Signature Tau Neuropathology in Gray and White Matter of Corticobasal Degeneration

Abstract

Corticobasal degeneration (CBD) is an adult-onset progressive neurodegenerative disorder characterized by L-dopa-resistant rigidity, focal cortical deficits, and variable dementia. The neuropathological hallmark of CBD is the deposition of filamentous inclusions in neurons and glia composed of hyperphosphorylated tau with only four microtubule-binding repeats (4R-tau). To characterize the regional burden of tau pathology in CBD, we studied 12 brains with the neuropathological diagnosis of CBD using biochemical and histochemical techniques. Eleven brain regions were evaluated including gray and white matter from frontal, parietal, temporal, and occipital lobes and cerebellum as well as basal ganglia. Although the distribution of tau pathology was variable, neuropathological and biochemical data showed a similar burden of tau abnormalities in frontal, temporal, and parietal lobes and basal ganglia of both hemispheres. This included abundant, sarkosyl-insoluble 4R-tau in both gray and white matter of two or more of these cortical regions and basal ganglia, and to a lesser extent, cerebellar white matter. The insoluble tau pathology in gray and white matter showed overlapping but distinct phosphorylated epitopes suggesting cell-type and subcellular localization (ie, cell bodies versus cell processes)-specific differences in tau phosphorylation. In contrast, soluble tau was composed of normal 4R/3R-tau ratios indicating no gross abnormality in tau splicing. Thus, although clinically heterogeneous, CBD is a distinct lobar and basal ganglionic tauopathy with selective aggregation of 4R-tau.

Criteria for the diagnosis of corticobasal degeneration

“…13 The presence of memory impairment in CBD is underscored by numerous series in which the clinical diagnoses of AD or atypical AD proved to be CBD. 12,13,15,16,21,23,39 Acalculia and visuospatial difficulties (with limited details) are rarely described in CBD. 15 Behavioral changes and executive dysfunction are common in CBD, underscored by many patients presenting with a behavioral variant frontotemporal dementia (FTD) syndrome.…”

“…15 Behavioral changes and executive dysfunction are common in CBD, underscored by many patients presenting with a behavioral variant frontotemporal dementia (FTD) syndrome. 13,15,16,20,33,[39][40][41] Symptoms include apathy, bizarre or antisocial behavior, personality changes, irritability, disinhibition, and hypersexuality. 13,15,16,39 Fifty-five percent of reviewed CBD cases had behavioral changes, often at presentation (table 2).…”

White matter imaging contributes to the multimodal diagnosis of frontotemporal lobar degeneration

“…4,11,27 This includes a TSA study of CSFdefined FTLD and AD, 27 though this previous TSA report was limited by reduced DTI resolution (12 directions) and a smaller cohort of patients. FTLD may exhibit greater WM changes than AD due to prominent underlying neuropathology in FTLD that specifically involves microglia in FTLD-tau 28 and glial lesions immunoreactive to TDP-43 in FTLD-TDP. 29 WM pathology is much more modest in AD.…”

Axonal Degeneration Induced by Targeted Expression of Mutant Human Tau in Oligodendrocytes of Transgenic Mice That Model Glial Tauopathies

“…For example, fibrillary aggregates in OLGs known as glial cytoplasmic inclusions (GCIs) are hallmark lesions of multiple system atrophy (MSA), and GCIs are composed of ␣-synuclein as well as tau but to a lesser extent (Murayama et al, 1992;Tu et al, 1998) (for review, see Richter-Landsberg, 2000). Other filamentous OLG inclusions known as coiled bodies are primarily composed of hyperphosphorylated tau (Chin and Goldman, 1996;Dickson et al, 1996;Forman et al, 2002), and these inclusions are characteristic of several frontotemporal dementias (FTDs) such as sporadic progressive supranuclear palsy (PSP), Pick's disease, and corticobasal degeneration (CBD), as well as hereditary FTD with parkinsonism linked to chromosome 17 (FTDP-17) (for review, see Komori, 1999;Forman et al, 2000;Richter-Landsberg, 2000). Although GCIs are associated with myelin abnormalities in MSA (Matsuo et al, 1998), altered myelination is not linked to accumulations of coiled bodies in most glial tauopathies despite widespread evidence of neurodegeneration.…”