A Population-Based Approach to the Argument on Brain-First and Body-First Pathogenesis of Lewy Body Disease.

OBJECTIVE: To explore the clinical progression of the brain-/body-first categories within Lewy body disease (LBD): Parkinson's disease (PD), dementia with Lewy bodies (DLB), and PD dementia. METHODS: We used of the Rochester Epidemiology Project to establish a population-based cohort of clinically diagnosed LBD. We used two definitions for differentiating between brain- and body-first LBD: a previously hypothesized body-first presentation in patients with rapid eye movement sleep behavior onset before motor symptoms onset; and an expanded definition of body-first LBD when a patient had at least 2 premotor symptoms between constipation, erectile dysfunction, rapid eye movement sleep behavior, anosmia, or neurogenic bladder. RESULTS: Brain-first patients were more likely to be diagnosed with PD (RR = 1.43, p = 0.003), whereas body-first patients were more likely to be diagnosed with DLB (RR = 3.15, p < 0.001). Under the expanded definition, there was no difference in LBD diagnosis between brain-first and body-first patients (PD: RR = 1.03, p = 0.10; DLB: RR = 0.88, p = 0.58) There were no patterns between brain- or body-first presentation, PD dementia under either definition (original: p = 0.09, expanded: p = 0.97), and no significant difference in motor symptoms between brain-first and body-first. INTERPRETATION: Our findings do not support the dichotomous classification of body-first and brain-first LBD with the currently proposed definition. Biological exposures resulting in PD and DLB are unlikely to converge on a binary classification of top-down or bottom-up synuclein pathology. ANN NEUROL 2024.

Substrate Enolate Intermediate and Mimic Captured in the Active Site of Streptomyces coelicolor Methylmalonyl-CoA Epimerase.

Methylmalonyl-CoA epimerase (MMCE) is proposed to use general acid-base catalysis, but the proposed catalytic glutamic acids are highly asymmetrical in the active site unlike many other racemases. To gain insight into the puzzling relationships between catalytic mechanism, structure, and substrate preference, we solved Streptomyces coelicolor MMCE structures with substrate or 2-nitropropionyl-CoA, an intermediate/transition state analogue. Both ligand bound structures have a planar methylmalonate/2-nitropropionyl moiety indicating a deprotonated C2 with ≥4 Šdistances to either catalytic acid. Both glutamates interact with the carboxylate/nitro group, either directly or through other residues. This suggests the proposed catalytic acids sequentially catalyze proton shifts between C2 and carboxylate of the substrate with an enolate intermediate. In addition, our structures provide a platform to design mutations for expanding substrate scope to support combinatorial biosynthesis.

Timeline of Rapid Eye Movement Sleep Behavior Disorder in Overt Alpha-Synucleinopathies.

OBJECTIVE: The aim was to analyze the timeline, prevalence, and survival of rapid eye movement (REM) sleep behavior disorder (RBD) in patients who developed alpha-synucleinopathies (Parkinson disease, dementia with Lewy bodies, and Parkinson disease dementia) compared with age- and sex-matched controls in a population-based incident-cohort study. METHODS: We used a population-based, 1991 to 2010 incident-cohort study of alpha-synucleinopathies. A movement-disorder specialist reviewed medical records to confirm diagnoses. RBD was diagnosed by reported dream-enactment symptoms or polysomnography. Probable RBD and polysomnographically confirmed RBD were analyzed separately and combined. RESULTS: Among the 444 incident cases of alpha-synucleinopathy, 86 were clinically diagnosed with RBD (19.8%), including 30 (35%) by polysomnography and 56 (65%) as probable. The prevalence of idiopathic RBD at alpha-synucleinopathy diagnosis was 3.4%, increasing to 23.8% after 15 years. Cumulative lifetime incidence was 53 times greater in alpha-synucleinopathy patients than in controls (odds ratio [OR] = 53.1, 95% confidence interval [CI]: 13.0-217.2, p < 0.0001), higher in dementia with Lewy bodies than in Parkinson disease (OR = 2.57, 95% CI: 1.50-4.40, p = 0.0004), and higher in men than in women with Parkinson disease, dementia with Lewy bodies, or Parkinson disease dementia (OR = 3.70, 95% CI: 2.07-6.62, p < 0.0001), but did not increase mortality risk. INTERPRETATION: Our cohort had RBD incidence of 3.4%. Overall RBD increased to 23.8% after 15 years, with an overall incidence of 2.5 cases per 100 person-years. With 53 times greater lifetime incidence in alpha-synucleinopathy patients than in controls, RBD was more likely to develop in dementia with Lewy bodies than in Parkinson disease or Parkinson disease dementia, and in men than in women, but did not increase mortality risk within our cohort. ANN NEUROL 2021;89:293-303.

Infections or Sepsis Preceding Clinically Diagnosed α-Synucleinopathies: A Case-Control Study.

BACKGROUND: Several studies have proposed a role for infections to induce an inflammatory response triggering Parkinson's disease. This remains controversial and the influence of severe infections on other α-synucleinopathies (Dementia with Lewy Bodies, Parkinson's disease dementia, and Multiple System Atrophy) has not been adequately investigated. OBJECTIVES: To assess the association between hospitalization-required infections or sepsis and risk of clinically diagnosed α-synucleinopathies. METHODS: Using the medical records-linkage system (Rochester Epidemiology Project), we identified all α-synucleinopathy cases of in Olmsted County (1991-2010). Cases were matched by symptom-onset age and sex to controls. We reviewed complete medical records to detect hospital-required infections or sepsis preceding clinical-motor onset of α-synucleinopathies. We used conditional logistic regression to calculate the odds ratio of all α-synucleinopathies, adjusting for medications, coffee, and smoking. RESULTS: There was no association between infection-related hospitalization (odds ratio: 1.05; 95% confidence interval: 0.78-1.40; P = 0.76) or sepsis (odds ratio: 0.86; 95% confidence interval: 0.40-1.85; P = 0.70) and all α-synucleinopathies in multivariable analyses. We did not identify any associations after stratifying for type of α-synucleinopathy, sex, and age at clinical-motor onset. We analyzed sepsis separately with similar results. CONCLUSION: We did not observe any associations between infections leading to hospitalization or sepsis and development of any α-synucleinopathies. © 2020 International Parkinson and Movement Disorder Society.

Lower Vitamin B12 Level at Multiple System Atrophy Diagnosis Is Associated With Shorter Survival.

BACKGROUND: Multiple system atrophy (MSA) is a neurodegenerative disorder from α-synuclein aggregation. in vitro studies suggest vitamin B12 may interrupt α-synuclein-mediated neurodegeneration. The objective of this study was to determine whether serum vitamin B12 level at MSA diagnosis is associated with survival. METHODS: One hundred eighty-two MSA patients evaluated at Mayo Clinic with vitamin B12 testing were studied. We determined the risk of death in relationship to serum vitamin B12 levels at MSA diagnosis, adjusting for predictors of poor survival. RESULTS: Predictors of shorter survival included vitamin B12 < 367 ng/L (HR, 1.8; 95% CI, 1.3-2.7), falls within 3 years of MSA diagnosis (HR, 1.6; 95% CI, 1.1-2.3), bladder symptoms (HR, 1.6; 95% CI, 1.0-2.6), urinary catheter requirement (HR, 1.7; 95% CI, 1.0-2.8), male sex (HR, 1.4; 95% CI, 1.0-2.0), and MSA-P subtype (HR, 1.5; 95% CI, 1.0-2.0). CONCLUSIONS: Low vitamin B12 levels are associated with shorter survival in MSA. Additional studies to explore this observation and assess the potential role of vitamin B12 as a modifiable survival factor are needed. © 2020 International Parkinson and Movement Disorder Society.

Sensitivity and Specificity of Diagnostic Criteria for Progressive Supranuclear Palsy.

BACKGROUND: In 2017, the International Parkinson and Movement Disorder Society put forward new clinical criteria for the diagnosis of PSP, recognizing diverse PSP phenotypes. In this study, we compared the sensitivity and specificity of the new criteria with the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria at different times. METHODS: Patients with clinical parkinsonism, clinical and/or neuropathological diagnosis of PSP, were identified from the Society for Progressive Supranuclear Palsy brain bank. All patients had neuropathologic diagnoses and detailed clinical examination performed by a neurologist at 1 of the 3 Mayo Clinic sites, in Florida, Arizona, and Minnesota. Clinical symptoms and signs were abstracted retrospectively in a blinded fashion and used to determine whether patients met either diagnostic criterion. Patients were divided into early and late disease stage groups using a 3-year cutoff. RESULTS: A total of 129 patients were included, of whom 66 had PSP pathology (51%). The remainder had other neurodegenerative diseases. The overall sensitivity of the International Parkinson and Movement Disorder Society criteria was 87.9%, compared with 45.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria, whereas the specificity of the International Parkinson and Movement Disorder Society probable PSP criteria was 85.7%, compared with 90.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy. Individual patients were noted to have features of multiple PSP phenotypes. CONCLUSION: The International Parkinson and Movement Disorder Society criteria recognize several phenotypes of progressive supranuclear palsy and hence have higher sensitivity than the previous criteria. © 2019 International Parkinson and Movement Disorder Society.

Prevalence of sleep disorders in Parkinson's disease patients in two neurology referral hospitals in Ethiopia.

BACKGROUND: Non motor symptoms (NMS) of Parkinson's disease (PD) are common and can be more disabling than motor symptoms. Sleep disorders can be seen in up to 98% of patients with Parkinson disease. Poor sleep quality has been associated with poverty and race, and yet there has been no prior report on sleep disorders in those with PD living in sub Saharan Africa. We wished to document the prevalence of sleep disorders in PD patients in Ethiopia. METHODS: We conducted a cross-sectional point prevalence study from July 1 to October 30, 2015 of all patients attending the neurology outpatient department in Tikur Anbessa and Zewuditu Memorial Hospitals, Addis Ababa, Ethiopia. Demographic data, clinical history and physical examination findings were collected from participants using a structured questionnaire. We used the Parkinson's disease sleep scale version two (PDSS-2) and Epworth Sleepiness Scale (ESS) to assess the sleep symptoms. RESULTS: Of the 155 patients surveyed, all patients reported some sleep problem. Over 43.9% of patients had a PDSS score > 18. The median score of ESS was 9 (IQR = 5-12), with 77/155 (49.7%) of the patients having possible or definite excessive daytime somnolence. A high EDSS score significantly associated with a Hoehn & Yahr score > 4 (p = 0.02). CONCLUSIONS: In Ethiopian PD patients, the prevalence of those with severe sleep disorders is the highest reported to date. The prevalence of possible/definite EDS is amongst the highest in the world. Further investigation into whether poverty or race explains this finding is needed.

Parkinson disease with and without Dementia: A prevalence study and future projections.

BACKGROUND: Limited population-based information is available on the co-occurrence of dementia and PD. However, projecting the prevalence of PD with and without dementia during the next 50 years is crucial for planning public-health and patient-care initiatives. OBJECTIVES: The objective of this study was to project the prevalence of PD with and without dementia in the United States by 2060. METHODS: We used the Rochester Epidemiology Project medical records-linkage system to identify all persons with PD with or without dementia residing in Olmsted County, Minnesota, on January 1, 2006. A movement disorders specialist reviewed the complete medical records of each person to confirm the presence of PD. We calculated the age- and sex-specific prevalence of PD with and without dementia and projected U.S. prevalence through 2060. RESULTS: We identified 296 persons with PD with and without dementia on the prevalence date (187 men, 109 women); the overall prevalence increased with age from 0.01% (30-39 years) to 2.83% (≥90 years). The prevalence of PD without dementia increased with age from 0.01% (30-39 years) to 1.25% (≥90 years). The prevalence of PD with dementia increased with age from 0.10% (60-69 years) to 1.59% (≥90 years). The prevalence was higher in men than in women for all subtypes and all age groups. We project by 2060 an approximate doubling of the number of persons with PD without dementia and a tripling of the number of persons with PD with dementia in the United States. CONCLUSIONS: The prevalence of PD with and without dementia increases with age and is higher in men than women. We project that the number of persons with PD in the United States will increase substantially by 2060. © 2018 International Parkinson and Movement Disorder Society.

Prevalence of and indications for antipsychotic use in Parkinson's disease.

BACKGROUND: The prevalence of patients with PD taking antipsychotics is unknown. OBJECTIVE: To measure the prevalence of patients with PD taking antipsychotics. METHODS: We used the medical records-linkage system of the Rochester Epidemiology Project to study the use of antipsychotic medication in all persons with Parkinson disease in Olmsted County, Minnesota on 1 January 2006. RESULTS: There were 296 patients with PD in Olmsted County on 1 January 2006. The overall prevalence of antipsychotic use was 9.8% (29 of 296); 95.5% (28 of 29) of the patients had dementia when initiating antipsychotics. The most frequent indication (71.4%; 20 of 28) was psychosis or behavior threatening to the patient or others. CONCLUSIONS: The prevalence of antipsychotic use in patients with PD is lower than expected from previously reported cumulative incidences. Dementia is highly prevalent in those starting antipsychotics. Most of the patients on antipsychotics had a reasonable risk-benefit ratio for taking them. © 2017 International Parkinson and Movement Disorder Society.

Clinicopathologic discrepancies in a population-based incidence study of parkinsonism in olmsted county: 1991-2010.

OBJECTIVE: The purpose of this study was to examine the discrepancies between the clinical diagnosis of parkinsonism and neuropathological findings in a population-based cohort with parkinsonian disorders. BACKGROUND: The specific clinical diagnosis of parkinsonism is challenging, and definite confirmation requires neuropathological evaluation. Currently, autopsies are seldom performed, and most brain autopsies represent atypical or diagnostically unresolved cases. METHODS: We used a defined population-based incidence cohort with clinical parkinsonism (n = 669) from the Rochester Epidemiology Project in Olmsted County, Minnesota, 1991-2010. We reviewed reports of all patients who underwent neuropathologic examination at autopsy (n = 60; 9%) and applied consensus pathologic guidelines for neurodegenerative disease diagnosis. RESULTS: Among the 60 patients examined pathologically, the median time from the last recorded clinical diagnosis to death was 7 years (range from 2 to 17 years). Clinical-pathological concordance was found in 52 cases (86.7%), whereas 8 (13.3%) had a clinical-pathological discrepancy. Four patients with a clinical diagnosis of idiopathic Parkinson's disease had no pathological evidence of Lewy bodies or α-synucleinopathy; of these, pathological diagnoses were Alzheimer's disease (2 cases), progressive supranuclear palsy (1 case), and vascular parkinsonism (1 case). Two patients with clinical diagnoses of "dementia with Lewy bodies" and one patient with an "unspecified parkinsonism" had a pathological diagnosis of Alzheimer's disease without concomitant α-synuclein lesions. One patient with clinically diagnosed "progressive supranuclear palsy" had indeterminate pathological findings without α-synuclein or Aß- or tau-immunoreactive lesions at autopsy. CONCLUSIONS: Overall, the clinical diagnoses of parkinsonian subtypes had good concordance with pathological confirmation (86.7%). However, clinical-pathological discrepancies were documented in 13.3%. © 2017 International Parkinson and Movement Disorder Society.

Incidence and time trends of drug-induced parkinsonism: A 30-year population-based study.

BACKGROUND: Epidemiological studies of drug-induced parkinsonism remain limited. OBJECTIVES: To investigate the incidence and time trends of drug-induced parkinsonism over 30 years in a geographically defined American population. METHODS: We used the medical records-linkage system of the Rochester Epidemiology Project to identify all persons in Olmsted County, Minnesota, who received a screening diagnostic code for parkinsonism from 1976 through 2005. A movement disorders specialist reviewed the complete medical records of each person to confirm the presence of drug-induced parkinsonism associated with dopamine-blocking or dopamine-depleting medications. RESULTS: Among 906 incident cases of parkinsonism from 1976 to 2005, 108 persons had drug-induced parkinsonism (11.9%). The average annual incidence rate of drug-induced parkinsonism was 3.3 per 100,000 person-years, was higher in women, and increased with older age. Drug-induced parkinsonism was the fifth-most common type of parkinsonism overall; however, it was the most common type among persons younger than age 40 years. Typical antipsychotic drugs were the most common class of drugs associated with parkinsonism, whereas atypical antipsychotic drugs were rarely involved. The incidence rate of drug-induced parkinsonism decreased 32.0% per decade (relative risk = 0.68; 95% confidence interval: 0.49-0.94) and 68.6% over the 30 years of the study. The decrease was similar in men (65.2%) and women (69.4%); however, the trend was significant only in women. CONCLUSIONS: The incidence of drug-induced parkinsonism increased with older age and was higher in women at all ages. Typical antipsychotic drugs were the most common cause. The incidence of drug-induced parkinsonism decreased over the 30 years of the study because of changes in drug use. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Clinical features and autonomic testing predict survival in multiple system atrophy.

Multiple system atrophy is characterized by autonomic failure along with motor symptoms of parkinsonism and/or cerebellar ataxia. There are differing reports on the influence of certain clinical features, including motor subtype (multiple system atrophy-parkinsonism versus multiple system atrophy-cerebellar ataxia), age of onset, gender, and early autonomic symptoms, on the survival in patients with multiple system atrophy. We sought to evaluate overall survival and predictors of survival in a large cohort of patients with multiple system atrophy seen at a single referral centre where objective autonomic testing is routinely performed for this indication. All cases of multiple system atrophy evaluated at Mayo Clinic, Rochester and assessed with an autonomic reflex screen between January 1998 and December 2012 were retrospectively reviewed. A total of 685 patients were identified; 594 met criteria for probable multiple system atrophy, and 91 for possible multiple system atrophy. Multiple system atrophy-parkinsonism was the predominant subtype in 430 patients (63%). Average age of onset was earlier in multiple system atrophy-cerebellar ataxia (58.4 years) compared to multiple system atrophy-parkinsonism (62.3 years; P < 0.001). Median disease duration from symptom onset to death was 7.51 years (95% confidence interval 7.18-7.78) while time from diagnosis to death was 3.33 years (95% confidence interval 2.92-3.59). There was no difference in survival between motor subtypes of multiple system atrophy (P = 0.232). An initial motor symptom was most common (61%) followed by autonomic onset (28%) and combined motor and autonomic symptoms (11%). The initial onset of either motor or autonomic symptoms did not influence length of survival. However, a number of clinical and autonomic laboratory features predicted unfavourable survival in a univariate analysis. A multivariate model retained the following unfavourable predictors of survival: (i) falls within 3 years of onset (hazard ratio 2.31, P < 0.0001); (ii) bladder symptoms (hazard ratio 1.96, P < 0.0001); (iii) urinary catheterization within 3 years of symptom onset (hazard ratio 1.67, P < 0.003); (iv) orthostatic intolerance within 1 year of symptom onset (hazard ratio 1.28, P < 0.014); (v) older age of onset (hazard ratio 1.02, P = 0.001); and (vi) degree of autonomic failure as measured by a validated composite autonomic severity score (hazard ratio 1.07, P < 0.0023). We conclude that carefully selected clinical features can be used to predict survival in patients with multiple system atrophy. Autonomic testing adds an additional, independent predictor of survival, demonstrating its value not only in the diagnosis of multiple system atrophy but also as prognostic marker.

Development and validation of a carers quality-of-life questionnaire for parkinsonism (PQoL Carers).

PURPOSE: Atypical parkinsonism (AP) has a considerable impact on the lives not only of patients but also of their carers. The aim of this study was to develop an instrument for assessing the quality of life (QoL) of carers of patients with AP. METHODS: A 40-item pool was generated from in-depth interviews with carers of patients with AP, a thorough review of the existing literature and consultation with movement disorder experts. Item refinement and reduction was performed using the results of pilot testing and a survey in 282 carers of multiple system atrophy (MSA) patients and 226 carers of progressive supranuclear palsy (PSP) patients. A validation study, with responses of 243 carers of MSA and 187 carers of PSP patients, was undertaken to evaluate the psychometric properties of the final 26-item scale. RESULTS: The validation study results suggest that the scale is unidimensional and has high internal consistency (Cronbach's α = 0.96). The correlations of scale scores with patients' health status and QoL measures, such as PDQ-39 summary score and EQ-5D index (Spearman's ρ = 0.56 and -0.31, respectively, P < 0.001), as well as carers' measures, such as Caregiver Burden Inventory (CBI) total and EQ-5D index (Spearman's ρ = 0.85 and -0.39, respectively, P < 0.001), document the convergent and concurrent validity of the scale. ANOVA results support the discriminant validity of the scale, as evidenced by its capacity to differentiate between carers with varying levels of self-reported health. CONCLUSIONS: The 26-item Parkinsonism Carers QoL (PQoL Carer) is a concise instrument with adequate psychometric qualities that can be used for clinical and research purposes.

Consensus paper: the role of the cerebellum in perceptual processes.

Various lines of evidence accumulated over the past 30 years indicate that the cerebellum, long recognized as essential for motor control, also has considerable influence on perceptual processes. In this paper, we bring together experts from psychology and neuroscience, with the aim of providing a succinct but comprehensive overview of key findings related to the involvement of the cerebellum in sensory perception. The contributions cover such topics as anatomical and functional connectivity, evolutionary and comparative perspectives, visual and auditory processing, biological motion perception, nociception, self-motion, timing, predictive processing, and perceptual sequencing. While no single explanation has yet emerged concerning the role of the cerebellum in perceptual processes, this consensus paper summarizes the impressive empirical evidence on this problem and highlights diversities as well as commonalities between existing hypotheses. In addition to work with healthy individuals and patients with cerebellar disorders, it is also apparent that several neurological conditions in which perceptual disturbances occur, including autism and schizophrenia, are associated with cerebellar pathology. A better understanding of the involvement of the cerebellum in perceptual processes will thus likely be important for identifying and treating perceptual deficits that may at present go unnoticed and untreated. This paper provides a useful framework for further debate and empirical investigations into the influence of the cerebellum on sensory perception.

Multiple system atrophy: prognostic indicators of survival.

Neurological and autonomic presentation in multiple system atrophy (MSA) may predict early mortality. Quantification of early autonomic failure as a mortality predictor is lacking. Early neurological and autonomic clinical features were retrospectively reviewed in 49 MSA cases (median age at onset, 56.1 years; 16 women) confirmed by autopsy at Mayo Clinic. When available, the 10-point composite autonomic severity score derived from the autonomic reflex screen provided quantification of the degree of autonomic failure and thermoregulatory sweat test quantitated body surface anhidrosis. Symptoms at onset were autonomic in 50%, parkinsonian in 30%, and cerebellar in 20% of cases. Survival (median [95% confidence interval]) was 8.6 [6.7-10.2] years. Survival was shorter in patients with early laboratory evidence of generalized (composite autonomic severity score ≥ 6) autonomic failure (7.0 [3.9-9.8] vs. 9.8 [4.6-13.8] years; P = 0.036), and early requirement of bladder catheterization (7.3 [3.1-10.2] vs. 13.7 [8.5-14.9] years; P = 0.003) compared with those without these clinical features. On Cox proportional analysis, prognostic indicators of shorter survival were older age at onset (hazard ratio [95% confidence interval], 1.04 [1.01-1.08]; P = 0.03), early requirement of bladder catheterization (7.9 [1.88-38.63]; P = 0.004), and early generalized (composite autonomic severity score ≥ 6) autonomic failure (2.8 [1.01-9.26]; P = 0.047). Gender, phenotype, and early development of gait instability, aid-requiring ambulation, orthostatic symptoms, neurogenic bladder, or significant anhidrosis (thermoregulatory sweat test ≥ 40%) were not indicators of shorter survival. Our data suggest that early development of severe generalized autonomic failure more than triples the risk of shorter survival in patients with MSA.

Insights on the G protein-coupled receptor helix 8 solution structure and orientation using a neurotensin receptor 1 peptide.

G-protein coupled receptors (GPCRs) are the largest class of membrane proteins encoded in the human genome with high pharmaceutical relevance and implications to human health. These receptors share a prevalent architecture of seven transmembrane helices followed by an intracellular, amphipathic helix 8 (H8) and a disordered C-terminal tail (Ctail). Technological advancements have led to over 1000 receptor structures in the last two decades, yet frequently H8 and the Ctail are conformationally heterogeneous or altogether absent. Here we synthesize a peptide comprising the neurotensin receptor 1 (NTS1) H8 and Ctail (H8-Ctail) to investigate its structural stability, conformational dynamics, and orientation in the presence of detergent and phospholipid micelles, which mimic the membrane. Circular dichroism (CD) and nuclear magnetic resonance (NMR) measurements confirm that zwitterionic 1,2-diheptanoyl-sn-glycero-3-phosphocholine is a potent stabilizer of H8 structure, whereas the commonly-used branched detergent lauryl maltose neopentyl glycol (LMNG) is unable to completely stabilize the helix - even at amounts four orders of magnitude greater than its critical micellar concentration. We then used NMR spectroscopy to assign the backbone chemical shifts. A series of temperature and lipid titrations were used to define the H8 boundaries as F376-R392 from chemical shift perturbations, changes in resonance intensity, and chemical-shift-derived phi/psi angles. Finally, the H8 azimuthal and tilt angles, defining the helix orientation relative of the membrane normal were measured using paramagnetic relaxation enhancement NMR. Taken together, our studies reveal the H8-Ctail region is sensitive to membrane physicochemical properties and is capable of more adaptive behavior than previously suggested by static structural techniques.

Impulse control disorders and use of dopamine agonists in early onset Parkinson's disease.

Introduction: Impulse control disorders (ICDs) are defined as excessive and repetitive behaviors that may affect Parkinson's disease (PD) patients exposed to dopamine agonists. Current data on ICDs in patients with early-onset Parkinson's disease (EOPD) is lacking. In this study we aim to assess the frequency of use of dopamine agonists, the prevalence of ICDs, and to explore potential factors associated with their development in patients with EOPD. Methods: We used the Mayo Clinic Data Explorer system to investigate a population-based cohort of EOPD patients between 1990 and 2022 at Mayo Clinic, Rochester, MN. We used ICD coding for parkinsonism; then, we reviewed all the clinical records and included only those patients with a clinical diagnosis of PD with symptoms onset at or before the age of 50, and who developed ICDs after using therapeutic doses of dopamine agonists. Results: A total of 831 (513 males and 318 females) patients with EOPD were included with a median age at symptom onset of 42 years of age (CI: 37-46). Dopamine agonists were used in 49.7% of all patients; of these, only 14.5% developed symptoms of one or more ICDs. Hypersexuality was the most commonly observed ICD (38.3%), and the only one having a statistically significant male predominance (p = 0.011). Conclusion: ICDs are common in EOPD, particularly when associated with the use of dopamine agonists.

Risk factors for Parkinson's disease may differ in men and women: an exploratory study.

Although several environmental and genetic risk or protective factors have been associated with Parkinson's disease (PD), their interactions overall and in men and women separately remain unknown. We used the medical records-linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (±1 year) and sex to a general population control. We considered the following 12 risk or protective factors: personal history of head trauma, pesticide use, immunologic diseases, anemia, hysterectomy (in women only), cigarette smoking, coffee consumption, and education; and family history of parkinsonism, essential tremor, dementia, or psychiatric disorders. We used recursive partitioning analyses to explore interactions overall and in men and women separately and used logistic regression analyses to test for interactions. In the overall group, we observed the independent effects of anemia, lack of coffee consumption (never vs. ever), and head trauma; however, the findings were different in men and women. In men, we observed the independent effects of lack of coffee consumption (never vs. ever), head trauma, and pesticide use, and a suggestive synergistic interaction between immunologic diseases and family history of dementia. By contrast, in women, anemia was the most important factor and we observed a suggestive synergistic interaction between anemia and higher education. Risk factors for PD and their interactions may differ in men and women.

Evaluation of the Patient With Paroxysmal Spells Mimicking Epileptic Seizures.

BACKGROUND: The diagnostic issue of paroxysmal spells, including epileptic seizure (ES) mimics, is one that neurologists frequently encounter. This review provides an up-to-date overview of the most common causes of ES mimics encountered in the outpatient setting. REVIEW SUMMARY: Paroxysmal spells are characterized by changes in awareness, attention, perception, or abnormal movements. These can be broadly classified as ES and nonepileptic spells (NES). NES mimics ES but are distinguished by their symptomatology and lack of epileptiform activity on electroencephalography. NES may have psychological or physiological underpinnings. Psychogenic non-ES are the most common mimics of ES. Physiological causes of NES include syncope, cerebrovascular, movement, and sleep-related disorders. CONCLUSIONS: Distinguishing NES from ES at times may be challenging even to the most experienced clinicians. However, detailed history with an emphasis on the clinical clues, including taking a moment-by-moment history of the event from the patient and observers and physical examination, helps create an appropriate differential diagnosis to guide further diagnostic testing. An accurate diagnosis of NES prevents iatrogenic harm, including unnecessary exposure to antiseizure medications and overuse of health care resources. It also allows for the correct specialist referral and appropriate treatment.

Withdrawal notice to "40-Year incidence of early-onset Parkinson's disease (EOPD) in Southeast Minnesota" [Park. Relat. Disord. 104 (2022) 64-67].

This article has been withdrawn at the request of the editor and publisher. The publisher regrets that an error occurred which led to the premature publication of this paper. This error bears no reflection on the article or its authors. The publisher apologizes to the authors and the readers for this unfortunate error. The full Elsevier Policy on Article Withdrawal can be found at (https://www.elsevier.com/about/policies/article-withdrawal).