Frontotemporal dementia (FTD) is a prevalent neurodegenerative disease of heterogeneous histopathology. Neuropathological subtypes are identified on the basis of the presence or absence of tau- or ubiquitin-positive neuronal inclusions. Our recent work has established four disease stages that are independent of neuropathological subtype and reflect the clinical and degenerative progression observed in FTD. The variability in the extent of neuronal loss, astrogliosis, and microvacuolation are, therefore, more likely to reflect disease stage with potentially predictable differences between cases at early versus late disease stages. Understanding the variability in these parameters may assist in determining the importance of diverse disease subtypes in FTD. We examined 21 cases of sporadic, behavioural variant FTD and quantified the progression of histopathological change. The neuropathology of early disease was marked by severe astrogliosis of both the frontal and temporal cortices and neuronal loss, which was more evident in upper cortical layers of the frontal lobe. In late disease, neuronal loss was evident from both layer III and V in frontal and temporal cortices, and particularly the CA1 sector of the hippocampus. In addition, we compared the neuropathology of Pick's disease, dementia lacking distinctive histopathology and FTD with motor neuron disease, and found no difference in these pathological subtypes on the basis of neuronal loss, astrogliosis or microvacuolation. These results show that the earliest cellular changes in FTD occur in glia, and that disease stage rather than FTD subtype determines the pattern and extent of neuronal degeneration.

Neurons rely on the release and subsequent cleavage of GSH to cysteinylglycine (CysGly) by astrocytes in order to maintain optimal intracellular GSH levels. In neurodegenerative diseases characterised by oxidative stress, neurons need an optimal GSH supply to defend themselves against free radicals released from activated microglia and astroglia. The rate of GSH synthesis is controlled largely by the activity of γ-glutamyl cysteine ligase. Expression of γ-glutamyl cysteine ligase and of the Xc- system, which facilitates cystine uptake, is regulated by the redox-sensitive transcription factor, nuclear factor erythroid-2-related factor 2 (Nrf2). Compounds that can activate the Nrf2-ARE pathway, referred to as ‘Nrf2 activators’ are receiving growing attention due to their potential as GSH-boosting drugs.This study compares four known Nrf2 activators, R-α-Lipoic acid (LA), tert-butylhydroquinone (TBHQ), sulforaphane (SFN) and Polygonum cuspidatum extract containing 50% resveratrol (PC-Res) for their effects on astroglial release of GSH and CysGly. GSH levels increased dose-dependently in response to all four drugs. Sulforaphane produced the most potent effect, increasing GSH by up to 2.4-fold. PC-Res increased GSH up to 1.6-fold, followed by TBHQ (1.5-fold) and LA (1.4-fold). GSH is processed by the ectoenzyme, γ-glutamyl transpeptidase, to form CysGly. Once again, SFN produced the most potent effect, increasing CysGly by up to 1.7-fold, compared to control cells. TBHQ and PC-Res both induced fold increases of 1.3, followed by LA with a fold increase of 1.2. The results from the present study showed that sulforaphane, followed by lipoic acid, resveratrol and Polygonum multiflorum were all identified as potent “GSH and Cys-Gly boosters”.

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