Differential impact of resilience on demoralization and depression in Parkinson disease.

Objectives: The objective of this study was to study the interrelations of demoralization, depression, and resilience in patients with Parkinson disease, and, more specifically, to determine if higher resilience in patients with Parkinson disease is associated with lower demoralization, lower depression, or both. Methods: Outpatients with Parkinson disease (N = 95) were assessed for demoralization, depression, and resilience, as well as sociodemographic, clinical, and treatment-related variables. Bivariable associations, standard regressions, linear regression with copula correction, and correspondence analysis were used to analyze the data. Results: Although the bivariable association between resilience and depression was statistically significant, the association ceased to be significant when demoralization was taken into consideration in both standard regressions and linear regression with copula correction. By contrast, the association between resilience and demoralization was significant when depression was not taken into consideration and continued to be significant when depression was taken into consideration. Correspondence analysis revealed that low resilience was strongly related to demoralization combined with depression, whereas normal resilience was closely correlated with depression without demoralization. Conclusion: These results expand our understanding of resilience by suggesting that it is a mechanism evolved to reduce or prevent demoralization and not just depression. Reducing demoralization and strengthening resilience as part of a comprehensive treatment plan are likely to improve the prognosis of Parkinson disease.

Suicidal risk and demoralization in Parkinson disease.

OBJECTIVE: We aimed to determine suicide risk and lifetime suicidal ideation in Parkinson disease (PD) patients versus controls and how depression, demoralization, and insomnia are associated with suicidality. METHODS: In this case-control study, PD patients and matched controls were recruited from movement disorder clinics, Michael J. Fox Foundation, and Research Match websites. Suicide risk and suicidal ideation were assessed using the Suicidal Behavior Questionnaire-revised (SBQ-R) and Columbia-Suicide Severity Rating Scale. Lifetime depression was assessed using the Brief Lifetime Depression Scale, sleep using Insomnia Severity Index (ISI), demoralization using Diagnostic Criteria for Psychosomatic Research and Kissane Demoralization Scales, and non-motor symptoms using UPDRS Non-Motor Aspects of Experiences of Daily Living scale (nM-EDL). RESULTS: 186 PD participants and 177 controls were matched for age (64.2 ± 7.7 years), sex (48.8% female), and socioeconomics. PD participants were not more likely than controls to have high suicide risk (SBQ-R ≥ 7) (7.5% vs. 11.3%; p = 0.22) or to have had a lifetime suicide plan or attempt (2.7% vs. 5.1%; p = 0.24), but were less likely to have had lifetime suicidal ideation (23.1% vs. 35.0%; p = 0.01). PD participants were more likely than controls to have lifetime depression history (34.4% vs. 20.9%; p = 0.004), and demoralization (19.9% vs. 10.7%; p = 0.02), and had higher ISI scores (8.7 ± 5.8 vs. 5.1 ± 4.5; p < 0.0001). PD patients with high versus normal suicide risk had higher nM-EDL scores (16.5 ± 6.8 vs. 10.7 ± 5.9; p = 0.002), and more demoralization (71.4% vs. 21.5%; p < 0.0001). CONCLUSIONS: Suicide risk is not elevated and suicidal ideation is uncommon in PD, despite the high prevalence of depression and demoralization.

Demoralization in Parkinson disease.

OBJECTIVE: To determine the prevalence and associated features of demoralization in Parkinson disease (PD). METHODS: Participants with PD and controls were prospectively recruited from outpatient movement disorder clinics and the community. Demoralization was defined as scoring positively on the Diagnostic Criteria for Psychosomatic Research, Demoralization questionnaire or Kissane Demoralization Scale score ≥24. Depression was defined as Patient Health Questionnaire-9 score ≥10. Forward stepwise logistic regression was used to determine the odds of having demoralization in the overall, control, and PD cohorts. RESULTS: Demoralization occurred in 18.1% of 94 participants with PD and 8.1% of 86 control participants (p = 0.05). These 2 groups were otherwise comparable in age, sex, education, economics, race, and marital status. Although demoralization was highly associated with depression, there were individuals with one and not the other. Among participants with PD, 7 of 19 (36.8%) depressed individuals were not demoralized, and 5 of 17 (29.4%) demoralized individuals were not depressed. In the overall cohort, having PD (odds ratio 2.60, 95% confidence interval 1.00-6.80, p = 0.051) was associated with demoralization, along with younger age and not currently being married. In the PD cohort, younger age and Unified Parkinson's Disease Rating Scale, part III score (per score 1) were associated with demoralization (odds ratio 1.06, 95% confidence interval 1.01-1.12, p = 0.02). CONCLUSIONS: Demoralization is common in PD and is associated with motor dysfunction. In demoralization, there is a prominent inability to cope, making it somewhat distinct from depression. Treatment approaches are also different, making it important to identify demoralization in patients with PD.

Velopharyngeal Dystonia: An Unusual Focal Task-specific Dystonia?

BACKGROUND: Velopharyngeal dysfunction produces a nasal speech pattern because of the inability to close the nasal airway during speech, most often associated with anatomical abnormalities of the palate. CASE REPORT: We describe two cases of possible velopharyngeal dystonia, a task-specific movement disorder causing a speech pattern similar to velopharyngeal dysfunction. Both patients experienced treatment response with anticholinergic medication. DISCUSSION: Dystonia affecting speech via involvement of the pharyngeal musculature may be an unrecognized etiology of voice disorders.

Deep Brain Stimulation Target Selection in an Advanced Parkinson's Disease Patient with Significant Tremor and Comorbid Depression.

CLINICAL VIGNETTE: A 67-year-old female with advanced Parkinson's disease (PD), medically refractory tremor, and a history of significant depression presented for evaluation of deep brain stimulation (DBS) candidacy. CLINICAL DILEMMA: Traditionally, the subthalamic nucleus (STN) has been preferred over the globus pallidus interna (GPi) as a DBS target for PD patients with levodopa-responsive fluctuations in rigidity and akinesia, for whom tremor is also a significant source of impairment. However, STN stimulation is avoided in patients with a significant pre-surgical history of mood disorder. CLINICAL SOLUTION: Bilateral DBS of the GPi led to significant short-term improvement in PD motor symptoms, including significant tremor reduction. GAP IN KNOWLEDGE: There is insufficient evidence to support or refute clinicians' traditional preference for STN stimulation in treating refractory PD tremor. Similarly, the available evidence for risk of worsening depression and/or suicidality after STN DBS is mixed. Both questions require further clarification to guide patient and clinician decision-making.

Contribution of Step Length to Increase Walking and Turning Speed as a Marker of Parkinson's Disease Progression.

When increasing ambulation speed in Parkinson's disease, step cadence increases more than stride length, indicating movement scaling difficulties that affect step generation in particular. We investigated whether step length variation when increasing ambulation speed was related to disease progression. Patients with Parkinson's disease (N = 39) and controls (N = 152) performed two timed ambulation tasks: at a 'free' (self-selected) pace and then at 'maximal' speed. The total number of steps (including during turns) and time to complete the task were clinically measured. The relative contribution of step length and cadence to increased ambulation speed was determined using two methods: the ratios of change in step length or in cadence to the change in ambulation speed, and the step length index. While the relative contribution of step length and cadence to increased ambulation speed was independent of age in both control and patient groups, in Parkinson's disease there was a negative correlation between time from diagnosis and the ratio of change in step length to change in ambulation speed (R = 0.54; p = 0.0004) and the step length index (R = 0.56, p = 0.0002). In parallel, there was a positive correlation between time since diagnosis and the ratio of change in cadence to change in ambulation speed (R = 0.57; p = 0.0002). The relative contribution of step length and cadence to increased ambulation speed is age invariant but a marker of Parkinson's disease advancement, and can be easily determined in the clinical setting.

Selenium as an electron acceptor during the catalytic mechanism of thioredoxin reductase.

Mammalian thioredoxin reductase (TR) is a pyridine nucleotide disulfide oxidoreductase that uses the rare amino acid selenocysteine (Sec) in place of the more commonly used amino acid cysteine (Cys) in the redox-active tetrapeptide Gly-Cys-Sec-Gly motif to catalyze thiol/disulfide exchange reactions. Sec can accelerate the rate of these exchange reactions (i) by being a better nucleophile than Cys, (ii) by being a better electrophile than Cys, (iii) by being a better leaving group than Cys, or (iv) by using a combination of all three of these factors, being more chemically reactive than Cys. The role of the selenolate as a nucleophile in the reaction mechanism was recently demonstrated by creating a mutant of human thioredoxin reductase-1 in which the Cys497-Sec498 dyad of the C-terminal redox center was mutated to either a Ser497-Cys498 dyad or a Cys497-Ser498 dyad. Both mutant enzymes were incubated with human thioredoxin (Trx) to determine which mutant formed a mixed disulfide bond complex. Only the mutant containing the Ser497-Cys498 dyad formed a complex, and this structure has been determined by X-ray crystallography [Fritz-Wolf, K., Kehr, S., Stumpf, M., Rahlfs, S., and Becker, K. (2011) Crystal structure of the human thioredoxin reductase-thioredoxin complex. Nat. Commun. 2, 383]. This experimental observation most likely means that the selenolate is the nucleophile initially attacking the disulfide bond of Trx because a complex resulted only when Cys was present in the second position of the dyad. As a nucleophile, the selenolate of Sec helps to accelerate the rate of this exchange reaction relative to Cys in the Sec → Cys mutant enzyme. Another thiol/disulfide exchange reaction that occurs in the enzymatic cycle of the enzyme is the transfer of electrons from the thiolate of the interchange Cys residue of the N-terminal redox center to the eight-membered selenosulfide ring of the C-terminal redox center. The selenium atom of the selenosulfide could accelerate this exchange reaction by being a good leaving group (attack at the sulfur atom) or by being a good electrophile (attack at the selenium atom). Here we provide strong evidence that the selenium atom is attacked in this exchange step. This was shown by creating a mutant enzyme containing a Gly-Gly-Seccoo- motif that had 0.5% of the activity of the wild-type enzyme. This mutant lacks the adjacent, resolving Cys residue, which acts by attacking the mixed selenosulfide bond that occurs between the enzyme and substrate. A similar result was obtained when Sec was replaced with homocysteine. These results highlight the role of selenium as an electron acceptor in the catalytic mechanism of thioredoxin reductase as well as its established role as a donor of an electron to the substrate.

Oxidative folding of lysozyme with aromatic dithiols, and aliphatic and aromatic monothiols.

In vitro protein folding of disulfide containing proteins is aided by the addition of a redox buffer, which is composed of a small molecule disulfide and/or a small molecule thiol. In this study, we examined redox buffers containing asymmetric dithiols 1-5, which possess an aromatic and aliphatic thiol, and symmetric dithiols 6 and 7, which possess two aromatic thiols, for their ability to fold reduced lysozyme at pH 7.0 and 8.0. Most in vivo protein folding catalysts are dithiols. When compared to glutathione and glutathione disulfide, the standard redox buffer, dithiols 1-5 improved the protein folding rates but not the yields. However, dithiols 6 and 7, and the corresponding monothiol 8 increased the folding rates 8-17 times and improved the yields 15-42% at 1mg/mL lysozyme. Moreover, aromatic dithiol 6 increased the in vitro folding yield as compared to the corresponding aromatic monothiol 8. Therefore, aromatic dithiols should be useful for protein folding, especially at high protein concentrations.

Comparison of the oxidative folding of lysozyme at a high protein concentration using aromatic thiols versus glutathione.

The production of proteins using recombinant DNA technology often requires the use of in vitro protein folding. In order to facilitate in vitro protein folding, a redox buffer is added to the protein folding mixture. The redox buffer is composed of a small molecule disulfide and/or a small molecule thiol. Recently, redox buffers containing aromatic thiols have been shown to be an improvement over traditional redox buffers such as glutathione. For in vitro protein folding to be relevant to protein production on a larger scale, high protein concentrations are required to avoid large volumes of folding buffer. Therefore, we investigated the in vitro folding of lysozyme at 1 mg/mL instead of the traditional 0.1 mg/mL. Aromatic thiols and aromatic disulfides were compared directly with glutathione and glutathione disulfide, the most commonly used redox buffer. Folding experiments at pH 7 using aromatic thiols increased the yield by 20-40% and the folding rate constants by as much as 11 times relative to glutathione. At pH 8, improvements in yields of up to 25% and up to a 7-fold increase in folding rate constants were demonstrated. The effect of aromatic disulfide concentration was also investigated.