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BackgroundPatients with Parkinson’s disease (PD) have variable rates of progression. More accurate prediction of progression could improve selection for clinical trials. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be further improved by blood biomarkers.ObjectiveTo determine if blood biomarkers (serum neurofilament light (NfL) and genetic status (glucocerebrosidase,GBAand apolipoprotein E (APOE))) are useful in addition to clinical measures for prognostic modelling in PD.MethodsWe evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients’ genetic (GBAandAPOE) status. We classified patients as having a favourable or an unfavourable outcome based on a previously validated model, and explored how blood biomarkers compared with clinical variables in distinguishing prognostic phenotypes .Results291 patients were assessed in this study. Baseline serum NfL was associated with baseline cognitive status. Nfl predicted a shorter time to dementia, postural instability and death (dementia—HR 2.64; postural instability—HR 1.32; mortality—HR 1.89) whereas APOEe4 status was associated with progression to dementia (dementia—HR 3.12, 95% CI 1.63 to 6.00). NfL levels and genetic variables predicted unfavourable progression to a similar extent as clinical predictors. The combination of clinical, NfL and genetic data produced a stronger prediction of unfavourable outcomes compared with age and gender (area under the curve: 0.74-age/gender vs 0.84-ALL p=0.0103).ConclusionsClinical trials of disease-modifying therapies might usefully stratify patients using clinical, genetic and NfL status at the time of recruitment.

BackgroundPick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by theMAPTgene. TheMAPTH2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association betweenMAPTH2 and risk of PiD.MethodsWe established the Pick’s disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped forMAPTH1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variantMAPTH1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521).FindingsOur primary analysis found that theMAPTH2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotypeMAPTH1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65).InterpretationThe PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, theMAPTH2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.FundingSee funding section

BackgroundBi-allelic pathogenic variants inGBA1are the cause of Gaucher disease (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. HeterozygousGBA1variants are also a common genetic risk factor for Parkinson’s disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk of PD.ObjectiveTo investigate the contribution of PD risk variants to risk of PD in patients with GD1.MethodsWe studied 225 patients with GD1, including 199 without PD and 26 with PD. All cases were genotyped and the genetic data was imputed using common pipelines.ResultsOn average, patients with GD1 with PD have a significantly higher PD genetic risk score than those without PD (P=0.021).ConclusionsOur results indicate that variants included in the PD genetic risk score were more frequent in patients with GD1 who developed PD, suggesting that common risk variants may affect underlying biological pathways.Supplemental datahere

ImportanceThere is a pressing need to understand the biology of Parkinson’s disease (PD) progression and to identify biological pathways as possible therapeutic targets.ObjectiveTo identify genomic variation associated with PD motor presentation and early stage progression.DesignGWAS meta-analysis of early PD motor progression, from multiple longitudinal cohorts, using MDS-UPDRS III clinical assessments.SettingMulticentreParticipants3572 unrelated European ancestry individuals diagnosed with PD from 6 studies.Main Outcomes and MeasuresLinear mixed effect models under an additive model corrected for age at diagnosis, gender, and the first 5 genetic principal components (PCs), with axial, limb, and total MDS-UPDRS III as outcomes of the model.ResultsWe identified an association between the PD axial rate of progression and variation at theGJA5locus at 1q12 (Beta = -0.25, SE = 0.04,P= 3.4e-10). Exploration of the regulation of gene expression in the region (cis-eQTL analysis) showed that the lead variant was associated with expression ofACP6, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTLs p-values in blood and brain RNA expression datasets: < 10−8in eQTLGen and 10−7in PsychEncode). In addition, we found a nominal association between axial motor presentation and theMAD1L1gene at 7q21.11 (Beta = 0.54, SE = 0.11,P= 1.6e-7), a gene previously associated with neuropsychiatric disease, and in the long non-coding RNALINC00511at 17q21.31 (Beta = -0.62, SE = 0.11,P= 6.3e-8). Further functional annotation allowed us to nominate the likely causal variants and determine that variants at 7q21.11 may be related to dysregulation ofMAD1L1expression. Variants atLINC00511may cause a disruption of a distal epigenetic regulation ofSOX9through an anchored chromatin loop.Conclusions and RelevanceOur large multicentre study sheds new light on the genetic architecture of PD progression, which is distinct from PD susceptibility. Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets to tackle disease progression.

In this season of public health crises and profound social unrest, we can draw inspiration from those who survived hard times and celebrated the American spirit. Here three students in an accelerated nursing program, poised for graduation in the coming year, join their insights and observation on the challenges facing this country with that of the famed troubadour of the Great Depression, Woody Guthrie. As nurses and public health practitioners, we commit to anthems of inclusion and justice for all.

BackgroundOpen science and collaboration are necessary to facilitate the advancement of Parkinson’s disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities.ObjectiveTo coordinate a virtual hackathon to develop novel PD research tools.Methods49 early career scientists from 12 countries collaborated in a virtual 3-day hackathon event in May 2021, during which they built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools.ResultsEach team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools.ConclusionHackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early career researchers. The resources generated can be used to accelerate research on the genetics of PD.

Introduction Chicago’s COVID-19 Rapid Response Team (CRRT) is a decentralized, interprofessional group of nurses, residents, students, and faculty who provide free COVID-19 testing for those living or working in congregate settings (i.e., shelters, long term care facilities, prisons and encampments) due to their increased risk. Individuals within these vulnerable populations regularly experience stigma, a lack of privacy, and healthcare discrimination as they are often in low-income and underserved communities. The CRRT tests in settings that are necessarily large (cafeterias, meeting areas, gymnasiums, recreation rooms), and provide little physical privacy. Regardless of patient circumstances, respecting patient dignity is a professional standard of care, and patient privacy is consistent with that standard. Methods Guided by trauma-informed care techniques, emancipatory nursing practice, and cultural safety methodology, student members of the CRRT initiated a project focused on expanding physical privacy protection for those undergoing COVID-19 testing. Conclusion Though the introduction of a portable privacy screen started as an initiative to safeguard the dignity for underserved populations, this call to action implores current and future health care providers to prioritize the ethical treatment of those most vulnerable by advocating for patient dignity and privacy.

BackgroundPatients with Parkinson’s disease (PD) have variable disease progression. More accurate prediction of progression could improve clinical trial design. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be improved by blood biomarkers.ObjectiveTo determine if serum neurofilament light (NfL) is a useful biomarker for prognostic modelling in PD.MethodsWe evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients’ genetic (GBA and APOE) status in a large clinical dataset. We classified patients as having a favourable or an unfavourable outcome based on a previously validated model and explored whether serum NfL could distinguish prognostic phenotypes. We compared NfL with baseline candidate predictor variables and studied the combination of clinical, serum and genetic data.ResultsSerum NfL was associated with patients’ cognitive status at baseline. Baseline NfL was associated with the progression of motor and functional impairment and with increased mortality (Survival HR 1.85, CI: 1.03-3.33, p=0.04). Baseline NfL levels predicted unfavourable progression to a similar extent as previously validated clinical predictors (AUC: 0.74 vs 0.78, p=0.22). The combination of clinical, genetic and biomarker data produced a strong predication of unfavourable outcomes as compared to age and gender alone (AUC: 0.71-age/gender vs 0.83-ALL p = 0.0076)ConclusionsBaseline serum NfL provides an objective measure of neurodegeneration in PD patients. Clinical trials of disease-modifying therapies might usefully stratify patients according using clinical, genetic and NfL status at the time of recruitment.

Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

INTRODUCTION Scientists are building detailed maps of the cellular composition in the human brain to learn about its development. In the human cortex, the largest area of the mammalian brain, neural circuits are formed through anatomical refinement, including axon and synaptic pruning, and the emergence of complex patterns of network activity during early fetal development. Cellular analyses in the human brain are restricted to postmortem material, which cannot reveal the process of development. Model organisms are, therefore, commonly used for studies of brain physiology, development, and pathogenesis, but the results from model organisms do not always translate to humans. RATIONALE Systems to model human neuron dynamics and their dysfunction in vivo are needed. While biopsy specimens and the generation of neurons from induced pluripotent stem cells (iPSCs) could provide the necessary human genetic background, two- and three-dimensional cultures lack factors that normally support neuronal development, including blood vessels, immune cells, and interaction with innervating neurons from other brain areas. On the basis of previous stem cell transplantation studies in mice, we reasoned that the physiological microenvironment of the adult mouse brain could support the growth of human cortical tissue grafts that had been generated from iPSC-derived neuronal progenitors. With human neurons implanted into the mouse brain, high-resolution, real-time in vivo monitoring of human neuron dynamics for periods of time spanning the range from subseconds to several months becomes feasible. RESULTS We found that transplanted human iPSC–derived neuronal progenitors consistently assembled into vascularized territories with complex cytoarchitecture, mimicking key features of the human fetal cortex, such as its large size and cell diversification. Single-cell-resolution intravital microscopy showed that human neuronal arbors were refined via branch-specific retraction, rather than degeneration. Human synaptic networks restructured over the course of 4 months, while maintaining balanced rates of synapse formation and elimination. Human functional neurons rapidly and consistently acquired oscillatory population activity, which persisted over the 5-month observation period. Lastly, we used cortical tissue grafts derived from the fibroblasts of two individuals with Down syndrome, caused by supernumerary chromosome 21. We found that neuronal synapses in cells derived from these individuals were overly stable and that oscillatory neural activity was reduced in these grafts, revealing in vivo cellular phenotypes not otherwise apparent. CONCLUSION By combining live imaging in a multistructured tissue environment in mice with a human-specific genetic background, we provide insights into the earliest stages of human axon, synaptic, and network activity development and uncover cellular phenotypes in Down syndrome. Our work provides an alternative experimental system that can be used to study other disorders affecting the developing human cortex.

portuguesDesafios diagnosticos surgem frequentemente quando lesoes multiplas do sistema nervoso central (SNC) nao acessiveis a biopsia estao presentes na Ressonância Magnetica (RM). O diagnostico diferencial e vasto, particularmente no contexto de exposicao a corticoides e/ou estado de imunodepressao. As lesoes benignas a considerar sao as doencas desmielinizantes, sarcoidose e outras doencas granulomatosas, e doencas infecciosas como a toxoplasmose nos pacientes imunodeprimidos e tuberculose. As lesoes malignas incluem o linfoma do SNC, glioblastoma multiforme e metastases cerebrais. Os autores descrevem o caso clinico de uma mulher de 75 anos com lupus eritematoso sistemico, medicada cronicamente com Hidroxicloroquina 400 mg, Deflazacorte 9 mg e Azatioprina 25 mg diariamente, que foi admitida no hospital com um quadro com cinco meses de evolucao de defices neurologicos progressivos. Este foi particularmente desafiante, uma vez que a doente era imunodeprimida, tinha lesoes multiplas do SNC que nao eram acessiveis a biopsia e a corticoterapia cronica alterou o padrao radiologico na RM cerebral, mascarando o diagnostico. O relato deste caso e revisao da literatura fornece mais evidencia sobre a perda das caracteristicas histologicas e radiologicas das lesoes do SNC sob corticoterapia, com um potencial atraso no diagnostico e subsequente pior prognostico. EnglishDiagnostic challenges often arise when multiple central nervous system (CNS) lesions not accessible to biopsy are present on Magnetic Resonance Imaging (MRI). The differential diagnosis is broad, particularly in the context of exposure to steroids and/or in the setting of immunosuppression. Benign lesions to be considered are demyelinating diseases, sarcoidosis and other granulomatous diseases, and infectious diseases such as toxoplasmosis in immunocompromised patients and tuberculosis. Malignant lesions include CNS lymphoma, glioblastoma multiforme and brain metastases. The authors describe the clinical case of a 75-year-old woman with systemic lupus erythematosus (SLE), chronically medicated with Hydroxychloroquine 400 mg, Deflazacort 9 mg and Azathioprine 25 mg daily, who presented to the hospital with a 5-month history of progressive neurological deficits. It was particularly challenging, because the patient was immunocompromised, had multiple CNS lesions that were not accessible to biopsy and chronic therapy with corticosteroids altered the radiological pattern on brain MRI, masquerading the diagnosis. By writing up this case and review of the literature, further evidence is provided for loss of distinctive histological and radiographic findings of CNS lesions on steroid therapy, with a potential delay in diagnosis and subsequent worse prognosis.

Mutations in the TANK-binding kinase 1 (TBK1) gene have recently been shown to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The phenotype is highly variable and has been associated with behavioral variant FTD, primary progressive aphasia, and pure ALS. We describe the clinical, anatomical, and pathological features of a patient who developed corticobasal syndrome (CBS)/progressive nonfluent aphasia (PNFA) overlap. The patient presented with progressive speech difficulties and later developed an asymmetric akinetic–rigid syndrome. Neuroimaging showed asymmetrical frontal atrophy, predominantly affecting the right side. There was a strong family history of neurodegenerative disease with four out of seven siblings developing either dementia or ALS in their 50s and 60s. The patient died at the age of 71 and the brain was donated for postmortem analysis. Histopathological examination showed frontotemporal lobar degeneration TDP-43 type A pathology. Genetic screening did not reveal a mutation in the GRN, MAPT, or C9orf72 genes, but exome sequencing revealed a novel p.E703X mutation in the TBK1 gene. Although segregation data were not available, this loss-of-function mutation is highly likely to be pathogenic because it is predicted to disrupt TBK1/optineurin interaction and impair cellular autophagy. In conclusion, we show that TBK1 mutations can be a cause of an atypical parkinsonian syndrome and screening should be considered in CBS patients with a family history of dementia or ALS.

A 62-year-old man presented with subacute horizontal binocular diplopia and slight gait imbalance, preceded by frequent episodes of vomiting. The patient had undergone two gastric surgeries for gastric ulcer in the past (in 1988 and 2002). Bilateral internuclear ophthalmoplaegia, conjugate vertical gaze palsy and mild tandem gait abnormalities were observed (video 1, part 1; figure 1). Upper gastrointestinal endoscopy and gastric emptying scintigraphy suggested a delay in gastric emptying. Brain MRI demonstrated hyperintense symmetric areas in the thalami, midbrain tegmentum, quadrigeminal plate and floor of the fourth ventricle, suggesting Wernicke encephalopathy (figure …

Paraneoplastic neurological syndromes are a group of rare and heterogeneous disorders complicating cancer through immune-mediated mechanisms. They typically arise before the diagnosis of malignancy, thus constituting its first clinical manifestation. A thorough search for the underlying tumour is necessary, as adequate tumour management is essential for both neurological prognosis and overall survival. The authors present the case of a 43 year-old woman who presented with a subacute cerebellar syndrome associated with the paraneoplastic anti-Yo antibody. Although paraneoplastic aetiology was immediately suspected, the diagnosis of the underlying tumour was not straightforward, as is often the case. This case report highlights the importance of directing tumour search for the most probable anatomic locations, according to patient demographics and risk factors as well as the type of onconeural antibodies present, and also the need to use the most sensitive diagnostic modalities appropriate for each target organ.