Central cholinergic presbyvestibulopathy network changes and imbalance in Parkinson's disease and older persons

Abstract
The management of dopamine resistant postural instability and gait difficulties (PIGD) features, such as falls,
represents perhaps the most important unmet clinical need in persons with Parkinson's disease (PD) and is a
major cause for reduced quality of life. The loss of functional abilities and quality of life associated with the
emergence of PIGD is further compromised by coinciding emergence of cognitive decline and dementia. This
may reflect progressive non-dopaminergic pathologies, such as cholinergic system changes. Vestibular
impairment, in particular more chronic bilateral vestibular dysfunction of older age (defined as
presbyvestibulopathy, PVP), is a significant contributor to imbalance and falls in older US adults. Unlike acute
vestibular disorders that are sporadic, PVP is also common in an age-associated disorder like PD. We have
novel preliminary data showing that the presence of PVP in PD is associated with imbalance independent from
nigrostriatal dopaminergic losses. Using a data-driven whole brain selection method of vesicular acetylcholine
transporter (VAChT) [18F]FEOBV PET brain regions, we also found that the presence of PVP in PD is
associated with cholinergic system changes most prominently in the medial geniculate nucleus (MGN) and by
medial temporal lobe structures involved in multimodal sensory processing, spatial orientation and navigation.
Lower cholinergic binding in the MGN and a composite measure of cholinergic binding in PVP-related specific
brain regions associated with presence of imbalance in people with PD. Given recent recognition of important
vestibular information processing functions of the MGN, our data suggest that this small metathalamic nucleus
may function as a key node in the central vestibular neural network. These observations in people with PD may
also be relevant for non-PD older adults with PVP. Cholinergic and dopaminergic losses not only occur in PD
but are also part of normal aging starting from young adulthood on. We have preliminary data showing that
age-associated vulnerability of cholinergic nerve terminal losses is most conspicuous in the MGN and
mesiotemporal lobe. This suggests that cholinergic vulnerability of normal aging may contribute to the
relationship between PVP and cholinergic system changes in PD. Conversely, age-associated vulnerability in
these structures may explain the high and increasing prevalence of PVP in non-PD older persons. We propose
to perform brain cholinergic [18F]FEOBV and dopamine transporter [11C]PE2I PET imaging and balance
assessment and vestibular testing in persons with PD and non-PD older adults. The overarching goal of this
study is to test the hypothesis that brain region-specific cholinergic system changes associate with the
presence of both PVP and fall status in persons with PD independent of dopaminergic losses. We also
propose to test the secondary hypothesis that age-associated cholinergic vulnerability in the MGN and
mediotemporal lobe associate with the presence of both PVP and fall status in non-PD older adults
independent of dopaminergic losses of normal aging.

Grant Number: 5R01AG073100-05
NIH Institute/Center: NIH
Principal Investigator: Nicolaas Bohnen