The TRACK-PD study: protocol of a longitudinal ultra-high field imaging study in Parkinson's disease.

BACKGROUND: The diagnosis of Parkinson's Disease (PD) remains a challenge and is currently based on the assessment of clinical symptoms. PD is also a heterogeneous disease with great variability in symptoms, disease course, and response to therapy. There is a general need for a better understanding of this heterogeneity and the interlinked long-term changes in brain function and structure in PD. Over the past years there is increasing interest in the value of new paradigms in Magnetic Resonance Imaging (MRI) and the potential of ultra-high field strength imaging in the diagnostic work-up of PD. With this multimodal 7 T MRI study, our objectives are: 1) To identify distinctive MRI characteristics in PD patients and to create a diagnostic tool based on these differences. 2) To correlate MRI characteristics to clinical phenotype, genetics and progression of symptoms. 3) To detect future imaging biomarkers for disease progression that could be valuable for the evaluation of new therapies. METHODS: The TRACK-PD study is a longitudinal observational study in a cohort of 130 recently diagnosed (≤ 3 years after diagnosis) PD patients and 60 age-matched healthy controls (HC). A 7 T MRI of the brain will be performed at baseline and repeated after 2 and 4 years. Complete assessment of motor, cognitive, neuropsychiatric and autonomic symptoms will be performed at baseline and follow-up visits with wearable sensors, validated questionnaires and rating scales. At baseline a blood DNA sample will also be collected. DISCUSSION: This is the first longitudinal, observational, 7 T MRI study in PD patients. With this study, an important contribution can be made to the improvement of the current diagnostic process in PD. Moreover, this study will be able to provide valuable information related to the different clinical phenotypes of PD and their correlating MRI characteristics. The long-term aim of this study is to better understand PD and develop new biomarkers for disease progression which may help new therapy development. Eventually, this may lead to predictive models for individual PD patients and towards personalized medicine in the future. TRIAL REGISTRATION: Dutch Trial Register, NL7558 . Registered March 11, 2019.

Ethics of Deep Brain Stimulation in Adolescent Patients with Refractory Tourette Syndrome: a Systematic Review and Two Case Discussions.

INTRODUCTION: Tourette Syndrome (TS) is a childhood onset disorder characterized by vocal and motor tics and often remits spontaneously during adolescence. For treatment refractory patients, Deep Brain Stimulation (DBS) may be considered. METHODS AND RESULTS: We discuss ethical problems encountered in two adolescent TS patients treated with DBS and systematically review the literature on the topic. Following surgery one patient experienced side effects without sufficient therapeutic effects and the stimulator was turned off. After a second series of behavioural treatment, he experienced a tic reduction of more than 50%. The second patient went through a period of behavioural disturbances that interfered with optimal programming, but eventually experienced a 70% tic reduction. Sixteen DBS surgeries in adolescent TS patients have been reported, none of which pays attention to ethical aspects. DISCUSSION: Specific ethical issues arise in adolescent TS patients undergoing DBS relating both to clinical practice as well as to research. Attention should be paid to selecting patients fairly, thorough examination and weighing of risks and benefits, protecting the health of children and adolescents receiving DBS, special issues concerning patient's autonomy, and the normative impact of quality of life. In research, registration of all TS cases in a central database covering a range of standardized information will facilitate further development of DBS for this indication. CONCLUSION: Clinical practice should be accompanied by ongoing ethical reflection, preferably covering not only theoretical thought but providing also insights in the views and perspectives of those concerned, that is patients, family members and professionals.

Functional connectivity disruptions correlate with cognitive phenotypes in Parkinson's disease.

Cognitive deficits in Parkinson's disease are thought to be related to altered functional brain connectivity. To date, cognitive-related changes in Parkinson's disease have never been explored with dense-EEG with the aim of establishing a relationship between the degree of cognitive impairment, on the one hand, and alterations in the functional connectivity of brain networks, on the other hand. This study was aimed at identifying altered brain networks associated with cognitive phenotypes in Parkinson's disease using dense-EEG data recorded during rest with eyes closed. Three groups of Parkinson's disease patients (N = 124) with different cognitive phenotypes coming from a data-driven cluster analysis, were studied: G1) cognitively intact patients (63), G2) patients with mild cognitive deficits (46) and G3) patients with severe cognitive deficits (15). Functional brain networks were identified using a dense-EEG source connectivity method. Pairwise functional connectivity was computed for 68 brain regions in different EEG frequency bands. Network statistics were assessed at both global (network topology) and local (inter-regional connections) level. Results revealed progressive disruptions in functional connectivity between the three patient groups, typically in the alpha band. Differences between G1 and G2 (p < 0.001, corrected using permutation test) were mainly frontotemporal alterations. A statistically significant correlation (ρ = 0.49, p < 0.001) was also obtained between a proposed network-based index and the patients' cognitive score. Global properties of network topology in patients were relatively intact. These findings indicate that functional connectivity decreases with the worsening of cognitive performance and loss of frontotemporal connectivity may be a promising neuromarker of cognitive impairment in Parkinson's disease.

Deep Brain Stimulation of the internal globus pallidus in refractory Tourette Syndrome.

OBJECTIVE: Deep Brain Stimulation in psychiatric disorders is becoming an increasingly performed surgery. At present, seven different targets have been stimulated in Tourette Syndrome, including the internal globus pallidus. We describe the effects on tics and comorbid behavioral disorders of Deep Brain Stimulation of the anterior internal globus pallidus in five patients with refractory Tourette Syndrome. METHODS: This study was performed as an open label study with follow-up assessment between 12 and 38 months. Patients were evaluated twice, one month before surgery and at long-term follow-up. Primary outcome was tic severity, assessed by several scales. Secondary outcomes were comorbid behavioral disorders, mood and cognition. The final position of the active contacts of the implanted electrodes was investigated and side effects were reported. RESULTS: Three males and two females were included with a mean age of 41.6 years (SD 9.7). The total post-operative score on the Yale Global Tic Severity Scale was significantly lower than the pre-operative score (42.2±4.8 versus 12.8±3.8, P=0.043). There was also a significant reduction on the modified Rush Video-Based Tic Rating Scale (13.0±2.0 versus 7.0±1.6, P=0.041) and in the total number of video-rated tics (259.6±107.3 versus 49.6±24.8, P=0.043). No significant difference on the secondary outcomes was found, however, there was an improvement on an individual level for obsessive-compulsive behavior. The final position of the active contacts was variable in our sample and no relationship between position and stimulation effects could be established. CONCLUSION: Our study suggests that Deep Brain Stimulation of the anterior internal globus pallidus is effective in reducing tic severity, and possibly also obsessive-compulsive behavior, in refractory Tourette patients without serious adverse events or side-effects.

A structural modeling analysis of anxiety and depression in patients undergoing coronary artery bypass graft surgery: a model generating approach.

The present study is a longitudinal study designed to explore structural relationships between anxiety, depression, personality, and background factors (e.g., gender, age, and complicated medical characteristics) in patients undergoing coronary artery bypass graft (CABG) surgery. At two timepoints before and two after CABG, 217 patients completed self-report questionnaires. To explore structural relationships, the structural equation modeling (SEM) method was applied. Using the model-generating approach, a model was developed, providing a good fit. The structural relationships revealed, in particular, the key position of neuroticism, which was related to both pre- and postoperative anxiety and depression. Relationships between anxiety and depression over time, both intra- and interrelationships, were relatively weak. Relationships between anxiety and depression at the same points in time were relatively strong, with preoperative depression leading to preoperative anxiety, and postoperative anxiety leading to postoperative depression. To provide a useful framework for development of intervention strategies, further research is needed to evaluate the plausibility of the final structural model.

The course of anxiety and depression in patients undergoing coronary artery bypass graft surgery.

A semilongitudinal study was designed to follow-up the course of anxiety and depression in patients undergoing coronary artery bypass graft (CABG) surgery. The focus was on possible effects of gender and age on variations in both mean level and interindividual differences over time. At two timepoints before and two after surgery, 217 patients completed self-report questionnaires. Multivariate testing revealed an overall decrease in mean levels of anxiety and depression in the postoperative period but different trends for men and women. Compared with men, women reported more anxiety and depression, both pre- and postoperatively, but showed a relatively stronger decrease in the early postoperative period. Regarding variations in interindividual differences over time, multivariate testing revealed different trends of depression for men and women. Women appeared to be most homogeneous in the early days after surgery, whereas interindividual differences for men showed a stable trend.

Prediction of quality of life after coronary artery bypass graft surgery: a review and evaluation of multiple, recent studies.

OBJECTIVE: To review studies predicting psychosocial outcome after coronary artery bypass graft surgery (CABG). METHODS: Seventeen prospective studies, appearing in the MEDLINE and PsycLIT data bases between 1986 and 1996, were reviewed regarding objectives, methodological issues, results, and clinical relevance. RESULTS: All studies reported that psychological factors bad predictive value. In particular, preoperative anxiety and depression predicted postoperative psychological maladjustment; social support, preoperative feelings of control, denial, and optimism contributed to psychological adjustment. CONCLUSIONS: Many specific psychological outcomes seem to be best predicted by preoperative assessment of functions in that specific area, especially in the case of anxiety and depression. Furthermore, personality factors including denial, optimism, control, and the need for support appear to be predictors of psychological outcome. Appropriate identification of predictive factors might improve the development of individually tailored interventions for patients at risk of postoperative psychological problems.

Variable FMR1 gene methylation of large expansions leads to variable phenotype in three males from one fragile X family.

The fragile X syndrome is caused by an expanded CGG repeat (> 200 units, full mutation) at the 5' end of the FMR1 gene, which is associated with methylation of a CpG island upstream of the FMR1 gene and down regulation of the transcription. We describe three related males with full mutations in the FMR1 gene, as defined by size, but with different percentages of unmethylated alleles (+/-90%, 35%, and 15%, respectively) as studied in leucocytes. Normal mental status was observed in the male who showed 90% lack of methylation, whereas his two cousins were retarded. The mentally normal male did show some minor facial features of the fragile X syndrome; the FMR protein was detectable in 75% of his leucocytes. In all three cases, the proportion of unmethylated FMR1 genes corresponded to the percentage of leucocytes showing FMR1 protein production. Our results indicated a direct relationship between methylation and the ability to produce FMR protein. These cases will be discussed in relation to the phenotypic effects of incompletely methylated full mutations in the FMR1 gene as observed by others.