By Makoto Ishii, MD, PhD
Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department
of Neurology, Weill Cornell Medical College
Two recent multicenter studies suggest that plasma biomarkers, including phosphorylated-tau181, could be used as cost-effective and more readily accessible biomarkers for the diagnosis and management of individuals with neurodegenerative dementias.
Gonzalez MC, Ashton NJ, Fernandes Gomes B, et al. Association of plasma p-tau181 and p-tau231 concentrations with cognitive decline in patients with probable dementia with Lewy bodies. JAMA Neurol 2022;79:32-37.
Chouliaras L, Thomas A, Malpetti M, et al. Differential levels of plasma biomarkers of neurodegeneration in Lewy body dementia, Alzheimer’s disease, frontotemporal dementia and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 2022; Jan 25. doi: 10.1136/jnnp-2021-327788. [Online ahead of print].
Although advances in cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of amyloid-beta and tau have made it possible to identify patients with Alzheimer’s disease (AD) pathology, CSF and PET biomarkers are invasive, expensive, or not readily available outside of academic medical centers and specialty clinics. Furthermore, CSF and PET biomarkers were developed for the diagnosis and clinical management of AD, and it is unclear if they have any clinical utility for non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). To address these concerns, there has been a significant effort to develop blood biomarkers that could differentiate patients with different neurodegenerative dementias and be used to monitor longitudinal changes. One of the most promising blood biomarkers is phosphorylated-tau (p-tau), including p-tau181 and p-tau231 species. However, plasma p-tau181 and p-tau 231 (as well as other potential blood biomarkers, such as neurofilament light [NfL], a marker for neuroaxonal damage, and glial fibrillar acidic protein [GFAP], a marker of astrocytic activation) have not been studied extensively in non-AD neurodegenerative dementias.
Gonzalez and colleagues recently reported in JAMA Neurology their findings of plasma p-tau181 and p-tau231 in patients with probable DLB, Parkinson’s disease, AD, and healthy controls. In this retrospective, multicenter study, baseline concentrations of plasma p-tau181 and p-tau231 were measured from 987 clinically diagnosed participants (DLB, 371; Parkinson’s disease, 204; AD, 207; and healthy controls, 205). Plasma p-tau181 and p-tau231 levels were significantly higher in the DLB group compared to the healthy control group but lower than the AD group and comparable to the Parkinson’s disease group. When DLB patients were stratified by CSF amyloid-beta42 levels, the DLB group with abnormal CSF amyloid-beta42 levels had higher p-tau181 and p-tau231 levels compared to the DLB group with normal CSF amyloid-beta42 levels. Finally, the study investigators found that p-tau181 and p-tau231 levels both were associated with more cognitive impairment in the DLB group at baseline as well as with more pronounced cognitive worsening over time. However, the significance was lost after adjusting for years of education.
In a separate retrospective, multicenter study reported in the Journal of Neurology, Neurosurgery and Psychiatry, Chouliaras and colleagues simultaneously measured levels of plasma p-tau181, amyloid-beta42, amyloid-beta40, NfL, and GFAP in 300 participants (controls, 73; amyloid-positive mild cognitive impairment and AD dementia [MCI+AD], 63; DLB, 117; FTD, 28; and PSP, 19). Plasma p-tau181 levels were the highest in the MCI+AD group. In contrast to the study by Gonzalez and colleagues, there was no significant difference in plasma p-tau181 levels between DLB and controls. The plasma amyloid-beta42/amyloid-beta40 ratio was lower in the MCI+AD group compared to controls, but there were no other significant differences between controls and the other non-MCI+AD dementia groups. Plasma NfL was elevated across all dementia groups compared to controls, with the highest levels in the FTD group. Plasma GFAP was elevated in the MCI+AD and DLB groups compared to controls. These plasma biomarkers could classify between MCI+AD and controls, FTD, and PSP with high accuracy, but they had limited ability in differentiating MCI+AD from DLB. When comparing DLB patients who were PET-amyloid-beta positive with DLB patients who were PET-amyloid-beta negative, there were no significant differences in the levels of the four plasma biomarkers, including p-tau181. Finally, plasma p-tau181 and GFAP were associated with baseline and longitudinal cognitive decline in a disease-specific manner, suggesting that some of the plasma biomarkers may be useful for prognostication.
COMMENTARY
These two studies highlight the recent advances and challenges in identifying plasma biomarkers for the diagnosis and management of neurodegenerative dementias. Both studies found that plasma p-tau181 levels were the highest in AD compared to all other groups. However, the results were conflicting as to whether plasma p-tau181 levels could be used to differentiate DLB from healthy controls and whether plasma p-tau181 levels were elevated in DLB with positive amyloid-beta pathology compared to DLB with the negative amyloid-beta pathology group. Some of the discrepancies between the two studies could be the result of the relatively small sample size in some of the groups and inherent differences in the biomarkers used to assess amyloid-beta pathology (i.e., CSF vs. PET). Also, for both studies, not all patients had CSF, PET, or postmortem confirmation of their diagnosis. Therefore, misclassification caused by an alternate diagnosis or mixed pathologies is possible for some patients.
Despite any study limitations, the two studies do support plasma biomarkers, in particular p-tau181, for differentiating AD from non-AD dementias; however, it may be challenging to discriminate AD from DLB because of overlapping pathologies. Furthermore, simultaneously using a panel of plasma biomarkers, such as was done by Chouliaras and colleagues, could help identify specific molecular signatures in the various neurodegenerative dementias that may lead to new diagnostic approaches.
Finally, there is some evidence from these two studies to suggest that plasma biomarkers may be useful for prognosticating cognitive decline in specific neurodegenerative dementias. Clearly, additional studies investigating plasma biomarkers in well-defined large study cohorts are needed to verify and validate the findings from these two studies. A few years ago, it would have been a dream to have a cost-effective and accessible blood test that not only could diagnose a patient with a neurodegenerative dementia but help prognosticate their clinical course. With these studies, we are, perhaps, two steps closer to realizing this dream.
