Treatment of Early Parkinson’s Disease

Simuni, Tanya; Lyons, Kelly E.; Pahwa, Rajesh; Hauser, Robert A.; Comella, Cynthia L.; Elmer, Lawrence; Weintraub, Daniel

doi:10.1159/000197104

Cited by 12 publications

(5 citation statements)

References 145 publications

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“…Previous studies have shown that the use of dopamine agonists has not been shown to correlate to olfaction. 16 We confirmed this result in our subset. In this study, the DBS group did have a higher average use of dopamine agonists, however most of this difference was due to a single outlier with very significant dosing.…”

Section: 2supporting

confidence: 83%

DBS-implanted Parkinson's Disease Patients Show Better Olfaction Than Those Treated Medically

Peters¹,

Ravin²,

Novák³

et al. 2010

Neurol. Bull.

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Dysosmia in PD (Parkinson's Disease) may result from changes in the olfactory apparatus or in structures involved in olfactory perception. Previous work 1,2 has suggested that deep brain stimulation (DBS) patients have improved odor discrimination in stimulation-on/medicationoff state in comparison to their own scores in a stimulation-off/ medication-off state. What remains unclear is whether it is the ON state itself or an effect of stimulation that leads to improved olfaction. In this study we evaluate dysosmia in two PD cohorts in the ON state, those treated with medication alone and those treated with medication and DBS.A prospective study geared at improving predictive value of olfactory testing with a battery of psychological tests enrolled 45 PD patients and 44 controls. Of the PD patients, 9 had bilateral STN (subthalamic nucleus) DBS and 36 were medically treated. Subset analysis of PD patients with and without DBS placement revealed no difference in apathy or depression. DBS patients had better olfaction on UPSIT (Univ of Pennsylvania Smell Identification Test) (p<0.05). No difference was noted in disease severity, gender, smoking status, medication dosing, use of dopamine agonists, or maximal olfactory sulcus depth on MRI. DBS patients were significantly younger, however inter-group differences in UPSIT scores exceeded those seen in our control cohort with similar ages.This study provides further data that DBS patients have improved olfaction. It also provides preliminary evidence that DBS with medication improves dysosmia to a greater extent than medication alone. This may result from indirect stimulation of olfactory processing centers or changes in olfactory circuitry metabolism.

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Section: 2supporting

confidence: 83%

DBS-implanted Parkinson's Disease Patients Show Better Olfaction Than Those Treated Medically

Peters¹,

Ravin²,

Novák³

et al. 2010

Neurol. Bull.

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“…This suggests that deficient cholinergic modulation of circuit function can be evident early, before motor symptoms, which could contribute to early cognitive dysfunction. On the other hand, while acetylcholinesterase inhibitors, including donepezil, have been used clinically to ameliorate cognitive decline in demented PD and Alzheimer’s patients (Simuni et al, 2009; Sharma, 2019; Armstrong and Okun, 2020), their effectiveness for improving mild cognitive impairment in early-stage PD is equivocal (Mamikonyan et al, 2015; Baik et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Cognitive Deficits and Altered Cholinergic Innervation in Young Adult Mice Carrying a Parkinson’s Disease LRRK2-G2019S Knockin Mutation

Hussein

Tielemans

Baxter

et al. 2022

Preprint

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Impaired executive function is a common and debilitating non-motor symptom of idiopathic and hereditary Parkinson's disease (PD), but there is little understanding of the underlying pathophysiological mechanisms and circuits. The G2019S mutation in the kinase domain of leucine-rich repeat kinase 2 (LRRK2) greatly increases risk for late-onset PD, and non-manifesting LRRK2-G2019S carriers also exhibit early and significant cognitive impairment. Here, we subjected young adult mice carrying a Lrrk2-G2019S knockin mutation to touchscreen-based operant tasks that measure attention, goal-directed learning and cognitive flexibility, all of which rely on prefrontal-striatal connectivity and are strongly modulated by cholinergic innervation. In a visuospatial attention task, mutant mice exhibited significantly more omissions and longer response latencies than controls that could not be attributed to deficits in motivation, visual sensory perception per se or locomotion, thereby suggesting impairment in divided attention and slower information processing speed. Pretreating mice with the acetylcholinesterase inhibitor donepezil normalized both higher omission rates and longer reward latencies in the mutants, but did not affect any performance metric in controls. Strikingly, cholinergic fiber density in mPFC and dorsomedial striatum was significantly sparser in mutants than in controls, while further behavioral interrogation of the mutants revealed significant impairments in action-outcome associations but preserved cognitive flexibility. These data suggest that the G2019S mutation impacts cholinergic innervation and impairs corticostriatal network function in young adulthood that may contribute to early PD-associated cognitive deficits.

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“…Clinically, DA replacement therapy using levodopa remains the gold standard for symptomatic relief in PD patients. However, due to the well-documented limitations of long-term DA replacement therapy and its widespread debilitating side-effects, neuroprotective strategies that slow or halt the disease progression are urgently needed ( Simuni et al, 2009a ; Simuni et al, 2009b ; Sarkar et al, 2016 ; Fabbri et al, 2020 ). Mitochondrial dysfunction, oxidative stress, neuroinflammation and impaired protein degradation are implicated as potential pathological mechanisms of PD, but key downstream signaling targets contributing to nigral dopaminergic neuronal degeneration are not well established.…”

Section: Introductionmentioning

confidence: 99%

Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease

et al. 2021

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Oxidative stress, neuroinflammation and apoptosis are some of the key etiological factors responsible for dopamin(DA)ergic degeneration during Parkinson’s disease (PD), yet the downstream molecular mechanisms underlying neurodegeneration are largely unknown. Recently, a genome-wide association study revealed the FYN gene to be associated with PD, suggesting that Fyn kinase could be a pharmacological target for PD. In this study, we report that Fyn-mediated PKCδ tyrosine (Y311) phosphorylation is a key event preceding its proteolytic activation in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinsonism. MPP+/MPTP induced Fyn kinase activation in N27 DAergic neuronal cells and the mouse substantia nigra. PKCδ-Y311 phosphorylation by activated Fyn initiates the apoptotic caspase-signaling cascade during DAergic degeneration. Pharmacological attenuation of Fyn activity protected DAergic neurons from MPP+-induced degeneration in primary mesencephalic neuronal cultures. We further employed Fyn wild-type and Fyn knockout (KO) mice to confirm whether Fyn is a valid pharmacological target of DAergic neurodegeneration. Primary mesencephalic neurons from Fyn KO mice were greatly protected from MPP+-induced DAergic cell death, neurite loss and DA reuptake loss. Furthermore, Fyn KO mice were significantly protected from MPTP-induced PKCδ-Y311 phosphorylation, behavioral deficits and nigral DAergic degeneration. This study thus unveils a mechanism by which Fyn regulates PKCδ′s pro-apoptotic function and DAergic degeneration. Pharmacological inhibitors directed at Fyn activation could prove to be a novel therapeutic target in the delay or halting of selective DAergic degeneration during PD.

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Treatment of Early Parkinson’s Disease

Cited by 12 publications

References 145 publications

DBS-implanted Parkinson's Disease Patients Show Better Olfaction Than Those Treated Medically

DBS-implanted Parkinson's Disease Patients Show Better Olfaction Than Those Treated Medically

Cognitive Deficits and Altered Cholinergic Innervation in Young Adult Mice Carrying a Parkinson’s Disease LRRK2-G2019S Knockin Mutation

Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson’s Disease

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