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Advances in Therapeutic Options for Gait and Balance in Parkinson’s Disease


PPN dysfunction–degeneration is associated with dopamine-resistant akinesia, one of the most disabling features of PD.65,74


Similarly,


experimental PPN destruction in non-human primates is associated with bradykinesia, akinesia, and prominent postural control deficits.73 Stimulation of the PPN increases movement in animals, while inhibition decreases it.74,75


treatment of PD and related disorders.


The Basal Forebrain Cholinergic System Cholinergic afferents to the cortex play an important role in a variety of cognitive functions, including attention, memory encoding, and executive function.76


Degeneration of basal forebrain cholinergic corticopetal projections is a prominent feature of PD, and cortical cholinergic deficits of PD exceed those of Alzheimer‘s disease.77


In the Braak model of


ascending pathology, basal forebrain degeneration occurs approximately concurrently with substantia nigra pars compacta degeneration. The degree of basal forebrain cholinergic system neurodegeneration, however, varies among PD patients, with some patients exhibiting relative preservation of cortical cholinergic innervation.78


Loss of cortical


cholinergic innervation is associated with cognitive deficits in PD and is likely to degrade the attentional and executive functions required for normal gait and postural functions.79


This inference is consistent with


recent rodent experiments in which animals with dual nigrostriatal dopaminergic and basal forebrain cholinergic lesions exhibit prominent motor performance deficits in tasks requiring sustained attention.80


Consequences of Multifocal Neurodegeneration in Parkinson’s Disease—Falls and Cholinergic Systems as an Example


Given that PD is a multisystem neurodegeneration, differences in the degree of or rate of degeneration of different central nervous systems may account for differences in phenotypic features. In early-stage PD there is evidence of uniform and severe dopaminergic denervation, but subcortical and cortical cholinergic denervation is more heterogeneous, with some PD subjects exhibiting diminished regional cholinergic innervation and others showing relatively normal regional cholinergic innervation. We showed previously that PD fallers (defined as falls not due to freezing) did not differ in the degree of nigrostriatal dopaminergic denervation but had significantly decreased PPN-thalamic and cortical cholinergic innervation compared with non-fallers (see Figure 3).81


Cholinergic system degeneration


is probably both a partial cause of and a marker for cognitive dysfunction in PD. Cholinergic system degeneration or dysfunction may also provide a conceptual framework to explain why patients with higher postural instability and gait disturbances in Lewy body parkinsonism are at increased risk of developing dementia.82,83


These data indicate the presence of heterogeneity of cholinergic denervation with PD. We also found evidence of heterogeneity of mobility impairments in our study. A 2 x 2 table shows that distinct subgroups with PD subjects have falls (not attributable to freezing) versus subjects having freezing of gait or a combination of the two (see Table 1). PD subjects with freezing of gait had lower dopamine activity in the caudate nucleus (–12.2 %, analysis of variance F=5.4, p<0.05) but not in the anterior (F=0.6, p=NS) or posterior putamen (F=0.30, p=NS) as shown by [C-11]dihydrotetrabenazine positron emission tomography. Freezing of gait may represent a failure of a dopaminergic compensatory striatofrontal mechanism in PD.


US NEUROLOGY No Falls


(Not due to FoG)


Yes FoG


No Yes 22


5 (51.2 %) 8 (18.6 %) 30 χ2 = 4.7 (p<0.05)


There are distinct subgroups of Parkinson’s disease patients showing either specific mobility impairments of freezing of gait (FoG) and falls (not related to FoG) alone, a combination of these impairments, or absence of these impairments.


Taken together, our findings suggest that specific mobility impairments may be related to neurodegeneration in specific brain regions.


The Locus Ceruleus


Other transmitter systems, such as central noradrenergic pathways, are affected in PD and may be involved in gait and balance deficits. Noradrenergic pathways have been implicated in alertness and other cortical attention functions important for gait control in PD.84


The locus


ceruleus is a small nucleus located in the pontine tegmentum and is the main source of norepinephrine for the brain and spinal cord.85 is significant degeneration of the locus ceruleus in PD.86


There


Non-specific White Matter Degeneration and Impaired Balance and Posture in Parkinson’s Disease Areas with altered signal intensity in white matter are encountered frequently on brain imaging studies in the elderly.87


(11.6 %) 8 (18.6 %) 13 43 16


Figure 3: In Vivo Positron Emission Tomography Findings of Pedunculopontine Nucleus-thalamus Cholinergic Activity in Parkinson’s Disease Non-fallers and Fallers


These findings have significant implications for the


0.020 0.022 0.024 0.026 0.028 0.030 0.032


PD Fallers PD Non-Fallers


Parkinson’s disease (PD) fallers had lower pedunculopontine nucleus (PPN)-thalamic cholinergic activity than PD non-fallers. THAL = thalamus.


Table 1: Subgroups of Parkinson’s Disease Patients with Freezing of Gait, Falls, a Combination, or None


27


These white matter abnormalities or leukoaraiosis are commonly associated with small-vessel 103


PPN-THAL acetylcholinesterase


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