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Hypothalamic pituitary adrenal (HPA) axis hyperactivity has been linked to learning and memory difficulties in a range of neurodegenerative and neuropsychiatric conditions. In Huntington's disease (HD), both declines in learning and memory and HPA axis dysfunction are present early in the disease. However, the relationship between specific learning and memory deficits and HPA axis functioning in HD has not been examined. The aim of this study was to investigate cortisol levels in relation to verbal learning and memory in pre-diagnosed (pre-HD) participants and patients at the early stages of diagnosed HD (early-HD). Cortisol concentration was assayed in saliva samples from 57 participants (17 early-HD, 20 pre-HD, and 20 controls) at four time-points across a 24-h period. Verbal memory was assessed using the California Verbal Learning Test-Second Edition (CVLT-II). We focused statistical analyses on the late evening cortisol concentration, and examined cortisol levels and verbal memory function in relation to diagnostic group (control, pre-HD, early-HD), and in a separate set of analyses combining pre-HD and early-HD (and excluding controls) we also examined cortisol and verbal memory performance in relation to the severity of HD-related motor signs. Of these two classification approaches, HD motor sign severity was more strongly associated with high evening cortisol levels and both reduced information encoding and memory retrieval. Separately, there was also a trend of higher cortisol levels in pre-HD. The findings suggest hypercortisolism and the underlying pathological changes may begin many years before a clinical diagnosis is made, but the memory decline associated with HPA axis disturbance may only become detectable once motor signs become pronounced.

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Background: Subtle progressive changes in speech motor function and cognition begin prior to diagnosis of Huntington’s disease (HD). Objective: To determine the nature of listener-rated speech differences in premanifest and early-stage HD (i.e., PreHD and EarlyHD), compared to neurologically healthy controls. Methods: We administered a speech battery to 60 adults (16 people with PreHD, 14 with EarlyHD, and 30 neurologically healthy controls), and conducted a cognitive test of processing speed/visual attention, the Symbol Digit Modalities Test (SDMT) on participants with HD. Voice recordings were rated by expert listeners and analyzed for acoustic and perceptual speech features. Results: Listeners perceived subtle differences in the speech of PreHD compared to controls, including abnormal pitch level and speech rate, reduced loudness and loudness inflection, altered voice quality, hypernasality, imprecise articulation, and reduced naturalness of speech. Listeners detected abnormal speech rate in PreHD compared to healthy speakers on a reading task, which correlated with slower speech rate from acoustic analysis and a lower cognitive performance score. In early-stage HD, continuous speech was characterized by longer pauses, a higher proportion of silence, and slower rate. Conclusion: Differences in speech and voice acoustic features are detectable in PreHD by expert listeners and align with some acoustically-derived objective speech measures. Slower speech rate in PreHD suggests altered oral motor control and/or subtle cognitive deficits that begin prior to diagnosis. Speakers with EarlyHD exhibited more silences compared to the PreHD and control groups, raising the likelihood of a link between speech and cognition that is not yet well characterized in HD.