Keywords
1. Alzheimer’s disease
2. Progressive supranuclear palsy
3. Tau protein isoforms
4. Neurofibrillary tangles
5. Neuropathology
In a groundbreaking study published in Acta Neuropathologica Communications (DOI: 10.1186/s40478-019-0708-4), a team of Japanese researchers led by Momoko Ebashi from the Tokyo Metropolitan Institute of Medical Science, has made significant advances in differentiating neurofibrillary tangles (NFTs) characteristic of Alzheimer’s disease (AD) from those found in progressive supranuclear palsy (PSP). This distinction has long been a challenge for neuropathologists, particularly in cases where there is comorbidity of AD and PSP.
The Challenge of Comorbidity in Neurodegenerative Diseases
Alzheimer’s disease and progressive supranuclear palsy are two distinct neurodegenerative disorders that share a common pathological hallmark—abnormal accumulations of the tau protein, known as NFTs. While these tangles are found in several brain disorders, their precise distribution and composition can provide essential clues for accurate diagnosis.
However, when both conditions are present in the same patient, parsing the contribution of each to the tau pathology can be daunting. Unfortunately, this comorbidity is not a rarity, and it can mask the clinical and pathological features that are specific to each disorder, complicating the prospects for personalized treatments.
Pioneering a Hybrid Approach to Solve the Diagnostic Puzzle
Ebashi et al. adopted a hybrid approach that leveraged histological and biochemical techniques to delineate AD-type from PSP-type tau lesions within the same brain. They closely examined five autopsied brains from individuals who had both AD and PSP pathology—a rare opportunity for in-depth research.
The researchers painstakingly analyzed 16 distinct brain regions, identifying areas where 3-repeat (3R) and 4-repeat (4R) tau isoforms coexisted or appeared exclusively. 4R tau isoforms, commonly observed across all regions in PSP, were contrasted with areas where 3R tau isoforms were either missing, indicative of typical PSP pathology, or predominantly present alongside 4R tau, highlighting AD-type pathology. This demarcation was particularly evident in areas such as the pontine nucleus, red nucleus, and globus pallidus—regions not typically implicated in AD. Conversely, 3R tau lesions were more prominent in areas linked to AD, like the hippocampal formation and neocortex, where neuronal 3R immunoreactivity dominated over 4R.
While both diseases featured tau pathology in the central grey matter, substantia nigra, and locus coeruleus, a predominance of 4R tau with a glial component pointed to a PSP origin. Nevertheless, the presence of 3R tau did not negate AD pathology, underscoring the intricacy of distinguishing the contributions of each disease to the overall tau deposition.
The Implications of Demixing Tau Lesions
The research conducted by Ebashi and colleagues is not just academically significant—it holds practical implications for the future of neurodegenerative disease diagnostics and potentially for therapeutics. Distinguishing between the impact of AD and PSP on tau lesions is a stride forward in enabling more precise diagnoses for patients with comorbid conditions. As a result, clinicians can tailor treatment strategies with greater specificity, targeting the underlying pathology more effectively.
In their article, which received support from Japan Society for the Promotion of Science (grants 16K14572 and 17H03555), the researchers underscore the possibility of further refinement in demixing tau lesions. This hinges on the identification of the biochemical differences between 4R tau in PSP and AD. However, until such distinguishing signatures are elucidated, the hybrid approach by Ebashi et al. stands as a novel method to navigate the complexity of comorbid neurodegenerative diseases.
The Progressive March Towards Early Detection and Intervention
While the immediate application of this research is in the postmortem diagnostic setting, it also has the potential to affect the strategies for early detection of these diseases. Ideally, similar histological and biochemical markers could be identified in living patients through advanced imaging or cerebrospinal fluid analysis, setting the stage for timely intervention before the diseases have progressed too far.
In the landscape of neurodegeneration where complexity is the norm, the study by Ebashi and her team is a beacon, illuminating the intricate interplay between AD and PSP. Their innovative approach to disentangling the contributions of 3R and 4R tau lesions represents a leap forward and bolsters the neuropathology field with new analytic tools to confront the challenges presented by these devastating diseases.
References
1. Ebashi M et al. (2019). Acta Neuropathol Commun, 7(1):71. DOI: 10.1186/s40478-019-0708-4.
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5. Cruz-Sanchez FF et al. (1992). Neurosci Lett, 136:43–46. DOI: 10.1016/0304-3940(92)90643-L.
In conclusion, as scientific inquiry deepens our understanding of neurodegenerative comorbidity, studies such as this offer tangible hope that a future with more precise diagnostic capabilities and targeted therapies is well within reach. The research has shown once again that innovation in the face of complexity can lead to remarkable advances that benefit both science and society.