Association of Gene Expression and Tremor Network Structure.

BACKGROUND: Transcriptomic changes in the essential tremor (ET)-associated cerebello-thalamo-cortical "tremor network" and their association to brain structure have not been investigated. OBJECTIVE: The aim was to characterize molecular changes associated with network-level imaging-derived phenotypes (IDP) found in ET. METHODS: We performed an imaging-transcriptomic study in British adults using imaging-genome-wide association study summary statistics (UK Biobank "BIG40" cohort; n = 33,224, aged 40-69 years). We imputed imaging-transcriptomic associations for 184 IDPs and analyzed functional enrichment of gene modules and aggregate network-level phenotypes. Validation was performed in cerebellar-tissue RNA-sequencing data from ET patients and controls (n = 55). RESULTS: Among 237,896 individual predicted gene expression levels for 6063 unique genes/transcripts, we detected 2269 genome-wide significant associations (Bonferroni P < 2.102e-7, 0.95%). These were concentrated in intracellular volume fraction measures of white matter pathways and in genes with putative links to tremor (MAPT, ARL17A, KANSL1, SPPL2C, LRRC37A4P, PLEKHM1, and FMNL1). Whole-tremor-network cortical thickness was associated with a gene module linked to mitochondrial organization and protein quality control (r = 0.91, P = 2e-70), whereas white-gray T1-weighted magnetic resonance imaging (MRI) contrast in the tremor network was associated with a gene module linked to sphingolipid synthesis and ethanolamine metabolism (r = -0.90, P = 2e-68). Imputed association effect sizes and RNA-sequencing log-fold change in the validation dataset were significantly correlated for cerebellar peduncular diffusion MRI phenotypes, and there was a close overlap of significant associations between both datasets for gray matter phenotypes (χ2 = 6.40, P = 0.006). CONCLUSIONS: The identified genes and processes are potential treatment targets for ET, and our results help characterize molecular changes that could in future be used for patient treatment selection or prognosis prediction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Unravelling Pathophysiology of Neurological and Psychiatric Complications of COVID-19 Using Brain Organoids.

Neuropsychiatric manifestations of coronavirus disease 2019 (COVID-19) have been increasingly recognized. However, the pathophysiology of COVID-19 in the central nervous system remains unclear. Brain organoid models derived from human pluripotent stem cells are potentially useful for the study of complex physiological and pathological processes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as they recapitulate cellular heterogeneity and function of individual tissues. We identified brain organoid studies that provided insight into the neurotropic properties of SARS-CoV-2. While SARS-CoV-2 was able to infect neurons, the extent of neurotropism was relatively limited. Conversely, choroidal epithelial cells consistently showed a high susceptibility to SARS-CoV-2 infection. Brain organoid studies also elucidated potential mechanism for cellular entry, demonstrated viral replication, and highlighted downstream cellular effects of SARS-CoV-2 infection. Collectively, they suggest that the neuropsychiatric manifestations of COVID-19 may be contributed by both direct neuronal invasion and indirect consequences of neuroinflammation. The use of high throughput evaluation, patient-derived organoids, and advent of "assembloids" will provide a better understanding and functional characterization of the neuropsychiatric symptoms seen in post-acute COVID-19 syndrome. With advancement of organoid technology, brain organoids offer a promising tool for unravelling pathophysiologic clues and potential therapeutic options for neuropsychiatric complications of COVID-19.

Parkinson's disease and cancer: a systematic review and meta-analysis on the influence of lifestyle habits, genetic variants, and gender.

PURPOSE: The relationship between Parkinson's disease (PD) and cancer has been debated. Gender and genetic influences on cancer development in PD is unclear. METHODS: Using QUOROM guidelines, we conducted a systematic review and meta-analysis on potential clinical and genetic factors influencing the PD and subsequent cancer relationship. English articles published in PubMed, Web of Science, and SCOPUS from 2010 to 30 August 2020 were considered for suitability. RESULTS: Of 46 studies identified, fourteen satisfied the inclusion criteria and were further analysed. Unadjusted risk ratios (RR) and 95% confidence intervals were computed to determine the PD and cancer relationship. PD patients have decreased subsequent cancer risks (RR = 0.87, 95% CI = 0.81-0.93), reduced risks of colon, rectal, and colorectal cancer (RR = 0.77, 95% CI = 0.63-0.94), lung cancer (RR = 0.62, 95% CI = 0.48-0.80), and increased brain cancer (R = 1.48, 95% CI = 1.02-2.13) and melanoma risk (R = 1.76, 95% CI = 1.23-2.50). Compared to idiopathic PD, LRRK2-G2019S carriers had increased general cancer risks (RR = 1.26, 95% CI = 1.09-1.46), particularly brain (RR = 2.41, 95% CI = 1.06-5.50), breast (RR = 2.57, 95% CI = 1.19-5.58), colon (RR = 1.83, 95% CI = 1.13-2.99), and haematological cancers (RR = 2.05, 95% CI = 1.07-3.92). Female PD patients have decreased general cancer risks compared to male PD patients in this analysis (RR = 0.83, 95% CI = 0.69-0.98). CONCLUSION: PD patients have reduced risks of colon, rectal, colorectal cancer and lung cancers and increased risks of brain cancer and melanoma. LRRK2-G2019S carriers have increased cancer risks, particularly brain, breast, colon and blood cancers. Female gender was associated with reduced risks. The role of ethnicity, comorbidities, and lifestyle habits on PD patients' subsequent cancer risk should be further investigated.

Does Cigarette Smoking Affect Cervical Laminoplasty Clinical and Radiologic Outcomes?

STUDY DESIGN: Retrospective review. OBJECTIVE: This study aimed to investigate if smokers have both poorer early clinical and radiologic outcomes in cervical laminoplasty when compared with nonsmokers. SUMMARY OF BACKGROUND DATA: Cigarette smoking had been reported to increase rates of pseudoarthrosis following spinal instrumentation with fusion. METHODOLOGY: A retrospective review of all patients who underwent open-door cervical laminoplasty was performed. Nurick, neck pain visual analog scale, and neck disability index scores were reviewed. Cervical lordosis, range of motion (ROM), and intervertebral disc height were measured. The rates and reasons for revision surgery were recorded and classified according to the etiology of laminoplasty revision surgery. RESULTS: Sixty patients were recruited, of which 20 patients (18 males, 2 females) were smokers and 40 patients (27 males, 13 females) were nonsmokers. There was no statistically significant difference between smokers and nonsmokers in preoperative and postoperative visual analog scale, neck disability index, and Nurick scores. A trend was noted toward a greater postoperative reduction in cervical lordosis (13±8 vs. 11±11 degrees). Furthermore, 41% of smokers versus 30% in nonsmokers had >10% loss of postoperative ROM, and 59% smokers versus 50% nonsmokers had >5% loss of postoperative ROM.Postoperative complications and intervertebral disc deterioration were similar in both groups. A higher reoperation rate was noted in smokers with 6 smokers (30%) as compared with 4 nonsmokers (10%), although this did not reach statistical significance. Among the smokers, 4 (20%) were because of cervical disease progression while 2 were technique related. In nonsmokers, all 4 (10%) were because of cervical disease progression. CONCLUSION: This study showed that while there was a nonstatistically significant trend noted toward higher rates of revision surgery in smokers, the laminoplasty outcomes were not significantly poorer in smokers. In heavy smokers with multilevel cervical myelopathy, laminoplasty may be the treatment of choice over anterior spinal decompression and fusion where a high risk of pseudoarthrosis is anticipated.

Longitudinal medication profile and cost savings in Parkinson's disease patients after bilateral subthalamic nucleus deep brain stimulation.

INTRODUCTION: Deep brain stimulation of the subthalamic nucleus (STN DBS) has been shown to reduce antiparkinsonian medication in Parkinson's disease. We aimed to investigate the changes in long-term medication profile with STN DBS. METHODS: Antiparkinsonian medication data for 56 patients were collected from as early as 3 years before STN DBS up to 10 years after. Cost spending on medication changes was analyzed. Mean levodopa equivalent daily dose (LEDD) was projected 10 years into the future based on preoperative data to create a comparator group wherein the patients did not undergo STN DBS. Use of neuroleptics and antidepressants was also recorded. RESULTS: LEDD requirement was significantly reduced by a mean of 31 ± 2% over 10 years after DBS, from 1049 ± 381 mg at pre-DBS baseline, to 713 ± 392 mg at 1 year post-DBS, and 712 ± 385 mg at 10 years post-DBS. This was associated with a mean reduction of 35 ± 3% in medicine cost. Modeled LEDD requirements for not having STN DBS were in the range of 1489 mg to 2721 mg at 10 years post-DBS (109-282% higher than the observed mean LEDD in DBS cohort). The proportion of patients increased from 5% before STN DBS to 14% at 10 year post-DBS for neuroleptics, and 11-23% for antidepressants. CONCLUSION: STN DBS led to LEDD reduction and antiparkinsonian medication cost savings in our South-East Asian cohort. Medication reduction with STN DBS in our cohort over the 10-year period was comparable to those reported in Western populations.

A Feasibility Study of a New Muscle Sparing "C3 Dome-Hybrid Open-Door Laminoplasty": A Surgical Technique, Clinical Outcome, and Learning Curve Description.

STUDY DESIGN: Retrospective case series to investigate the result of a new C3 dome-hybrid open-door laminoplasty technique. OBJECTIVE: This study reports the design and feasibility of a new hybrid laminoplasty technique aimed to reduce the complications of the conventional laminoplasty, with the incorporation of C3 dome-osteotomy, an open-door C4-6 instrumented laminoplasty and C7 cephalad dome-osteotomy. SUMMARY OF BACKGROUND DATA: Recent findings showed that the preservation of the dorsal muscles attached at either C2 or C7 cervical spine reduced the complications of C3-C7 open-door laminoplasty. METHODS: A retrospective review of consecutive patients who underwent the C3 dome-hybrid laminoplasty technique by a single surgeon with at least 2 years follow-up was performed. The surgical technique was described in detail. Clinical and radiological outcome data were analyzed. RESULTS: Twenty six patients with cervical cord compression who underwent C3 dome-hybrid laminoplasty were recruited. The mean postoperative follow-up was 45.6 ±â€Š24.7 (24-101) months. Significant improvements were observed in the preoperative to postoperative mean Japanese Orthopaedic Association (JOA) score (13→15, P < 0.001), Nurick grade (2.3→1.2, P < 0.001), neck disability index (NDI) (23→11, P = 0.011), 36-item short form survey (SF-36) physical component score (40→46, P = 0.027), and neck visual analogue scale (VAS) (3.1→0.3, P < 0.001). There was no significant loss in cervical lordosis from 12° preoperatively to 8° at final follow-up. Postoperative cervical range of motion (ROM) was preserved at 85% and 78% of the preoperative ROM at 2 years and at final follow-up, respectively. When comparing the first 10 patients with the next 16 patients, there was a reduction in mean operation time from 252 ±â€Š75 to 208 ±â€Š7 minutes, mean blood loss from 359 ±â€Š326 to 211 ±â€Š177 mL, and median hospital stay from 7 days (interquartile range [IQR]: 34) to 5 days (IQR: 6).At final follow-up, no patients had revision surgery, spinal infection, C5 palsy, symptomatic cervical kyphosis, or axial neck pain. CONCLUSION: The new C3 dome-hybrid laminoplasty technique is safe, feasible, and reproducible with good clinical outcomes. This technique may be considered as an alternative to traditional laminoplasty for patients with C3-C7 multi-level myelopathic disease. LEVEL OF EVIDENCE: 3.