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Neurodegenerative Disease Parkinson’s Disease cerebrovascular disease.88 In otherwise normal older adults, white

matter abnormalities have been associated with subtle abnormalities of balance and gait.89–91

As white matter changes are associated

with motor dysfunction in otherwise normal elderly adults, comorbid leukoaraiosis could be predicted to contribute also to clinical features in PD. We recently reported that comorbid white matter disease is a greater determinant of axial motor impairment and stooped posture than nigrostriatal dopaminergic denervation in PD.92

This conclusion

is consistent with an emerging theme in neurodegeneration research: the importance of interactions among vascular, neuro-inflammatory, and neurodegenerative pathologies.93

It is possible that aggressive

management of vascular or inflammatory risk factors in PD patients, especially when initiated early in the disease course, could reduce the severity of axial motor dysfunction in PD.

Cholinergic Pharmacotherapy and Motor Functions These relationships between cholinergic deficits and gait/posture abnormalities raise the question as to whether cholinergic therapy may have a place in the management of mobility problems in PD. Results of a recent placebo-controlled clinical trial showed that treatment with the acetylcholinesterase inhibitor donepezil for six weeks reduced the frequency of falls by about 50 % in frequently falling PD subjects (defined as falling or nearly falling more than two times per week).94

Subjects with

the highest baseline rate of falls demonstrated the most improvement. However, donepezil did not improve performance on the Berg balance scale, balance confidence scores, or parkinsonian motor scores. One subject withdrew from the study owing to worsening of tremor. While this result needs to be replicated in a larger study, the outcome is encouraging. Interestingly, two subjects with freezing of gait did not appear to benefit from donepezil. Donepezil effects could be mediated by effects in multiple cholinergic pathways. There could be cortical cognitive benefits of improved attention or executive functions95–97 PPN-thalamus projection function.70

or improved subcortical

The variable outcomes in this small study, with worsening of tremor in one subject and reduced falls in frequently falling subjects, suggests that caution is in order and that careful selection of patients for cholinergic drug therapy of motor functions will be needed. Cholinergic denervation in PD, especially in non-demented PD subjects, is variable, with some subjects exhibiting relatively preserved cholinergic pathways. Further studies are needed to determine the relationship between specific motor phenotypes in PD and the degree and regional distribution of cholinergic denervation so that an appropriate subset of patients can be selected for potentially beneficial cholinergic augmentation therapy to treat imbalance and falls in PD. Preliminary data, however, indicate that the subgroup of PD patients with frequent falls (two or more per week) may be suitable candidates for future cholinergic augmentation studies.

Cholinesterase inhibitors will augment cholinergic neurotransmission in all cholinergic pathways, potentially decreasing the therapeutic index of this drug class. An emerging potential alternative is selective targeting of nicotinic cholinergic receptors. These ligand-gated ion channels are composed of a variety of subunits with differential distribution of receptor subtypes throughout the brain. Receptor-subtype-specific compounds exist and are under development. Some of these compounds may allow


modulation of specific cholinergic pathways. Sarter et al. predict that one family of selective nicotinic agonists will specifically enhance cortical attentional mechanisms.98

compounds of this type may ameliorate the executive–attentional deficits that contribute to gait and postural control problems.

Noradrenergic Pharmacotherapy and Mobility in Parkinson’s Disease

The amphetamine derivative methylphenidate inhibits catecholamine re-uptake, increasing brain dopamine and norepinephrine levels. Methylphenidate is used to treat patients with attention-deficit and hyperactivity disorder. Early observations of methylphenidate effects in PD suggest that this compound is not useful for ameliorating cognitive and affective symptoms, but in certain cases it improves attention.99 The effects of methylphenidate on motor deficits are somewhat controversial. Some small, open-label pilot studies have suggested that low-dose methylphenidate may improve gait, and especially freezing, in patients with severe PD, without the need for exogenous levodopa.99–101 This result was not confirmed by other trials.102,103

A recent randomized,

Atomoxetine is a selective inhibitor of norepinephrine uptake; a small study failed to find significant benefits in gait and balance scores with atomoxetine in PD.105

placebo-controlled, double-blind six-month trial showed that methylphenidate in doses up to 80 mg per day did not improve gait and tended to worsen measures of motor function, sleepiness, and quality of life.104

Effects of Subthalamic Nucleus or Pallidal Deep Brain Stimulation on Gait and Balance in Parkinson’s Disease

Deep Brain Stimulation for Parkinson’s Disease— Indications and Targets

Deep brain stimulation (DBS) is a surgical procedure in which a stimulating electrode is implanted within an identified target in the brain and is connected by wires to a pulse generator implanted under the skin overlying the chest. When the generator is turned on, electrical signals are delivered to the brain and improve the symptoms of PD. DBS is considered for PD patients with significant motor fluctuations, characterized by wearing-off or dyskinesias, despite optimal medical management. PD patients with medication-refractory tremor may also be candidates for DBS.106,107

There are three surgical targets for PD: the

ventralis intermedius nucleus of the thalamus, the STN, and the globus pallidus interna (GPi). Stimulation of the STN and GPi can improve three of the cardinal symptoms of PD (rest tremor, bradykinesia, and rigidity). It is well accepted that stimulation of the ventralis intermedius nucleus of the thalamus helps parkinsonian tremor only and does not improve bradykinesia or rigidity.108

Therefore, there is no literature on the effects

of thalamic stimulation on gait and balance in PD. The effects of STN or GPi stimulation on gait and balance have been documented but remain somewhat controversial.

Deep Brain Stimulation for Parkinson’s Disease— Short-term Effects on Gait and Balance

Bakker et al. performed a systematic review of early studies examining the effect of STN and GPi DBS on PIGD symptoms in PD.109

Nine studies

reported the effects of bilateral GPi stimulation and 10 studies reported the effects of bilateral STN stimulation. Most of the studies included in


In PD patients with cortical cholinergic deficits,

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