Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by loss of dopaminergic neurons resulting in bradykinesia, tremor, gait abnormalities, and numerous non‐motor complications. The prevalence and economic burden of PD is increasing due to an aging population. However, there are currently no drugs to halt the progression of this disease. Although loss of dopamine in the basal ganglia is recognized as the hallmark of PD, the molecular mechanisms underlying this loss and subsequent brain dysfunction remain poorly characterized. The majority of PD animal models involve the administration of neurotoxins that target dopaminergic neurons leading to their degeneration, however these models correlate poorly with the disease progression in humans. More accurate models may utilize genetic modulation of PD‐related genes and exhibit progressive neurodegeneration. Here, we report the development of a high‐throughput assay for monitoring dopaminergic neurodegeneration in Caenorhabditis elegans (C. elegans). Two strains of C. elegans containing human PD‐linked genes were used, one expressing mutant (A53T) alpha‐synuclein, and the other expressing mutant (G2019S) leucine‐rich repeat kinase 2 (LRRK2). Both strains express GFP in their dopaminergic neurons and the lines were further crossed into a neuronal RNAi‐sensitive background strain expressing mCherry under a pharyngeal promoter. This allows for the accurate measurement of dopaminergic neurons (via GFP) and a normalization and sorting control of the total number of worms plated (via mCherry). Daily measurements of GFP/mCherry fluorescence intensity were performed using laser cytometry of worms sorted into 384‐well microplates. Robust temporal degeneration of dopaminergic neurons was found to occur within the first eight days of adulthood in the C. elegans models of PD, but not in a wild‐type control strain. The LRRK2 model was particularly severe as total GFP intensity dropped by 75–85% during the time of assay. We determined a signal (cell loss) to baseline ratio of approximately 4‐fold, sufficient for screening applications. Our results indicate that this assay provides a reproducible high‐throughput measurement of dopaminergic neurodegeneration using an in vivo model. Future studies may exploit this model to conduct quantitative high‐throughput screens to identify small molecules capable of inhibiting this neurodegeneration or to use RNAi libraries to identify genes mediating the neurodegenerative response, and hence new drug targets for the treatment of PD. Support or Funding Information This study is supported by the intramural program of the NINDS/NIH

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons resulting in bradykinesia, tremor, gait abnormalities, and numerous non‐motor complications. Knowledge of the molecular mechanisms underlying dopaminergic neuron death remains limited, partially due to the lack of accurate disease models. Here, we report the development of a high‐throughput assay for monitoring dopaminergic neurodegeneration in Caenorhabditis elegans (C. elegans). Two transgenic strains of C. elegans containing human PD‐linked genes were used, one expressing mutant (A53T) alpha‐synuclein, and the other expressing mutant (G2019S) leucine‐rich repeat kinase 2 (LRRK2). Both strains express GFP in their dopaminergic neurons and were crossed into a neuronal‐RNAi sensitive background expressing mCherry under a pharyngeal promoter. This allows for the accurate measurement of neuronal viability (via GFP) and a normalization and sorting control of the total number of worms plated (via mCherry). Daily laser cytometry readings of GFP/mCherry fluorescence intensity revealed that robust temporal degeneration occurs within the first eight days of adulthood in both PD models, but not in a wild‐type control strain. We determined a signal (cell loss) to baseline ratio of approximately 4‐fold, sufficient for screening applications. Particularly in the case of the mutant LRRK2 model, neurodegeneration is severe: between day 3 and day 8 of adulthood, total GFP fluorescence intensity drops by 75‐85%. In the LRRK2 mutants, administration of selective LRRK2 inhibitors (LRRK2‐IN‐1 and CZC 25146) confers neuroprotection in a dose‐dependent manner. Similarly, using high content imaging, we found that the LRRK2 mutant‐expressing worms displayed susceptibility to RNA interference. Administration of RNAi targeting LRRK2 slowed the course of the neurodegeneration in these worms. Similarly, administration of RNAi targeting GFP resulted in about 50% reduction of the mean GFP intensity at day 5. Our results indicate that this assay provides a reproducible, high‐throughput measurement of dopaminergic neurodegeneration using an in vivo model. Future studies may exploit this model to conduct quantitative high‐throughput screens to identify small molecules that inhibit neurodegeneration or use RNAi libraries to identify genes mediating the neurodegenerative response, and hence new drug targets for PD treatment.

Objective: The objective of this study is to assess whether patient participation in specific activities and perceived social support correlate with speech perception following cochlear implantation. Setting: Tertiary referral hospital Methods: Adult cochlear implantation patients implanted in their poorer hearing ear between January 2019 and December 2020 completed the Functional Social Support Questionnaire (FSSQ) and a modified version of the Victoria Lifestyle Study-Activities Lifestyle Questionnaire (VLS-ALQ). Demographics, FSSQ score, and individual activities were correlated with implanted ear and binaural AzBio scores. Results: Twenty-three patients completed the survey and had at least 6 months of follow-up with appropriate speech perception testing. The average age at survey completion was 71.7 (SD, 9.1). Average pure-tone average in the contralateral ear was 70.1 (SD: 20) dB. The majority (N = 21, 91.3%) wore a hearing aid in the contralateral ear following cochlear implantation. Mean AzBioQuiet score improvement was 60.6% (range: 20%–99%) in the implanted ear and 42.6% (range: −2% to 67%) binaurally. Work-related social support correlated positively with improvement in the implanted ear (Pearson’s R = 0.473; 95% CI, 0.075-0.741; P = 0.023). Improvement in the implanted ear correlated positively with creative writing (R = 0.542; 95% CI, 0.167-0.780; P = 0.008), attending films (R = 0.448; 95% CI, 0.044-0.726; P = 0.032), going out with friends (R = 0.423; 95% CI, 0.013-0.711; P = 0.044) listening to audiobooks (R = 0.433; 95% CI, 0.025-0.717; P = 0.039), and public speaking (R = 0.468; 95% CI, 0.069-0.738; P = 0.024). Gains in binaural performance correlated positively with watching TV news (R = 0.819; 95% CI, 0.509-0.941; P < 0.001) and negatively with eating at restaurants (R = −0.532; 95% CI, −0.829 to −0.002; P = 0.05). Conclusions: Activities that provide intellectual stimulation and engage auditory faculties correlate with greater speech perception testing improvements in adult cochlear implantation patients.