The relationship between oestrogen and executive functioning in ALS females with emerging Frontotemporal Lobar Degeneration (FTLD) supports a neuroendocrine model of FTLD attenuation

Abstract

Objective: The prevalence of ALS cognitive or behavioural impairment (ci or bi) consistent with Frontotemporal Degeneration (FTLD) approachs 50%, while ∼5-10% progress to dementia. Our goal was to explore ci and bi differencs between bulbar and limb onset, as well as the neuroprotective potential of oestrogen in emerging FTLD. Methods: We applied Mann Whitney U to evaluate differences in cognitive and behavioural profiles between site of onset in 78 female and 83 male non-demented ALS participants classified by current consensus criteria with ci. For females, we also examined differences by oestrogen level. Findings: Between group analyses found significantly worse Letter Fluency (LF) for bulbar onset, and worse Category Fluency (CF) for bulbar females. Significantly worse performance was found for low oestrogen females for LF and Similarities, with significantly worse LF for low oestrogen bulbar onset. No significant differences were found for behavioural subgroups, while moderate-severe range traits were higher in occurrence for bulbar and low oestrogen bulbar onset. Conclusions: Findings support our previously published mesocortical pathway associated “bottom-up” model of FTLD emergence in ALSbi, extending it with a hierarchal hypothesis involving ascending cerebellar pathways in ALSci and ALSbi, further suggesting a role for oestrogen in mitigating female FTLD progression.

Key words:

• Frontotemporal lobar degeneration
• gender
• oestrogen
• amyotrophic lateral sclerosis
• executive functioning
• cognitive decline
• behavioural decline

Acknowledgments

The authors are deeply grateful to the patients and caregivers for their willingness to participate in this study.

Declaration of interest

This work was supported in part by the Paul and Harriett Campbell fund for ALS Research and the Zimmerman Family Love Fund. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilised in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.