and removes beta-amyloid from the brain and was recently approved by the FDA to treat AD, including for patients living with mild cognitive impairment or mild dementia.

brain and alzheimers disease month image

Amyloid angiopathy is present in about 80% of AD cases, so susceptibility-weighted imaging is crucial to screen for cases that would be eligible for anti-amyloid therapies, Dr. Chiang noted. It’s also important to note hemosiderin deposition when considering other causes of cognitive dysfunction, such as subdural hematomas and traumatic brain injury.

A biomarker for neuroinflammation— the “I” category of VISX—is what Dr. Chiang calls the “holy grail.” Now, research using PET is being undertaken to pursue this challenge. Translocator protein (TSPO)-PET is a technique to quantify neuroinflammation in patients. It identifies the expression of 18-kDA, a translocator protein on “activated” microglia whose expression correlates with brain amyloid and longitudinal cognitive decline.

“However, a lot of recent papers suggest TSPO may actually measure microglial density and not activation,” Dr. Chiang said. This means TSPO may not be a direct biomarker for inflammation. “There’s also an issue with specificity. It’s not just expressed by microglia, but also by astrocytes, endothelial cells and vascular smooth muscle cells. In addition, its binding affinity is not ideal. Basically, they’re imperfect tracers for inflammation.”

New tracers for neuroinflammation that have been studied in animal models include those that target cannabinoid-2 receptors and cyclo-oxygenase-2. These tracers await testing in humans.

Alpha- ynuclein (the “S” in VISX) is a protein that has been found to play an important role in Parkinson’s Disease, Lewy Body dementia and other neurodegenerative diseases. It’s role in AD is currently being evaluated. Dr. Chiang noted that most patients with AD have a mixed etiology of dementia. Examining a cohort from the Mayo Clinic in Jacksonville, FL, investigators found that less than half of postmortem AD brains showed “pure” amyloid and tau pathology. The remainder demonstrated combinations of amyloid/ tau plus alpha synuclein, TAR DNA-binding protein 43 (TDP-43, a nuclear RNA/ DNA-binding protein involved in RNA regulation that is associated with several neurodegenerative conditions), hippocampal sclerosis and other pathologies.

“We have good biomarkers for amyloid and tau, but now there’s a race on to develop biomarkers for these other proteinopathies” Dr. Chiang said. "The race is proving to be challenging. A recent PET tracer was found to bind to alpha synuclein in multiple system atrophy, but unfortunately not in Parkinson's disease or Lewy body dementia.”

Dr. Chiang has also explored “glia-lymphatics” as part of the “X” category.

“I think one of the most exciting recent developments in neuroscience is the discovery of a glial-lymphatic fluid clearance pathway in which the cerebrospinal fluid surrounding our brain actually tracks into the brain via perivascular spaces, mixes with the interstitial fluid and leaves the intracranial space via lymphatics and veins,” she said. “Many of my colleagues are looking at this system using dynamic PET techniques, following PET tracers over time to see how quickly the proteins get cleared by the ventricular system.”

A lot of research is being done with both imaging and fluid biomarkers to help categorize all these different processes, Dr. Chiang said.

As for the continuing research in AD and its various pathologic processes, Dr. Chiang noted, “Radiologists don’t work in a vacuum, so both imaging and fluid biomarkers will play major roles in our quest to accurately diagnose, treat, and monitor Alzheimer’s disease.”

For More Information

Read previous RSNA News stories on Alzheimer's disease research: