Parkinson disease (PD) is a progressive neurodegenerative condition causing serious motor and non-motor disability over time. Falls are common in PD and represent the most severe motor disability. Although nigrostriatal dopaminergic denervation has been recognized as a key pathobiological mechanism, there is general consensus that the majority of postural control and gait impairments associated with falls in PD are resistant to dopaminergic treatment. Therefore, there is a need to further explore non-dopaminergic mechanisms of gait control in PD. Recent neuropathological studies show that PD is a multi-system neurodegeneration syndrome that also affects multiple non-dopaminergic transmitters. For example, the pedunculopontine nucleus (PPN), a brainstem locomotor center, also degenerates in PD and PPN dysfunction has been associated with dopamine-resistant akinesia. The PPN has cholinergic and non-cholinergic neurons and provides the major cholinergic input to the thalamus. Preliminary results from our current RR&D project B4213R suggest that cholinergic denervation, especially of the thalamus, rather than the degree of nigrostriatal dopaminergic denervation is associated with falls in PD. Apart from primary neuronal dopaminergic and non- dopaminergic degeneration, general cortical dysfunction, especially of the frontal lobe, may affect gait control in PD. Furthermore, the presence of common age-associated factors, such as brain small vessel disease (BSVD) may also affect mobility functions in PD. BSVD is also more common in patients with PD likely due to their more sedentary lifestyle, and has been found to independently contribute to higher fall risk. The presence of BSVD is associated with reduced cortical perfusion and may affect cortical neurotransmitter functions non- selectively. Therefore, a critical challenge in multi-system neurodegeneration and aging is how to implicate a specific system in the pathophysiology of symptoms when other systems simultaneously decline. Longitudinal study designs have a particular advantage in the study of neurodegenerative disorders and aging as they allow a unique within-subject analysis of interval changes of multiple variables over time and relate them to baseline functions. Therefore, the overarching goal of the current proposal is to repeat brain MRI, global cortical cerebral blood flow (CBF, derived from dynamic PET imaging), dopaminergic and cholinergic PET imaging, clinical, mobility, functional and cognitive assessments in project B4213R participants at their 3.5-year anniversary of their enrollment in the study. Cortical CBF data extracted from the dynamic PET imaging set will enable global assessment of cortical function to study global cortical factors involved in gait control. The CBF data will also allow analysis of effects of global cortical function on mobility versus possible specific transmitter effects, if present. In addition, we propose to perform GABAergic PET imaging using the [C-11]Flumazenil radioligand in a subset of patients to determine if possible thalamic effects on mobility are specific for thalamic cholinergic denervation or represent global thalamic dysfunction.

Public Health Relevance

. Costs of Parkinson disease and associated morbidity are an increasing source of expense for the VA because of the disproportionately elderly population of veterans. Improved insights in postural and gait functions are, therefore, directly relevant to the diagnosis and preventive care of elderly veterans with PD. The proposed study will allow prognostic assessment to identify risk factors for gait and balance problems such as falls, in veterans with Parkinson disease. The project will apply imaging techniques of brain magnetic resonance imaging (MRI) and positron emission tomography (PET) to study anatomic and chemical changes in the brain, including information on global brain blood flow, specific neurotransmitters such as dopamine, acetylcholine, and GABA, and small vessel disease. Identification of the key mechanism that is most contributory to the development of mobility disability in PD will allow more precise targeting of future therapeutic interventions.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Veterans Health Administration
Ann Arbor
United States
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Bohnen, Jeffrey L B; Müller, Martijn L T M; Haugen, Jacob et al. (2017) Mentally stimulating activities associate with better cognitive performance in Parkinson disease. J Neural Transm (Vienna) 124:1205-1212
Bohnen, Nicolaas I; Haugen, Jacob; Ridder, Andrew et al. (2017) Color discrimination errors associate with axial motor impairments in Parkinson's disease. Mov Disord Clin Pract 4:864-869
Ridder, A; Müller, M L T M; Kotagal, V et al. (2017) Impaired contrast sensitivity is associated with more severe cognitive impairment in Parkinson disease. Parkinsonism Relat Disord 34:15-19
Kim, Kamin; Müller, Martijn L T M; Bohnen, Nicolaas I et al. (2017) Thalamic cholinergic innervation makes a specific bottom-up contribution to signal detection: Evidence from Parkinson's disease patients with defined cholinergic losses. Neuroimage 149:295-304
Haugen, Jacob; Müller, Martijn L T M; Kotagal, Vikas et al. (2016) Prevalence of impaired odor identification in Parkinson disease with imaging evidence of nigrostriatal denervation. J Neural Transm (Vienna) 123:421-4
Fasano, Alfonso; Herman, Talia; Tessitore, Alessandro et al. (2015) Neuroimaging of Freezing of Gait. J Parkinsons Dis 5:241-54
Bohnen, Nicolaas I; Albin, Roger L; Müller, Martijn L T M et al. (2015) Frequency of cholinergic and caudate nucleus dopaminergic deficits across the predemented cognitive spectrum of Parkinson disease and evidence of interaction effects. JAMA Neurol 72:194-200
Müller, Martijn L T M; Albin, Roger L; Kotagal, Vikas et al. (2013) Thalamic cholinergic innervation and postural sensory integration function in Parkinson's disease. Brain 136:3282-9
Bohnen, Nicolaas I; Frey, Kirk A; Studenski, Stephanie et al. (2013) Gait speed in Parkinson disease correlates with cholinergic degeneration. Neurology 81:1611-6