Development and Optimization of A High-Throughput 3D Rat Purkinje Neuron Culture to Study Paraneoplastic Cerebellar Degeneration

Improved understanding of the mechanisms involved in neurodegenerative disease has been hampered by the lack of robust cellular models that faithfully replicate in vivo features. Here, we present a refined protocol for generating age-dependent, well-developed and synaptically active rat Purkinje neurons in a 3D cell network culture which are responsive to a disease inducer. Using our model, we found that the application of autoantibody Yo, a paraneoplastic cerebellar degeneration (PCD) inducer, alters the structure of the dendritic arbour of cultured Purkinje neurons. The numbers of dendrites per branch-order, the branch-order in itself and the dendritic length were reduced by anti-Yo, proving a functional role for anti-Yo in the pathogenesis of PCD. Our new ex-vivo model is flexible and can be used to investigate disease mechanisms that disturb Purkinje neuron function and communication in 3D. Since it is possible to use the approach in a multi-well format, this method also has high-throughput screening potential.

Essential Tremor: Five New Things

ABSTRACTPurpose of the review:To highlight five new things in the research and clinical aspects of essential tremor (ET).Recent findings:The introduction of a new definition of ET and a new category “ET plus” were the major themes of the recent consensus statement. This new change demands a change in the approach to the clinical diagnosis of ET and related diseases. From the pathogenesis standpoint, the cerebellar neurodegenerative model seems to have numerous evidence in its favor compared to the olivary model which has largely fallen out of favor. From the standpoint of therapeutics, magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has enriched the therapeutic armamentarium.Summary:There has been considerable progress in the field of ET. We discuss five new things in this article which include- (i) new definition (ii) ET plus (iii) approach to the diagnosis of ET, (iv) cerebellar degeneration, and (v) MRgFUS thalamotomy.

Paraneoplastic Cerebellar Degeneration with Anti-CV2/CRMP5 Antibodies in Ovarian Cancer: Case Report and Review of the Literature

Paraneoplastic neurological syndromes (PNS) are rare presentations of an underlying oncological disease and more unusual during an oncological disease. They most likely present in small-cell lung carcinomas and thymomas, but present in <1% of the gynecological neoplasms. Acknowledging the pathophysiology is essential for management, explaining its clinical presentation, and future research. We present a patient with an underlying gynecological cancer that during her disease developed a PNS with an unusual autoantibody (anti-CV2/CRMP5) mediating the disease. We report a case of a 62-year-old female diagnosed with ovarian cancer who in the course of her disease developed neurological symptoms associated with cerebellar degeneration. After ruling out differential diagnoses such as metastases, a PNS was suspected and studied, in which anti-CV2/CRMP5 antibodies were positive. With her clinical presentation, radiological features, autoantibody positivity on cerebrospinal fluid, and an underlying oncological disease, cerebellar degeneration was diagnosed. The pathophysiology of PNS is not fully understood; therefore, its diagnosis and management are complex. Diagnosis is based on clinical presentation and specific antibodies associated. Unfortunately, patients have a bad prognosis and diminished quality of life, and therefore a multidisciplinary approach is needed. It is important to mention that the presentation of PNS does not mandatorily appear before the diagnosis of cancer, and multiple cases have been reported in which patients with an underlying oncological disease develop these syndromes. As medical oncologists and neurologists, we must consider and study these syndromes as a possible etiology in cases with an underlying cancer who develop neurological symptoms in the course of their disease.

Distinct Contributions of the Cerebellum and Basal Ganglia to Arithmetic Procedures

Humans exhibit complex mathematical skills, often attributed to the exceptionally large neocortex. Using a neuropsychological approach, we report that degeneration within two subcortical structures, the basal ganglia and cerebellum, impairs performance in symbolic arithmetic. Moreover, we identify distinct computational impairments in individuals with Parkinson’s disease (PD) or cerebellar degeneration (CD). The CD group exhibited a disproportionate cost when arithmetic sum increased, suggesting that the cerebellum is critical for iterative procedures required for calculations. The PD group exhibited a disproportionate cost for equations with an increasing number of addends, suggesting that the basal ganglia are critical for the coordination of multiple cognitive operations. In Experiment 2, the two patient groups exhibited intact practice gains for repeated equations at odds with an alternative hypothesis that these impairments were related to memory retrieval. Overall, the results provide a novel demonstration of the contribution of subcortical structures to the computations required for complex cognition.