Antiparkinsonian Medication Research Articles

Excessive phase synchronization in cortical activation during locomotion in persons with Parkinson's disease

IntroductionParkinson's disease (PD) is characterized by gait disturbances, which become severe during the advanced stages of the disease. Though gait impairments in Parkinson's disease have been extensively described in terms of spatiotemporal gait parameters, little is known regarding associated patterns of cortical activity. The objective of the present study is to test if interhemispheric synchronization differs between participants with PD and healthy elderly controls (NPD). We analyzed electroencephalography (EEG) signals recorded during bilateral movements, i.e., locomotion and hand tapping. MethodsFifteen participants with PD (‘OFF’ their anti-parkinsonian medications) and eight NPD were assessed during quiet standing, straight-line walking, turning, and hand tapping tasks. Using a 32-electrode EEG array, we quantified the synchronization in periodic cortical activation between the brain hemispheres (interhemispheric phase synchronization; inter-PS). Theta, alpha, beta, and gamma bands were evaluated. ResultsIn all bands, inter-PS was significantly higher for the PD group as compared with the NPD group during standing and walking (p < 0.001) and during bimanual tasks (p = 0.026). ConclusionsPersons with PD exhibit increased inter-PS as compared with NPD participants. These findings support previous evidence from animal studies, that bilateral cortical hypersynchronization emerges from the asymmetric neural degeneration that is at the base of the disease. Future studies should elucidate the long-term temporal development of this hypersynchronization and its clinical relevance (e.g., can it ‘serve’ as prodromal marker?).

A dynamic and screening-compatible nanoluciferase-based complementation assay enables profiling of individual GPCR–G protein interactions

G protein-coupled receptors (GPCRs) are currently the target of more than 30% of the marketed medicines. However, there is an important medical need for ligands with improved pharmacological activities on validated drug targets. Moreover, most of these ligands remain poorly characterized, notably because of a lack of pharmacological tools. Thus, there is an important demand for innovative assays that can detect and drive the design of compounds with novel or improved pharmacological properties. In particular, a functional and screening-compatible GPCR-G protein interaction assay is still unavailable. Here, we report on a nanoluciferase-based complementation technique to detect ligands that promote a GPCR-G protein interaction. We demonstrate that our system can be used to profile compounds with regard to the G proteins they activate through a given GPCR. Furthermore, we established a proof of applicability of screening for distinct G proteins on dopamine receptor D2 whose differential coupling to Gαi/o family members has been extensively studied. In a D2-Gαi1versus D2-Gαo screening, we retrieved five agonists that are currently being used in antiparkinsonian medications. We determined that in this assay, piribedil and pergolide are full agonists for the recruitment of Gαi1 but are partial agonists for Gαo, that the agonist activity of ropinirole is biased in favor of Gαi1 recruitment, and that the agonist activity of apomorphine is biased for Gαo We propose that this newly developed assay could be used to develop molecules that selectively modulate a particular G protein pathway.

Effectiveness of Integrative Therapy for Parkinson's Disease Management.

Objectives: To investigate the effectiveness of integrative therapy on prevalence and length of hospitalization and management of major complications of Parkinson’s disease (PD) in the South Korea.Methods: This study was a retrospective cohort analysis conducted using the National Health Insurance Service-National Sample Cohort in the South Korea. Patients over 65 years old who were newly diagnosed with PD during 2007–2011 were identified. The integrative therapy group was defined as patients treated with both Korean medicine (KM) and biomedicine, and the monotherapy group consisted of patients treated with biomedicine alone. From PD diagnosis to 2013, the prevalence and annual length of hospitalization because of PD and major complications (dementia, depression and pneumonia/sepsis) were analyzed using logistic regression, ANOVA and t-tests after propensity score (PS) matching with a 1:1 ratio.Results: After PS estimation and matching, the cohort used in the analysis included 228 subjects (114 integrative therapy group, 114 monotherapy group). Sex, age, index year, comorbidity, severity of disability, neurologic care, and anti-parkinsonism medication (levodopa, ropinirole, pramipexole, selegiline) were adjusted in both groups. The prevalence of hospitalization due to pneumonia/sepsis was 0.50 times (95% C.I.: 0.26–0.96) lower in the integrative therapy group than the monotherapy group, which was statistically significant (p = 0.038). The prevalence and annual length of total hospitalization and hospitalization because of PD, dementia, and depression in the integrative therapy group showed positive results compared to the monotherapy group, but these differences were not statistically significant.Conclusion: It has not been clearly identified that integrative therapy with KM and biomedicine for PD management is better treatment for patients compared to biomedicine monotherapy; however, we found a clue of better result in integrated therapy. Therefore, further investigation by increasing the number of subjects is needed to confirm the findings presented herein.

Dopamine Transporter Imaging in Parkinson Disease: Progressive Changes and Therapeutic Modification after Anti-parkinsonian Medications.

Parkinson disease (PD) is a slowly progressive neurodegenerative disease characterized by the loss of dopaminergic neurons and terminals in the nigrostriatal system. Dopamine transporter (DAT) imaging is widely performed for the differential diagnosis of PD and other degenerative parkinsonism from essential tremor, vascular parkinsonism, and drug-induced parkinsonism. DAT is the plasma membrane carrier specific to dopamine neurons that are responsible for re-uptaking dopamine from the synaptic cleft back into the nerve ending. DAT binding might reflect striatal presynaptic dysfunction or DAT expression in PD patients. Longitudinal studies of DAT imaging have reported progressive changes from early PD patients. This imaging may be used as a progressive biomarker. Follow-up DAT imaging for therapeutic interventions has been applied for several anti-parkinsonian drugs. We herein review the progressive changes and therapeutic modification of DAT binding by anti-PD medications in early PD patients.

Management of delirium in Parkinson's disease.

Delirium is an acute and fluctuating disturbance of attention and awareness. Pre-existing cognitive disturbances or dementia are the most significant risk factors for developing delirium and precipitating factors such as drug treatment, infections, trauma, or surgery may trigger delirium. Patients with Parkinson's disease (PD) are at an increased risk for delirium which may be underdiagnosed due to phenomenological overlap between delirium and chronic neuropsychiatric features of PD or side effects of dopaminergic medication. Prognosis of delirium is detrimental in many cases including permanent cognitive decline, motor impairment, and increased mortality. Management of delirium comprises of pharmacological and non-pharmacological measures. Pharmacotherapy is aimed at treating medical precipitating factors such as infections, pain, and sleep deprivation. Adjustments of anti-parkinsonian medication are recommended to prevent or treat delirium, but no hard evidence in this respect is available from controlled studies. Administration of neuroleptics and other psychoactive drugs in the treatment of delirium is controversially discussed and should be reserved for patients with severe agitation or distressing psychosis. Non-pharmacological interventions to prevent or palliate delirium are based on withdrawing precipitating or distressing factors, and to provide sensory, emotional and environmental support. Appropriate instruments to detect and assess delirium in PD are needed, and efforts are warranted to improve understanding and treatment of this severe and common disorder.

Trimetazidine and parkinsonism: A prospective study

BackgroundAlthough trimetazidine may induce parkinsonian symptoms in some patients, no systematic characterization has been reported on parkinsonism occurring during trimetazidine treatment since the first case reports. ObjectiveTo systematically investigate parkinsonism occurring during trimetazidine use. MethodsThirty-three consecutive patients on trimetazidine treatment with previously unrecognized parkinsonian symptoms were enrolled. Detailed neurological and neuropsychological examinations were performed at baseline and 1 and 12 months after trimetazidine withdrawal. In cases with persisting parkinsonian symptoms and suspected de novo Parkinson's disease, antiparkinsonian treatment was initiated. Twenty of the 33 patients underwent DaTSCAN imaging. ResultsAfter trimetazidine withdrawal, parkinsonism was completely resolved in 11 cases. The comparison of baseline data of patients with reversible and persisting parkinsonism showed that trimetazidine-induced reversible parkinsonism was mainly characterized by akinesia, rigidity, postural instability and gait disturbances (PIGD; PIGD scores: 5.3 ± 3.8 vs. 2.0 ± 1.6 points, p = 0.006) rather than tremors (tremor scores: 1.5 ± 2.2 vs. 7.7 ± 4.6 points, p = 0.000). Trimetazidine-induced reversible parkinsonism was also more symmetrical (asymmetry index: 3.1 ± 3.6 vs. 40.1 ± 22.2, p = 0.000) and milder in severity (MDS-UPDRS Part III. scores: 10.5 ± 19. vs. 30.5 ± 11.3, p = 0.040) than nonreversible parkinsonism. DaTSCAN images were normal in all trimetazidine-induced reversible parkinsonism patients, while these images were abnormal in every patient with nonreversible parkinsonism. In cases of nonreversible parkinsonism, preexisting, incipient Parkinson's disease was suspected by clinical appearance and a good response to antiparkinsonian medication. ConclusionsMild and symmetrical appearance of parkinsonism with normal DaTSCAN results can indicate drug-induced parkinsonism. Trimetazidine discontinuation generally results in permanent remission in such cases.

Frequency and Risk Factors Association of Fall Among the Idiopathic Parkinson’s Patients in Jashore, Bangladesh

Parkinson’s disease is the second most common neuro degenerative disease worldwide. Fall is common scenario in our day to day clinical practice among the older people but it is more common among the Parkinson’s people. The study was conducted to assess the frequency of fall and to ascertain the risk association among the idiopathic Parkinson’s patients. This observational study was conducted from July to December, 2018 in the district of Jashore, Bangladesh. Both the male and female clinically diagnosed as idiopathic Parkinson’s disease without taking antiparkinsonian medication were recruited in the study. Those having Parkinson’s disease due to stroke or secondary causes, orthostatic hypotension, taking anti parkinsonian drugs and the drugs may mimicking Parkinson’s disease were excluded from the study. A total 111 patients were analyzed of which 69.4% (N=77) male and 30.6% (N=34) female with the mean age of our participants was 66±10 years. The event of fall among the idiopathic Parkinson’s patients was 36.9% in the last one year where single, two and three or more episodes of fall were 20.7%, 3.6% and 12.6% respectively. No significant difference observed between faller and non-fallers among different demographic characteristics including age (<i>p: 0.091</i>) sex (<i>p: 0.058</i>) educational level (<i>p: 0.235</i>), occupational status (<i>p: 0.220</i>) and residency (<i>p: 0.547</i>). Experience of fall found more in high BMI (<i>p: 0.037</i>), hypertensive (<i>p: 0.018</i>), diabetic (<i>p: 0.009</i>) and in patients receiving multiple medications (<i>p: 0.011</i>). But duration of Parkinsonism (<i>p: 0.835</i>) does not increase fall. Based on this study, we have found that there is high frequency of fall among the idiopathic Parkinson’s patients. So, earlier identification and potential strategies to remove the risk factors may prevent falls and falls related events, thus finally reducing the morbidity and mortality in the Parkinson’s patients.

Successful use of regional anesthesia in an elderly with Parkinson's disease

Parkinson's disease (PD) is a relatively common neurological disorder which an anesthesiologist often encounters, especially with an increasing elderly surgical population. PD is associated with certain physiological aberrancies in the cardiovascular, respiratory, autonomic, and neurological systems that can have profound anesthetic implications. Drugs used in anesthesia may also interact with antiparkinsonian medications. There is controversy about the optimal anesthetic management of patients with PD. However, both general and regional anesthesia have been successfully used and described in these patients. We describe a case of a 65-year-old male with recently diagnosed PD posted for rectopexy. The patient underwent regional anesthesia successfully, and the perioperative period was uneventful. Hence, anesthetic management of patients with PD involves comprehensive evaluation, careful consideration, and meticulous planning to prevent and manage the complications that arise perioperatively.

Psychotic symptoms in Parkinson’s disease: Etiology, prevalence and treatment

Introduction. Parkinson?s disease is the second most common neurodegenerative disease with as many as 50-70% of patients experiencing psychotic symptoms during the course of the illness. Our aim was to provide an evidence-based review on the etiology, prevalence and management of psychotic symptoms in Parkinson?s disease. Material and Methods. We used references from the ?Medline? database published from 1999 to 2019. Results. The most common psychotic symptoms in Parkinson?s disease are visual hallucinations, which occur in 25-30% of patients, acoustic hallucinations in about 20%, and delusions in around 5% of these patients. The etiology of psychotic symptoms is not fully clarified, but researchers suggest a complex interrelationship of factors associated with the disease itself and the factors associated with antiparkinsonian medications. After exclusion of other etiologic causes of psychotic symptoms, it is necessary to revise the type and dose of antiparkinsonian drugs. Although pimavanserin has recently been approved by the United States Food and Drug Administration, the current treatment of choice for psychotic symptoms in Parkinson?s disease is still quetiapine. Only patients who do not tolerate or do not respond to quetiapine are treated with clozapine, which has been proven more effective, but with significant side effects. Conclusion. Timely diagnosis and adequate treatment of psychotic symptoms in Parkinson?s disease are essential, because they dramatically affect the quality of life of patients and their families. Therefore, it is necessary to establish more effective tools for screening and treatment of psychotic symptoms in Parkinson?s disease.

Neuroleptic Malignant Syndrome, a Sequalae of Multiple Administration of Antipsychotics: A Case Report

Neuroleptic malignant syndrome (NMS) is a lethal adverse drug reaction (ADR) that is often attributed to the administration of dopamine blockers, antiemetic agents as well as anti-parkinsonism medication withdrawal. We describe a challenging case of NMS, with malignant catatonia as a differential diagnosis, who was difficult to respond to treatment. The patient developed severe complications following her exposure to rapid titration using high doses of olanzapine, which was abruptly converted to chlorpromazine due to lack of efficacy, in addition to administering multiple as needed (PRN) medications for agitation. Hyperthermia, muscle rigidity, dysautonomia, mental status changes, catatonia, and some laboratory derangement were reported in this case. It is possible that factors such as naïve patients, high doses of neuroleptics, a switch from one agent to another, rapid escalation, and the increased use of parenteral therapy for managing of agitation acted collectively or individually as risk factors for developing NMS. Health care professionals should be cautious about the cumulative dose of antipsychotics used per day, including PRN medications. The delay in recognizing the early symptoms of NMS could put patients at higher risk of mortality. Lastly, it is pivotal to exclude other infectious or autoimmune etiologies before treating as NMS case.

Recent advancements in lateral trunk flexion in Parkinson disease.

Understanding the pathophysiologic underpinnings of lateral trunk flexion (LTF) in Parkinson disease (PD) has been growing. Adjusting antiparkinsonian medications, botulinum toxin, or surgical intervention has been found efficacious in some patients. Nevertheless, these treatments remain limited, often resulting in inadequate outcomes. We review patients with LTF with PD, including recent advancements in treatment and neuroimaging examination. The basal ganglia system is a major contributing factor to LTF, and the therapeutic intervention also targets the basal ganglia system, including dystonic contraction. The perceptions of the postural verticality or spatial cognition of the correct body orientation promote the severity of LTF or result in a chronic condition with irreversible structural deformities. The combination of pharmacologic interventions with nonpharmacologic interventions, such as rehabilitation, might be needed to manage LTF, and the initiation of these treatments should be started as early as possible.

Somatosensory Training Improves Proprioception and Untrained Motor Function in Parkinson's Disease.

Background: Proprioceptive impairment is a common feature of Parkinson's disease (PD). Proprioceptive function is only partially restored with anti-parkinsonian medication or deep brain stimulation. Behavioral exercises focusing on somatosensation have been promoted to overcome this therapeutic gap. However, conclusive evidence on the effectiveness of such somatosensory-focused behavioral training for improving somatosensory function is lacking. Moreover, it is unclear, if such training has any effect on motor performance in PD.Objective: To investigate, whether proprioception improves with a somatosensory focused, robot-aided training in people with PD (PWPs), and whether enhanced proprioception translates to improved motor performance.Method: Thirteen PWPs of mild-moderate clinical severity were assessed and trained ON medication using a robotic wrist exoskeleton. Thirteen healthy elderly participants served as controls. Training involved making increasingly accurate, continuous, precise small amplitude wrist flexion/extension movements. Wrist position sense acuity, as a marker of proprioception function, and spatial error during wrist pointing, as a marker of untrained motor performance, were recorded twice before and once after training. Functional hand writing kinematics exhibited during training were evaluated in the PD group for determining training-induced changes.Results: Training improved position sense acuity in all PWPs (mean change: 28%; p < 0.001) and healthy controls (mean change: 23%; p < 0.01). Second, 10/13 PD participants and 10/13 healthy control participants had reduced spatial movement error in the untrained wrist pointing task after training. Third, spatial error for the functional handwriting tasks (line tracing and tracking) did not improve with training in the PD group.Conclusion: Proprioceptive function in mild to moderate PD is trainable and improves with a somatosensory-focused motor training. Learning showed a local transfer within the trained joint degree-of-freedom as improved spatial accuracy in an unpracticed motor task. No learning gains were observed for the untrained functional handwriting task, indicating that training may be specific to the trained joint degree-of-freedom.

Impulse Control Disorders and Dopamine-Related Creativity: Pathogenesis and Mechanism, Short Review, and Hypothesis.

Impulse control disorder (ICD), including pathological gambling, hypersexuality, and compulsive shopping has been linked to antiparkinsonian medication, especially dopamine agonists. The mechanism of ICD is not completely clear, but it seems that ICD is the result of an activation of dopamine receptors, mostly D3 in the ventral striatum. Patients treated with dopamine agonists that have preferential affinity for D3 (including ropinirole and pramipexole) are much more prone to develop ICD. In addition, a genetic component is probably present, especially in young patients. Finally, environment and lifestyle may also play a role: those patients engaged in physical, social, and artistic activities are probably less likely to develop ICD compared to those patients with poor physical activity living in isolated environments.

Safety and tolerability of IRL790 in Parkinson\u2019s disease with levodopa-induced dyskinesia\u2014a phase 1b trial

IRL790 is a novel compound with psychomotor stabilizing properties primarily targeting the dopamine D3 receptor. IRL790 is developed as an experimental treatment for levodopa-induced dyskinesia (LID), impulse control disorder, and psychosis in Parkinson’s disease (PD). The primary objective was to investigate the safety and tolerability of IRL790 in PD patients with LID in a randomized controlled trial. PD patients with peak-dose dyskinesia were randomized to placebo or IRL790 treatment (1:3 ratio) for 4 weeks. Study drug was given as an adjunct treatment to the patients’ regular stable antiparkinsonian medication. Dosing was individually titrated for 14 days, whereafter dosing was kept stable for an additional 14 days. Fifteen patients were randomized to treatment and 13 patients completed the 4-week treatment. Adverse events were mostly reported during the titration phase of the trial. They were mainly central nervous system related and could be mitigated by dose adjustments. There were no serious adverse events. There were no clinically significant changes in vital signs, electrocardiogram, and laboratory parameters due to the treatment. The average dose in the stable dose phase was 18 mg daily, yielding a 2-h post-dose plasma concentration of average 229 nM on day 28. Assessments for motor function showed a numeric reduction in dyskinesia. It is concluded that IRL790 can be safely administered to patients with advanced PD. The results will be of guidance for the design of phase 2 studies.

Efficacy, acceptability and tolerability of antipsychotics in patients with schizophrenia and comorbid substance use. A systematic review and meta-analysis

Patients with schizophrenia and substance related comorbidity or substance induced psychotic disorder are difficult to treat. Although the prevalence of a comorbid substance use is approximately 40% in schizophrenia, such patients are usually excluded from clinical trials. We therefore performed a random-effects meta-analysis of all randomized controlled antipsychotic drug trials in this patient subgroup. We searched multiple databases up to May, 2018. The primary outcome was the reduction of substance user; secondary outcomes were craving, mean reduction of substance use, overall change in schizophrenia symptoms, positive and negative symptoms, response, dropouts, quality of life, social functioning, weight gain, sedation, prolactin, extrapyramidal side effects and use of antiparkinsonian medication. We identified 27 references from 19 RCTs published from 1999 to March 2017 including 1742 participants. The most frequent types of substance abuse were cannabis (8 studies) and cocaine (6 studies) use/dependence. Clozapine was superior to other antipsychotics for reduction of substance use and risperidone to olanzapine for craving. Olanzapine, clozapine and risperidone showed superiority for symptom reduction compared to some other drugs. When reported, results of side-effects followed known patterns. The evidence-base is considerable (19 RCTs), however, firm conclusions cannot be drawn due to small sample sizes of individual studies and insufficient reporting.

Intersegmental coordination patterns are differently affected in Parkinson's disease and cerebellar ataxia.

The law of intersegmental coordination (Borghese et al. 1996) may be altered in pathological conditions. Here we investigated the contribution of the basal ganglia (BG) and the cerebellum to lower limb intersegmental coordination by inspecting the plane's orientation and other parameters pertinent to this law in patients with idiopathic Parkinson's disease (PD) or cerebellar ataxia (CA). We also applied a mathematical model that successfully accounts for the intersegmental law of coordination observed in control subjects (Barliya et al. 2009). In the present study, we compared the planarity index (PI), covariation plane (CVP) orientation, and CVP orientation predicted by the model in 11 PD patients, 8 CA patients, and two groups of healthy subjects matched for age, height, weight, and gender to each patient group (Ctrl_PD and Ctrl_CA). Controls were instructed to alter their gait speed to match those of their respective patient group. PD patients were examined after overnight withdrawal of anti-parkinsonian medications (PD-off-med) and then on medication (PD-on-med). PI was above 96% in all gait conditions in all groups suggesting that the law of intersegmental coordination is preserved in both BG and cerebellar pathology. However, the measured and predicted CVP orientations rotated in PD-on-med and PD-off-med compared with Ctrl_PD and in CA vs. Ctrl_CA. These rotations caused by PD and CA were in opposite directions suggesting differences in the roles of the BG and cerebellum in intersegmental coordination during human locomotion. NEW & NOTEWORTHY Kinematic and muscular synergies may have a role in overcoming motor redundancies, which may be reflected in intersegmental covariation. Basal ganglia and cerebellar networks were suggested to be involved in crafting and modulating synergies. We thus compared intersegmental coordination in Parkinson's disease and cerebellar disease patients and found opposite effects in some aspects. Further research integrating muscle activities as well as biomechanical and neural control modeling are needed to account for these findings.

A Nationwide Survey of Parkinson's Disease Medicines Availability and Affordability in Nigeria.

Limited access to medicines can impact negatively on outcomes in people with Parkinson's disease (PD). The study objectives were to determine the availability and assess the affordability of antiparkinsonian medications in pharmacies across Nigeria. This was a cross-sectional nationwide study utilizing the World Health Organization/Health Action Initiative methodology. Strategically selected private- and public-sector pharmacies in the six geopolitical zones of Nigeria were surveyed for availability of medicines for management of early and advanced PD. The nine categories were: levodopa/peripheral decarboxylase inhibitors, dopamine receptor agonists, monoamine oxidase type B inhibitors, anticholinergics, catechol-o-methyl transferase inhibitors, atypical antipsychotics, antidepressants, antidementia drugs, and miscellaneous (e.g., drugs for orthostatism, urinary incontinence, and sleep disturbance). Unaffordability was defined as paying more than 1 days' wages (>N600 or > US$1.67) for a standard 30-day supply. One hundred twenty-three pharmacies were surveyed (62 private [50.4%] and 61 public sector [49.6%]; range of 15-25 pharmacies in each geopolitical zone). Private exceeded public-sector availability across all nine categories of PD medicines (P < 0.05). The most available medicines were dopamine receptor agonists (68.3%; predominantly ergot-derived bromocriptine), anticholinergics (56.1%; mainly trihexyphenidyl), and l-dopa formulations (48%; mainly 250/25 l-dopa/carbidopa). Only two medications (trihexyphenidyl tablets and biperiden injection) were affordable. The average number of day's minimum wages for a 30-day supply of PD medicines was 41.3 days (range, 1-371). PD medicines access is limited in Nigeria. Strategies, including engagement of stakeholders to consider interventions to improve and prioritize PD medicines access, are urgently warranted.

Bee Venom Acupuncture in Addition to Anti-Parkinsonian Medications may Improve Activities of Daily Living and Motor Symptoms More Than Medication Alone in Idiopathic Parkinson's Disease

Bee Venom Acupuncture in Addition to Anti-Parkinsonian Medications may Improve Activities of Daily Living and Motor Symptoms More Than Medication Alone in Idiopathic Parkinson's Disease

Gastrointestinal Dysfunction in Parkinson's Disease.

During the past 25years, there has been an explosion of information regarding the occurrence of gastrointestinal dysfunction in Parkinson's disease. In this review, the clinical features of gastrointestinal dysfunction in Parkinson's disease will be described and information regarding the potential role of the enteric nervous system and the gut microbiome in the genesis of Parkinson's disease will be addressed. Recognition is growing regarding the role that gastroparesis and small intestinal dysfunction may play in Parkinson's disease, especially with regard to erratic responses to anti-Parkinson medication. The presence of enteric nervous system involvement in Parkinson's disease is now well established, but whether the enteric nervous system is the starting point for Parkinson's disease pathology remains a source of debate. The potential role of the gut microbiome also is beginning to emerge. Gastrointestinal dysfunction is a prominent nonmotor feature of Parkinson's disease and dysfunction can be found along the entire length of the gastrointestinal tract. The enteric nervous system is clearly involved in Parkinson's disease. Whether it is the initial source of pathology is still a source of controversy. There also is growing recognition of the role that the gut microbiome may play in Parkinson's disease, but much more research is needed to fully assess this aspect of the disorder.

Altered Functional Interactions of Inhibition Regions in Cognitively Normal Parkinson's Disease.

Deficient inhibitory control in Parkinson’s disease (PD) is often observed in situations requiring inhibition of impulsive or prepotent behaviors. Although activation of the right-hemisphere frontal-basal ganglia response inhibition network is partly altered in PD, disturbances in interactions of these regions are poorly understood, especially in patients without cognitive impairment. The present study investigated context-dependent connectivity of response inhibition regions in PD patients with normal cognition and control participants who underwent fMRI while performing a stop signal task. PD participants were tested off antiparkinsonian medication. To determine if functional disturbances depended on underlying brain structure, aberrant connectivity was correlated with brain volume and white-matter tissue diffusivity. We found no group differences in response inhibition proficiency. Yet the PD group showed functional reorganization in the long-range connectivity of inhibition regions, despite preserved within network connectivity. Successful inhibition in PD differed from the controls by strengthened connectivity of cortical regions, namely the right dorsolateral prefrontal cortex, pre-supplementary motor area and right caudal inferior frontal gyrus, largely with ventral and dorsal attention regions, but also the substantia nigra and default mode network regions. Successful inhibition in controls was distinguished by strengthened connectivity of the right rostral inferior frontal gyrus and subcortical inhibition nodes (right caudate, substantia nigra, and subthalamic nucleus). In both groups, the strength of context-dependent connectivity correlated with various indices of response inhibition performance. Mechanisms that may underlie aberrantly stronger context-specific connectivity include reduced coherence within reorganized systems, compensatory mechanisms, and/or the reorganization of intrinsic networks. In PD, but not controls, abnormally strengthened connectivity was linked to individual differences in underlying brain volumes and tissue diffusivity, despite no group differences in structural variables. The pattern of structural-functional associations suggested that subtle decreases in tissue diffusivity of underlying tracts and posterior cortical volumes may undermine the enhancement of normal cortical-striatal connectivity or cause strengthening in cortical-cortical connectivity. These novel findings demonstrate that functionally reorganized interactions of inhibition regions predates the development of inhibition deficits and clinically significant cognitive impairment in PD. We speculate that altered interactions of inhibition regions with attention-related networks and the dopaminergic system may presage future decline in inhibitory control.