A perceptive plus in Parkinson's disease

Himmelberg, Marc M.; West, Ryan J. H.; Wade, Alex R.; Elliott, Christopher J.H.

doi:10.1002/mds.27240

Cited by 4 publications

(3 citation statements)

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“…Furthermore, we have illustrated that there are variations in how these EOPD mutations affect neural gain control across Drosophila lifespan, indicating that these mutations have unique effects upon underlying cellular processes that lead to a common outcome: visual loss and cell death. Overall, it appears that these PD-related mutations are heterochronic: mutations lead to stronger neural signaling (increased sensory response may be beneficial in escaping behavior) in young flies but are detrimental in older flies (a loss of vision would hinder escape behavior) ( Himmelberg et al 2018 ). Should these findings in fly models prove applicable to the human situation, it would suggest that prodromal PD may be linked to changes in central nervous system processing that could, potentially, confer advantages in early life at the cost of degenerative disease in old age.…”

Section: Discussionmentioning

confidence: 99%

Abnormal visual gain control and excitotoxicity in early-onset Parkinson’s disease Drosophila models

Himmelberg

West

Elliott

et al. 2018

Journal of Neurophysiology

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The excitotoxic theory of Parkinson’s disease (PD) hypothesizes that a pathophysiological degeneration of dopaminergic neurons stems from neural hyperactivity at early stages of disease, leading to mitochondrial stress and cell death. Recent research has harnessed the visual system of Drosophila PD models to probe this hypothesis. Here, we investigate whether abnormal visual sensitivity and excitotoxicity occur in early-onset PD (EOPD) Drosophila models DJ-1αΔ72, DJ-1βΔ93, and PINK15. We used an electroretinogram to record steady-state visually evoked potentials driven by temporal contrast stimuli. At 1 day of age, all EOPD mutants had a twofold increase in response amplitudes compared with w̄ controls. Furthermore, we found that excitotoxicity occurs in older EOPD models after increased neural activity is triggered by visual stimulation. In an additional analysis, we used a linear discriminant analysis to test whether there were subtle variations in neural gain control that could be used to classify Drosophila into their correct age and genotype. The discriminant analysis was highly accurate, classifying Drosophila into their correct genotypic class at all age groups at 50–70% accuracy (20% chance baseline). Differences in cellular processes link to subtle alterations in neural network operation in young flies, all of which lead to the same pathogenic outcome. Our data are the first to quantify abnormal gain control and excitotoxicity in EOPD Drosophila mutants. We conclude that EOPD mutations may be linked to more sensitive neuronal signaling in prodromal animals that may cause the expression of PD symptomologies later in life.NEW & NOTEWORTHY Steady-state visually evoked potential response amplitudes to multivariate temporal contrast stimuli were recorded in early-onset PD Drosophila models. Our data indicate that abnormal gain control and a subsequent visual loss occur in these PD mutants, supporting a broader excitotoxicity hypothesis in genetic PD. Furthermore, linear discriminant analysis could accurately classify Drosophila into their correct genotype at different ages throughout their lifespan. Our results suggest increased neural signaling in prodromal PD patients.

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Section: Discussionmentioning

confidence: 99%

Abnormal visual gain control and excitotoxicity in early-onset Parkinson’s disease Drosophila models

Himmelberg

West

Elliott

et al. 2018

Journal of Neurophysiology

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“…are the responses between these two classes now indistinguishable). Further, with evidence for visual biomarkers in a range of simple fly models of PD, and now a more complex rodent model, it may soon be possible to translate such methods and classify human PD patients into their correct genotype based on similar electrophysiological response profiles 48 .…”

Section: Svm Can Accurately Classify Rats Into Their Correct Group Usmentioning

confidence: 99%

Classification of α-synuclein-induced changes in the AAV α-synuclein rat model of Parkinson’s disease using electrophysiological measurements of visual processing

Østergaard

Himmelberg

Laursen

et al. 2020

Sci Rep

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Biomarkers suitable for early diagnosis and monitoring disease progression are the cornerstone of developing disease-modifying treatments for neurodegenerative diseases such as Parkinson's disease (PD). Besides motor complications, PD is also characterized by deficits in visual processing. Here, we investigate how virally-mediated overexpression of α-synuclein in the substantia nigra pars compacta impacts visual processing in a well-established rodent model of PD. After a unilateral injection of vector, human α-synuclein was detected in the striatum and superior colliculus (SC). In parallel, there was a significant delay in the latency of the transient VEPs from the affected side of the SC in late stages of the disease. Inhibition of leucine-rich repeat kinase using PFE360 failed to rescue the VEP delay and instead increased the latency of the VEP waveform. A support vector machine classifier accurately classified rats according to their `disease state' using frequency-domain data from steadystate visual evoked potentials (SSVEP). Overall, these findings indicate that the latency of the rodent VEP is sensitive to changes mediated by the increased expression of α-synuclein and especially when full overexpression is obtained, whereas the SSVEP facilitated detection of α-synuclein across reflects all stages of PD model progression. Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting ~ 0.2 to 3.0% of the population. It is characterised by the core motor symptoms bradykinesia, resting tremor, rigidity, and postural instability 1,2. PD is also characterized by secondary non-motor symptoms such as hyposmia, constipation, orthostatic hypotension, depression, sleep disorders, decline in cognitive abilities, and deficits in visual processing. Many of these are present already at early stages of PD, whereas classical motor-related symptoms are present in the middle stages 3,4. The pathogenesis of PD develops during prodromal stages of the disease 5. Consequently, there is a high unmet need for validation of new biomarkers that can be used to assess new disease-modifying drug treatments in early or prodromal stages of PD 6. According to the Braak staging hypothesis, PD is a progressive synucleinopathic disorder in which six disease stages are associated with a progressive pathology to neurological structures 7. Pathological hallmarks of PD are the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) 8 and Lewy bodies in addition to 'Lewy neurites': pathological inclusions of aggregated α-synuclein protein in neurons 9,10. Duplications

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“…Today, various advanced treatments such as DBS, radiofrequency, MR–guided focused ultrasound (MRgFUS), gamma knife, levodopa-carbidopa intestinal gel (LCIG), and apomorphine are available, although the availability of treatments varies depending on country and region. Clinical practice guidelines for early treatment of PD have been published in various countries and are often recommended by experts [ 19 , 20 , 21 ]. Standard pharmacological and non-pharmacological treatments are required during treatment, and the need for personalized medicine becomes more obvious when aiming to achieve an appropriate symptomatic and disease-modifying treatment with the right dose, right time, and minimum side effects in a specific patient.…”

Section: Introductionmentioning

confidence: 99%

Personalized Medicine in Parkinson’s Disease: New Options for Advanced Treatments

Mishima

Fujioka

Morishita

et al. 2021

JPM

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Parkinson’s disease (PD) presents varying motor and non-motor features in each patient owing to their different backgrounds, such as age, gender, genetics, and environmental factors. Furthermore, in the advanced stages, troublesome symptoms vary between patients due to motor and non-motor complications. The treatment of PD has made great progress over recent decades and has directly contributed to an improvement in patients’ quality of life, especially through the progression of advanced treatment. Deep brain stimulation, radiofrequency, MR–guided focused ultrasound, gamma knife, levodopa-carbidopa intestinal gel, and apomorphine are now used in the clinical setting for this disease. With multiple treatment options currently available for all stages of PD, we here discuss the most recent options for advanced treatment, including cell therapy in advanced PD, from the perspective of personalized medicine.

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A perceptive plus in Parkinson's disease

Abstract: Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 641805.

Cited by 4 publications

References 5 publications

Abnormal visual gain control and excitotoxicity in early-onset Parkinson’s disease Drosophila models

Abnormal visual gain control and excitotoxicity in early-onset Parkinson’s disease Drosophila models

Classification of α-synuclein-induced changes in the AAV α-synuclein rat model of Parkinson’s disease using electrophysiological measurements of visual processing

Personalized Medicine in Parkinson’s Disease: New Options for Advanced Treatments

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