Dataset Information

α4β2^* Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance Disorders.

ABSTRACT:

Objective

Attentional deficits following degeneration of brain cholinergic systems contribute to gait-balance deficits in Parkinson disease (PD). As a step toward assessing whether α4β2* nicotinic acetylcholine receptor (nAChR) stimulation improves gait-balance function, we assessed target engagement of the α4β2* nAChR partial agonist varenicline.

Methods

Nondemented PD participants with cholinergic deficits were identified with [¹⁸ F]fluoroethoxybenzovesamicol positron emission tomography (PET). α4β2* 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 α4β2* nicotinic acetylcholine receptors, was tolerated well, enhanced attention, and altered gait performance. These results are consistent with target engagement. α4β2* agonists may be worth further evaluation for mitigation of gait and balance disorders in PD. ANN NEUROL 2021;90:130-142.

SUBMITTER: Albin RL

PROVIDER: S-EPMC9013471 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Nicotine, the principal reinforcing compound in tobacco, acts in the brain by activating neuronal nicotinic acetylcholine receptors (nAChRs). This review summarizes our current knowledge regarding how the α5 accessory nAChR subunit, encoded by the CHRNA5 gene, differentially modulates α4β2* and α3β4* receptors at the cellular level. Genome-wide association studies have linked a gene cluster in chromosomal region 15q25 to increased susceptibility to nicotine addiction, lung cancer, chronic obstructive pulmonary disease, and peripheral arterial disease. Interestingly, this gene cluster contains a non-synonymous single-nucleotide polymorphism (SNP) in the human CHRNA5 gene, causing an aspartic acid (D) to asparagine (N) substitution at amino acid position 398 in the α5 nAChR subunit. Although other SNPs have been associated with tobacco smoking behavior, efforts have focused predominantly on the D398 and N398 variants in the α5 subunit. In recent years, significant progress has been made toward understanding the role that the α5 nAChR subunit-and the role of the D398 and N398 variants-plays on nAChR function at the cellular level. These insights stem primarily from a wide range of experimental models, including receptors expressed heterologously in Xenopus oocytes, various cell lines, and neurons derived from human induced pluripotent stem cells (iPSCs), as well as endogenous receptors in genetically engineered mice and-more recently-rats. Despite providing a wealth of available data, however, these studies have yielded conflicting results, and our understanding of the modulatory role that the α5 subunit plays remains incomplete. Here, we review these reports and the various techniques used for expression and analysis in order to examine how the α5 subunit modulates key functions in α4β2* and α3β4* receptors, including receptor trafficking, sensitivity, efficacy, and desensitization. In addition, we highlight the strikingly different role that the α5 subunit plays in Ca2+ signaling between α4β2* and α3β4* receptors, and we discuss whether the N398 α5 subunit variant can partially replace the D398 variant.

Project description:Impaired mobility and falls are clinically important complications of Parkinson's disease (PD) and a major detractor from quality of life for which there are limited therapies. Pathological, neuroimaging and clinical evidence suggest that degeneration of cholinergic systems may contribute to impairments of balance and gait in PD. The proposed trial will examine the effects of augmentation of the cholinergic system on balance and gait.The study is a single-site, proof of concept, randomized, double-blind, cross-over trial in patients with PD. Each treatment period will be 6 weeks with a 6-week washout between treatments for a total of 18 weeks for each subject. Donepezil in 2.5 mg capsules or identical appearing placebo capsules will be increased from two per day (5 mg) to four capsules (10 mg) after 3 weeks, if tolerated. Subjects will have idiopathic Parkinson's disease, Hoehn and Yahr stages 2 to 4. We anticipate recruiting up to 100 subjects for screening to have 54 enrolled and 44 subjects complete both phases of treatment. Dropouts will be replaced. As this is a crossover trial, all subjects will be exposed to both donepezil and to placebo. The primary outcome measures will be the root mean square of the mediolateral sway when standing and the variability of the stride duration when walking for two minutes. Secondary outcomes will be the computerized Attention Network Test to examine three domains of attention and the Short-latency Afferent Inhibition (SAI), a physiological marker obtained with transcranial magnetic stimulation as a putative marker of cholinergic activity.The results of this study will be the most direct test of the hypothesized role of cholinergic neurotransmission in gait and balance. The study is exploratory because we do not know whether donepezil will affect gait, balance or attention, nor which measures of gait, balance or attention will be sensitive to drug manipulation. We hypothesize that change in cholinergic activity, as measured with SAI, will predict the relative effectiveness of donepezil on gait and balance. Our immediate goal is to determine the potential utility of cholinergic manipulation as a strategy for preventing or treating balance and gait dysfunction in PD. The findings of this trial are intended to lead to more sharply focused questions about the role of cholinergic neurotransmission in balance and gait and eventually to Phase II B trials to determine clinical utility of cholinergic manipulation to prevent falls and improve mobility.This trial is registered at clinical trials.gov ( NCT02206620).

Project description:ObjectiveTo assess the effect of exercise training by using the Nintendo Wii Fit video game and balance board system on balance and gait in adults with Parkinson disease (PD).DesignA prospective interventional cohort study.SettingAn outpatient group exercise class.ParticipantsTen subjects with PD, Hoehn and Yahr stages 2.5 or 3, with a mean age of 67.1 years; 4 men, 6 women.InterventionsThe subjects participated in supervised group exercise sessions 3 times per week for 8 weeks by practicing 3 different Wii balance board games (marble tracking, skiing, and bubble rafting) adjusted for their individualized function level. The subjects trained for 10 minutes per game, a total of 30 minutes training per session.Main outcome measurementsPre-and postexercise training, a physical therapist evaluated subjects' function by using the Berg Balance Scale, Dynamic Gait Index, and Sharpened Romberg with eyes open and closed. Postural sway was assessed at rest and with tracking tasks by using the Wii balance board. The subjects rated their confidence in balance by using the Activities-specific Balance Confidence scale and depression on the Geriatric Depression Scale.ResultsBalance as measured by the Berg Balance Scale improved significantly, with an increase of 3.3 points (P = .016). The Dynamic Gait Index improved as well (mean increase, 2.8; P = .004), as did postural sway measured with the balance board (decreased variance in stance with eyes open by 31%; P = .049). Although the Sharpened Romberg with eyes closed increased by 6.85 points and with eyes opened by 3.3 points, improvements neared significance only for eyes closed (P = .07 versus P = .188). There were no significant changes on patient ratings for the Activities-specific Balance Confidence (mean decrease, -1%; P = .922) or the Geriatric Depression Scale (mean increase, 2.2; P = .188).ConclusionsAn 8-week exercise training class by using the Wii Fit balance board improved selective measures of balance and gait in adults with PD. However, no significant changes were seen in mood or confidence regarding balance.

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α4β2^* Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance Disorders.

Objective

Methods

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Dataset Information

α4β2* Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance Disorders.

Objective

Methods

Results

Interpretation

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

α4β2^* Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance Disorders.