LRRK2 G2019S variant is associated with transcriptional changes in Parkinson's disease human myeloid cells under proinflammatory environment.

The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson's disease (PD). LRRK2, although ubiquitously expressed, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation under baseline culture conditions and following exposure to the proinflammatory factors IFNγ and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFNγ stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.

Anti-TIF-1α/γ Antibody-Positive Dermatomyositis Associated With Metastatic Prostatic Adenocarcinoma.

ABSTRACT: Dermatomyositis (DM) is an autoimmune myopathy characterized by proximal muscle weakness and distinct skin findings. DM is associated with an increased risk of malignancy in adults. We describe a case of dermatomyositis with unusually severe oropharyngeal dysphagia and respiratory muscle weakness on presentation, who was found to have underlying metastatic prostate cancer. Prostate cancer is uncommonly associated with DM. The patient tested positive for antitranscription intermediate family-1 (anti-TIF-1, also known as anti-p155/410) antibodies, which are linked to malignancy-associated DM in adults and are associated with dysphagia and more severe cutaneous findings.

Education in Neurology Resident Documentation Using Payroll Simulation.

BACKGROUND: Approaches for teaching neurology documentation include didactic lectures, workshops, and face-to-face meetings. Few studies have assessed their effectiveness. OBJECTIVE: To improve the quality of neurology resident documentation through payroll simulation. METHODS: A documentation checklist was created based on Medicaid and Medicare evaluation and management (E/M) guidelines. In the preintervention phase, neurology follow-up clinic charts were reviewed over a 16-week period by evaluators blinded to the notes' authors. Current E/M level, ideal E/M level, and financial loss were calculated by the evaluators. Ideal E/M level was defined as the highest billable level based on the documented problems, alongside a supporting history and examination. We implemented an educational intervention that consisted of a 1-hour didactic lecture, followed by e-mail feedback "paystubs" every 2 weeks detailing the number of patients seen, income generated, income loss, and areas for improvement. Follow-up charts were assessed in a similar fashion over a 16-week postintervention period. RESULTS: Ten of 11 residents (91%) participated. Of 214 charts that were reviewed preintervention, 114 (53%) had insufficient documentation to support the ideal E/M level, leading to a financial loss of 24% ($5,800). Inadequate documentation was seen in all 3 components: history (47%), examination (27%), and medical decision making (37%). Underdocumentation did not differ across residency years. Postintervention, underdocumentation was reduced to 14% of 273 visits (P < .001), with a reduction in the financial loss to 6% ($1,880). CONCLUSIONS: Improved documentation and increased potential reimbursement was attained following a didactic lecture and a 16-week period in which individual, specific feedback to neurology residents was provided.

Case Studies in Tremor.

Tremor is a frequent patient complaint in the neurologist's office. Nevertheless, despite the routine nature of this office presentation, misdiagnosis of common tremors is not an infrequent practice. In addition, there are less common causes of tremor that can be missed if the clinician is not aware of key features. An organized and methodical history and neurologic examination are essential in developing the differential diagnosis in tremor patients and ultimately in achieving the correct diagnosis. Awareness of key historical features associated with tremor and knowledge of the movement disorders examination will improve tremor assessment.

Clozapine Treatment for Impulse Control Disorders in Parkinson's Disease Patients: A Case Series.

Impulse control disorders (ICDs) are nonmotor complications of dopaminergic medications characterized by problems in behavioral self-control. Common management involves discontinuing or lowering dopaminergic medication, often producing motor worsening. We performed a retrospective chart review of Parkinson's disease (PD) patients treated with clozapine for ICDs. Four patients treated with clozapine for ICD were identified. Three patients were men. All 4 took dopaminergic medications at the time that ICDs developed; all received dopamine agonist therapy. ICDs included compulsive shopping, binge drinking, and hypersexuality. All 4 patients had complete resolution of symptoms while taking clozapine (12.5-37.5 mg). Two patients discontinued clozapine because of side effects. Larger studies are needed to further evaluate clozapine's role in treating PD patients with ICD.

Spatial Discrimination Threshold Abnormalities are not Detected in a Pilot Study of DYT6 Dystonia Mutation Carriers.

BACKGROUND: Spatial discrimination thresholds (SDTs) assess somatosensory integration, and provide a window into better understanding the pathophysiology of dystonia. They are abnormal in some focal dystonias, but normal in DYT1 dystonia. It is unknown whether SDTs are altered in DYT6 gene mutation carriers (C). METHODS: SDTs were assessed in 17 DYT6 C (including eight manifesting carriers), 15 DYT1 C (including seven manifesting carriers) and 34 controls, using a standardized grating orientation task. Subjects were asked to recognize the orientation of Johnson-Van Boven-Philips (JVP) dome gratings on either index fingertip until 40% or more answers were incorrect. SDTs between indexes were calculated and averaged, with a final SDT assigned to each subject, and tertiles for control SDTs were constructed. RESULTS: SDTs of DYT6 C or DYT1 C were comparable to those of controls, and not more likely to be in the worst tertile (p = 0.8 for DYT6 C vs. controls and p = 1.0 for DYT1 C vs. controls). This was independent of gene expression. DISCUSSION: DYT6 carriers do not have impaired SDTs with the JVP dome paradigm. The normal SDT pattern thus suggests shared sensory physiologic patterns with DYT1 dystonia.