Surgical and Hardware-Related Adverse Events of Deep Brain Stimulation: A Ten-Year Single-Center Experience.

INTRODUCTION: Although deep brain stimulation (DBS) is effective for treating a number of neurological and psychiatric indications, surgical and hardware-related adverse events (AEs) can occur that affect quality of life. This study aimed to give an overview of the nature and frequency of those AEs in our center and to describe the way they were managed. Furthermore, an attempt was made at identifying possible risk factors for AEs to inform possible future preventive measures. MATERIALS AND METHODS: Patients undergoing DBS-related procedures between January 2011 and July 2020 were retrospectively analyzed to inventory AEs. The mean follow-up time was 43 ± 31 months. Univariate logistic regression analysis was used to assess the predictive value of selected demographic and clinical variables. RESULTS: From January 2011 to July 2020, 508 DBS-related procedures were performed including 201 implantations of brain electrodes in 200 patients and 307 implantable pulse generator (IPG) replacements in 142 patients. Surgical or hardware-related AEs following initial implantation affected 40 of 200 patients (20%) and resolved without permanent sequelae in all instances. The most frequent AEs were surgical site infections (SSIs) (9.95%, 20/201) and wire tethering (2.49%, 5/201), followed by hardware failure (1.99%, 4/201), skin erosion (1.0%, 2/201), pain (0.5%, 1/201), lead migration (0.52%, 2/386 electrode sites), and hematoma (0.52%, 2/386 electrode sites). The overall rate of AEs for IPG replacement was 5.6% (17/305). No surgical, ie, staged or nonstaged, electrode fixation, or patient-related risk factors were identified for SSI or wire tethering. CONCLUSIONS: Major AEs including intracranial surgery-related AEs or AEs requiring surgical removal or revision of hardware are rare. In particular, aggressive treatment is required in SSIs involving multiple sites or when Staphylococcus aureus is identified. For future benchmarking, the development of a uniform reporting system for surgical and hardware-related AEs in DBS surgery would be useful.

Cognitive Behavioral Therapy for Anxiety in Parkinson's Disease: A Randomized Controlled Trial.

BACKGROUND: Anxiety disorders are among the most prevalent and disabling neuropsychiatric syndromes in patients with Parkinson's disease (PD), but no randomized controlled treatment trials of anxiety have been published to date. OBJECTIVE: The aim of this study was to assess the effectiveness of cognitive behavioral therapy (CBT) in the treatment of anxiety in patients with PD. METHODS: Forty-eight patients with PD with anxiety were randomized 1:1 between CBT and clinical monitoring only (CMO). The CBT program was developed to specifically address anxiety symptoms in PD and consisted of 10 weekly sessions. Assessments were conducted by blinded assessors at baseline, at the end of the intervention, after 3 months, and after 6 months (CBT group only). Main outcome measures were the Hamilton Anxiety Rating Scale (HARS) and the Parkinson Anxiety Scale (PAS). RESULTS: Both the CBT and CMO groups showed clinically relevant improvement. Although there was no between-group difference in outcome on the Hamilton Anxiety Rating Scale (6.7-point reduction in the CBT group versus 3.9-point reduction in the CMO group; P = 0.15), there was both a statistically significant and a clinically relevant between-group difference on the total PAS in favor of CBT (9.9-point reduction in the CBT group versus 5.2-point reduction in the CMO group; P = 0.012), which was due to improvement on the PAS subscales for episodic (situational) anxiety and avoidance behavior. This greater improvement was maintained at 3- and 6-month follow-ups. CONCLUSION: CBT is an effective treatment for anxiety in patients with PD and reduces situational and social anxiety, as well as avoidance behavior. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Rapid Dynamic Naturalistic Monitoring of Bradykinesia in Parkinson's Disease Using a Wrist-Worn Accelerometer.

Motor fluctuations in Parkinson's disease are characterized by unpredictability in the timing and duration of dopaminergic therapeutic benefits on symptoms, including bradykinesia and rigidity. These fluctuations significantly impair the quality of life of many Parkinson's patients. However, current clinical evaluation tools are not designed for the continuous, naturalistic (real-world) symptom monitoring needed to optimize clinical therapy to treat fluctuations. Although commercially available wearable motor monitoring, used over multiple days, can augment neurological decision making, the feasibility of rapid and dynamic detection of motor fluctuations is unclear. So far, applied wearable monitoring algorithms are trained on group data. In this study, we investigated the influence of individual model training on short timescale classification of naturalistic bradykinesia fluctuations in Parkinson's patients using a single-wrist accelerometer. As part of the Parkinson@Home study protocol, 20 Parkinson patients were recorded with bilateral wrist accelerometers for a one hour OFF medication session and a one hour ON medication session during unconstrained activities in their own homes. Kinematic metrics were extracted from the accelerometer data from the bodyside with the largest unilateral bradykinesia fluctuations across medication states. The kinematic accelerometer features were compared over the 1 h duration of recording, and medication-state classification analyses were performed on 1 min segments of data. Then, we analyzed the influence of individual versus group model training, data window length, and total number of training patients included in group model training, on classification. Statistically significant areas under the curves (AUCs) for medication induced bradykinesia fluctuation classification were seen in 85% of the Parkinson patients at the single minute timescale using the group models. Individually trained models performed at the same level as the group trained models (mean AUC both 0.70, standard deviation respectively 0.18 and 0.10) despite the small individual training dataset. AUCs of the group models improved as the length of the feature windows was increased to 300 s, and with additional training patient datasets. We were able to show that medication-induced fluctuations in bradykinesia can be classified using wrist-worn accelerometry at the time scale of a single minute. Rapid, naturalistic Parkinson motor monitoring has the clinical potential to evaluate dynamic symptomatic and therapeutic fluctuations and help tailor treatments on a fast timescale.

Usability of the Experience Sampling Method in Parkinson's Disease on a Group and Individual Level.

BACKGROUND: Around 50% of PD patients experience motor fluctuations, which are often accompanied by mood fluctuations. The nature of the relationship between motor and mood fluctuations remains unknown. It is suggested that the experience sampling method can reveal such associations on both a group and individual level. Revealing group patterns may enhance our understanding of symptom interactions and lead to more general treatment recommendations, whereas analyses in individual patients can be used to establish a personalized treatment plan. OBJECTIVES: To explore the usability of routinely collected experience sampling method data over a brief period of time to detect associations between motor fluctuations, affective state, and contextual factors in PD patients with motor fluctuations on a group level and on an individual level. METHODS: Eleven patients with motor fluctuations collected data at 10 semirandom moments over the day for 5 consecutive days. RESULTS: On a group level, multilevel analyses showed significant associations between all motor symptoms and positive affect. Being at home was associated with increased balance problems and rigidity. Analyses on an individual level revealed much less significant associations that mostly, but not always, were in line with the results on a group level. CONCLUSION: This exploratory study showed significant associations between affective state, motor symptoms, and contextual factors in a group of PD patients with motor fluctuations, but less so in individual patients. Given that the ultimate aim is to use the experience sampling method as an aid to personalize treatments, the sensitivity of the approach needs to be increased. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Feasibility of a Cognitive Training Game in Parkinson's Disease: The Randomized Parkin'Play Study.

Cognitive training (CT) shows modest positive effects on cognitive function in patients with Parkinson's disease (PD). Gamification may enhance adherence to traditional CT, but this has not been studied yet. Here, we investigated the feasibility of a gamified CT. We performed a randomized controlled trial including PD patients with mild cognitive impairment. Participants were randomly allocated to a 12-week home-based gamified CT intervention or waiting-list control group. Assessments were performed at baseline and at weeks 12 and 24. Forty-one patients were included (21 intervention and 20 waiting-list controls). Sixty-three percent of the intervention group trained >50% of the recommended sessions, while 81% voluntarily continued training after 12 weeks. After 24 weeks, 87.5% graded the game to be satisfactory. Global cognition scores improved after 24 weeks. Home-based gamified CT shows acceptable feasibility in patients with PD, and we observed preliminary indications for efficacy. Larger trials are needed to establish this efficacy.

Network analysis of symptoms in a Parkinson patient using experience sampling data: An n = 1 study.

BACKGROUND: Around 50% of Parkinson's disease patients experience motor fluctuations after long-term treatment with levodopa. These fluctuations may be accompanied by mood fluctuations. Routine cross-sectional assessments cannot capture the extent of these motor and mood fluctuations and their possible associations. Experience sampling techniques that use frequently repeated measurements of symptoms over time are able to capture such fluctuations. Based on such data, longitudinal associations between symptoms can be studied using network analysis. AIM: The purpose of this study is to identify longitudinal associations between motor symptoms and mood states in a patient with Parkinson's disease. METHODS: A 53-year-old man with Parkinson's disease and motor fluctuations collected experience sampling data during 34 consecutive days. A set of dependent variables included tremor, rigidity, balance problems, and "on/off" state, and the mood variables anxiety, cheerful, and "down." Independent variables were the same variables assessed at the preceding measurement. Regression coefficients were calculated and presented in a network graph. RESULTS: In this patient, anxiety and cheerfulness had a central position within the symptom network. Higher anxiety was prospectively associated with increased rigidity and tremor and with feeling "down." Cheerfulness was associated with less tremor. Balance problems were not influenced by cheerfulness nor anxiety, but increased balance problems were associated with reduced cheerfulness at the next assessment. Feeling "down" did not influence self-reported motor symptom severity at the next assessment. CONCLUSION: This n = 1 study shows that network analysis of experience sampling data may reveal longitudinal associations of self-reported motor symptoms and mood states that may have relevance for treatment strategies. © 2018 International Parkinson and Movement Disorder Society.

Frequency of mood and anxiety fluctuations in Parkinson's disease patients with motor fluctuations: A systematic review.

After 5 years of treatment with levodopa, approximately 40% to 50% of patients with Parkinson's disease (PD) develop motor complications such as dyskinesias or motor fluctuations. These are often accompanied by nonmotor fluctuations, such as fluctuations in mood symptoms. The aim of this systematic review is to assess the frequency of such mood fluctuations in PD patients with motor fluctuations and to explore the association between these mood fluctuations and motor fluctuations. We performed a systematic literature search in PubMed, Medline, and the Cochrane Library. This search yielded 10 studies, of which 9 were included after quality assessment. The frequency of anxiety fluctuations in PD patients with motor fluctuations ranged from 3.1% to 67.7% with a weighted mean of 35.4%. The frequency of fluctuations in depressive symptoms ranged from 2.1% to 71.4%, with a weighted mean of 34.9%. The frequency of fluctuations in symptoms of panic ranged from 3.1% to 54.5%, with a weighted mean of 37.1%. Symptoms of anxiety and depression are mostly present in the "off" state. We conclude that mood fluctuations occur frequently in PD patients with motor fluctuations. The methodology used to assess mood fluctuation varies widely and there is a lack of a generally accepted assessment procedure for fluctuating symptoms. Research would benefit from a more uniform approach to assessment of nonmotor fluctuations. © 2018 International Parkinson and Movement Disorder Society.

An update on adaptive deep brain stimulation in Parkinson's disease.

Advancing conventional open-loop DBS as a therapy for PD is crucial for overcoming important issues such as the delicate balance between beneficial and adverse effects and limited battery longevity that are currently associated with treatment. Closed-loop or adaptive DBS aims to overcome these limitations by real-time adjustment of stimulation parameters based on continuous feedback input signals that are representative of the patient's clinical state. The focus of this update is to discuss the most recent developments regarding potential input signals and possible stimulation parameter modulation for adaptive DBS in PD. Potential input signals for adaptive DBS include basal ganglia local field potentials, cortical recordings (electrocorticography), wearable sensors, and eHealth and mHealth devices. Furthermore, adaptive DBS can be applied with different approaches of stimulation parameter modulation, the feasibility of which can be adapted depending on specific PD phenotypes. Implementation of technological developments like machine learning show potential in the design of such approaches; however, energy consumption deserves further attention. Furthermore, we discuss future considerations regarding the clinical implementation of adaptive DBS in PD. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Prevalence of anxiety in Parkinson's disease: A systematic review and meta-analysis.

OBJECTIVE: Prevalence rates of anxiety disorders in Parkinson's disease (PD) vary widely, ranging from 6% up to 55%. The aim of this systematic review was to calculate the average point prevalence of anxiety disorders and clinically relevant anxiety symptoms in PD. METHODS: Using PubMed, we carried out a systematic literature search for studies reporting Diagnostic and Statistical Manual-defined anxiety disorders or clinically relevant anxiety symptoms assessed by an anxiety rating scale. RESULTS: A total of 49 articles were included and assessed for quality, and 45 articles fulfilled the quality criteria. The average point prevalence of anxiety disorders in PD was 31%, with nonepisodic anxiety being more prevalent than episodic anxiety. Generalized anxiety disorder was the most frequent in 14%, followed by social phobia (13.8%), anxiety not otherwise specified (13.3%), and specific phobia (13.0%). Panic disorder with or without phobia was present in 6.8% of PD patients. Of the patients, 31% fulfilled the criteria for current multiple anxiety disorders. Based on anxiety rating scale cutoff scores, clinically significant anxiety symptoms were present in a weighted average of 25.7%. CONCLUSION: This systematic review confirms that anxiety, although often unrecognized, is very common and highlights the need for efficient identification of anxiety in PD. © 2016 International Parkinson and Movement Disorder Society.

Modeling anxiety in Parkinson's disease.

BACKGROUND: The aim of this work was to construct a model for anxiety in PD and compare the relative contributions of PD-specific and -nonspecific general population risk factors for anxiety in this model. METHODS: Structural equation modeling of associations of risk factors with the anxiety outcome using a cross-sectional data set of 342 patients with PD were used. RESULTS: A model with acceptable to good fit was generated that explained 65% of the variance in anxiety scores. A previous history of depression and the severity of the depressive symptoms scored on the Hamilton Depression Rating Scale were the only nonspecific variables with a direct effect on anxiety. The presence of motor fluctuations and disease-related decline in activities of daily living were PD-specific markers of anxiety. Nonspecific risk factors had a greater influence in the model than PD-specific risk factors. Standardized regression coefficients suggested that the Hamilton Depression Rating Scale score was the most important contributor to the variation in anxiety. A post-hoc analysis showed that the effects of the following variables on anxiety levels were fully mediated by depression: sex; family history of depression; previous history of anxiety; cognitive status; difficulties in non-disease-specific activities of daily living; and severity of motor signs. CONCLUSION: In this cross-sectional study, we showed that nonspecific general population risk factors are more important markers for anxiety than PD-specific risk factors. Depression was the most prominent marker. PD-specific markers for anxiety appear to be more situational and related to off periods and disease-specific disturbances of activities of daily living.

The Parkin'Play study: protocol of a phase II randomized controlled trial to assess the effects of a health game on cognition in Parkinson's disease.

BACKGROUND: In Parkinson's disease (PD), cognitive impairment is an important non-motor symptom heralding the development of dementia. Effective treatments to slow down the rate of cognitive decline in PD patients with mild cognitive impairment are lacking. Here, we describe the design of the Parkin'Play study, which assesses the effects of a cognitive health game intervention on cognition in PD. METHODS/DESIGN: This study is a multicentre, phase-II, open-randomized clinical trial that aims to recruit 222 PD patients with mild cognitive impairment. Eligible patients have PD, Hoehn & Yahr stages I-III, are aged between 40 and 75 years, and have cognitive impairment but no dementia. The intervention group (n = 111) will be trained using a web-based health game targeting multiple cognitive domains. The control group (n = 111) will be placed on a waiting list. In order to increase compliance the health game adapts to the subjects' performance, is enjoyable, and can be played at home. From each group, 20 patients will undergo fMRI to test for potential functional brain changes underlying treatment. The primary outcome after 12 weeks of training is cognitive function, as assessed by a standard neuropsychological assessment battery and an online cognitive assessment. The neuropsychological assessment battery covers the following domains: executive function, memory, visual perception, visuoconstruction and language. A compound score for overall cognitive function will be calculated as the mean score of all test Z-scores based on the distribution of scores for both groups taken together. Secondary outcomes at follow-up visits up to 24 weeks include various motor and non-motor symptoms, compliance, and biological endpoints (fMRI). DISCUSSION: This study aims at evaluating whether a cognitive intervention among PD patients leads to an increased cognitive performance on targeted domains. Strengths of this study are a unique web-based health game intervention, the large sample size, a control group without intervention and innovations designed to increase compliance. TRIAL REGISTRATION: NTR5637 on 7-jan-2016.

TREMOR12: An Open-Source Mobile App for Tremor Quantification.

BACKGROUND: Evaluating the effect of treatment of tremor is mostly performed with clinical rating scales. Mobile applications facilitate a more rapid, objective, and quantitative evaluation of treatment effect. Existing mobile apps do not offer raw data access, which limits algorithm development. OBJECTIVE: To develop a novel open-source mobile app for tremor quantification. METHODS: TREMOR12 is an open-source mobile app that samples acceleration, rotation, rotation speed, and gravity, each in 3 axes and time-stamped in a frequency up to 100 Hz. The raw measurement data can be exported as a comma-separated value file for further analysis in the TREMOR12P data processing module. The app was evaluated with 3 patients suffering from essential tremor, who were between 55 and 71 years of age. RESULTS: This proof-of-concept study shows that the TREMOR12 app is able to detect and register tremor characteristics such as acceleration, rotation, rotation speed, and gravity in a simple and nonburdensome way. The app is compatible with current regulatory oversight by the European Union (MEDDEV regulations) and the Food and Drug Administration (FDA) guidance on mobile medical applications. CONCLUSION: TREMOR12 offers low-cost tremor quantification for research purposes and algorithm development, and may help to improve treatment evaluation.

Sialylation of Campylobacter jejuni endotoxin promotes dendritic cell-mediated B cell responses through CD14-dependent production of IFN-ß and TNF-α.

Campylobacter jejuni is the most common bacterial cause of human gastroenteritis and often precedes development of Guillain-Barré syndrome (GBS), a life-threatening paralytic disease. The incorporation of the carbohydrate sialic acid into C. jejuni lipooligosaccharides (LOS) is associated with increased severity of gastroenteritis and with induction of GBS; however, the underlying mechanisms remain completely unknown. In this study, we demonstrate that sialic acids in C. jejuni endotoxin enhance the rapid production of IFN-ß and TNF-α by human dendritic cells (DCs). Using neutralizing Abs and receptors it was shown that these DC-derived cytokines promote the proliferation of human mucosal B cells in a T cell-independent manner. The production of both IFN-ß and TNF-α by DCs in response to LOS requires CD14, and the amplified response of DCs to sialylated C. jejuni LOS is CD14 dependent. Together, these results indicate that sialylation of C. jejuni LOS increases DC activation and promotes subsequent B cell responses through CD14-driven production of IFN-ß and TNF-α. This enhanced DC/B cell response may explain the increased pathogenicity of sialylated C. jejuni and may be key to the initiation of B cell-mediated autoimmunity in GBS.

Habenula volume change in Parkinson's disease: A 7T MRI study.

OBJECTIVE: Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and early non-motor symptoms. The habenula is implicated in the pathophysiology of depression. This study investigates habenular volume in PD patients without clinical depression to show the changes in PD unrelated to depression. METHODS: The study used high-resolution 7 Tesla MRI data from the TRACK-PD study involving 104 PD patients and 44 healthy controls (HCs). The habenula was manually segmented, and volumes were measured, considering demographic data and depression scores via the Beck Depression Inventory (BDI). RESULTS: No significant correlation was found between habenular volume and BDI scores in PD patients or HCs. However, the PD group exhibited a significantly larger mean and right habenular volume than HCs. Although PD patients showed higher BDI scores, indicating more subthreshold depression, these did not correlate with the habenular volume. CONCLUSION: The results suggest that while the habenula may be involved in the symptoms of PD, its role in depression within this cohort is unclear. The changes might be related to the role of the habenula in motor symptoms. This study provides a new perspective on the role of the habenula in PD, but future research could lead to a greater understanding of the neuroanatomical features of the habenula in PD.

The habenula in Parkinson's disease: Anatomy, function, and implications for mood disorders - A narrative review.

Parkinson's disease (PD), a widespread neurodegenerative disorder, often coexists with mood disorders. Degeneration of serotonergic neurons in brainstem raphe nuclei have been linked to depression and anxiety. Additionally, the locus coeruleus and its noradrenergic neurons are among the first areas to degenerate in PD and contribute to stress, emotional memory, motor, sensory, and autonomic symptoms. Another brain region of interest is habenula, which is especially related to anti-reward processing, and its function has recently been linked to PD and to mood-related symptoms. There are several neuroimaging studies that investigated role of the habenula in mood disorders. Differences in habenular size and hemispheric symmetry were found in healthy controls compared to individuals with mood disorders. The lateral habenula, as a link between the dopaminergic and serotonergic systems, is thought to contribute to depressive symptoms in PD. However, there is only one imaging study about role of habenula in mood disorders in PD, although the relationship between PD and mood disorders is known. There is little known about habenula pathology in PD but given these observations, the question arises whether habenular dysfunction could play a role in PD and the development of PD-related mood disorders. In this review, we evaluate neuroimaging techniques and studies that investigated the habenula in the context of PD and mood disorders. Future studies are important to understand habenula's role in PD patients with mood disorders. Thus, new potential diagnostic and treatment opportunities would be found for mood disorders in PD.

Brain vascularization in deep brain stimulation surgeries: epilepsy, Parkinson's disease, and obsessive-compulsive disorder.

BACKGROUND: In our experience, we encountered more blood vessels during deep brain stimulation (DBS) surgeries in epilepsy. In this study, we have quantified and compared the cerebral vascularization in epilepsy, Parkinson's disease (PD) and obsessive-compulsive disorder (OCD). METHODS: A retrospective observational study in 15 epilepsy and 15 PD patients was performed. The amount, location, and size of blood vessels within 5 millimeters (mm) of all DBS electrode trajectories (N.=120) for both targets (anterior nucleus of the thalamus: ANT and subthalamic nucleus: STN) in both patient groups were quantified and compared on a Medtronic workstation (Dublin, Ireland). Additionally, blood vessels in the trajectories (N.=120) of another group of 15 PD (STN) and 15 OCD (ventral capsule-ventral striatum [VC-VS]) patients were quantified and compared (trajectories N.=120), also to the first group. Statistical analyses were performed with SPSS version 27.0 (descriptive statistics, independent samples t-tests, Mann Whitney U Test, ANOVA Test and post-hoc Tukey Test). A P value <0.05 was considered statistically significant. RESULTS: Our results showed a significant greater amount of cerebral blood vessels in epilepsy patients (10 SD±4) compared to PD (PD1 6 SD±1 and PD2 5 SD±3) and OCD (5 SD±1) with P<0.0001. Also, all other subanalyses showed more vascularization in the epilepsy group. CONCLUSIONS: Our results show that the brain of epilepsy patients seems to be more vascularized compared to PD and OCD patients. This can make the surgical planning for DBS more challenging, and the use of multiple trajectories limited.

Neuromelanin related ultra-high field signal intensity of the locus coeruleus differs between Parkinson's disease and controls.

INTRODUCTION: Neuromelanin related signal changes in catecholaminergic nuclei are considered as a promising MRI biomarker in Parkinson's disease (PD). Until now, most studies have investigated the substantia nigra (SN), while signal changes might be more prominent in the locus coeruleus (LC). Ultra-high field MRI improves the visualisation of these small brainstem regions and might support the development of imaging biomarkers in PD. OBJECTIVES: To compare signal intensity of the SN and LC on Magnetization Transfer MRI between PD patients and healthy controls (HC) and to explore its association with cognitive performance in PD. METHODS: This study was conducted using data from the TRACK-PD study, a longitudinal 7T MRI study. A total of 78 early-stage PD patients and 36 HC were included. A mask for the SN and LC was automatically segmented and manually corrected. Neuromelanin related signal intensity of the SN and LC was compared between PD and HC. RESULTS: PD participants showed a lower contrast-to-noise ratio (CNR) in the right SN (p = 0.029) and left LC (p = 0.027). After adding age as a confounder, the CNR of the right SN did not significantly differ anymore between PD and HC (p = 0.055). Additionally, a significant positive correlation was found between the SN CNR and memory function. DISCUSSION: This study confirms that neuromelanin related signal intensity of the LC differs between early-stage PD patients and HC. No significant difference was found in the SN. This supports the theory of bottom-up disease progression in PD. Furthermore, loss of SN integrity might influence working memory or learning capabilities in PD patients.

Cognitive Behavioral Therapy for Anxiety in Parkinson's Disease Induces Functional Brain Changes.

BACKGROUND: Cognitive behavioral therapy (CBT) reduces anxiety symptoms in patients with Parkinson's disease (PD). OBJECTIVE: The objective of this study was to identify changes in functional connectivity in the brain after CBT for anxiety in patients with PD. METHODS: Thirty-five patients with PD and clinically significant anxiety were randomized over two groups: CBT plus clinical monitoring (10 CBT sessions) or clinical monitoring only (CMO). Changes in severity of anxiety symptoms were assessed with the Parkinson Anxiety Scale (PAS). Resting-state functional brain MRI was performed at baseline and after the intervention. Functional networks were extracted by an Independent Component Analysis (ICA). Functional connectivity (FC) changes between structures involved in the PD-related anxiety circuits, such as the fear circuit (involving limbic, frontal, and cingulate structures) and the cortico-striato-thalamo-cortical limbic circuit, and both within and between functional networks were compared between groups and regressed with anxiety symptoms changes. RESULTS: Compared to CMO, CBT reduced the FC between the right thalamus and the bilateral orbitofrontal cortices and increased the striato-frontal FC. CBT also increased the fronto-parietal FC within the central executive network (CEN) and between the CEN and the salience network. After CBT, improvement of PAS-score was associated with an increased striato-cingulate and parieto-temporal FC, and a decreased FC within the default-mode network and between the dorsal attentional network and the language network. CONCLUSION: CBT in PD-patients improves anxiety symptoms and is associated with functional changes reversing the imbalance between PD-related anxiety circuits and reinforcing cognitive control on emotional processing.

Parkinsonism in Genetic Neurodevelopmental Disorders: A Systematic Review.

Background: With advances in clinical genetic testing, associations between genetic neurodevelopmental disorders and parkinsonism are increasingly recognized. In this review, we aimed to provide a comprehensive overview of reports on parkinsonism in genetic neurodevelopmental disorders and summarize findings related to genetic diagnosis, clinical features and proposed disease mechanisms. Methods: A systematic literature review was conducted in PubMed and Embase on June 15, 2021. Search terms for parkinsonism and genetic neurodevelopmental disorders, using generic terms and the Human Phenotype Ontology, were combined. Study characteristics and descriptive data were extracted from the articles using a modified version of the Cochrane Consumers and Communication Review Group's data extraction template. The protocol was registered in PROSPERO (CRD42020191035). Results: The literature search yielded 208 reports for data-extraction, describing 69 genetic disorders in 422 patients. The five most reported from most to least frequent were: 22q11.2 deletion syndrome, beta-propeller protein-associated neurodegeneration, Down syndrome, cerebrotendinous xanthomatosis, and Rett syndrome. Notable findings were an almost equal male to female ratio, an early median age of motor onset (26 years old) and rigidity being more common than rest tremor. Results of dopaminergic imaging and response to antiparkinsonian medication often supported the neurodegenerative nature of parkinsonism. Moreover, neuropathology results showed neuronal loss in the majority of cases. Proposed disease mechanisms included aberrant mitochondrial function and disruptions in neurotransmitter metabolism, endosomal trafficking, and the autophagic-lysosomal and ubiquitin-proteasome system. Conclusion: Parkinsonism has been reported in many GNDs. Findings from this study may provide clues for further research and improve management of patients with GNDs and/or parkinsonism.

TLR4-mediated sensing of Campylobacter jejuni by dendritic cells is determined by sialylation.

In Guillain-Barré syndrome (GBS), ganglioside mimicry of Campylobacter jejuni lipo-oligosaccharide (LOS) drives the production of cross-reactive Abs to peripheral nerve gangliosides. We determined whether sialic acid residues in C. jejuni LOS modulate dendritic cell (DC) activation and subsequent B cell proliferation as a possible mechanism for the aberrant humoral immune response in GBS. Highly purified sialylated LOS of C. jejuni isolates from three GBS patients induced human DC maturation and secretion of inflammatory cytokines that were inhibited by anti-TLR4 neutralizing Abs. The extent of TLR4 signaling and DC activation was greater with LOS of the wild type isolates than with nonsialylated LOS of the corresponding sialyltransferase gene knockout (cst-II mutant) strains, indicating that sialylation boosts the DC response to C. jejuni LOS. Supernatants of LOS-activated DCs induced B cell proliferation after cross-linking of surface Igs in the absence of T cells. Lower B cell proliferation indices were found with DC supernatants after DC stimulation with cst-II mutant or neuraminidase desialylated LOS. This study showed that sialylation of C. jejuni LOS enhances human DC activation and subsequent B cell proliferation, which may contribute to the development of cross-reactive anti-ganglioside Abs found in GBS patients following C. jejuni infection.