Cortical ubiquitin-positive inclusions in frontotemporal dementia without motor neuron disease: a quantitative immunocytochemical study

Abstract

Ubiquitin-positive tau-negative inclusions were initially described in the rare form of frontotemporal dementia (FTD) associated with motor neuron disease. However, recent studies have indicated that these inclusions are also present in typical FTD, which is usually characterized by nonspecific histological changes. To examine the contribution of these inclusions to neuronal loss and to explore their relationship with disease duration, we performed a quantitative immunocytochemical analysis of 38 typical FTD cases. Relationships between neuron and ubiquitin inclusion densities as well as between duration of illness and neuropathological parameters was studied using linear regression in both univariate and multivariate models. Ubiquitin-positive tau-negative intracytoplasmic inclusions were present in 65.8% of cases in the dentate gyrus, 57.9% in temporal cortex and 31.6% in frontal cortex. The highest densities of ubiquitin-positive inclusions were consistently observed in the dentate gyrus, followed by the temporal and frontal cortex. There was no statistically significant relationship between neuron and ubiquitin-positive inclusion densities in any of the areas studied. In contrast, ubiquitin-positive inclusion densities in the dentate gyrus were negatively related to the duration of illness. Our data suggest that the development of ubiquitin-related pathology is the rule and not the exception in typical FTD, yet is not causally related to neuronal loss. They also reveal that the development of ubiquitin-positive inclusion densities in the dentate gyrus may be associated with a more aggressive form of the disease.

Proteomic Analysis of Hippocampal Dentate Granule Cells in Frontotemporal Lobar Degeneration: Application of Laser Capture Technology

“…Recent studies have suggested that FTLD-U is the most common of these subtypes, accounting for approximately half of all FTLD cases (Graff-Radford and Woodruff, 2007; Snowden et al, 2007). The histopathologic hallmark of FTLD-U is the presence of ubiquitin-positive, tau and α-synuclein-negative intraneuronal inclusions primarily in the hippocampal dentate gyrus and frontotemporal cortex (Kovari et al, 2004). Interestingly, a similar pathology is also seen in cases of FTLD-U with concomitant motor neuron disease (MND), which suggests that FTLD-U and MND share a common pathogenesis (Forman et al, 2006).…”

Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders

“…HC pathways in PiD may be particularly vulnerable to tau pathology (Garcia-Sierra et al 2000), but occasional a-and b-synuclein-immunoreactive PB have also been observed in the DG in this disorder (Mori et al 2002). A similar distribution of pathology is present in sporadic FTLD-TDP, although to a lesser extent (Yang and Schmitt 2001;Woulfe et al 2001;Rosso et al 2001;Arai et al 2003, Kovari et al 2004Yaguchi et al 2004;Mackenzie et al 2006), including cases with hippocampal sclerosis (HS) (Probst et al 2007), the latter often exhibiting neuronal loss in the subiculum and CA1 (Josephs and Dickson 2007). TDP-43 immunoreactive dendrites have also been observed in HC neurons in the form of RNA granules co-localized with the post-synaptic protein PDS-95 (Wang et al 2008).…”

Survival in the pre-senile dementia frontotemporal lobar degeneration with TDP-43 proteinopathy: effects of genetic, demographic and neuropathological variables

“…Little pathology was observed to extend into CA3/4 in these cases [10]. To quantify pathology in the dentate gyrus [38,41,64], the sample field was aligned with the upper edge of the granule cell layer. The NCI are rounded, spicular, or skein-like in shape [24,65], while the GI morphologically resemble the 'coiled bodies' reported in various tauopathies such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and argyrophilic grain disease (AGD).…”

“…A specific pathological subtype of FTLD, viz., FTLD with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP), previously called FTLD with ubiquitin-immunoreactive inclusions (FTLD-U) [38,64], is characterized by a variable neocortical and allocortical atrophy principally affecting the frontal and temporal lobes. In addition, there is neuronal loss, microvacuolation of superficial cortical laminae, and a reactive astrocytosis [10,19].…”