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Neurodegenerative Disease Parkinson’s Disease


Figure 2: Post Mortem Findings of Reduced Pedunculopontine Nucleus Acetylcholinesterase Containing Neurons Showing Lower Activity in Parkinson’s Disease Fallers Compared with Non-fallers73


1,000 1,200


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0 PD Fallers PD = Parkinson’s disease.


Cognitive Deficits, Gait Variability, and Falls in Parkinson’s Disease


Alterations in cognitive function (and presumably general cortical function) are linked to gait disturbances.46


In a simple, elegant study,


Lundin-Olsson et al. showed that older adults who could not walk and talk (‘stopped walking while talking’) were at higher risk for falling, while those subjects who could walk and talk at the same time were much less prone to falls.47


PD Non-Fallers The Pedunculopontine Nucleus


The pedunculopontine nucleus–laterodorsal tegmental complex (PPN-LDTC; hereafter referred to as the PPN) is a brainstem locomotor center64


which degenerates in PD.65 dorsolateral part of the ponto-mesencephalic tegmentum.66,67


The PPN is located in the An


This observation suggests that simultaneous performance of two attention-demanding tasks (walking and talking) may cause competition for cognitive resources or a challenge for the brain to appropriately prioritize the two tasks, a so-called ‘posture-first’ strategy.


Selective cognitive impairments, especially executive function and attentional deficits, are commonly present in patients with mild, early PD.48,49


Dual tasking represents an executive cognitive function heavily dependent on basic operations of working memory and attention.50 Gait and balance are challenged when concurrent tasks have to be performed, which may lead to increased gait variability.51–53


Cognitive or complex sensorimotor (such as carrying a tray) dual interference tasks produce significant differences in gait parameters between PD and control subjects.54–56


important point is that the PPN should not be regarded as synonymous with the mesencephalic locomotor region. The latter is a physiologic construct defined by stimulation experiments. The PPN is probably a component of the mesencephalic locomotor region, which appears to be larger than the anatomically defined PPN. Definitions of the PPN vary and there is still debate about its borders, constituents, and internal organization. The PPN is composed of cholinergic and non-cholinergic neurons with a wide array of neurotransmitters and neuropeptides, and neuromodulators expressed by PPN neurons.68,69


PPN neurons exhibit


a wide variety of connections across much of the neuraxis, including important connections to several subcortical regions, other brainstem structures, and the spinal cord.69


The PPN is connected reciprocally with


the limbic system, several basal ganglia nuclei (globus pallidus, substantia nigra, STN), and the brainstem reticular formation (for careful reviews see Alam et al.67


and Winn69 ). The robust interconnections between the


PPN and the basal ganglia have led some to regard the PPN as an integral component of the basal ganglia system.70


Camicioli et al., for example,


examined the effects of a simultaneous verbal fluency task on walking in PD subjects with freezing of gait and found that these subjects exhibited a greater increase in the number of steps needed to complete the walk when performing the verbal fluency task.54


Modulation of gait variability, considered a reflection of ability to regulate gait, deteriorates in PD.22,57,58


other tasks may lead to increased gait variability.51–53


Competing demands of gait and Yogev et al. have


reported on the increased swing phase duration variability in PD patients compared with control persons.52


Springer et al. and Yogev


et al. reported correlations between executive dysfunction and gait variability under usual walking conditions. These correlations became stronger under dual task conditions among elderly non-demented fallers and among patients with PD.52,59


that executive cognitive impairment, especially the limited ability to 102 Some PPN neurons may receive


inputs from the deep cerebellar nucleus, a potential link between the basal ganglia and cerebellar motor systems. The caudally directed corticolimbic–ventral striatal–ventral pallidal–PPN–pontomedullary reticular nuclei–spinal cord pathway seems to be involved in the initiation, acceleration, deceleration, and termination of locomotion.66


This pathway


is under the control of the deep cerebellar and basal ganglia nuclei at the level of the PPN, particularly via potent inputs from the medial globus pallidus, substantia nigra pars reticulata, and STN.


The PPN sends profuse ascending cholinergic efferent fibers to almost all the thalamic nuclei,64


measure of PPN integrity. The PPN degenerates in akinetic disorders such as PD and progressive supranuclear palsy.61


These data support the concept


loss of cholinergic PPN neurons (34 %) in PD fallers compared with PD non-fallers (see Figure 2).73


US NEUROLOGY There are reports that


about 50 % of the large cholinergic neurons of the lateral PPN degenerate in PD.61,63,71–73


A recent study reported post mortem findings of greater and thalamic cholinergic terminal density is a


perform dual tasking, has a negative impact on gait functions, increases gait variability, and results in increased risk of falling.59,60


These data


emphasize the importance of cortical dysfunction in gait control in PD patients. A significant component of this cortical dysfunction may be attributable to loss of cholinergic innervation (see below).


Multisystem Degeneration in Parkinson’s Disease—Recent Emphasis on Mobility Impairments and Non-dopaminergic Systems Although nigrostriatal dopaminergic denervation is a key pathobiologic mechanism in PD, there is also converging evidence of degeneration of other monoaminergic (serotonin and norepinephrine) and cholinergic neurotransmitter systems.61,62


The cholinergic system has been implicated


in mobility functions in PD not only because of its cortical role in directing attention but also secondary to degeneration of cholinergic cells in the peduncolopontine nucleus in the brainstem.63


Acetylcholinesterase-containing neurons


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