Prodromal Dementia with Lewy Bodies: A Case Series of the 3 Prodromal Types from Clinical Practice.

Prodromal dementia with Lewy bodies (DLB) refers to a state prior to the onset of dementia with clinical signs or symptoms that may indicate the future development of DLB. Prodromal symptoms can include not only cognitive deficits but also a mix of clinical features including sleep disorders, autonomic dysfunction, and neuro-psychiatric disturbances. While diagnostic criteria for the subtypes of prodromal DLB were recently published, they are largely used in research settings. However, these criteria have important implications for clinical practice. Recognition of prodromal DLB stages can lead to identifying deficits sooner, improved patient and family counseling, and advance care planning. This case series presents examples of the 3 subtypes of prodromal DLB - mild cognitive impairment onset, delirium onset, and psychiatric onset - to help clinicians identify individuals who may be on a trajectory to develop DLB.

Identification and Management of Persistent Stimulation-Induced Dyskinesia Associated with STN DBS: The See-Saw Dilemma.

Clinical vignette: A 73-year-old woman with Parkinson's disease (PD) underwent implantation of bilateral subthalamic nucleus deep brain stimulators (STN-DBS) to address bilateral upper extremity medication-refractory tremor. Post-operatively, she experienced a "see-saw effect" where small increases in stimulation resulted in improvement in one symptom (tremor) with concurrent worsening in another (dyskinesia). Clinical dilemma: SID is usually considered a positive predictor of DBS outcome. However, there are cases where SID cannot be optimized. Lead location and pre-operative characteristics may contribute to this adverse effect. If the combination of programming and medication adjustments fails to resolve SID, what can be done to "rescue" the outcome? Clinical solution: Management of SID requires a gradual and steadfast programming approach. Post-operative lead localization can guide advanced programming and decision-making. Rescue surgical interventions may be considered. Gap in knowledge: In cases where SID is persistent despite deploying persistent optimization strategies, there is limited guidance on next steps.

Neuroimaging Pearls from the MDS Congress Video Challenge. Part 2: Acquired Disorders.

The MDS Video Challenge continues to be the one of most widely attended sessions at the International Congress. Although the primary focus of this event is the presentation of complex and challenging cases through videos, a number of cases over the years have also presented an unusual or important neuroimaging finding related to the case. We reviewed the previous Video Challenge cases and present here a selection of those cases which incorporated such imaging findings. We have compiled these "imaging pearls" into two anthologies. The first focuses on pearls where the underlying diagnosis was a genetic condition. This second anthology focuses on imaging pearls in cases where the underlying condition was acquired. For each case we present brief clinical details along with neuroimaging findings, the characteristic imaging findings of that disorder and, finally, the differential diagnosis for the imaging findings seen.

A randomized clinical trial of burst vs. spaced physical therapy for Parkinsons disease.

INTRODUCTION: The optimal timing for physical therapy (PT) delivery in Parkinson's disease (PD) is unknown. Our objective was to determine whether spacing physical therapy visits over a longer period of time is beneficial for maintenance of physical function in PD. METHODS: A single center, single-blinded, randomized controlled trial of PD participants. Participants (n = 30) were randomized to either burst (two PT sessions weekly for 6 weeks) or spaced (one PT session every 2 weeks for 6 months) PT. 11 participants in each arm completed the study and were analyzed. The primary outcome measure was the Timed Up and Go (TUG) test at baseline and 6 months. The burst group had an additional outcome measure timepoint at the completion of PT at 6 weeks. RESULTS: Neither group achieved a minimal clinically significant benefit in the TUG score (3.5s) at 6 months. The spaced PT TUG scores were maintained when comparing baseline (7.8 ± 1.5s) and 6 month timepoints (7.8 ± 2.6s, p = 0.594). The burst group TUG scores comparing baseline (9.8 ± 3.8s) to 6 weeks (9.1 ± 3.0s) also was maintained (p = 0.365). The burst group worsened, however, when measuring the period from 6 weeks to 6 months (12.1 ± 7.6s, p = 0.034). CONCLUSIONS: The spaced PT group had stability of the TUG mobility measure at 6 months, while the burst group had a significant worsening once PT was discontinued after 6 weeks. It is feasible to test these approaches in a future larger comparative effectiveness study.

Effect of a Mediterranean diet intervention on gastrointestinal function in Parkinson's disease (the MEDI-PD study): study protocol for a randomised controlled trial.

INTRODUCTION: Constipation is a common and sometimes debilitating non-motor symptom of Parkinson's disease (PD) that can result in intestinal inflammation and microbial dysbiosis. The Mediterranean diet, rich in fermentable fibres and anti-inflammatory phenolic compounds, is associated with reduced risk of developing PD and slower progression of parkinsonism. The Mediterranean diet is often recommended for people with PD; however, no studies to date examine this diet as a therapeutic intervention to modulate gastrointestinal (GI) dysfunction. METHODS AND ANALYSIS: This is a randomised, controlled, parallel study. During a 2-week run-in, participants with PD and constipation symptoms (n=52) will undergo baseline nutritional and neurological assessments and provide a stool sample. Participants will be stratified by sex and Hoehn and Yahr stage and randomised to follow standard of care for constipation (control) or standard of care plus a Mediterranean diet (intervention) for 8 weeks. A study dietitian will provide dietary instruction and weekly follow-up via telephone to both groups to support adherence and monitor adverse events. Questionnaires will assess dietary intake and GI function including stool frequency, form, symptoms and laxative usage. Measurements completed at baseline will be repeated at 4 and 8 weeks of the intervention. The primary outcome is to evaluate the difference between mean change (final-baseline) in Gastrointestinal Symptom Rating Scale (GSRS) constipation syndrome scores for the control versus intervention groups. Secondary outcomes will assess stool frequency and form, weekly GSRS syndrome scores, digestive quality of life, laxative usage, faecal microbial communities and inflammatory markers, anxiety, depression, quality life, body weight and composition, dietary fibre intake and Mediterranean diet adherence. ETHICS AND DISSEMINATION: The study has received University of Florida Institutional Review Board-01 approval (IRB202001333). Findings will be disseminated via conference presentations, lectures and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04683900.

Regulation of nucleolin expression by miR-194, miR-206, and HuR.

Nucleolin is a proliferation-associated protein that is overexpressed in multiple types of cancer. The mechanisms leading to overexpression of nucleolin in specific cancers are not fully understood. This study found that nucleolin is notably elevated in breast cancer cell lines MCF-7 and MDA-231 compared to nonmalignant breast epithelial MCF-10A cells. In silico analyses revealed the presence of putative binding sites for microRNAs miR-194 and miR-206 in the 3'-untranslated region (3'-UTR) of Ncl mRNA. Transfection of the three cell lines with pre-miR-194 or pre-miR-206 specifically decreased the Ncl mRNA and protein expression. Treatments of the cells with antagomiR-194 or antagomiR-206 upregulated nucleolin expression ~2- to 3-fold. Co-transfection of cells with a reporter vector containing the Ncl 3'-UTR downstream from the Renilla luciferase gene and pre-miR-194 or pre-miR-206 led to a ~3-fold decrease in Renilla/firefly luciferase activity. Cytoplasmic levels of the RNA-binding protein HuR were higher in MCF-7 and MDA-231 cells than those in MCF-10A cells. RNA immunoprecipitation assays demonstrated that HuR binds to Ncl mRNA in all the three cell types. ShRNA-mediated knock-down of HuR induced a decrease in nucleolin expression, while exogenous expression of HuR led to upregulation of nucleolin expression. Analysis of the polysome-monosome distribution of Ncl mRNA in HuR knock-down cells demonstrated that HuR enhances the translation efficiency of Ncl mRNA. These findings demonstrate that nucleolin expression is down-regulated by miR-194 and miR-206 and upregulated by HuR.

In vitro comparison of bradykinin degradation by aliskiren, a renin inhibitor, and an inhibitor of angiotensin-converting enzyme.

INTRODUCTION: Angiotensin-converting enzyme (ACE) inhibitors cause angioedema due to diminished degradation of bradykinin. Angiotensin receptor blockers may occasionally cause angioedema but the mechanism is unknown, and are generally considered safe, even in those who have reacted to ACE inhibitors. We determined whether aliskiren, a renin inhibitor, has an effect on the rate of bradykinin degradation. METHODS: The ability of renin to metabolize bradykinin was studied and the rate of bradykinin degradation compared in the presence or absence of aliskiren. Enalapril, a known ACE inhibitor that causes angioedema served as positive control. RESULTS: Renin was unable to digest bradykinin, indicating that a renin inhibitor is unlikely to affect the rate of bradykinin degradation. In a plasma system, aliskiren had no effect on the rate of bradykinin degradation while enalapril inhibited it appreciably. An inhibitory effect of aliskiren on the rate of bradykinin degradation by human pulmonary endothelial cells was observed, estimated to be about 5% of that of enalapril. CONCLUSION: Aliskiren has no effect upon the rate of bradykinin degradation in plasma and a minimal effect employing vascular endothelial cells. The latter suggests inhibition of a non-renin enzyme that is a minor contributor to bradykinin degradation.

Treatment of episodes of hereditary angioedema with C1 inhibitor: serial assessment of observed abnormalities of the plasma bradykinin-forming pathway and fibrinolysis.

BACKGROUND: Hereditary angioedema (HAE) is typically the result of a deficiency of C1 inhibitor (C1-INH) with gene defects that lead to diminished plasma levels or the production of a dysfunctional protein. Replacement therapy with C1-INH has been shown to be effective in ameliorating episodes of swelling. We have reported elevated baseline levels of bradykinin, C4a, and plasmin-alpha2-antiplasmin complexes in the plasma of patients with HAE compared with the plasma of healthy controls. The production of factor XII fragment on in vitro activation of plasma with HAE has also been observed. OBJECTIVE: To perform serial assessment of abnormalities of the bradykinin-forming pathway and fibrinolysis in patients with HAE after treatment of episodes of swelling with intravenous C1-INH. METHODS: We obtained samples of plasma from 9 patients with HAE at a quiescent period (baseline), during an attack of swelling, and at 1, 4, and 12 hours after termination of an infusion of C1-INH. Factor XIIa, kallikrein, and plasmin were each measured by cleavage of synthetic substrates specific for each item. RESULTS: Each enzyme was strikingly elevated at baseline compared with the levels in pooled healthy plasma, and there was a progressive decline of activity to normal for factor XIIa and plasmin. Kallikrein decreased in 7 of the 9 patients at 1 hour and then decreased in all patients. Bradykinin levels were elevated at the outset in all patients, increased prominently during an attack of swelling, decreased to baseline after 1 hour, and then decreased toward normal by 4 and 12 hours. CONCLUSION: The plasma levels of factor XIIa, kallikrein, and bradykinin decreased when measured serially subsequent to the infusion of nanofiltered C1-INH.