As is the case with nearly any biomedical endeavor, the inability to easily peek into the body’s inner workings severely stymies research. While progress has been made in cancer and other diseases, the brain has proven to be a tough nut to crack.
That may be changing soon, with the advent of new tests for Parkinson’s and Alzheimer’s diseases, including diagnostics that may make it easier to screen more people and methods that could deliver more information on the mechanisms behind the degenerative diseases affecting the human nervous system.
Typical diagnoses can rely on subjective measures tracking the memory loss or mobility issues. This can vary from patient to patient as well as physician to physician, but above all requires expensive time investments; waiting periods between exams can be necessary to establish trends of cognitive decline, but that may be time patients nor drug developers can afford.
More objective diagnostic measures exist, such as painful spinal taps to collect cerebrospinal fluid or expensive PET scans to confirm neural activity. But these methods are hard to translate to a large and aging population.
But in 2022, developers expect to see new screening technologies start to come to the fore. Some of the most exciting developments include novel methods for examining the buildup of certain proteins within the brain as well as the wider use of blood-based screening to help guide people through treatments and aid in recruitment to research studies.
Picturing the brain in vitro
This month, researchers at the Oxford Parkinson’s Disease Centre demonstrated the underlying principles of a potentially new type of test for the condition. The researchers, funded by the charity Parkinson’s UK, hope their findings will set the stage for a test to identify Parkinson’s in its early stages and help separate out those patients from others who may only have muscle atrophy or essential tremor, conditions with overlapping symptoms that can mask the correct diagnosis.
“Such a test would enable the newly diagnosed to access vital treatment and support to manage their Parkinson’s symptoms sooner,” Beckie Port, research communications manager at Parkinson’s UK, said in a December statement. “An early diagnostic test could also speed up research into new drugs that slow the condition, which could prevent people from ever developing symptoms associated with Parkinson’s.”
Parkinson’s disease and some types of dementia are partly driven by the formation of sticky clumps of neural proteins within the brain. Misfolded alpha-synuclein proteins tend to glom onto each other and form masses known as Lewy bodies, which are associated with nerve cell death.
By taking a sample of cerebrospinal fluid from the lower spine through a lumbar puncture, the researchers mixed specimens with specially tagged alpha-synuclein particles using a method called real-time quaking-induced conversion—the scientific description for shaking up the sample and seeing how the proteins within react. After mixing the fluids together, they were able to see whether the characteristic protein clumps began to grow.
The Oxford test, based on previous alpha-synuclein research, demonstrated it could correctly and reproducibly identify 89% of people with Parkinson’s, while also ruling out 96% of people who do not have the condition. The findings were published in the journal Brain.
Additional research will be needed to link the test to measurements of Parkinson’s progression, as there was no link found between results and symptom severity, but the tool has shown it can provide a window into the molecular machinery of the brain.
“We now need to understand what the differences are in the clumping of alpha-synuclein between Parkinson’s, dementia with Lewy bodies and [multiple system atrophy],” said Laura Parkkinen, Ph.D., head of neuropathology research at the Oxford center.
Alpha-synuclein is at the center of much Parkinson’s research, including at biotech companies such as AC Immune, which is chasing the protein as a target for PET imaging tracers as well as antibody treatments and vaccines.
“You cannot look into the Parkinson’s brain today. It's not possible,” AC Immune co-founder and CEO Andrea Pfeifer said in an interview with Fierce Biotech’s Annalee Armstrong. “There is no tool.”
“You need a proper diagnostic, and this is why next year we expect [to see] the first alpha-synuclein imaging agent as a breakthrough,” Pfeifer said.
The Michael J. Fox Foundation for Parkinson’s Research has been funding efforts to develop an alpha-synuclein imaging agent, including through a $10 million competition in 2020. The foundation also recently awarded AC Immune about $1.5 million in grants to chase alpha-synuclein and other pathways with small molecule inhibitors.
Spotting Alzheimer's in blood drops
It’s a similar story in Alzheimer’s, where subjective diagnoses often come too late for treatment to be effective, while also slowing down recruitment efforts for clinical trials looking to explore investigational therapies in the first place. Intensive brain scans, meanwhile, can be too expensive for widespread use and come with doses of radiation.
One company developing an Alzheimer’s blood test is C2N Diagnostics, which began rolling out its assay in late 2020. Offered to patients showing the early signs of memory loss, the test relies on mass spectrometry to measure amyloid beta peptides and different versions of apolipoprotein E floating in the bloodstream, both common risk factors for Alzheimer’s.
Though the test cannot diagnose Alzheimer’s on its own, the Fierce 15 winner said its noninvasive diagnostic can be used as a tool in wider clinical assessments. C2N says its PrecivityAD test can help predict the state of amyloid plaques in the brain, one of the hallmarks of the neurodegenerative condition. Recent data demonstrated an accuracy that largely matches up with PET scans.
“The cost of Alzheimer’s phase 3 trials is $300 million to $400 million with half of that devoted to screening and enrollment,” Howard Fillit, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, said last year in a statement as C2N’s test was first rolled out.
“Investing in biomarker research has been a core goal for the ADDF, because having reliable, accessible and affordable biomarkers for Alzheimer’s diagnosis is step one in finding drugs to prevent, slow and even cure the disease,” Fillit said.
In addition, with the FDA’s approval this year of Biogen’s amyloid-targeting Aduhelm treatment, diagnostic tests that provide objective measurements of that biomarker could be in high demand.
Companies are also working on tests for another major protein at play in Alzheimer’s, known as tau. Certain types of tau may better illustrate the progression of the disease when measured in blood samples compared to amyloid beta, according to test developer Quanterix, which produces technology that has been used in Biogen’s and Eli Lilly’s clinical trials.
“The assays represent a new frontier in Alzheimer’s disease clinical research, enabling new trial designs focused on patients at earlier stages of disease and facilitating accelerated and more efficient trial enrollment,” Quanterix CEO Kevin Hrusovsky said in a statement in November during the 2021 Clinical Trials On Alzheimer’s Disease conference.
The company’s Simoa test has been examined by researchers at the University of California, San Francisco, supported by the National Institutes of Health. They found the blood test, which searches for a tau protein dubbed pTau-181, mirrored results with spinal fluid diagnostics and PET scans and was also able to separate those people out from patients with rare neurodegenerative diseases known as frontotemporal lobar degeneration.
Currently available for research use only, Quanterix’s blood test garnered an FDA breakthrough designation in October as the company continues to develop the tool into an aid for clinically diagnosing Alzheimer’s. This includes testing patients over the age of 50 who show early signs of cognitive decline.
Lastly, a separate bloodborne protein biomarker known as neurofilament light chain could help identify people with one of several neurodegenerative conditions such as amyotrophic lateral sclerosis, also known as ALS, as well as Parkinson’s, frontotemporal dementia and dementia related to Down syndrome.
“It is exciting that all that could be needed is a simple blood test, which is better tolerated in Down syndrome individuals than brain scans,” said paper co-author Andre Strydom, a professor in intellectual disabilities at King’s College London.
“For the first time we have shown across a number of disorders that a single biomarker can indicate the presence of underlying neurodegeneration with excellent accuracy,” said Abdul Hye, Ph.D., a researcher at King’s College London and joint senior author of the team’s findings published earlier this year in Nature Communications.
Neurofilament light chain enters the bloodstream following damage to nerve fibers. The test found that while elevated protein levels alone could not differentiate between various conditions, it could indicate rarer courses of Parkinson’s and help identify patients with Down syndrome that may or may not also have dementia.
“Though it is not specific for any one disorder, it could help in services such as memory clinics as a rapid screening tool to identify whether memory, thinking or psychiatric problems are a result of neurodegeneration,” Hye said.
The study, conducted in collaboration with Lund University in Sweden, also provided age-related cutoff levels for neurofilament light chain blood concentrations. Levels over a particular amount for a patient at a particular age would help expedite a diagnosis, the researchers said. The cutoff points were 90% accurate in highlighting neurodegeneration in people over age 65 and 100% accurate in detecting motor neuron disease and Down syndrome dementia.
While about 850,000 people currently live with dementia in the U.K., that number is projected to grow to 1.6 million by 2040. Similar trends are seen the world over, underscoring the need for preventive measures to be provided as early as possible, and reliable biomarkers—bound for substantial progress next year—will bring the field closer to that reality.