Impact of COVID-19 pandemic on physician-scientist trainees to faculty one year into the pandemic.

PURPOSE: Physician-scientists play a crucial role in advancing biomedical sciences. Proportionally fewer physicians are actively engaged in scientific pursuits, attributed to attrition in the training and retention pipeline. This national study evaluated the ongoing and longer-term impact of the COVID-19 pandemic on stress levels, research productivity, and optimism for physician-scientists at all levels of training. METHODS: A multi-institutional cross-sectional survey of medical students, graduate students, and residents/fellows/junior faculty (RFJF) was conducted from April to August 2021 to assess the impact of COVID-19 on individual stress, productivity, and optimism. Multivariate regression analyses were performed to identify associated variables and unsupervised variable clustering techniques were employed to identify highly correlated responses. RESULTS: A total 677 respondents completed the survey, representing different stages of physician-scientist training. Respondents report high levels of stress (medical students: 85%, graduate students: 63%, RFJF: 85%) attributed to impaired productivity concerns, concern about health of family and friends, impact on personal health and impairment in training or career development. Many cited impaired productivity (medical students: 65% graduate students: 79%, RFJF: 78%) associated with pandemic impacts on training, labs closures and loss of facility/resource access, and social isolation. Optimism levels were low (medical students: 37%, graduate students: 38% and RFJF: 39%) with females less likely to be optimistic and more likely to report concerns of long-term effects of COVID-19. Optimism about the future was correlated with not worrying about the long-term effects of COVID-19. Since the COVID-19 pandemic, all respondents reported increased prioritization of time with family/friends (67%) and personal health (62%) over career (25%) and research (24%). CONCLUSIONS: This national survey highlights the significant and protracted impact of the COVID-19 pandemic on stress levels, productivity, and optimism among physician-scientists and trainees. These findings underscore the urgent need for tailored support, including mental health, academic, and career development assistance for this biomedical workforce.

Determinants of hyponatremia following a traumatic brain injury.

BACKGROUND: Hyponatremia is common in patients with central nervous system disease. It may prolong hospitalization and increase morbidity and mortality. However, the incidence and risks factors remain largely unknown in traumatic brain injury (TBI). The objectives of this study are to characterize hyponatremia in TBI patients and find its main risk factors. METHODS: All patients admitted with a diagnosis of acute TBI over a 1-year period were included, except patients with known chronic hyponatremia, those who died within 72 h, and those receiving hyperosmolar therapy to treat their intracranial hypertension. Sodium levels throughout hospitalization were collected. Post-traumatic hyponatremia was defined as follows: borderline (1-2 points below normal and 1-2 days duration) and significant (more than 2 points below normal and/or more than 2 days duration). Demographic data, GCS, mechanism of injury, and CT findings were collected. These factors were correlated to the incidence of hyponatremia. RESULTS: Hyponatremia was found in 29% of the 283 included patients and was significant in 2/3 of the cases. Significant hyponatremia had a narrower peak, between 7 and 11 days, while borderline hyponatremia started earlier and was more distributed in time. Factors associated with hyponatremia were greater age (p = 0.004), worse ISS (p = 0.017), worse Marshall Grade on CT (p = 0.007), and a diffuse pattern of injury on CT (p < 0.001). Significant hyponatremia was associated with: a diffuse pattern of injury on CT (p = 0.032), the presence of intracerebral hemorrhage (p = 0.027), and multiple lesions on CT (p = 0.043). CONCLUSIONS: Post-traumatic hyponatremia is common and can lead to serious consequences in TBI patients. Adequate monitoring and treatment are therefore important. Older patients and those with more significant injury on CT are more at risk.

Metabolic determinants of B-cell selection.

B-cells are antibody-producing cells of the adaptive immune system. Approximately 75% of all newly generated B-cells in the bone marrow are autoreactive and express potentially harmful autoantibodies. To prevent autoimmune disease, the immune system has evolved a powerful mechanism to eliminate autoreactive B-cells, termed negative B-cell selection. While designed to remove autoreactive clones during early B-cell development, our laboratory recently discovered that transformed B-cells in leukemia and lymphoma are also subject to negative selection. Indeed, besides the risk of developing autoimmune disease, B-cells are inherently prone to malignant transformation: to produce high-affinity antibodies, B-cells undergo multiple rounds of somatic immunoglobulin gene recombination and hypermutation. Reflecting high frequencies of DNA-breaks, adaptive immune protection by B-cells comes with a dramatically increased risk of development of leukemia and lymphoma. Of note, B-cells exist under conditions of chronic restriction of energy metabolism. Here we discuss how these metabolic gatekeeper functions during B-cell development provide a common mechanism for the removal of autoreactive and premalignant B-cells to safeguard against both autoimmune diseases and B-cell malignancies.

GCH1 mutations in hereditary spastic paraplegia.

GCH1 mutations have been associated with dopa-responsive dystonia (DRD), Parkinson's disease (PD) and tetrahydrobiopterin (BH4 )-deficient hyperphenylalaninemia B. Recently, GCH1 mutations have been reported in five patients with hereditary spastic paraplegia (HSP). Here, we analyzed a total of 400 HSP patients (291 families) from different centers across Canada by whole exome sequencing (WES). Three patients with heterozygous GCH1 variants were identified: monozygotic twins with a p.(Ser77_Leu82del) variant, and a patient with a p.(Val205Glu) variant. The former variant is predicted to be likely pathogenic and the latter is pathogenic. The three patients presented with childhood-onset lower limb spasticity, hyperreflexia and abnormal plantar responses. One of the patients had diurnal fluctuations, and none had parkinsonism or dystonia. Phenotypic differences between the monozygotic twins were observed, who responded well to levodopa treatment. Pathway enrichment analysis suggested that GCH1 shares processes and pathways with other HSP-associated genes, and structural analysis of the variants indicated a disruptive effect. In conclusion, GCH1 mutations may cause HSP; therefore, we suggest a levodopa trial in HSP patients and including GCH1 in the screening panels of HSP genes. Clinical differences between monozygotic twins suggest that environmental factors, epigenetics, and stochasticity could play a role in the clinical presentation.

Evidence for Non-Mendelian Inheritance in Spastic Paraplegia 7.

BACKGROUND: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP). OBJECTIVES: We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP. METHODS: We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole-exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls. RESULTS: The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24-6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49-13.07, P = 0.005). Similar results were obtained after including only genetically-undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05-365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. CONCLUSIONS: Our results provide evidence for complex inheritance in SPG7-associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society.

Clinical Characterization of Traumatic Acute Interhemispheric Subdural Hematoma.

OBJECT: Interhemispheric subdural hematomas (IHSDHs) are thought to be rare. Surgical management of these lesions presents a challenge as they are in close proximity to the sagittal sinus and bridging veins. IHSDHs are poorly characterized clinically and their exact incidence is unknown. There are also no clear guidelines for the management of IHSDH. METHODS: This is a retrospective review of all admitted patients with a diagnosis of traumatic brain injury over a 4-year period at a Level I trauma centre. Clinical characteristics of all patients with subdural hematoma (SDH) and IHSDH were collected. RESULTS: Of 2165 admissions, 1182 patients had acute traumatic SDHs, 420 patients had IHSDHs (1.9% of admissions and 35.5% of SDH), 35 (8.3% of IHSDH) were ≥8 mm in width. IHSDH was isolated in 16 (3.8%) of the cases. Average age was 61.7 ± 21.5 years for all IHSDHs and 77.1 ± 10.4 for large IHSDH (p < 0.001). For large IHSDH, a transient loss of consciousness (LOC) occurred in 51.5% of individuals, post-traumatic amnesia (PTA) in 47.8% of cases, and motor weakness in 37.9% of patients. Five of the large IHSDH patients presented with motor deficits directly related to the IHSDH, and weakness resolved in four of these five individuals. None were treated surgically. Progression of IHSDH width occurred in one patient. CONCLUSION: IHSDHs are often referred to as rare entities. Our results show they are common. Conservative management is appropriate to manage most IHSDHs, as most resolve spontaneously, and their symptoms resolve as well.

SPTAN1 variants as a potential cause for autosomal recessive hereditary spastic paraplegia.

More than 80 known or suspected genes/loci have been reported to be involved in hereditary spastic paraplegia (HSP). Genetic and clinical overlap have been reported between HSP and other neurological condition, yet about 50% of HSP patients remain genetically undiagnosed. To identify novel genes involved in HSP, we performed a genetic analysis of 383 HSP patients from 289 families with HSP. Two patients with biallelic SPTAN1 variants were identified; one carried the c.2572G>T p.(Ala858Ser) and c.4283C>G p.(Ala1428Gly) variants, and the second also carried the c.2572G>T p.(Ala858Ser) variant, and an additional variant, c.6990G>C p.(Met2330Ile). In silico predictive and structural analyses suggested that these variants are likely to be deleterious. SPTAN1 was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed vs. expected number of loss-of-function variants (8 vs. 142.7, p < 5 × 10-15). Using public databases of animal models and previously published data, we have found previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. This study expands the phenotype of SPTAN1 mutations, which at the heterozygous state, when occurred de novo, may cause early infantile epileptic encephalopathy-5 (EIEE5). Our results further suggest that SPTAN1 may cause autosomal recessive HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.

Tuning Responses to Polatuzumab Vedotin in B-cell Lymphoma.

Polatuzumab vedotin, an antibody-drug conjugate targeting CD79B, is the first new drug approved for first-line therapy of diffuse large B-cell lymphoma in more than two decades, although factors determining treatment responses to polatuzumab vedotin remain unknown. Two new studies identified central mechanisms of lower sensitivity, namely reduced accessibility of the CD79B epitope through N-linked glycosylation of CD79B and lower CD79B surface expression levels due to the activity of the KLHL6 E3 ligase. See related article by Corcoran et al., p. 1653 (6) See related article by Meriranta et al. (7).

Genetic Modeling of B-cell State Transitions for Rational Design of Lymphoma Therapies.

The use of genomic data to analyze primary endpoints for clinical trials in diffuse large B-cell lymphomas (DLBCL) significantly improved the development of rational drug combinations for genetically defined patient subsets. Recent genetic mouse models and their ability to recapitulate transitions between germinal center exit and memory B-cell characteristics in DLBCL will accelerate the development of rationale-based clinical trials. See related article by Flümann et al., p. 78 (3). See related article by Venturutti et al., (5).

Impact of COVID-19 Pandemic on Physician-Scientist Trainees to Faculty One Year into the Pandemic.

Purpose: Physician-scientists play a crucial role in advancing biomedical sciences. Proportionally fewer physicians are actively engaged in scientific pursuits, attributed to attrition in the training and retention pipeline. This national study evaluated the ongoing and longer-term impact of the COVID-19 pandemic on research productivity for physician-scientists at all levels of training. Methods: A survey of medical students, graduate students, and residents/fellows/junior faculty (RFJF) was conducted from April to August 2021 to assess the impact of COVID-19 on individual stress, productivity, and optimism. Multivariate regression analyses were performed to identify associated variables and unsupervised variable clustering techniques were employed to identify highly correlated responses. Results: A total 677 respondents completed the survey, representing different stages of physician-scientist training. Respondents report high levels of stress (medical students: 85%, graduate students: 63%, RFJF: 85%) attributed to impaired productivity concerns, concern about health of family and friends, impact on personal health and impairment in training or career development. Many cited impaired productivity (medical students: 65% graduate students: 79%, RFJF: 78%) associated with pandemic impacts on training, labs closures and loss of facility/resource access, and social isolation. Optimism levels were low (medical students: 37%, graduate students: 38% and RFJF: 39%) with females less likely to be optimistic and more likely to report concerns of long-term effects of COVID-19. Optimism about the future was correlated with not worrying about the long-term effects of COVID-19. Since the COVID-19 pandemic, all respondents reported increased prioritization of time with family/friends (67%) and personal health (62%) over career (25%) and research (24%). Conclusions: This national survey highlights the significant and protracted impact of the COVID-19 pandemic on stress levels, productivity, and optimism among physician-scientists and trainees. These findings underscore the urgent need for tailored support, including mental health, academic, and career development assistance for this biomedical workforce.

Dynamic phosphatase-recruitment controls B-cell selection and oncogenic signaling.

Initiation of B-cell receptor (BCR) 1 signaling, and subsequent antigen-encounter in germinal centers 2,3 represent milestones of B-lymphocyte development that are both marked by sharp increases of CD25 surface-expression. Oncogenic signaling in B-cell leukemia (B-ALL) 4 and lymphoma 5 also induced CD25-surface expression. While CD25 is known as an IL2-receptor chain on T- and NK-cells 6-9 , the significance of its expression on B-cells was unclear. Our experiments based on genetic mouse models and engineered patient-derived xenografts revealed that, rather than functioning as an IL2-receptor chain, CD25 expressed on B-cells assembled an inhibitory complex including PKCδ and SHIP1 and SHP1 phosphatases for feedback control of BCR-signaling or its oncogenic mimics. Recapitulating phenotypes of genetic ablation of PKCδ 10 - 12 , SHIP1 13,14 and SHP1 14, 15,16 , conditional CD25-deletion decimated early B-cell subsets but expanded mature B-cell populations and induced autoimmunity. In B-cell malignancies arising from early (B-ALL) and late (lymphoma) stages of B-cell development, CD25-loss induced cell death in the former and accelerated proliferation in the latter. Clinical outcome annotations mirrored opposite effects of CD25-deletion: high CD25 expression levels predicted poor clinical outcomes for patients with B-ALL, in contrast to favorable outcomes for lymphoma-patients. Biochemical and interactome studies revealed a critical role of CD25 in BCR-feedback regulation: BCR-signaling induced PKCδ-mediated phosphorylation of CD25 on its cytoplasmic tail (S 268 ). Genetic rescue experiments identified CD25-S 268 tail-phosphorylation as central structural requirement to recruit SHIP1 and SHP1 phosphatases to curb BCR-signaling. A single point mutation CD25 S268A abolished recruitment and activation of SHIP1 and SHP1 to limit duration and strength of BCR-signaling. Loss of phosphatase-function, autonomous BCR-signaling and Ca 2+ -oscillations induced anergy and negative selection during early B-cell development, as opposed to excessive proliferation and autoantibody production in mature B-cells. These findings highlight the previously unrecognized role of CD25 in assembling inhibitory phosphatases to control oncogenic signaling in B-cell malignancies and negative selection to prevent autoimmune disease.

Targeted engagement of ß-catenin-Ikaros complexes in refractory B-cell malignancies.

In most cell types, nuclear ß-catenin functions as prominent oncogenic driver and pairs with TCF7-family factors for transcriptional activation of MYC. Surprisingly, B-lymphoid malignancies not only lacked expression and activating lesions of ß-catenin but critically depended on GSK3ß for effective ß-catenin degradation. Our interactome studies in B-lymphoid tumors revealed that ß-catenin formed repressive complexes with lymphoid-specific Ikaros factors at the expense of TCF7. Instead of MYC-activation, ß-catenin was essential to enable Ikaros-mediated recruitment of nucleosome remodeling and deacetylation (NuRD) complexes for transcriptional repression of MYC. To leverage this previously unrecognized vulnerability of B-cell-specific repressive ß-catenin-Ikaros-complexes in refractory B-cell malignancies, we examined GSK3ß small molecule inhibitors to subvert ß-catenin degradation. Clinically approved GSK3ß-inhibitors that achieved favorable safety prof les at micromolar concentrations in clinical trials for neurological disorders and solid tumors were effective at low nanomolar concentrations in B-cell malignancies, induced massive accumulation of ß-catenin, repression of MYC and acute cell death. Preclinical in vivo treatment experiments in patient-derived xenografts validated small molecule GSK3ß-inhibitors for targeted engagement of lymphoid-specific ß-catenin-Ikaros complexes as a novel strategy to overcome conventional mechanisms of drug-resistance in refractory malignancies. HIGHLIGHTS: Unlike other cell lineages, B-cells express nuclear ß-catenin protein at low baseline levels and depend on GSK3ß for its degradation.In B-cells, ß-catenin forms unique complexes with lymphoid-specific Ikaros factors and is required for Ikaros-mediated tumor suppression and assembly of repressive NuRD complexes. CRISPR-based knockin mutation of a single Ikaros-binding motif in a lymphoid MYC superenhancer region reversed ß-catenin-dependent Myc repression and induction of cell death. The discovery of GSK3ß-dependent degradation of ß-catenin as unique B-lymphoid vulnerability provides a rationale to repurpose clinically approved GSK3ß-inhibitors for the treatment of refractory B-cell malignancies. GRAPHICAL ABSTRACT: Abundant nuclear ß-cateninß-catenin pairs with TCF7 factors for transcriptional activation of MYCB-cells rely on efficient degradation of ß-catenin by GSK3ßB-cell-specific expression of Ikaros factors Unique vulnerability in B-cell tumors: GSK3ß-inhibitors induce nuclear accumulation of ß-catenin.ß-catenin pairs with B-cell-specific Ikaros factors for transcriptional repression of MYC.

Use of mobile health technologies for postoperative care in paediatric surgery: A systematic review.

INTRODUCTION: Mobile health (mHealth) is the use of mobile communication devices such as smartphones, wireless patient monitoring devices and tablet computers to deliver health services. Paediatric surgery patient care could potentially benefit from these technologies. This systematic review summarises the current literature on the use of mHealth for postoperative care after children's surgery. METHODS: Seven databases were searched by a senior medical librarian. Studies were included if they reported the use of mHealth systems for postoperative care for children <18 years old. Data extraction and risk of bias assessment were performed in duplicate. RESULTS: A total of 18 studies were included after screening. mHealth use was varied and included appointment or medication reminders, postoperative monitoring and postoperative instruction delivery. mHealth systems included texting systems and mobile applications, and were implemented for a wide range of surgical conditions and countries. DISCUSSION: Studies showed that mHealth systems can increase the postoperative follow-up appointment attendance rate (p < 0.001), decrease the rate of postoperative complications and returns to the emergency department and reliably monitor postoperative pain. mHealth systems were generally appreciated by patients. Most non-randomised and randomised studies had many methodological problems, including lack of appropriate control groups, lack of blinding and a tendency to devote more time to the care of the intervention group. mHealth systems have the potential to improve postoperative care, but the lack of high-quality research evaluating their impact calls for further studies exploring evidence-based mHealth implementation.

SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies.

SYK and ZAP70 nonreceptor tyrosine kinases serve essential roles in initiating B-cell receptor (BCR) and T-cell receptor (TCR) signaling in B- and T-lymphocytes, respectively. Despite their structural and functional similarity, expression of SYK and ZAP70 is strictly separated during B- and T-lymphocyte development, the reason for which was not known. Aberrant co-expression of ZAP70 with SYK was first identified in B-cell chronic lymphocytic leukemia (CLL) and is considered a biomarker of aggressive disease and poor clinical outcomes. We recently found that aberrant ZAP70 co-expression not only functions as an oncogenic driver in CLL but also in various other B-cell malignancies, including acute lymphoblastic leukemia (B-ALL) and mantle cell lymphoma. Thereby, aberrantly expressed ZAP70 redirects SYK and BCR-downstream signaling from NFAT towards activation of the PI3K-pathway. In the sole presence of SYK, pathological BCR-signaling in autoreactive or premalignant cells induces NFAT-activation and NFAT-dependent anergy and negative selection. In contrast, negative selection of pathological B-cells is subverted when ZAP70 diverts SYK from activation of NFAT towards tonic PI3K-signaling, which promotes survival instead of cell death. We discuss here how both B-cell malignancies and autoimmune diseases frequently evolve to harness this mechanism, highlighting the importance of developmental separation of the two kinases as an essential safeguard.

Genetic, structural and clinical analysis of spastic paraplegia 4.

INTRODUCTION: Spastic paraplegia type 4 (SPG4), resulting from heterozygous mutations in the SPAST gene, is the most common form among the heterogeneous group of hereditary spastic paraplegias (HSPs). We aimed to study genetic and clinical characteristics of SPG4 across Canada. METHODS: The SPAST gene was analyzed in a total of 696 HSP patients from 431 families by either HSP-gene panel sequencing or whole exome sequencing (WES). We used Multiplex ligation-dependent probe amplification to analyze copy number variations (CNVs), and performed in silico structural analysis of selected mutations. Clinical characteristics of patients were assessed, and long-term follow-up was done to study genotype-phenotype correlations. RESULTS: We identified 157 SPG4 patients from 65 families who carried 41 different SPAST mutations, six of which are novel and six are CNVs. We report novel aspects of mutations occurring in Arg499, a case with homozygous mutation, a family with probable compound heterozygous mutations, three patients with de novo mutations, three cases with pathogenic synonymous mutation, co-occurrence of SPG4 and clinically isolated syndrome, and novel or rarely reported signs and symptoms seen in SPG4 patients. CONCLUSION: Our study demonstrates that SPG4 is a heterogeneous type of HSP, with diverse genetic features and clinical manifestations. In rare cases, biallelic inheritance, de novo mutation, pathogenic synonymous mutations and CNVs should be considered.

Genetic Events Inhibiting Apoptosis in Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is curable with chemoimmunotherapy in ~65% of patients. One of the hallmarks of the pathogenesis and resistance to therapy in DLBCL is inhibition of apoptosis, which allows malignant cells to survive and acquire further alterations. Inhibition of apoptosis can be the result of genetic events inhibiting the intrinsic or extrinsic apoptotic pathways, as well as their modulators, such as the inhibitor of apoptosis proteins, P53, and components of the NF-kB pathway. Mechanisms of dysregulation include upregulation of anti-apoptotic proteins and downregulation of pro-apoptotic proteins via point mutations, amplifications, deletions, translocations, and influences of other proteins. Understanding the factors contributing to resistance to apoptosis in DLBCL is crucial in order to be able to develop targeted therapies that could improve outcomes by restoring apoptosis in malignant cells. This review describes the genetic events inhibiting apoptosis in DLBCL, provides a perspective of their interactions in lymphomagenesis, and discusses their implication for the future of DLBCL therapy.

Tau and MAPT genetics in tauopathies and synucleinopathies.

MAPT encodes the microtubule-associated protein tau, which is the main component of neurofibrillary tangles (NFTs) and found in other protein aggregates. These aggregates are among the pathological hallmarks of primary tauopathies such as frontotemporal dementia (FTD). Abnormal tau can also be observed in secondary tauopathies such as Alzheimer's disease (AD) and synucleinopathies such as Parkinson's disease (PD). On top of pathological findings, genetic data also links MAPT to these disorders. MAPT variations are a cause or risk factors for many tauopathies and synucleinopathies and are associated with certain clinical and pathological features in affected individuals. In addition to clinical, pathological, and genetic overlap, evidence also suggests that tau and alpha-synuclein may interact on the molecular level, and thus might collaborate in the neurodegenerative process. Understanding the role of MAPT variations in tauopathies and synucleinopathies is therefore essential to elucidate the role of tau in the pathogenesis and phenotype of those disorders, and ultimately to develop targeted therapies. In this review, we describe the role of MAPT genetic variations in tauopathies and synucleinopathies, several genotype-phenotype and pathological features, and discuss their implications for the classification and treatment of those disorders.

Investigating the relationship between the SNCA gene and cognitive abilities in idiopathic Parkinson's disease using machine learning.

Cognitive impairments are prevalent in Parkinson's disease (PD), but the underlying mechanisms of their development are unknown. In this study, we aimed to predict global cognition (GC) in PD with machine learning (ML) using structural neuroimaging, genetics and clinical and demographic characteristics. As a post-hoc analysis, we aimed to explore the connection between novel selected features and GC more precisely and to investigate whether this relationship is specific to GC or is driven by specific cognitive domains. 101 idiopathic PD patients had a cognitive assessment, structural MRI and blood draw. ML was performed on 102 input features including demographics, cortical thickness and subcortical measures, and several genetic variants (APOE, MAPT, SNCA, etc.). Using the combination of RRELIEFF and Support Vector Regression, 11 features were found to be predictive of GC including sex, rs894280, Edinburgh Handedness Inventory, UPDRS-III, education, five cortical thickness measures (R-parahippocampal, L-entorhinal, R-rostral anterior cingulate, L-middle temporal, and R-transverse temporal), and R-caudate volume. The rs894280 of SNCA gene was selected as the most novel finding of ML. Post-hoc analysis revealed a robust association between rs894280 and GC, attention, and visuospatial abilities. This variant indicates a potential role for the SNCA gene in cognitive impairments of idiopathic PD.

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk.

Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype.

BACKGROUND: Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness, with or without additional symptoms. Mutations in ATP13A2, known to cause Kufor-Rakeb syndrome (KRS), have been recently implicated in HSP. METHODS: Whole-exome sequencing was done in a Canada-wide HSP cohort. RESULTS: Three additional patients with homozygous ATP13A2 mutations were identified, representing 0.7% of all HSP families. Spastic paraplegia was the predominant feature, all patients suffered from psychiatric symptoms, and one patient had developed seizures. Of the identified mutations, c.2126G>C;(p.[Arg709Thr]) is novel, c.2158G>T;(p.[Gly720Trp]) has not been reported in ATP13A2-related diseases, and c.2473_2474insAAdelC;p.[Leu825Asnfs*32]) has been previously reported in KRS but not in HSP. Structural analysis of the mutations suggested a disruptive effect, and enrichment analysis suggested the potential involvement of specific pathways. CONCLUSION: Our study suggests that in HSP patients with psychiatric symptoms, ATP13A2 mutations should be suspected, especially if they also have extrapyramidal symptoms.