Peer Reviewed Alzheimer's
Posted July 28, 2021
Dr. Claudio Soto, University of Texas Health Science Center at Houston
Dr. Claudio Soto
Early diagnosis of Alzheimer’s disease (AD) and related dementias after a traumatic brain injury (TBI) is critical for maximizing therapeutic benefit and ensuring individuals are able to receive proper care. Unfortunately, many individuals and their families only receive an accurate diagnosis for the particular disorder too late in the disease progression for potential treatments, or even only post-mortem. To address the current gap in early diagnosis, a Fiscal Year 2016 Peer Reviewed Alzheimer’s Research Program (PRARP) award to the University of Texas Health Science Center at Houston is under the direction of Dr. Claudio Soto, who is examining the utility of a technology of cyclic amplification of protein misfolding to detect small quantities of misfolded protein aggregates circulating in biological fluids to better diagnose post-TBI neurodegenerative disease.
Previous studies have suggested that different types of brain disorders are produced by the accumulation of different shapes of aggregated (clumped) proteins. The more aggregated protein present in a person, the worse their condition generally is. For the PRARP award, Dr. Soto and colleagues had two goals: (1) To see if it was possible to amplify incredibly minute amounts of disease-related aggregates, such as the amounts that would be present in the very earliest disease stages for earlier detection, and (2) determine if differences in those aggregates could determine whether a person had a disease produced by TBI.
Dr. Soto and his team adapted the protein misfolding cyclic amplification (PCMA) method, initially developed to detect abnormal prion proteins, to detect tau and amyloid-beta oligomers amplified from TBI and AD patient samples. The PMCA method starts with an incredibly tiny amount of template or seed (present in biological fluids from a patient) and performs a series of amplification reactions using that template to direct substrate protein to copy and aggregate, much like what is seen during the disease process. Following amplification, there may be as much as a billion-fold more aggregates present, which can then be assessed using different assays to estimate their size, shape, and other characteristics. This methodology shares similarity with the polymerase chain reaction, where DNA is amplified from raw components using a primer template to produce sufficient amounts of material for further analysis.
In addition to its use in TBI and AD, the team also optimized the technique to detect alpha synuclein, a protein that plays a major role in several brain disorders, including Parkinson’s disease (PD). Work published in Nature by Dr. Soto and his team, supported by this PRARP award, reported detecting alpha-synculein aggregates from patients with both PD and multiple system atrophy (MSA). Incredibly, aggregates from PD were distinguishable from those of MSA patients, two diseases that are very difficult to differentiate by clinical tests. Moreover, the team showed that aggregates present in brain and in cerebrospinal fluid are the same, suggesting the PMCA could faithfully replicate shape characteristics from patient derived-templates using the same raw substrate. The team were able to determine, with 95% accuracy, which individual had PD versus which had MSA. In addition, signals could not be detected from samples from people with other neurological disorders unrelated to alpha synculein (Shahnawaz et al., 2020).
This technique has potential to differentiate between not only different types of alpha synculein disorders, but for TBI, AD, and other types of neurological diseases with aggregated protein hallmarks. For patients with neurological diseases and brain injuries, this may open up opportunities for earlier, more specific treatments and clinical care.
Shahnawaz M, Mukherjee A, Pritzkow S, Mendez N, Rabadia P, Liu X, Hu B, Schmeichel A, Singer W, Wu G, Tsai AL, Shirani H, Nilsson KPR, Low PA, and Soto C. 2020. Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy. Nature 578(7794):273-277. doi: 10.1038/s41586-020-1984-7. Epub 2020 PMID: 32025029; PMCID: PMC7066875.