Bradykinesia in Alzheimer’s disease and its neurophysiological substrates

Highlights

• Clinical observations indicate that bradykinesia can be observed in Alzheimer’s disease (AD).

• We here found that movement slowness in AD correlates with measures of cholinergic dysfunction.

• This study provides information on the pathophysiology of altered voluntary motor control in AD.

Abstract

Objective

Alzheimer’s disease is primarily characterized by cognitive decline; recent studies, however, emphasize the occurrence of motor impairment in this condition. Here, we investigate whether motor impairment, objectively evaluated with kinematic techniques, correlates with neurophysiological measures of the primary motor cortex in Alzheimer’s disease.

Methods

Twenty patients and 20 healthy subjects were enrolled. Repetitive finger tapping was assessed by means of a motion analysis system. Primary motor cortex excitability was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and short-latency afferent inhibition. Plasticity-like mechanisms were indexed according to changes in motor-evoked potential amplitude induced by the intermittent theta-burst stimulation.

Results

Patients displayed slowness and altered rhythm during finger tapping. Movement slowness correlated with reduced short-latency afferent inhibition in patients, thus suggesting that degeneration of the cholinergic system may also be involved in motor impairment in Alzheimer’s disease. Moreover, altered movement rhythm in patients correlated with worse scores in the Frontal Assessment Battery.

Conclusion

This study provides new information on the pathophysiology of altered voluntary movements in Alzheimer’s disease.

Significance

The study results suggest that a cortical cholinergic deficit may underlie movement slowness in Alzheimer’s disease.

Introduction

Alzheimer’s disease (AD) is a neurodegenerative condition mainly characterized by cognitive decline (Scheltens et al., 2016). However, recent studies have emphasized the occurrence of motor impairment in this condition (Scarmeas et al., 2005, Vöglein et al., 2019). A range of motor symptoms and signs, including slowed voluntary movement (bradykinesia), have been reported in 15–50% of patients with AD (Tsolaki et al., 2001, Scarmeas et al., 2004, Scarmeas et al., 2005). Motor signs predict cognitive and functional decline (Scarmeas et al., 2005) and correlate with the deposition of amyloid-β in the basal ganglia and in other areas (Del Campo et al., 2016, Vöglein et al., 2019). It has also been suggested that amyloid-mediated degeneration of the cholinergic system may account for AD-related motor impairment (Schirinzi et al., 2018). Despite clinical observations, only a limited number of studies have quantitatively assessed voluntary movement abnormalities in AD (Roalf et al., 2018, Suzumura et al., 2018). Roalf et al. evaluated motor performance by objectively analyzing finger tapping and observed a reduced number of taps, a longer inter-tap interval and higher intra-individual variability in AD patients than in healthy controls (Roalf et al., 2018). Suzumura et al. also studied finger dexterity and confirmed abnormalities in movement rhythm in AD (Suzumura et al., 2018).

Since corticospinal output from the primary motor cortex (M1) is a major pathway for the control of skilled movement, it is reasonable to assume that M1 dysfunction in AD contributes to movement abnormalities. Studies on animal models of AD have revealed structural and functional changes in M1 (Battaglia et al., 2007, Iaccarino et al., 2016). The hypothesis of M1 involvement in AD is supported by neurophysiological studies in patients based on transcranial magnetic stimulation (TMS) (Di Lazzaro et al., 2004, Di Lazzaro et al., 2002, Ferreri et al., 2003, Ferreri et al., 2011a, Ferreri et al., 2016, Inghilleri et al., 2006, Julkunen et al., 2008, Guerra et al., 2011, Guerra et al., 2015, Wegrzyn et al., 2013, Cantone et al., 2014, Nardone et al., 2014, Di Lorenzo et al., 2019, Di Lorenzo et al., 2016). Major neurophysiological abnormalities in M1 are decreased motor cortical inhibition, defective cholinergic neurotransmission, as detected by reduced short-latency afferent inhibition (SAI), and reduced long-term potentiation (LTP)-like plasticity (Di Lazzaro et al., 2004, Di Lazzaro et al., 2002, Inghilleri et al., 2006, Battaglia et al., 2007, Ferreri et al., 2011a, Ferreri et al., 2016, Guerra et al., 2011, Terranova et al., 2013, Wegrzyn et al., 2013, Cantone et al., 2014, Nardone et al., 2014, Di Lorenzo et al., 2019, Di Lorenzo et al., 2016, Schirinzi et al., 2018). These abnormalities are present in the early disease stages and deteriorate as the disease progresses (Ferreri et al., 2011a, Trebbastoni et al., 2015).

To our knowledge, data on possible correlations between voluntary movement abnormalities and neurophysiological abnormalities in M1 in AD are lacking. Gaining an insight into this issue might provide a better understanding of motor impairment in AD and its underlying pathophysiological mechanisms. In the present study, we specifically investigated possible relationships between movement kinematics and neurophysiological changes in M1 in AD patients. Voluntary movement was objectively assessed during repetitive finger tapping (Bologna et al., 2018, Bologna et al., 2016). We evaluated movement amplitude, velocity and rhythm, as well as the amplitude and velocity decrement (sequence effect) during movement repetition (Bologna et al., 2018, Bologna et al., 2016). We measured M1 excitability and plasticity at rest using various TMS techniques (Tokimura et al., 2000, Huang et al., 2005, Berardelli et al., 2008, Bologna et al., 2017a, Di Lorenzo et al., 2019). AD patient data were compared with those from healthy subjects.