Astrogliopathy predominates the earliest stage of corticobasal degeneration pathology

Abstract

SEE KOBYLECKI AND MANN DOI101093/AWW267 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Animal models have shown that tau seeding and propagation are strain- and neural network-specific. The study of preclinical cases is valuable to gain insights into early pathological features of corticobasal degeneration and its progression. Three preclinical corticobasal degeneration cases and six age-matched end-stage corticobasal degeneration cases were included in this study. Tau immunohistochemistry performed in 20 brain regions and quantitative assessment of regional tau load using image analysis were performed. Semi-quantitative grading of tau-positive cellular lesions and neuronal loss in the frontal, parietal and temporal cortices, striatum, substantia nigra and subthalamic nucleus were assessed. All preclinical cases were clinically asymptomatic but had widespread tau lesions in the typically affected regions in corticobasal degeneration and the pathognomonic astrocytic plaques were the most prominent lesion type in the anterior frontal and striatal regions. Mean total tau load (sum of all regional tau load) of end-stage corticobasal degeneration cases were nine times greater than that of the preclinical cases (P = 0.04) and less tau load was found in all regions of the preclinical cases. An anterior-to-posterior tau load ratio in the frontal cortex in preclinical cases was 12-fold greater than in end-stage corticobasal degeneration cases. Relatively greater tau burden in the anterior frontal cortex, striatum and subthalamic nucleus suggests the striatal afferent connection to the dorsolateral prefrontal cortex and basal ganglia circuitry are the earliest neural network connections affected by corticobasal degeneration-related tau pathology. Differential distribution of the tau pathology to selective cortical regions in these preclinical cases implies phenotypic presentation may be predetermined at a very early stage of the disease process. Neuronal loss of the substantia nigra was either absent or very mild in the preclinical cases and was moderate to severe in end-stage corticobasal degeneration cases (P < 0.05). Our findings suggest that a threshold of pathological burden in the 'right' anatomical regions needs to be reached before the onset of clinical symptoms. The early prominence of the astrocytic plaques in relation to sparse neuronal lesions leads one to speculate that corticobasal degeneration may begin as an astrogliopathy at a very early disease stage but neuronal lesions gradually take over as the predominant lesion type in advanced disease.

CNS inflammation and neurodegeneration

“…Dysfunction of astrocytes has broadly been termed astrogliopathy. Aging-related tau astrogliopathy (ARTAG) describes the pathological accumulation of abnormally phosphorylated tau protein in astrocytes that is found in AD, frontal temporal lobe dementias (29), and corticobasal degeneration (30). Neuromyelitis optica (NMO) presents with optic neuritis and myelitis and can mimic MS. NMO is associated with the presence of aqua- (42)(43)(44).…”

Astrogliopathy in Tauopathies

“…Interestingly, tau-containing astrocytes are early lesions in PSP, CBD and FTLD-tau [28,[74][75][76].…”

Untangling the tauopathies: Current concepts of tau pathology and neurodegeneration

“…In asymptomatic CBD cases, the brunt of tau pathology is observed in the astroglia in the form of astrocytic plaques rather than neuronal tau lesions such as neurofibrillary tangles, pretangles and threads [23]. This intriguing finding leads us to propose that CBD may be an astrogliopathy with secondary neuronal tauopathy, and as the disease progresses, neuronal tau inclusions become predominant in end-stage disease [23,26].…”

“…Recently, our group has characterised early CBD pathology in a quantitative study of three asymptomatic cases [23]. In these three cases, the pathognomonic 4R tau-positive astrocytic plaques are predominantly observed in the anterior frontal cortex and striatum.…”

“…This intriguing finding leads us to propose that CBD may be an astrogliopathy with secondary neuronal tauopathy, and as the disease progresses, neuronal tau inclusions become predominant in end-stage disease [23,26].…”