👤 David Devos

Speech impairment is a recognized but unpredictable adverse effect of sub-thalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD). To evaluate the prevalence of speech impairment 1 year after STN-DBS in PD patients and to determine the predictive factors for speech outcome following STN-DBS. Data for 417 patients from the French national PREDISTIM study were collected preoperatively. The combined effect of medical treatment and surgery on speech was compared using specific items from dedicated clinical scales (MDS-UPDRS III.1: primary endpoint) and patient self-assessment questionnaires (items 34 and 35 of the PDQ39: secondary endpoints). For each variable, three patient groups were generated according to speech outcome at 1 year: worsening, stability, and improvement. In the second step analysis, the three groups were compared for demographic and clinical variables at baseline and STN-DBS parameters. There was a significant deterioration in speech of all considered items 1 year after combined STN-DBS and dopaminergic treatment. Four predictive factors for speech deterioration were detected: (i) the absence of preoperative speech impairment (p < 0.001); (ii) severity of motor activity of daily living (MDS-UPDRS II off total score) (p = 0.037); (iii) high-intensity stimulation of the left electrode (i.e., above 3.6 V) (p = 0.046); and (iv) the absence of any change in non-motor experiences of daily life (MDS-UPDRS I total score) (p = 0.048). Speech outcome should be carefully monitored after STN-DBS, especially in PD patients without preoperative speech impairment, with motor difficulties in daily-living activities, and with increased left electrode intensity. ClinicalTrials.gov identifier: NCT02360683. Show less

Myeloid sarcoma (MS), previously known as granulocytic sarcoma or chloroma, is a rare neoplastic condition defined as a tumor mass consisting of myeloblasts or immature myeloid cells occurring at an extramedullary site. Clinical presentation is diverse and determined by a tumor mass effect or local organ dysfunction. We report the case of a 25-year-old previously healthy male with rapidly progressive shortness of breath. A chest CT scan demonstrated a heterogenous anterosuperior mediastinal mass with pleural and pericardial invasion. A diagnosis of MS with both myeloid and lymphoid characteristics was made by pathologic, morphologic, and immunophenotypic investigation. Next generation analysis revealed a pathogenic TP53 mutation (c.1035₁₀₃₆insCT, p.Glu346Leufs*25). After 4 cycles of chemotherapy only a partial metabolic response and tumor size reduction was obtained. A pretransplant bone marrow biopsy revealed the progression of disease to acute myeloid leukemia. Cytogenetic analysis demonstrated a t(10; 11)(p12;q21). Fluorescence in situ hybridization confirmed the presence of a PICALM-MLLT10 fusion gene. MS with a mediastinal localization is rare and often misdiagnosed as malignant lymphoma. Acute leukemia harboring a PICALM-MLLT10 fusion gene is characterized by a mixed T cell and myeloid phenotype. The rearrangement is a rare recurrent translocation associated with specific clinical features, as illustrated in this case report. Show less

Recent experimental evidence suggests that transcellular propagation of fibrillar protein aggregates drives the progression of neurodegenerative diseases in a prion-like manner. This phenomenon is now well described in cell and animal models and involves the release of protein aggregates into the extracellular space. Free aggregates then enter neighboring cells to seed further fibrillization. The mechanism by which aggregated extracellular proteins such as tau and α-synuclein bind and enter cells to trigger intracellular fibril formation is unknown. Prior work indicates that prion protein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface to transmit pathologic processes. Here, we find that tau fibril uptake also occurs via HSPG binding. This is blocked in cultured cells and primary neurons by heparin, chlorate, heparinase, and genetic knockdown of a key HSPG synthetic enzyme, Ext1. Interference with tau binding to HSPGs prevents recombinant tau fibrils from inducing intracellular aggregation and blocks transcellular aggregate propagation. In vivo, a heparin mimetic, F6, blocks neuronal uptake of stereotactically injected tau fibrils. Finally, uptake and seeding by α-synuclein fibrils, but not huntingtin fibrils, occurs by the same mechanism as tau. This work suggests a unifying mechanism of cell uptake and propagation for tauopathy and synucleinopathy. Show less