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-nigroluysian 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 circuitspecific 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.

Synaptic Loss in Primary Tauopathies Revealed by [11C]UCB‐J Positron Emission Tomography

“…In PSP, from postmortem studies, these include basal ganglia, thalamus, substantia nigra, premotor cortex, as well as the dentate nucleus and cerebellar white matter. In CBD, areas associated with the disease include cortex, thalamus, basal ganglia, and brainstem, without cerebellar involvement 48‐50 . However, in our study, the loss of synapses in PSP is global across the cortex, and not confined to the premotor and motor areas, and extends beyond the substantia nigra in the brainstem with pontine and medullary involvement.…”

Multicenter Validation of Metabolic Abnormalities Related to PSP According to the MDS‐PSP Criteria

“…Moreover, these results are in line with some neuropathological studies that described similar networks implied and differences in the global distribution and severity of tau pathology between PSP variants. 3,4,53,54 In fact, a recent neuropathological study observed common early vulnerability patterns that characterize all PSP clinical subtypes jointly (pallido-nigro-luysian axis), but different dynamics of propagation. 54 In other words, our findings suggest that despite the existence of probable neuropathological and functional differences between PSP variants, they may also share a common pattern that can serve as a PSP biomarker to discriminate PSP variants from PD patients and HCs.…”

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

“…Despite the accumulation of abnormal tau being the basis of all tauopathies, these diseases differ from each other with regard to the brain areas affected, the kind of tau aggregates, and the cell types in which the aggregates are found, which is either neurons or astrocyte or oligodendrocytes. For example in PSP, different from AD, pathological tau accumulations start in the neurons of subcortical and brainstem nuclei, in the oligodendrocytes of the globus pallidus, and in the astrocytes of the striatum, followed by tau accumulation in cortical astrocytes, neurons, and oligodendrocyte, respectively, with a fronto-parietal to temporal to occipital sequence [ 177 ].…”