Search

This study investigated binding of [18F]AV-1451 to neuromelanin in the substantia nigra of patients with Parkinson’s disease (PD) and progressive supranuclear palsy (PSP). [18F]AV-1451 is a positron emission tomography radiotracer designed to bind pathological tau. A post-mortem study using [18F]AV-1451 discovered off-target binding properties to neuromelanin in the substantia nigra. A subsequent clinical study reported a 30% decrease in [18F]AV-1451 binding in the midbrain of PD patients. A total of 12 patients and 10 healthy age-matched controls were recruited. An anatomical MRI and a 90-min PET scan, using [18F]AV-1451, were acquired from all participants. The standardized uptake value ratio (SUVR) from 60 to 90 min post-injection was calculated for the substantia nigra, using the cerebellar cortex as the reference region. The substantia nigra was delineated using automated region of interest software. An independent samples ANOVA and LSD post hoc testing were used to test for differences in [18F]AV-1451 SUVR between groups. Substantia nigra SUVR from 60 to 90 min was significantly greater in HC compared to both PSP and PD groups. Although the PD group had the lowest SUVR, there was no significant difference in substantia nigra uptake between PD and PSP. [18F]AV-1451 may be the first PET radiotracer capable of imaging neurodegeneration of the substantia nigra in parkinsonisms. Further testing must be done in PD and atypical parkinsonian disorders to support this off-target use of [18F]AV-1451.

Progressive supranuclear palsy is a rare form of atypical Parkinsonism that differs neuropathologically from other parkinsonian disorders. While many parkinsonian disorders such as Parkinson’s disease, Lewy body dementia, and multiple system atrophy are classified as synucleinopathies, progressive supranuclear palsy is coined a tauopathy due to the aggregation of pathological tau in the brain. [18F]AV-1451 (also known as [18F]-T807) is a positron emission tomography radiotracer that binds to paired helical filaments of tau in Alzheimer’s disease. We investigated whether [18F]AV-1451 could be used as biomarker for the diagnosis and disease progression monitoring in progressive supranuclear palsy. Six progressive supranuclear palsy, six Parkinson’s disease, and 10 age-matched healthy controls were recruited. An anatomical MRI and a 90-min PET scan, using [18F]AV-1451, were acquired from all participants. The standardized uptake value ratio from 60 to 90 min post-injection was calculated in each region of interest, using the cerebellar cortex as a reference region. No significant differences in standardized uptake value ratios were detected in our progressive supranuclear palsy group compared to the two control groups. [18F]AV-1451 may bind selectivity to the paired helical filaments in Alzheimer’s disease, which differ from the straight conformation of tau filaments in progressive supranuclear palsy.

The recent development of positron emission tomography radiotracers targeting pathological tau in vivo has led to numerous human trials. While investigations have primarily focused on the most common tauopathy, Alzheimer’s disease, it is imperative that testing also be performed in parkinsonian tauopathies, such as progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia and parkinsonism linked to chromosome 17. Tau aggregates differ in isoforms and conformations across disorders, and as a result one radiotracer may not be appropriate for all tauopathies. In this review, we evaluate the preclinical and clinical reports of current tau radiotracers in parkinsonian disorders. These radiotracers include [18F]FDDNP, [11C]PBB3, [18F]THK-5317, [18F]THK-5351, and [18F]AV-1451 ([18F]T807). There are concerns of off-target binding with [18F]FDDNP and [11C]PBB3, which may increase the signal to noise ratio and thereby decrease the efficacy of these radiotracers. Testing in [18F]THK-5317, [18F]THK-5351, and [18F]AV-1451 has been performed in progressive supranuclear palsy, while [18F]THK-5317 and [18F]AV-1451 have also been tested in corticobasal degeneration patients. [18F]THK-5317 and [18F]THK-5351 have demonstrated binding in brain regions known to be afflicted with pathological tau; however, due to small sample sizes these studies should be replicated before concluding their appropriateness in parkinsonian tauopathies. [18F]AV-1451 has demonstrated mixed results in progressive supranuclear palsy patients and post-mortem analysis shows minimal to no binding to non-Alzheimer’s disease tauopathies brain slices.

Neuroinflammatory processes including activated microglia have been reported to play an important role in Parkinson’s disease (PD). Increased expression of translocator protein (TSPO) has been observed after brain injury and inflammation in neurodegenerative diseases. Positron emission tomography (PET) radioligand targeting TSPO allows for the quantification of neuroinflammation in vivo. Based on the genotype of the rs6791 polymorphism in the TSPO gene, we included 25 mixed-affinity binders (MABs) (14 PD patients and 11 age-matched healthy controls (HC)) and 27 high-affinity binders (HABs) (16 PD patients and 11 age-matched HC) to assess regional differences in the second-generation radioligand [18F]-FEPPA between PD patients and HC. FEPPA total distribution volume (V T) values in cortical as well as subcortical brain regions were derived from a two-tissue compartment model with arterial plasma as an input function. Our results revealed a significant main effect of genotype on [18F]-FEPPA V T in every brain region, but no main effect of disease or disease × genotype interaction in any brain region. The overall percentage difference of the mean FEPPA V T between HC-MABs and HC-HABs was 32.6% (SD = 2.09) and for PD-MABs and PD-HABs was 43.1% (SD = 1.21). Future investigations are needed to determine the significance of [18F]-FEPPA as a biomarker of neuroinflammation as well as the importance of the rs6971 polymorphism and its clinical consequence in PD.

Parkinson's disease (PD) is typically known for its cardinal motor symptoms, but a growing body of literature is recognizing a multitude of important nonmotor symptoms as well. Anxiety is one of the most common nonmotor symptoms of PD; unfortunately, neither the management of anxiety nor its influence on motor symptoms is well understood. While recent literature indicates a correlation between motor symptoms and anxiety in PD, it remains uncertain whether one symptom acts as the underlying cause of the other. This review considers the cyclic interaction between anxiety and motor symptoms in PD, each exacerbating the other when they coexist. It may be critically important to disentangle if one symptom serves as an underlying cause of the other, since this might dictate appropriate treatment. Neuroanatomical substrates as well as the treatments for both motor symptoms and anxiety are discussed in detail to consider the evidence-base for the management of PD.

Background Neuroinflammatory processes including activated microglia have been reported to play an important role in Parkinson’s disease (PD). Increased expression of translocator protein (TSPO) has been observed after brain injury and inflammation in neurodegenerative diseases. Positron emission tomography (PET) radioligand targeting TSPO allows for the quantification of neuroinflammation in vivo. Methods Based on the genotype of the rs6791 polymorphism in the TSPO gene, we included 25 mixed-affinity binders (MABs) (14 PD patients and 11 age-matched healthy controls (HC)) and 27 high-affinity binders (HABs) (16 PD patients and 11 age-matched HC) to assess regional differences in the second-generation radioligand [18F]-FEPPA between PD patients and HC. FEPPA total distribution volume (V T) values in cortical as well as subcortical brain regions were derived from a two-tissue compartment model with arterial plasma as an input function. Results Our results revealed a significant main effect of genotype on [18F]-FEPPA V T in every brain region, but no main effect of disease or disease × genotype interaction in any brain region. The overall percentage difference of the mean FEPPA V T between HC-MABs and HC-HABs was 32.6% (SD = 2.09) and for PD-MABs and PD-HABs was 43.1% (SD = 1.21). Conclusions Future investigations are needed to determine the significance of [18F]-FEPPA as a biomarker of neuroinflammation as well as the importance of the rs6971 polymorphism and its clinical consequence in PD.

PURPOSE OF REVIEW This review examines the current literature on tau imaging in atypical parkinsonian disorders and other tauopathies. RECENT FINDINGS There are a number of tau PET radiotracers that have demonstrated promising preliminary results in atypical parkinsonian disorders, such as progressive supranuclear palsy and corticobasal degeneration. These radiotracers were capable of selectively labeling tau in vitro and in vivo, with high affinity. Other radiotracers tested more extensively in patients with Alzheimer's disease have also been able to successfully image tau deposition. SUMMARY The development of tau radioligands for PET has led to the current testing of these tracers in clinical studies, many of which concentrate on patients with Alzheimer's disease. Atypical parkinsonian disorders such as progressive supranuclear palsy and corticobasal degeneration are now being investigated as well. These disorders can be very difficult to diagnose, because of their clinical overlap with other parkinsonian disorders. Imaging tau using PET could serve as a diagnostic biomarker for these tauopathies and provide a means of assessing treatment that targets tau burden.