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Freezing of gait and cognitive deficits

Only a limited number of studies have directly examined the relationship between the transient, episodic gait changes and the cognitive deficits in PD. Still, several lines of work suggest that there is indeed a connection and perhaps even a cause and effect relationship, with the cognitive alterations exacerbating or leading to these deficits. This work largely focuses on one of the episodic gait disturbances in PD, i.e. FOG.

FOG affects 50-80% of patients with PD and leads to a high risk of falls and reduced quality of life [2, 100, 153-155]. As noted, the mechanisms underlying FOG are largely unknown. Some have suggested that internal or external triggers (e.g. emotional reaction, change in the walking environment) may operate on the background of an altered gait pattern to cause a further transient deterioration in locomotion control, which leads to FOG [69, 156, 157]. One possibility is that mental capacity and affect may play a role as triggers of FOG [69]. Indeed, ‘panic attacks’ have been associated with FOG [158], and Amboni et al. [72] observed that

FOG was correlated with lower scores in cognitive tests related to frontal lobe and executive functions in patients with PD. In the study by Amboni et al., PD patients who suffered from FOG (PD + FOG) scored lower on tests of executive functions including verbal fluency, the clock test, and the frontal assessment battery, whereas scores on the MMSE and the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores were no different in the subjects with and without FOG. Other studies also suggest that executive function is especially impaired among PD + FOG patients [74, 75]. These findings support a possible role of frontal-cognitive impairment in PD + FOG patients.

How might frontal-cognitive impairment induce FOG? It is helpful to examine the inter-ictal gait pattern of PD + FOG patients and compare it with that of PD patients who do not experience FOG (PD - FOG). Although the walking pattern of both groups appeared to be similar between freezing episodes (e.g. inter-ictal stride time and gait speed are no different in PD - FOG and PD + FOG [159-161]), subtle changes in the gait pattern of PD + FOG patients have been observed. These include an increased stride-to-stride variability [159], increased gait asymmetry [156], and altered bilateral coordination in walking periods isolated from freezing episodes [31] in PD + FOG compared with PD - FOG patients (see Fig. 8.5). The findings regarding asymmetry and bilateral coordination might contribute to the relatively high incidence of FOG during turns [28], as turning is a task that demands a high level of bilateral coordination.

Support for the idea that turns are especially sensitive to cognitive loading comes from our analysis of data from 213 community-living, relatively healthy older adults (mean age 76.6 ± 5.8 years) [162]. Subjects walked for 2 minutes at a self-selected pace, back and forth along a 25-m- long corridor, including 180° turns at each end with and without dual-tasking (serial seven subtractions). During turns, but not during straight-line walking, stride-to-stride time variability was significantly higher (p < 0.008) in the dual-tasking condition compared with the baseline walking

[162] . We have also reported that turning ability was associated with specific cognitive functions

[163] . Turns require more attention and cognitive resources than straight-line walking. This may help to explain, in part, why turns are associated with FOG.

Three gait attributes (i.e. gait variability, gait asymmetry, and bilateral coordination of walking) are more impaired in PD + FOG than in PD - FOG patients [100, 156, 159]. Changes in gait variability, gait asymmetry, and the bilateral coordination of walking therefore appear to be associated with FOG. Taken together, these studies suggest that irregular central timing mechanisms of gait motor programmes are associated with freezing. Since dual-tasking is known to have a large impact on these three aspects of gait in PD, one can speculate further that the dual-task effect will be even greater in PD + FOG patients with executive function impairments that are apparently even greater than those seen in PD - FOG patients [72]. In one of the few studies on the effect of dual- tasking on gait with reference to susceptibility to FOG in PD, Camicioli et al. [101] found that PD + FOG patients exhibited a greater increase in the number of steps needed to complete walking during dual-tasking. The findings suggest that PD + FOG may be more dependent on attention, and supports idea that the dual-task effects on gait are larger in PD + FOG than in PD - FOG.

Dagan et al. [164] investigated this issue in a study of 30 PD patients with motor response fluctuations during the ‘on’ state. Twenty patients had a history of FOG and 10 were non-freezers. Patients walked 80 m at a comfortable pace and then repeated the walking task while performing serial seven subtractions. Gait variability, gait asymmetry, and the phase coordination index tended to increase (i.e. become worse) in the PD + FOG patients during usual walking and became much worse during dual-tasking. The changes were accompanied by a marked reduction in gait speed during dual-tasking. Multivariable regression showed that executive function and anxiety made a significant contribution to this ‘dual-task cost’ in gait variability and gait speed.

Stepping phase values are plotted for one patient with Parkinson's disease

Fig. 8.5 Stepping phase values are plotted for one patient with Parkinson's disease (PD) + freezing of gait (Fog) and one patient from the pD - Fog group, both in the 'off' and 'on' states. A marked inability to consistently generate a 180° phase is observed in PD + FOG, but not in PD - FOG, during the 'off' state. The deviation in the phase (ф), from 180° ^ABS), was 29° for the PD + FOG patient and 3.8° for the PD - FOG patient. During the 'off' state, the PD + FOG patient was more inconsistent in phase generation (фот = 15%) in comparison with the PD - FOG patient (фот = 2.4%). in these examples, improvement is seen during the 'on' state for the PD + FOG patient, but not for the PD - FOG patient. PCi, phase coordination index.

Springer and Exp Brain Res, A new measure for quantifying the bilateral coordination of human gait: effects of aging and Parkinson’s disease 181,2007, 561-570, Plotnik M, Giladi N, Hausdorff JM, Fig. 2 ©2007 with kind permission from Springer Science and Business Media.

These findings further suggest that in advanced PD, a poor emotional state and reduced executive function aggravate the effects of dual-tasking, especially in patients susceptible to FOG [164].

Some of the most intriguing evidence linking attention to FOG comes from the study by Devos et al. [165]. They examined the effects of methylphenidate (MPH; Ritalin®), a drug extensively used in the therapy of attention deficits, mainly in children but also in older adults [166-168]. Although the mechanism underlying the efficacy of MPH is not fully understood [169], its effect on attention has been well established. In addition to other changes in motor function and gait in response to the 3-month pilot study of the effects of MPH in patients with advanced PD, Devos et al. [165] observed a reduction in the number of FOG episodes in response to MPH. This reported reduction in the frequency of FOG episodes could be explained in a number of different ways; one possibility is that MPH improved attentional abilities and that this in turn led to a reduction in FOG, perhaps by enabling patients to better allocate resources among competing tasks. Other mechanisms, however, could also account for this improvement. Nevertheless, this finding and the results of a subsequent randomized controlled trial [170] with similar results further support the association between executive function and FOG.

The idea that disease-related alterations in executive function and attention influence the continuous gait changes and fall risk in PD is also supported by preliminary work using pharmacological interventions [171]. Assuming that executive function and attention deficits alter gait, enhancement of these cognitive domains could improve gait. An open-label pilot study examined this idea, testing the hypothesis that MPH may improve gait and reduce fall risk in patients with PD [172]. Auriel et al. [172] evaluated the effect of a single dose (20 mg) of MPH on cognitive function, gait performance, and markers of fall risk in 21 patients with PD (mean age 70.2 ± 9.2 years). Patients took their antiparkinsonian medications in the morning, performed baseline testing, received a single dose of MPH, and were then re-tested about 2 hours later. Significant increases in a computerized battery index of attention (p < 0.013) and executive function (p <

0.05) were observed in response to MPH. In contrast, scores of memory, visuospatial orientation, and hand-eye coordination were unchanged. Significant improvements were also observed in the Timed Up and Go test, a classic measure of fall risk (p < 0.001), gait speed (p < 0.005), and stride time variability (p < 0.013) (see Table 8.1). The dual-tasking effect on stride-to-stride variability was also significantly reduced (p < 0.05), demonstrating that a single dose (20 mg) of MPH not only significantly improved attention and executive function in patients with PD, but also resulted in improvements in gait speed, gait variability, and markers of fall risk. A similar study in healthy older adults where a placebo was also administered supported this finding [173]. In addition, a 3-month open-label pilot study of MPH in patients with advanced PD found marked improvement in stride length and other measures of mobility [165]. These findings support the idea that gait disturbances in PD are related to executive function and attention. Moreau et al. [170] have also confirmed the effectiveness of MPH in improving slow gait and freezing in advanced PD patients receiving subthalamic nucleus stimulation in a multicentre randomized control trial.

In patients with mild PD, recruitment of attentional resources may serve as a compensatory mechanism to improve gait [121, 174]. This may be sufficient to help restore, to some degree, a functional gait pattern. In patients with advanced PD, however, both motor and cognitive functions deteriorate further, potentially limiting the ability to utilize cognitive resources and attention to compensate for the impaired motor function. Gait may become even more ‘fragile’ and sensitive to external perturbations, increasing the demand for attentional resources. The potential

Table 8.1 Effects of methylphenidate (MPH) on gait and mobility in patients with Parkinson's disease

Before MPH

After MPH

p-value

Timed up and go (s)

11.9 ± 3.8

10.6 ± 2.3

0.0001

Gait speed (m/s)

1.07 ± 0.19

1.13 ± 0.21

0.005

Average stride time (ms)

1114±85

1100±79

0.068

Stride time variability (%)

2.28 ± 0.63

2.00 ± 0.47

0.013

Auriel E, Hausdorff JM, Herman T, simon Es, Giladi N, Effects of methylphenidate on cognitive function and gait in patients with Parkinson’s disease: a pilot study, Clin Neuropharmacol, 29, 15-17, ©2006.

Cognitive impairment commonly leads to and predicts dementia, whereas gait abnormalities increase the risk for falling

Fig. 8.6 Cognitive impairment commonly leads to and predicts dementia, whereas gait abnormalities increase the risk for falling (horizontal arrows). cognitive impairment and gait abnormalities, as well as dementia and falls, have been found to be associated with each other (diagonal arrows). Moreover, according to recent evidence, gait abnormalities predict dementia and cognitive impairment increases fall risk (grey arrows). Based on the close relationship between cognition and gait, on the one hand, integrated tools for risk estimation are needed (bracket), but on the other hand possible lines of intervention (black arrows) could include enhancing cognition to improve gait and reduce fall risk and gait training to reduce dementia risk.

cognitive contributions to gait and falls: evidence and implications /Amboni M, Barone p, Hausdorff JM/ Mov Disord 28 / Copyright ©2013.

protective effect of cognitive compensation strategies against decline in gait speed is greater in subjects with a higher cognitive reserve [170]. This might suggest that cognitive reserve plays a pivotal role in regulating changes in both age-related and disease-related gait impairment [57, 175]. Perhaps this explains why cognitive challenges (i.e. dual-tasking) impact on gait, especially during gait conditions known to be associated with FOG (e.g. turns) and how they combine to determine the likelihood that FOG will occur [100, 157, 176, 177].

 
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