Czy znacznik PET Tau może pomóc w diagnozie FTD? Badanie bada, jak znacznik działa w innych tauopatiach
Badanie opublikowane w Naukowa medycyna translacyjna explores how well the brain imaging tau PET tracer F-MK-6240 (flortaucipir) captures the presence of underlying protein clumps seen in post-mortem Alzheimer’s tissue. It explores how effectively the tracer could be used to recognize early stages of Alzheimer’s disease and detect a similar but separate disorder called primary age-related tauopathy (PART). The study results provide new insights into the tracer’s sensitivity and specificity for tau. These findings can indicate whether a tracer can be used as a “biomarker”, a readout to detect the presence or severity of a specific disease. Biomarkers are critical for accurate and early diagnosis, as well as tracking disease progression and measuring if potential treatments are working in clinical trials.
Like Alzheimer’s disease, corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), both forms of FTD, are associated with the białko tau. They are characterized by the protein’s structure being altered through the process of phosphorylation, which causes abnormal accumulations of the tau known as neurofibrillary tangles. Primary age-related tauopathy (PART) is yet another disorder which also has tau clumps but is not FTD or Alzheimer’s. Collectively, these disorders are known as “tauopathies”, but may differ between the type of tau, the amount, the location, and the types of other disrupted proteins. Thus, imaging tracers need to be tested for each disorder to see if they are useful for diagnosis, or for distinguishing between disorders.
The AFTD is dedicated to advancing biomarkers for diagnosis, The AFTD funds biomarker research, with a dedicated Biomarkers Initiative which awarded ~$5 million from 2016-2021, and a new Biomarkers Initiative starting in 2025.
Flortaucipir binds to a form of tau common in neurodegenerative diseases; by binding, the slight radiation of the tracer makes these accumulations visible to a PET scanner. While tau accumulations detected in some brain regions can contribute to a diagnosis, the lack of tau can contribute to a differential diagnosis by ruling out tauopathies. However, scientists are still uncertain if flortaucipir binding can accurately indicate the presence of tau tangles.
“We need to be cautious when using these molecular PET scans to determine eligibility for treatment, especially if treatment aims to target early stages of the disease,” lead author Keith Josephs, MD, told AlzForum.
Flortaucipir in Alzheimer’s Disease and PART
The study by Josephs and researchers from Mayo Clinic is the largest yet to combine data on flortaucipir na żywo (in a living person) and post-mortem. The study included 248 participants, including people with Alzheimer’s disease and primary age-related tauopathy (PART), as well as people without tauopathy to serve as controls.
To measure the sensitivity of flortaucipir, the researchers compared its binding to what is known as Braak staging, a clinical method used to classify the intensity of Alzheimer’s or Parkinson’s pathology. Braak staging uses numbers (one through six) to indicate where tau tangles have spread in the brain by looking at the tissue post-mortem. Higher numbers indicate advanced stages of disease.
According to the study results, flortaucipir was detected in people with tau protein tangles at Braak stages five and six but had a far weaker signal in stages four and below. Plaques made of the amyloid protein increased the flortaucipir signal in people at lower Braak stages. In general, flortaucipir was able to identify people with higher tau levels but not those with lower levels at earlier stages of Alzheimer’s. Writing to Alzforum, researcher Rik Ossenkoppele, Ph.D., noted, “The inability of flortaucipir to detect [PART] is a very important observation because the field has been misinformed by several in vivo PET studies that have used inappropriate thresholds (i.e., too low for tau PET and too high for amyloid PET) to suggest that flortaucipir can be used to detect PART in vivo.”
Crucially, flortaucipir failed to flag tangles in participants with PART, which typically has lower tau levels than Alzheimer’s. Writing to Alzforum, researcher Rik Ossenkoppele, Ph.D., noted, “The inability of flortaucipir to detect [PART] is a very important observation because the field has been misinformed by several in vivo PET studies that have used inappropriate thresholds (i.e., too low for tau PET and too high for amyloid PET) to suggest that flortaucipir can be used to detect PART na żywo.”
The authors also investigated whether flortaucipir could discriminate PART diagnoses from controls (no neurodegenerative disease) based on the tau signals from different brain regions. It was found that while the tracer had 80% sensitivity, meaning a low chance of false positives, it only had 60% specificity, indicating a significant chance of a false negative. Further, Flortaucipir did not reliably discriminate between people with Alzheimer’s and those with early progression Alzheimer’s disease, and the authors warned this could result in people with Alzheimer’s being misdiagnosed with PART.
Josephs told Alzforum that whether other tau-based PET tracers could outperform flortaucipir is unknown. “I am not aware of any other [beta] amyloid or tau tracers that have been shown to be more sensitive to lower levels of AD pathology using autopsy-confirmed data,” he said. “More sensitive PET tracers are clearly needed.”
Flortaucipir in FTD
Previous studies have suggested that flortaucipir also has limited sensitivity and specificity to tau-based forms of FTD. In a 2019 study led by UCSF, researchers evaluated the performance of the tracer in a cohort of 45 participants with various forms of FTD, including wariant behawioralny FTD (bvFTD), pierwotna postępująca afazja (PPA), CBS, PSP, and different FTD-causing gene mutations. The results of the PET scans from the FTD cohort were compared to a 53-person control group.
The study authors noted that the binding flortaucipir through the brain and the frequency matched the expected distribution in FTD disorders like nfvPPA, CBS, and a bvFTD subtype associated with tau. However, compared to the control participants, the researchers noticed a lack of significant flortaucipir binding and considerable overlap in binding patterns between participants with FTD and control participants. This suggests that flortaucipir was not able to reliably detect disease.
Researchers found that flortaucipir also has a low binding affinity to forms of tau not associated with Alzheimer’s disease and does not bind to TDP-43. However, positive signals in people whose FTD is TDP-43-based led the authors to question the tracer’s specificity.
Like Josephs, the authors of the 2019 study called for a more sensitive and specific tau tracer, though they also highlighted the potential applications of flortaucipir. When an FTD pathology can be confidently predicted based on presenting symptoms or the presence of an FTD-causing genetic mutation, the authors note that the tracer could be used to study how tau spreads in relation to the progression of symptoms.
While further studies are needed to assess the utility of flortaucipir for FTD better, researchers have demonstrated that the tracer has potential uses in studying FTD and as a differential diagnostic tool.
Are you interested in participating in a clinical trial like those mentioned above? AFTD’s Studia poszukujące uczestników page features trials actively recruiting people with FTD, care partners, and family members. The Rejestr Zaburzeń FTD can help you keep apprised of upcoming studies and offers the chance to share your lived experience with scientists.
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