Abstract:The pathophysiology of postural instability in Parkinson's disease remains poorly understood. Normal postural function depends in part on the ability of the postural control system to integrate visual, proprioceptive, and vestibular sensory information. Degeneration of cholinergic neurons in the brainstem pedunculopontine nucleus complex and their thalamic efferent terminals has been implicated in postural control deficits in Parkinson's disease. Our aim was to investigate the relationship of cholinergic termi… Show more
“…The absence of an influence of ChEIs, including donepezil, on parkinsonism has been reported in previous studies, along with improvement in a few of these studies, which reinforces the interpretations drawn from this analysis [7,10,11,22,34]. Our finding is also in accordance with accumulating evidence of cholinergic involvement in PD; degeneration of multiple cholinergic projection systems occurs early in PD [35], cholinergic degeneration plays a role in some aspects of motor symptoms including postural control [36] and gait [37], and treatment with donepezil produces reductions in the number of falls in frequently falling patients with PD [38]. …”
Background/Aims: The aim of this study was to clarify the effects of donepezil on extrapyramidal symptoms in patients with dementia with Lewy bodies (DLB). Methods: Using pooled datasets from phase 2 and 3, 12-week randomized, placebo-controlled trials (RCT, n = 281) and 52-week open-label long-term extension trials (OLE, n = 241) of donepezil in DLB, the effects of donepezil on the incidence of extrapyramidal adverse events (AEs) and on the Unified Parkinson's Disease Rating Scale (UPDRS) part III were assessed, and potential baseline factors affecting the AEs were explored. Results: The RCT analysis did not show significant differences between the placebo and active (3, 5, and 10 mg donepezil) groups in extrapyramidal AE incidence (3.8 and 6.5%, p = 0.569) and change in the UPDRS (mean ± SD: -0.2 ± 4.3 and -0.6 ± 6.5, p = 0.562). In the OLE analysis (5 and 10 mg donepezil), the incidence did not increase chronologically; all AEs leading to a dose reduction or discontinuation except one were relieved. The UPDRS was unchanged for 52 weeks. An exploratory multivariate logistic regression analysis of the RCTs revealed that donepezil treatment was not a significant factor affecting the AEs. Baseline severity of parkinsonism was a predisposing factor for worsening of parkinsonism without significant interactions between donepezil and baseline severity. Conclusion: DLB can safely be treated with donepezil without relevant worsening of extrapyramidal symptoms, but treatment requires careful attention to symptom progression when administered to patients with relatively severe parkinsonism.
“…The absence of an influence of ChEIs, including donepezil, on parkinsonism has been reported in previous studies, along with improvement in a few of these studies, which reinforces the interpretations drawn from this analysis [7,10,11,22,34]. Our finding is also in accordance with accumulating evidence of cholinergic involvement in PD; degeneration of multiple cholinergic projection systems occurs early in PD [35], cholinergic degeneration plays a role in some aspects of motor symptoms including postural control [36] and gait [37], and treatment with donepezil produces reductions in the number of falls in frequently falling patients with PD [38]. …”
Background/Aims: The aim of this study was to clarify the effects of donepezil on extrapyramidal symptoms in patients with dementia with Lewy bodies (DLB). Methods: Using pooled datasets from phase 2 and 3, 12-week randomized, placebo-controlled trials (RCT, n = 281) and 52-week open-label long-term extension trials (OLE, n = 241) of donepezil in DLB, the effects of donepezil on the incidence of extrapyramidal adverse events (AEs) and on the Unified Parkinson's Disease Rating Scale (UPDRS) part III were assessed, and potential baseline factors affecting the AEs were explored. Results: The RCT analysis did not show significant differences between the placebo and active (3, 5, and 10 mg donepezil) groups in extrapyramidal AE incidence (3.8 and 6.5%, p = 0.569) and change in the UPDRS (mean ± SD: -0.2 ± 4.3 and -0.6 ± 6.5, p = 0.562). In the OLE analysis (5 and 10 mg donepezil), the incidence did not increase chronologically; all AEs leading to a dose reduction or discontinuation except one were relieved. The UPDRS was unchanged for 52 weeks. An exploratory multivariate logistic regression analysis of the RCTs revealed that donepezil treatment was not a significant factor affecting the AEs. Baseline severity of parkinsonism was a predisposing factor for worsening of parkinsonism without significant interactions between donepezil and baseline severity. Conclusion: DLB can safely be treated with donepezil without relevant worsening of extrapyramidal symptoms, but treatment requires careful attention to symptom progression when administered to patients with relatively severe parkinsonism.
“…Increased postural sway has been associated with thalamic cholinergic denervation in subjects with PD [22]. The effects specifically on SOT condition 4 support a role for the PPN-thalamic cholinergic projections in sensory integration [22]. The decreased ML RMS in the active phase of the study during one of the most problematic balance conditions for PD is when the sensory integration is between somatosensory altered information and visual-vestibular information.…”
Section: Resultsmentioning
confidence: 87%
“…Perhaps the fall reduction seen in the study of Chung et al could be attributable to improvements in both balance and executive function since an increase in mediolateral postural sway has been associated with falls [20,21] and cognitive impairments have been associated with falls [14]. Increased postural sway has been associated with thalamic cholinergic denervation in subjects with PD [22]. The effects specifically on SOT condition 4 support a role for the PPN-thalamic cholinergic projections in sensory integration [22].…”
BackgroundMost falls in Parkinson's disease (PD) appear to be due to a primary balance dysfunction rather than an environmental factor [1]. Accumulating evidence suggests that balance dysfunction cannot only be attributed to changes in the dopaminergic system that seems to be responsible for most of the other motor symptoms in PD [1]. The interventions often helpful in improving other PD symptoms, dopaminergic medications and deep brain stimulation, do not consistently improve balance and falls [2,3]. Degeneration in other brain areas, such as cholinergic cortex, the adrenergic locus coeruleus or the cholinergic/glutaminergic pedunculopontine nucleus may be the origin of the balance problems associated with PD [4].Cholinesterase inhibitors have a positive impact on global assessments, cognitive function, behavioral disturbances, and activities of daily living in persons with PD with Dementia, Lewy Body Dementia, and PD with Cognitive impairment but without dementia (CIND) [5]. A pooled estimate of therapeutic benefit of cholinesterase inhibitors on cognitive function was found with a standard mean difference (SMD) of -0.34 (95% CI -0.46 to -0.23, p<0.00001) versus placebo. A study enrolling 23 subjects in a cross-over design, showed a reduction in falls in persons with PD without dementia when taking donepezil for six weeks. Fall frequency per day decreased from 0.25 ± 0.08 on placebo to 0.13 ± 0.03 on donepezil (p<0.05) [6].It is not clear the exact role cholinergic function plays in gait, balance, and falls. It is clear that functional walking without falls requires executive function, such as the ability to switch attention quickly [7]. The relationship between cholinergic function and falls has been demonstrated with PET imaging [8]. The cholinergic system, specifically the pendunculopontine nucleus (PPN), may have direct effects on gait and balance. Loss of PPN cells is correlated with balance performance and may affect attention [9][10][11]. There are also extensive cholinergic projections to the cerebral cortex with the nucleus basalis of Meyert that suplies the marjority of input to the frontoparietal attention Abstract Background: Cholinesterase inhibitors have been reported to reduce falls in a double blind pilot study. The mechanism by which cholinesterase inhibitors reduce falls is unknown.
“…16 Cholinergic system dysfunction has been implicated in some components of postural instability and gait difficulties (PIGD) in PD, in particular falls and sensory processing during postural control, but not with overall severity of axial motor impairments. 17 Postural control and gait functions are mediated by widespread neural networks that cannot be captured by a simplistic model of single neurotransmitter system changes. There is increasing interest in dysfunction of colocalized neurotransmitter functions in PD to better understand the complexity of the multisystem nature of neurodegeneration.…”
Section: * S Supporting Informationmentioning
confidence: 99%
“…19−21 Excessive GABAergic activity in the pons has been confirmed by in vivo MR spectroscopy in patients with PD. 22 As the pedunculopontine nucleus is the major modulator of the thalamus and its related central role of postural control in PD, 17 the presence of overactive GABAergic inhibition in the brainstem in PD would auger novel pharmacological approaches to block excessive GABAergic inhibition in PD. In particular, intravenous FMZ has been shown to rapidly improve motor impairments in PD patients.…”
Clarithromycin is a potential treatment for hypersomnia acting through proposed negative allosteric modulation of GABA A receptors. We were interested whether this therapeutic benefit might extend to Parkinson's disease (PD) patients because GABAergic neurotransmission is implicated in postural control. Prior to initiating clinical studies in PD patients, we wished to better understand clarithromycin's mechanism of action. In this work we investigated whether the proposed activity of clarithromycin at the GABA A receptor is associated with the benzodiazepine binding site using in vivo [ 11 C]flumazenil positron emission tomography (PET) in primates and ex vivo [ 3 H]flumazenil autoradiography in rat brain. While the studies demonstrate that clarithromycin does not change the K d of FMZ, nor does it competitively displace FMZ, there is preliminary evidence from the primate PET imaging studies that clarithromycin delays dissociation and washout of flumazenil from the primate brain in a dosedependent fashion. These findings would be consistent with the proposed GABA A allosteric modulator function of clarithromycin. While the results are only preliminary, further investigation of the interaction of clarithromycin with GABA receptors and/or GABAergic medications is warranted, and therapeutic applications of clarithromycin alone or in combination with flumazenil, to treat hyper-GABAergic status in PD at minimally effective doses, should also be pursued.
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