Longitudinal monitoring of tau aggregation in progressive supranuclear palsy with [18F]PI-2620 PET

Abstract

Introduction: Progressive supranuclear palsy (PSP), a 4-repeat tauopathy, can be visualized using [¹⁸F]PI-2620 tau positron emission tomography (PET). However, the value of sequential [¹⁸F]PI-2620 imaging for tracking tau accumulation during the disease course has not yet been investigated.

Methods: Twenty-three PSP patients underwent two [¹⁸F]PI-2620 PET scans (interval: 21.4 ± 4.3 months) and were compared to cross-sectional data from 25 healthy controls. Regional volume of distribution ratio values were analyzed for longitudinal tau changes, clinical correlations, and network-based propagation. Post mortem analyses examined neuronal density and AT8 tau pathology.

Results: Subcortical tau PET signals increased, strongest in the globus pallidus internus (P < 0.0001). Patients with low baseline tau showed the largest increases. Despite clinical worsening (Progressive Supranuclear Palsy Rating Scale +48%), tau PET change did not correlate with symptom progression. Tau accumulation followed functional connectivity (R = 0.34, P < 0.0001). Post mortem data linked elevated tau PET to higher AT8 burden despite neuronal loss.

Discussion: [¹⁸F]PI-2620 PET enables monitoring of tau progression in PSP, indicating network-based tau propagation with saturation in advanced stages.

Keywords: 4‐repeat tauopathies; disease monitoring; progressive supranuclear palsy; tau positron emission tomography; tau spreading.

FIGURE 1

Longitudinal increases in subcortical tau positron emission tomography (PET) signal in patients with progressive supranuclear palsy (PSP). A, Axial [¹⁸F]PI‐2620 tau PET images at baseline (BL) and follow‐up (FUP) for patients with PSP (top row), the single healthy control subject with longitudinal imaging, and the cross‐sectional averaged healthy controls (bottom row) illustrate elevated tracer uptake in subcortical nuclei of PSP over time. B, Box plots show regional tau PET binding (volume of distribution ratio [VTr]) at BL and mean FUP (21.4 months) for multiple subcortical and cortical regions, including the internal part of the globus pallidus (GPi), external part of the globus pallidus (GPe), putamen (PUT), subthalamic nucleus (STN), substantia nigra (SN), dorsal midbrain (DMB), dentate nucleus (DN), dorsolateral prefrontal cortex (DLPFC), and medial prefrontal cortex (MPFC). Paired t tests were used to assess temporal differences in tau PET VTr. P values < 0.0332, 0.0021, 0.0002, and 0.0001 are shown as *, **, ***, and ****, respectively. C, Individual trajectories of GPi tau PET signal over time confirm a robust increase in most patients. Blue markers denote diagnostic certainty levels at baseline and follow‐up according to Movement Disorder Society Progressive Supranuclear Palsy criteria. The gray marker represents the single healthy control with longitudinal data. Gray dashed lines indicate the mean ± standard deviation of the healthy control group at baseline for reference.

FIGURE 2

Individual‐level progression of tau positron emission tomography (PET) signals in patients with progressive supranuclear palsy (PSP). A, Averaged axial [^{1 8}F]PI‐2620 tau PET images at baseline (BL) and follow‐up (FUP) illustrate progressive subcortical and cortical tracer uptake. Images are shown as volume of distribution ratio (VTr) z score maps normalized to the healthy control group. B, Axial [¹⁸F]PI‐2620 tau PET images showing the percentage difference (%Δ FUP – BL), highlighting spatial patterns of longitudinal change across the brain. C, Heatmaps show the distribution of elevated tau PET signal (z scores) across subcortical and cortical regions at baseline (left) and follow‐up (right) for each individual. Colors indicate the degree of deviation from the healthy control mean in z scores. Numbers at the bottom indicate how many individuals exceeded the 1 standard deviation threshold in each region. DLPFC, dorsolateral prefrontal cortex; DMB, dorsal midbrain; DN, dentate nucleus; GPe, external part of the globus pallidus; GPi, globus pallidus; MPFC, medial prefrontal cortex; PSP‐CBS, progressive supranuclear palsy with corticobasal syndrome; PSP‐F, progressive supranuclear palsy with frontal presentation; PSP‐P, progressive supranuclear palsy with predominant Parkinsonism; PSP‐PGF, progressive supranuclear palsy with progressive gait freezing; SN, substantia nigra; STN, subthalamic nucleus.

FIGURE 3

Baseline tau burden predicts longitudinal change in tau positron emission tomography (PET) signals of the basal ganglia. A, Linear regression model depicts negative association between baseline GPi tau PET signal (volume of distribution ratio [VTr]) and change over time (ΔVTr, follow‐up minus baseline) in progressive supranuclear palsy (PSP). Shaded area indicates 95% confidence interval. B, Representative axial [¹⁸F]PI‐2620 tau PET images at baseline and follow‐up from individuals with PSP‐P, PSP‐CBS, and PSP‐RS, compared to a healthy control (HC). Arrows indicate increasing (↑) or stable (→) GPi signal over time. GPi, globus pallidus; PSP‐CBS, progressive supranuclear palsy with corticobasal syndrome; PSP‐P, progressive supranuclear palsy with predominant Parkinsonism; PSP‐RS, progressive supranuclear palsy with Richardson's syndrome.

FIGURE 4

Clinical progression and its relationship to tau positron emission tomography (PET) signal in progressive supranuclear palsy (PSP). A, Line plots showing individual clinical scores at baseline (BL) and follow‐up (FUP) for the PSP Rating Scale, UPDRS‐III, Montreal Cognitive Assessment (MoCA), and Schwab and England Activities of Daily Living scale (SEADL). B, The alluvial chart illustrates diagnostic transitions over time, showing how individuals progressed from “suggestive of” (s.o.) or possible PSP to probable PSP, or remained as a probable PSP at follow‐up according to Movement Disorder Society criteria. C, Scatter plot depicts globus pallidus (GPi) tau PET z scores at BL and FUP plotted against respective PSP Rating Scale scores at the same timepoint. D, Scatter plot shows the change in GPi tau PET z scores from baseline to follow‐up (ΔFUP – BL) in relation to the corresponding change in PSP Rating Scale scores.

FIGURE 5

Association between functional connectivity and covariance in longitudinal tau positron emission tomography (PET) change. A, B, Scatter plot depicts the positive association between inter‐regional functional connectivity and covariance in tau PET accumulation rates at the subcortex (A) and whole‐brain (B) level. Shaded area indicates 95% confidence interval. C, Boxplot depicts the association between connectivity to tau epicenters (defined as the 5% of regions with fastest tau accumulation per subject) and brain‐wide tau PET accumulation. D, Boxplots depict a connectivity‐defined gradient of tau PET accumulation rates across epicenters and octiles (Q1–Q8) of decreasing connectivity to epicenters. Boxplots are displayed as median (center line) ± interquartile range (box boundaries) with whiskers. A one‐way analysis of variance with Bonferroni post hoc tests was used to assess differences between epicenters and octiles. P values < 0.0332 to 0.0001 are indicated as * and **, corresponding to the differences between Q1 and Q2, and between the epicenter and Q1, respectively.

FIGURE 6

Relationship between tau positron emission tomography (PET) signal and neuronal density in the globus pallidus. A, Non‐linear quadratic regression of neuronal density (cells/mm²) and disease duration. B, C, Residuals from the linear regression between tau PET and neuronal density are color‐coded as positive (green) or negative (red) and plotted against AT8 positive area. Linear regression lines (including 95% confidence intervals) were calculated in samples derived from seven patients with definite progressive supranuclear palsy (PSP). D, Representative coronal [¹⁸F]PI‐2620 tau PET images of the globus pallidus and corresponding hematoxylin and eosin (H&E) as well as AT8 stained sections are shown for three PSP cases. White arrows summarize the observed directionality between tau PET signal intensity, neuronal abundance, and AT8 occupancy. Scale bars: overview image = 1 mm (dotted line); high‐magnification image = 20 µm (straight line). R indicates Pearson correlation coefficient. VTr, volume of distribution ratio.