Distribution patterns of tau pathology in progressive supranuclear palsy

Abstract

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.

Keywords: Coiled body; Neurofibrillary tangle; Progressive supranuclear palsy; Propagation; Richardson syndrome; Sequential involvement; Stage; Tau; Tauopathy; Tufted astrocyte.

Fig. 1

Distribution map of total tau semiquantitative scores (0–3) in PSP-Richardson syndrome (PSP-RS), PSP-frontal variant (PSP-F), PSP-Parkinsonism (PSP-P), PSP-postural instability (PSP-PI), PSP-speech-language variant (PSP-SL) and PSP-corticobasal syndrome (PSP-CBS). Black boxes indicate that that anatomical region was not examined. White box indicates score 0, yellow score 1, orange score 2, and red score 3 for semiquantitative scoring. Columns indicate anatomical regions, rows indicate individual patients. If more than six brain regions were not available the cases are not shown in this figure. OC Occipital, TE temporal, PA parietal, FR frontal, MC motor cortex, AM amygdala, HI hippocampus, ST striatum, TH thalamus and subthalamic nucleus, GP globus pallidus, TG midbrain tegmentum, SN substantia nigra, LC locus coeruleus, PB pontine base, MO medulla oblongata, DE/CB dentate nucleus and cerebellar white matter

Fig. 2

Heat mapping of total tau scores in PSP-Richardson syndrome (PSP-RS), PSP-frontal variant (PSP-F), PSP-Parkinsonism (PSP-P), PSP-postural instability (PSP-PI), PSP-speech-language variant (PSP-SL) and PSP-corticobasal syndrome (PSP-CBS). The severity of tau pathology ranges from white (none) through yellow and orange to red (severe). Gray colored cortical regions indicate that the region was not evaluated

Fig. 3

Graphic representation of semiquantitative scores of different cellular tau pathologies (a neuronal, b astroglial, c oligodendroglial) in PSP clinical subtypes. To avoid overcrowding of the graphs, three subtypes are shown in bars and three with lines. Significant (p < 0.05) results of Mann–Whitney test are shown for each comparison in D (blue box indicates neuronal, N, red box for astroglial, A, and green for oligodendroglial, O). OC Occipital cortex, TE temporal cortex, PA parietal cortex, FR frontal cortex, MC motor cortex, AM amygdala, HI hippocampus, ST striatum, TH thalamus and subthalamic nucleus, GP globus pallidus, TG midbrain tegmentum, SN substantia nigra, LC locus coeruleus, PB pontine base, MO medulla oblongata, DE/CB dentate nucleus and cerebellar white matter

Fig. 4

Heatmap showing the development of tau pathology based on conditional probability matrix of total tau pathology scores in pooled cases of different clinical subtypes. The dark red color indicates early and the yellow-white later involvement. Areas colored with gray were not included in the present study

Fig. 5

Distribution map of cellular tau pathology semiquantitative scores (0–3) in PSP-RS cases (n = 81). White box indicates score 0, yellow score 1, orange score 2, and red score 3 for semiquantitative scoring. Presence of Lewy-body pathology above Braak stage 2 or TDP-43 proteinopathy is indicated + , absence by −. Black boxes indicate that that anatomical region was not examined. On the right the proposed stages are indicated. Blue outlined boxes highlight the anatomical regions which were considered for the staging. OC Occipital, TE temporal, PA parietal, FR frontal, MC motor cortex, AM amygdala, HI hippocampus, ST striatum, TH/STN thalamus and subthalamic nucleus, GP globus pallidus, TG midbrain tegmentum, SN substantia nigra, LC locus coeruleus, PB pontine base, MO medulla oblongata, DE/Cbll dentate nucleus and cerebellar white matter

Fig. 6

Summary of the conditional probability analyses (see online supplemental file). The upper image represents whether the anatomical regions listed in the left show high, substantial, or moderate probability with a p significance value below 0.01 to precede the involvement of the anatomical regions listed on the top. The lower image represents whether the anatomical regions listed in the left show high, substantial, or moderate probability with a p significance value below 0.05 or fair probability (with p < 0.01) to precede the involvement of the anatomical regions listed on the top.: N neuronal, A astroglial, O oligodendroglial, OC Occipital, TE temporal, PA parietal, FR frontal, MC motor cortex, AM amygdala, HI hippocampus, ST striatum, TH thalamus and subthalamic nucleus, GP globus pallidus, TG midbrain tegmentum, SN substantia nigra, LC locus coeruleus, PB pontine base, MO medulla oblongata, DE/CB dentate nucleus and cerebellar white matter

Fig. 7

Sequences of PSP related tau pathology based on the conditional probability matrix and stratified for accumulation of neuronal, astroglial, and oligodendroglial tau pathologies. Note that frontal lobe includes frontal and motor cortices. Note that neuronal tau pathology is frequently seen in the hippocampus and locus coeruleus in stage 1; however, eventually this may be related to concomitant Alzheimer’s disease or primary age-related tauopathy (PART) pathogenesis. To indicate that locus coeruleus is frequently affected early, but alone might be associated with other disease conditions such as AD/PART, we used italic letters

Fig. 8

Proposed staging schema for the neuropathological practice. −/ +  Indicates single cell involvement; + indicates mild; +  + / +  +  + indicates moderate/severe involvement. GP globus pallidus, STN subthalamic nucleus, STR striatum, FR frontal, DE/CB dentate nucleus and cerebellar white matter, OC occipital. This can be applied to all clinical subtypes. The evaluator should focus on different cell types in different brain regions: in GP and DE/CB neuronal (N) or oligodendroglial (O); in the STN neuronal; in the STR and FR and OC cortices astroglial (A). The brain schema is a conceptual summary of the tabularized schema in the lower panel; thus the color coding of different brain regions reflect the variability in scores (or-or) required for a stage