Objective: We examine the trajectories of and the dynamic interplay between cognitive functioning and depressive symptoms in patients with Parkinson's disease (PD) in comparison to healthy controls ...(HC) from an intraindividual perspective. Method: The DeNoPa study is a single-center, observational, longitudinal study with biennial follow-ups over 8 years. The present analyses are based on 123 PD (79 male) and 107 HC (64 male) with a mean age of 64.1 years (SD = 8.3). PD and HC completed a battery of neuropsychological tests and scales assessing depressive symptoms. We used a random-intercept cross-lagged panel model (RI-CLPM) to study their trajectories and the dynamic interplay. Results: Cognitive abilities of PD were on average d = −0.67 worse at baseline and d = −1.22 at 8-years follow-up in comparison to HC. Depressive symptoms in PD showed large variability and followed a U-shaped trajectory. From an intraindividual perspective, greater impairments in cognitive abilities were subsequently associated with increased depressive symptoms (b = −0.60, p = .03), whereas the effect in the opposite direction was not significant. Conclusions: We found indication that a decline on a global composite scale of cognition can be seen as a precursor of depressive symptoms in patients with PD. To counter cognitive losses and the subsequent mood deterioration, patient education and early cognitive (and behavioral) enrichment seem promising candidates for treatment.
Key Points
Question: What is the dynamic interplay between cognitive functioning and depressive symptoms in patients with Parkinson's disease? Findings: From an intraindividual perspective, a decrease in cognitive functioning was subsequently associated with increased depressive symptoms, but not vice versa. Importance: To counter cognitive losses and the subsequent mood deterioration, patient education and early cognitive (and behavioral) enrichment seem promising candidates for treatment. Next Steps: Intensive longitudinal data collection using smartphones may allow for a more fine-grained assessment and modeling of the dynamic interplay of nonmotor symptoms in patients with Parkinson's disease.
This was a longitudinal single-center cohort study to comprehensively explore multimodal progression markers for Parkinson disease (PD) in patients with recently diagnosed PD (n = 123) and ...age-matched, neurologically healthy controls (HC; n = 106).
Thirty tests at baseline and after 24 months covered nonmotor symptoms (NMS), cognitive function, and REM sleep behavior disorder (RBD) by polysomnography (PSG), voxel-based morphometry (VBM) of the brain by MRI, and CSF markers. Linear mixed-effect models were used to estimate differences of rates of change and to provide standardized effect sizes (d) with 95% confidence intervals (CI).
A composite panel of 10 informative markers was identified. Significant relative worsening (PD vs HC) was seen with the following markers: the Unified Parkinson's Disease Rating Scale I (d 0.39; CI 0.09-0.70), the Autonomic Scale for Outcomes in Parkinson's Disease (d 0.25; CI 0.06-0.46), the Epworth Sleepiness Scale (d 0.47; CI 0.24-0.71), the RBD Screening Questionnaire (d 0.44; CI 0.25-0.64), and RBD by PSG (d 0.37; CI 0.19-0.55) as well as VBM units of cortical gray matter (d -0.2; CI -0.3 to -0.09) and hippocampus (d -0.15; CI -0.27 to -0.03). Markers with a relative improvement included the Nonmotor Symptom (Severity) Scale (d -0.19; CI -0.36 to -0.02) and 2 depression scales (Beck Depression Inventory d -0.18; CI -0.36 to 0; Montgomery-Åsberg Depression Rating Scale d -0.26; CI -0.47 to -0.04). Unexpectedly, cognitive measures and select laboratory markers were not significantly changed in PD vs HC participants.
Current CSF biomarkers and cognitive scales do not represent useful progression markers. However, sleep and imaging measures, and to some extent NMS, assessed using adequate scales, may be more informative markers to quantify progression.
To determine nonmotor signs (NMS) and evaluate the utility of several diagnostic tools in patients with de novo Parkinson disease (PD).
This is a large single-center study of the DeNoPa cohort, ...including frequency-matched healthy controls. This study covers motor signs, NMS, and a combination of diagnostic tests including olfactory testing, transcranial sonography of substantia nigra (TCS), and polysomnography (PSG). We report the frequency and characteristics of NMS and the outcomes of nonmotor tests at the time of diagnosis.
Cross-sectional analyses of baseline investigations identified significant differences in the NMS Questionnaire (NMSQuest) and the Scopa-AUT Gastrointestinal score in 159 drug-naïve PD patients vs 110 controls. In addition, patients with PD showed reduced olfactory function, hyperechogenicity on TCS, and higher frequency of REM sleep behavior disorder (RBD). In exploring predictive markers, we found that the combination of several investigations, i.e., the NMSQuest, Scopa-AUT Gastrointestinal score, and Smell Identification Test reached an area under the receiver operating characteristic curve (AUC) of 0.913 (95% confidence interval CI 0.878-0.948). With the addition of serum cholesterol and mean heart rate values, the AUC value reached 0.919 (95% CI 886-0.953); when TCS and PSG were added, the AUC increased to 0.963 (95% CI 0.943-0.982).
We show feasibility and utility of standardized data acquisition in a large, single-center cohort of patients with de novo PD and matched healthy controls. The baseline results from our prospective investigations reached a value of >0.9 sensitivity and specificity for biological markers when we added routine laboratory investigations and quantified nonmotor features including sleep.
Male sex represents one of the major risk factors for severe COVID-19 outcome. However, underlying mechanisms that mediate sex-dependent disease outcome are as yet unknown. Here, we identify the ...CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (also known as aromatase) as a host factor that contributes to worsened disease outcome in SARS-CoV-2-infected males. We analyzed exome sequencing data obtained from a human COVID-19 cohort (n = 2,866) using a machine-learning approach and identify a CYP19A1-activity-increasing mutation to be associated with the development of severe disease in men but not women. We further analyzed human autopsy-derived lungs (n = 86) and detect increased pulmonary CYP19A1 expression at the time point of death in men compared with women. In the golden hamster model, we show that SARS-CoV-2 infection causes increased CYP19A1 expression in the lung that is associated with dysregulated plasma sex hormone levels and reduced long-term pulmonary function in males but not females. Treatment of SARS-CoV-2-infected hamsters with a clinically approved CYP19A1 inhibitor (letrozole) improves impaired lung function and supports recovery of imbalanced sex hormones specifically in males. Our study identifies CYP19A1 as a contributor to sex-specific SARS-CoV-2 disease outcome in males. Furthermore, inhibition of CYP19A1 by the clinically approved drug letrozole may furnish a new therapeutic strategy for individualized patient management and treatment.
The contribution of DRAK2 death-associated protein kinase (DAPK)-related apoptosis-inducing kinase 2 to anti-viral memory T cell responses following infection with mouse hepatitis virus (MHV) was ...examined. DRAK2 is a lymphoid-enriched serine/threonine kinase that is an important regulatory molecule involved in modulating T cell responses. Memory T cells derived from MHV-immunized Drak2− / − mice exhibited amplified proliferation and IFN-γ secretion following stimulation with viral epitopes. Transfer of Drak2− / − memory T cells into Rag1− / − mice infected intracerebrally with MHV resulted in accelerated clearance of virus from the brain. Thus, DRAK2 may be a novel target for stimulating protective immunity to viral pathogens.
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