Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers.

OBJECTIVE: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. METHODS: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. RESULTS: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36-60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = -2.35 to -1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = -2.14 to -1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = -1.80 to -1.18). INTERPRETATION: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424-435.

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.

Diagnosis and Management of Dystonia.

PURPOSE OF REVIEW: This article highlights the clinical and diagnostic tools used to assess and classify dystonia and provides an overview of the treatment approach. RECENT FINDINGS: In the past 4 years, the definition and classification of dystonia have been revised, and new genes have been identified in patients with isolated hereditary dystonia (DYT23, DYT24, and DYT25). Expanded phenotypes were reported in patients with combined dystonia, such as those with mutations in ATP1A3. Treatment offerings have expanded as there are more neurotoxins, and deep brain stimulation has been employed successfully in diverse populations of patients with dystonia. SUMMARY: Diagnosis of dystonia rests upon a clinical assessment that requires the examiner to understand the characteristic disease features that are elicited through a careful history and physical examination. The revised classification system uses two distinct nonoverlapping axes: clinical features and etiology. A growing understanding exists of both isolated and combined dystonia as new genes are identified and our knowledge of the phenotypic presentation of previously reported genes has expanded. Genetic testing is commercially available for some of these conditions. Treatment options for dystonia include pharmacologic therapy, chemodenervation, and surgical intervention. Deep brain stimulation benefits many patients with various types of dystonia.

LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease.

Leucine rich repeat kinase (LRRK2) G2019S mutations are presumed to cause PD through a toxic gain of function of the protein kinase. Small molecule kinase inhibitors have been developed for the treatment of certain cancers, and some antioncogenic agents such as sunitinib, may nonspecifically inhibit LRRK2. Few studies, however, have assessed cancer risk in LRRK2 mutation carriers. To explore this risk, we evaluated records of Ashkenazi Jewish (AJ) PD patients participating in genetic research. Charts were reviewed for 163 unrelated AJ PD patients, 31 of whom harbored the G2019S mutation. History of cancer was queried at baseline intake using a form reviewing medical conditions, and charts were reviewed for all follow-up visits. 9/31 LRRK2 G2019S mutation carriers had nonskin cancers, whereas 15/132 without mutations had nonskin cancers, representing an almost threefold increased risk in this group (HR 2.9, 95% CI 1.3-6.6). Age at first nonskin cancer was younger in the LRRK2 carriers (56.0 years) than the noncarriers (62.0 years), but was not significant. 67% of the LRRK2 carriers had their cancer before the onset of PD, whereas only 40% of noncarriers developed their first nonskin cancer before onset of PD. While further evaluation is warranted, our findings indicate an increased risk of nonskin cancers in LRRK2 G2019S mutation carriers, which may be related to toxic gain of function of mutated LRRK2.