Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease.

OBJECTIVE: To determine how single nucleotide variants (SNVs) and copy number variants (CNVs) contribute to molecular diagnosis in familial Parkinson disease (PD), we integrated exome sequencing (ES) and genome-wide array-based comparative genomic hybridization (aCGH) and further probed CNV structure to reveal mutational mechanisms. METHODS: We performed ES on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated ES and aCGH data for pathogenic SNVs and CNVs at Mendelian PD gene loci. We confirmed SNVs via Sanger sequencing and further characterized CNVs with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing. RESULTS: Using ES, we discovered individuals with known pathogenic SNVs in GBA (p.Glu365Lys, p.Thr408Met, p.Asn409Ser, and p.Leu483Pro) and LRRK2 (p.Arg1441Gly and p.Gly2019Ser). Two subjects were each double heterozygotes for variants in GBA and LRRK2. Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.Asn52Metfs*29, p.Thr240Met, p.Pro437Leu, and p.Trp453*) and likely disrupting CNVs at the PRKN locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors. CONCLUSIONS: Integrated ES and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PRKN CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

Assessment of the Progression of Poststroke Depression in Ischemic Stroke Patients Using the Patient Health Questionnaire-9.

BACKGROUND: Poststroke depression (PSD) affects one-third of stroke patients and is linked with higher stroke morbidity, mortality, and recurrence. Current guidelines do not direct when to screen for PSD, and predictors of PSD are not well understood. We sought to understand progression of PSD symptoms early after ischemic stroke, identify predictors of PSD, and describe the use of antidepressants in PSD. METHODS: We collected demographic, clinical, and PSD (Patient Health Questionnaire-9; PHQ-9) data from ischemic stroke patients hospitalized at our Comprehensive Stroke Center and followed up in our clinic. PHQ-9 was obtained during hospitalization and again in clinic within 180 days of discharge. We performed univariate analysis and logistic regression to detect variables associated with PSD. RESULTS: Among 201 patients, PSD symptoms (PHQ-9 > 4) were identified in 30% of patients during hospitalization and 46% during follow-up (54% of which had no symptoms during hospitalization). At follow-up, 36% were worse by PHQ-9 category. In univariate analysis, follow-up modified Rankin Scale (mRS) greater than or equal to 2 (P = .03) and antidepressant prescription (P < .001) were associated with worsening PHQ-9 category. In logistic regression analysis, follow-up mRS greater than or equal to 2 (P = .02), posterior circulation stroke (P = .03), and antidepressant prescription (P < .01) were associated with worsening PHQ-9 category. CONCLUSIONS: Almost half of ischemic stroke patients develop PSD symptoms and more than one-third worsen between hospitalization and follow-up. Poststroke disability (mRS ≥ 2) and posterior circulation stroke were associated with worsening PSD. Worsening PSD symptoms prompted treatment change in 29% of patients. Screening for PSD during hospitalization should be repeated during early follow-up.

A Retrospective Study to Identify Novel Factors Associated with Post-stroke Anxiety.

BACKGROUND AND PURPOSE: Post-stroke anxiety (PSA) is common and disabling. PSA should be considered as an important outcome in stroke. However, there is a lack of understanding of factors that may be linked to PSA. The purpose of this study was to determine the frequency of PSA and sociodemographic and clinical factors associated with PSA in a cohort of racially and ethnically diverse stroke patients. METHODS: We conducted a retrospective study of ischemic and hemorrhagic stroke patients seen in a stroke outpatient clinic from August 1, 2017 to June 30, 2018. Patients were eligible if a Generalized Anxiety Disorder 7-Item (GAD-7) instrument was available. GAD-7 scores greater than or equal to 10 indicated the presence of moderate to severe PSA. Multivariable logistic regression was used to identify independent sociodemographic and clinical factors associated with PSA. RESULTS: Records from 289 stroke patients with a GAD-7 instrument were analyzed. PSA was common (21%; GAD-7 ≥ 10). Fifty-seven percent of females had a GAD-7 greater than or equal to 10 compared to 41% of females who had a GAD-7 less than 10 (P = .03). Multivariable analysis found that self-reported nonmarried status (odds ratio, 3.27; 95% confidence interval, 1.44-7.44), excessive fatigue (odds ratio, 4.46; 95% confidence interval, 1.87-10.63), and depression (odds ratio, 1.24; 95% confidence interval, 1.16-1.33) were independently associated with PSA. CONCLUSIONS: PSA may occur more frequently in those who report non-married, excessive fatigue, or depression. Trials of PSA interventions should consider the potential impact of social support, depression, and comorbid conditions contributing to post-stroke fatigue, including sleep apnea.

Does care in a specialised stroke prevention clinic improve poststroke blood pressure control: a protocol for a randomised comparative effectiveness study.

INTRODUCTION: Hypertension is a major risk factor for recurrent stroke, and blood pressure (BP) reduction is associated with decreased risk of stroke recurrence. However, many stroke survivors have poorly controlled BP after their initial stroke. The Stroke Transitions Education and Prevention (STEP) Clinic was established to provide a comprehensive approach to stroke risk factor reduction. METHODS AND ANALYSIS: This randomised comparative effectiveness study was designed to assess the impact of care in the STEP clinic versus usual care on poststroke BP reduction. Eligible hospitalised patients with ischaemic stroke, haemorrhagic stroke or transient ischaemic attack are scheduled for a clinic screening visit within 4 weeks of discharge if they meet baseline inclusion criteria. At the clinic visit, patients who have uncontrolled BP, defined as automated office BP ≥135/85 mm Hg are randomised (1:1) to either the STEP clinic or usual care for management. STEP clinic patients receive instructions to self-monitor, a BP monitor, sleep apnoea screening, dietary counselling, review of BP monitoring records and adjustment of medications. Patients are followed by a neurologist and a stroke-trained nurse practitioner. Usual care participants are seen by a neurologist and recommendations for secondary prevention are sent to primary care providers. The primary outcome is the difference in mean daytime ambulatory systolic BP at 6 months, assessed using linear regression analysis. Secondary outcomes include 24 hours ambulatory BP, medication adherence and medication self-efficacy, and composite cardiovascular events. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Boards at the McGovern Medical School at the University of Texas Health Sciences Center and the Georgetown University School of Medicine. Uninsured and Spanish-speaking patients are included in the study. TRIAL REGISTRATION NUMBER: NCT02591394; Pre-results.