α4ß2* Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance Disorders.

OBJECTIVE: Attentional deficits following degeneration of brain cholinergic systems contribute to gait-balance deficits in Parkinson disease (PD). As a step toward assessing whether α4ß2* nicotinic acetylcholine receptor (nAChR) stimulation improves gait-balance function, we assessed target engagement of the α4ß2* nAChR partial agonist varenicline. METHODS: Nondemented PD participants with cholinergic deficits were identified with [18 F]fluoroethoxybenzovesamicol positron emission tomography (PET). α4ß2* nAChR occupancy after subacute oral varenicline treatment was measured with [18 F]flubatine PET. With a dose selected from the nAChR occupancy experiment, varenicline effects on gait, balance, and cognition were assessed in a double-masked placebo-controlled crossover study. Primary endpoints were normal pace gait speed and a measure of postural stability. RESULTS: Varenicline doses (0.25mg per day, 0.25mg twice daily [b.i.d.], 0.5mg b.i.d., and 1.0mg b.i.d.) produced 60 to 70% receptor occupancy. We selected 0.5mg orally b.i.d for the crossover study. Thirty-three participants completed the crossover study with excellent tolerability. Varenicline had no significant impact on the postural stability measure and caused slower normal pace gait speed. Varenicline narrowed the difference in normal pace gait speed between dual task and no dual task gait conditions, reduced dual task cost, and improved sustained attention test performance. We obtained identical conclusions in 28 participants with treatment compliance confirmed by plasma varenicline measurements. INTERPRETATION: Varenicline occupied α4ß2* nicotinic acetylcholine receptors, was tolerated well, enhanced attention, and altered gait performance. These results are consistent with target engagement. α4ß2* agonists may be worth further evaluation for mitigation of gait and balance disorders in PD. ANN NEUROL 2021;90:130-142.

Age and Life-Sustaining Treatment Preferences in Parkinson Disease.

OBJECTIVE: Advance Care Planning (ACP) is one of 10 key elements in the American Academy of Neurology Parkinson disease (PD) clinical practice quality measures. We know little about how aging influences ACP views in people with PD. METHODS: We conducted a cross-sectional survey of 39 participants (mean age 70.3 years; range: 52-81) with PD to explore correlations between older age and life-sustaining treatment preferences while controlling for confounders including years of education, Montreal Cognitive Assessment score and Movement Disorders Society Unified Parkinson's disease Rating Scale motor score. Scenarios asked participants to choose their level of interest in pursuing life-sustaining measures in the setting of specific medical illnesses including stroke, metastatic cancer, severe heart attack, and dementia. All participants were men and were recruited from the Veterans Affairs Ann Arbor Healthcare System. RESULTS: In the hypothetical stroke, metastatic colon cancer, and dementia scenarios, older age correlated with more aggressive care goals related to the use cardiopulmonary resuscitation to treat cardiopulmonary arrest. CONCLUSIONS: Advancing age in PD may correlate with paradoxically more aggressive goals as it relates to life-sustaining treatment preferences including cardiopulmonary resuscitation. This may reflect a response to heightened concern among older adults with PD about the potential for compromised autonomy in the setting of aging.

Fatigue in Parkinson's Disease Associates with Lower Ambulatory Diastolic Blood Pressure.

BACKGROUND/OBJECTIVE: Fatigue is a common debilitating symptom in Parkinson's disease (PD) of unclear etiology. Hypotension and blood pressure variability are common in PD though their relationship to other non-motor symptoms is less well understood. METHODS: We conducted a cross-sectional study to explore differences in 24-hour ambulatory blood pressure measurements in PD subjects (n = 35) with and without fatigue. Subjects underwent hourly systolic (SBP) and diastolic (DBP) blood pressure testing in their home environment. The presence of fatigue was assessed using the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 1. We compared blood pressure measurements in fatigued vs. non-fatigued PD subjects, assessed over 4 epochs: overnight, morning, midday, and evening. RESULTS: PD subjects with symptoms of fatigue demonstrated lower mean DBP, compared to those without fatigue (67.8±4.8 mmHg vs. 75.6±9.4 t = 2.57, p = 0.014). These intergroup differences were most notable in the morning. The two groups did not differ in scoring on the Survey of Autonomic Symptoms or on an office-based blood assessment of SBP or DBP performed on the day of 24-hour monitor initiation. CONCLUSIONS: Fatigue in PD may be a clinical manifestation of low-grade systemic hypotension.