Early auditory and imbalance measures in a mouse model of Alzheimer's Disease-Supplement

目前，550万（约10%）65岁以上的美国人患有阿尔茨海默病（AD）

Currently, 5.5 million Americans (~10%) over age 65 have Alzheimer's disease (AD), and this number will more than double by 2050. AD is definitively diagnosed from post-mortem analyses of neurodegenera- tion with the presence of β-amyloid (Aβ) containing plaques and tau-containing neurofibrillary tangles. As Aβ accumulation in the brain can precede cognitive impairment by decades, treatments aimed at facilitating clearance of Aβ are most effective at early stages, when the disease is difficult to diagnose. The inability to detect AD early enough to apply meaningful interventions is a major barrier to AD's successful manage- ment. AD patients have a higher prevalence of vestibular impairment relative to healthy age-matched controls, with postural sway serving as an excellent predictor of the overall cognitive assessment score in AD. Gait metrics discriminated better between patients with mild cognitive impairments and healthy con- trols, more so than verbal-fluency tests. Additionally, patients with AD have difficulty suppressing incongru- ent brain signals when maintaining balance compared to age-matched controls. In addition to vestibular imbalances, AD patients have difficulties understanding speech in background noise, a deficit known as auditory processing disorder (APD). The mechanisms of APD are unclear, yet circuitry in auditory-specific regions of the brainstem are known to play a role in speech processing and noise masking. Moreover, better peripheral frequency resolution thresholds correlate with improved hearing in noise abilities. Preclinical models have been extremely useful to test hypotheses about AD pathophysiology and to assess putative interventions. However, it is unknown if current AD mouse models exhibit alterations in postural sway, gait, or APD, as observed in early pre-dementia AD patients. It is also not well established if increased Aβ deposition occurs in the brainstems of AD mouse models, similar to post-mortem histological evidence of early Aβ deposition in brainstems of patients with little evidence of cognitive impairment. We propose to measure mouse homologues of these early AD symptoms in the 5xFAD AD mouse model crossed to mouse lines without age-related hearing loss. In Aim 1, we will measure sway and gait distur- bances. In Aim 2, we will use auditory brainstem responses (ABRs) measured in simultaneous notched noise to measure peripheral frequency resolution thresholds and auditory filter shapes. Lastly, we will determine if these deficits correlate with plaque deposition, demyelination, or inflammation in the vestibular and auditory brainstem and CNS. The impact of this proposal will be in developing robust preclinical assays of early AD, paving the way to develop and test future therapeutics for pre-dementia AD.