Comparison of different risk scores for Parkinson disease in a population-based 10-year study.

BACKGROUND AND PURPOSE: Different algorithms aiming to identify individuals at risk of Parkinson disease (PD) have been proposed. Comparative studies of these scores and their recent updates in the general elder population are needed. METHODS: We have previously applied the "basic" PREDICT-PD algorithm, designed for remote screening, and the original and updated Movement Disorder Society (MDS) criteria for prodromal PD to the longitudinal population-based Bruneck study cohort. We have now additionally employed the "enhanced" PREDICT-PD algorithm (which includes motor assessment, olfaction, probable rapid eye movement sleep behaviour disorder status, pesticide exposure, and diabetes as additional factors). Risk scores were calculated based on comprehensive baseline assessments (2005) in 574 subjects aged 55-94 years (290 females), and cases of incident PD were identified at 5-year (n = 11) and 10-year follow-up (n = 9). We analysed the association of the different log-transformed risk scores with incident PD at follow-up (calculated per 1-SD unit change). RESULTS: The enhanced PREDICT-PD algorithm was associated with incident PD over 10-years of follow-up, yielding higher odds for incident PD (odds ratio [OR] = 4.61, 95% confidence interval [CI] = 2.68-7.93, p < 0.001) compared with the basic PREDICT-PD score (OR = 2.38, 95% CI = 1.49-3.79, p < 0.001). The updated MDS prodromal criteria yielded a numerically higher OR of 7.13 (95% CI = 3.49-14.54, p < 0.001) in comparison with the original criteria as well as the enhanced PREDICT-PD algorithm, with overlapping 95% CIs. CONCLUSIONS: The enhanced PREDICT-PD algorithm was significantly associated with incident PD. The consistent performance of both the enhanced PREDICT-PD algorithm and the updated MDS prodromal criteria compared to their original versions supports their use in PD risk screening.

Associations of Gait Disorders and Recurrent Falls in Older People: A Prospective Population-Based Study.

BACKGROUND: Recurrent falls represent a major source of serious adverse health outcomes in the general older population. Gait impairment has been linked to recurrent falls, but there are only limited long-term data on this association. OBJECTIVES: The objective of the study was to investigate the association of gait disorders (GDs) and gait tests with future falls in an existing longitudinal population-based cohort. METHOD: The study was performed in participants of the Bruneck Study cohort 2010 aged 60-97 years, with prospective 5-year follow-up. At baseline, participants underwent a clinical gait assessment (to determine neurological and non-neurological GDs according to an established classification) and were also evaluated by quantitative and semiquantitative gait tests (Hauser Index, Tinetti balance and gait test, and gait speed). Logistic regression analysis adjusted for age and sex was used to determine the relationship of baseline variables with incident recurrent falls at 5-year follow-up. RESULTS: Of 328 included participants, 22 (6.7%) reported recurrent falls at follow-up. Baseline presence of GDs was associated with recurrent falls at follow-up (odds ratio [OR] 4.2; 95% confidence interval [CI] 1.6-11.1; p = 0.004), and this effect was largely driven by neurological GDs (OR 5.5; 95% CI 1.7-17.4; p = 0.004). All 3 simple gait tests were predictive for incident falls (Hauser Index, p = 0.002; Tinetti test, p = 0.006; and gait speed, p < 0.001). CONCLUSIONS: Clinical assessment of GDs and gait tests both had independent significant predictive value for recurrent falls over a 5-year follow-up period. This highlights the potential of such assessments for early fall risk screening and timely implementation of fall-preventive measures.

Long-term life history predicts current gut microbiome in a population-based cohort study.

Extensive scientific and clinical microbiome studies have explored contemporary variation and dynamics of the gut microbiome in human health and disease1-3, yet the role of long-term life history effects has been underinvestigated. Here, we analyzed the current, quantitative microbiome composition in the older adult Bruneck Study cohort (Italians, Bruneck, n = 304 (male, 154; female, 150); age 65-98 years) with extensive clinical, demographic, lifestyle and nutritional data collected over the past 26 years4. Multivariate analysis of historical variables indicated that medication history, historical physical activity, past dietary habits and specific past laboratory blood parameters explain a significant fraction of current quantitative microbiome variation in older adults, enlarging the explanatory power of contemporary covariates by 33.4%. Prediction of current enterotype by a combination of past and contemporary host variables revealed good levels of predictability (area under the curve (AUC), 0.78-0.83), with Prevotella and dysbiotic Bacteroides 2 being the best predicted enterotypes. These findings demonstrate long-term life history effects on the microbiota and provide insights into lifestyle variables and their role in maintaining a healthy gut microbiota in later life.

PCSK9 Activity Is Potentiated Through HDL Binding.

Rationale: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and high-density lipoprotein (HDL) remains unexplored. Objective: This study sought to interrogate the novel relationship between PCSK9 and HDL in humans. Methods and Results: Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck (n=656) study revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein-C3, an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 times points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apolipoprotein-C3 from HDL and lower levels of small HDL as measured by nuclear magnetic resonance. Crosslinking mass spectrometry (XLMS) upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin and apolipoprotein-E within the HDL proteome, that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalisation and multimerisation. Conclusions: This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipaemia as a driver of PCSK9 and apolipoprotein-C3 release from HDL.

Dietary spermidine improves cognitive function.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.

Characterization of gait variability in multiple system atrophy and Parkinson's disease.

BACKGROUND: Gait impairment is a pivotal feature of parkinsonian syndromes and increased gait variability is associated with postural instability and a higher risk of falls. OBJECTIVES: We compared gait variability at different walking velocities between and within groups of patients with Parkinson-variant multiple system atrophy, idiopathic Parkinson's disease, and a control group of older adults. METHODS: Gait metrics were recorded in 11 multiple system atrophy, 12 Parkinson's disease patients, and 18 controls using sensor-based gait analysis. Gait variability was analyzed for stride, swing and stance time, stride length and gait velocity. Values were compared between and within the groups at self-paced comfortable, fast and slow walking speed. RESULTS: Multiple system atrophy patients displayed higher gait variability except for stride time at all velocities compared with controls, while Parkinson's patients did not. Compared with Parkinson's disease, multiple system atrophy patients displayed higher variability of swing time, stride length and gait velocity at comfortable speed and at slow speed for swing and stance time, stride length and gait velocity (all P < 0.05). Stride time variability was significantly higher in slow compared to comfortable walking in patients with multiple system atrophy (P = 0.014). Variability parameters significantly correlated with the postural instability/gait difficulty subscore in both disease groups. Conversely, significant correlations between variability parameters and MDS-UPDRS III score was observed only for multiple system atrophy patients. CONCLUSION: This analysis suggests that gait variability parameters reflect the major axial impairment and postural instability displayed by multiple system atrophy patients compared with Parkinson's disease patients and controls.

Application of a Simple Parkinson's Disease Risk Score in a Longitudinal Population-Based Cohort.

BACKGROUND: Identifying individuals at risk of developing Parkinson's disease (PD) is critical to define target populations for future neuroprotective trials. OBJECTIVE: The objective of this study was to apply the PREDICT-PD algorithm of risk indicators for PD in a prospective community-based study (the Bruneck study), representative of the general elderly population. METHODS: PREDICT-PD risk scores were calculated based on risk factor assessments obtained at baseline (2005, n = 574 participants). Cases of incident PD were identified at 5-year and 10-year follow-ups. Participants with PD or secondary parkinsonism at baseline were excluded (n = 35). We analyzed the association of log-transformed risk scores with the presence of well-established markers as surrogates for PD risk at baseline and with incident PD at follow-up. RESULTS: A total of 20 participants with incident PD were identified during follow-up (11 after 5 years and 9 after 10 years). Baseline PREDICT-PD risk scores were associated with incident PD with odds ratios of 2.09 (95% confidence interval, 1.35-3.25; P = 0.001) after 5 years and of 1.95 (1.36-2.79; P < 0.001) after 10 years of follow-up per doubling of risk scores. In addition, higher PREDICT-PD scores were significantly correlated with established PD risk markers (olfactory dysfunction, signs of rapid eye movement sleep behavior disorder and motor deficits) and significantly associated with higher probability for prodromal PD according to the Movement Disorder Society research criteria at baseline. CONCLUSIONS: The PREDICT-PD score was associated with an increased risk for incident PD in our sample and may represent a useful first screening step in future algorithms aiming to identify cases of prodromal PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Associations of Serum Dickkopf-1 and Sclerostin With Cardiovascular Events: Results From the Prospective Bruneck Study.

Background Dickkopf-1 and sclerostin have been implicated in atherosclerosis and vascular calcification. We aimed to quantify the association of their serum levels with incident cardiovascular disease (CVD) in the general population. Methods and Results Among 706 participants of the prospective, population-based Bruneck Study, mean±SD of serum levels were 44.5±14.7 pmol/L for dickkopf-1 and 47.1±17.5 pmol/L for sclerostin. The primary outcome was a composite CVD end point composed of ischemic or hemorrhagic stroke, transient ischemic attack, myocardial infarction, angina pectoris, peripheral vascular disease, and revascularization procedures. Over a median follow-up duration of 15.6 years, 179 CVD events occurred. For the primary CVD outcome, multivariable-adjusted hazard ratios (HRs) per SD higher level were 1.20 for dickkopf-1 (95% CI, 1.02-1.42; P=0.028) and 0.92 for sclerostin (95% CI, 0.78-1.08; P=0.286). Secondary outcome analyses revealed that the association of dickkopf-1 was primarily driven by ischemic and hemorrhagic stroke (67 events; HR, 1.37; 95% CI, 1.06-1.78; P=0.017), whereas no increase in risk was observed for transient ischemic attack (22 events; HR, 0.87; 95% CI, 0.53-1.44; P=0.593), myocardial infarction (45 events; HR, 1.10; 95% CI, 0.78-1.54; P=0.598), or for other CVD (45 events; HR, 1.25; 95% CI, 0.88-1.76; P=0.209). Conclusions In this prospective, population-based study, elevated baseline levels of dickkopf-1, but not sclerostin, were independently associated with incident cardiovascular events, which was mainly driven by stroke. Our findings support the hypothesis of a role of dickkopf-1 in the pathogenesis of CVD.

Midbrain hyperechogenicity, hyposmia, mild parkinsonian signs and risk for incident Parkinson's disease over 10 years: A prospective population-based study.

INTRODUCTION: Associations of substantia nigra (SN) hyperechogenicity on transcranial sonography, olfactory dysfunction, and mild parkinsonian signs (MPS) with incident Parkinson's disease (PD) have only been studied over limited periods of follow-up and their long-term predictive properties are unclear. We aimed to prospectively assess the risk for incident PD over 10 years in community-dwelling elderly individuals with these risk markers. METHODS: SN-hyperechogenicity, olfactory function, and MPS were assessed in the prospective population-based Bruneck Study (2005 in-person assessment; n = 574, aged 55-94 years). Cases of incident PD were identified at 5-year and 10-year follow-up visits. We estimated relative risks of baseline markers for incident cases. RESULTS: After excluding 35 cases with PD or secondary parkinsonism at baseline, a total of 20 cases of incident PD were identified from the remaining 539 participants (11 at 5 years and 9 at 10 years). Relative risks for incident PD over the 10-year follow-up period were 7.43 (2.71-20.39), 3.60 (1.48-8.78), and 5.52 (2.43-12.57) for baseline SN-hyperechogenicity, hyposmia, and mild parkinsonian signs, respectively. While risk of hyposmia for incident PD was similar for the two sequential 5-year periods studied, relative risks of SN-hyperechogenicity and MPS were higher for the first five years as compared to later. CONCLUSION: Our findings extend the established risk relationship of SN-hyperechogenicity, hyposmia, and MPS with incident PD beyond 5 years of follow-up.

Performance of the Movement Disorders Society criteria for prodromal Parkinson's disease: A population-based 10-year study.

OBJECTIVE: We aimed to identify prodromal Parkinson's disease (PD) and its predictive accuracy for incident PD in an unselected elderly population and to estimate the relevance of this approach for future neuroprotection trials. METHODS: We applied the recently published Movement Disorders Society (MDS) research criteria for prodromal PD to participants of the prospective population-based Bruneck Study of the 2005 assessment (n = 574, ages 55-94 years). Cases of incident PD were identified at 3-year, 5-year, and 10-year follow-up visits. We calculated predictive accuracies of baseline prodromal PD status for incident cases, and, based on them, estimated sample sizes for neuroprotection trials with conversion to PD as the primary outcome. RESULTS: Baseline status of probable prodromal PD (n = 12) had a specificity in predicting incident PD of 98.8% (95% confidence interval, 97.3%-99.5%), a sensitivity of 66.7% (29.6%-90.8%), and a positive predictive value of 40.0% (16.7%-68.8%) over 3 years. Specificity remained stable with increasing follow-up time, sensitivity decreased to 54.6% (28.0%-78.8%) over 5 years and to 35.0% (18.0%-56.8%) over 10 years, whereas positive predictive value rose to 60.0% (31.2%-83.3%) and 77.8% (44.3%-94.7%), respectively. Sample size estimates at 80% power in an intention-to-treat approach ranged from 108 to 540 patients with probable prodromal PD depending on trial duration (3-5 years) and effect size of the agent (30%-50%). CONCLUSIONS: Our findings show that the MDS criteria for prodromal PD yield moderate to high predictive power for incident PD in a community-based setting and may thus be helpful to define target populations of future neuroprotection trials. © 2018 International Parkinson and Movement Disorder Society.

Prodromal Parkinson's disease as defined per MDS research criteria in the general elderly community.

BACKGROUND: Recently, the International Parkinson and Movement Disorder Society has defined research criteria for prodromal Parkinson's disease (PD), but to date their predictive value has not yet been tested in population-based cohorts. METHODS: We retrospectively applied these criteria to the longitudinal Bruneck Study cohort aged 55-94 years using recorded data on all included risk and prodromal markers that are quick and easily assessable. RESULTS: After excluding participants with idiopathic PD or secondary parkinsonism, prevalence of probable prodromal PD in the remaining 539 participants was 2.2% (95% confidence interval, 1.2%-3.9%). Of 488 participants followed up over 5 years, 11 developed incident PD. Sensitivity of "probable prodromal PD" status for incident PD was 54.6% (95% confidence interval, 28.0%-78.8%), specificity was 99.2% (97.8%-99.8%), positive predictive value was 60.0% (31.2%-83.3%), and negative predictive value was 99.0% (97.5%-99.6%). CONCLUSIONS: Our findings suggest that the new research criteria for prodromal PD are a promising tool to identify cases of incident PD over 5 years, arguing for their usefulness in defining target populations for disease-prevention trials. © 2016 International Parkinson and Movement Disorder Society.

[Not Available]. / Auswirkungen der Migrane auf die Lebens-qualitat von Kindern und Jugendlichen.

Background Migraine is one of the most common pain symptoms in childhood, a chronic disease with recurrent symptoms that lead to a reduction of daily activities during the intercritical periods, with an impact of the quality of life. Objective The aim of this publication is to investigate, in which extent migraine affects the quality of life of children and adolescents, how strong they are restricted in everyday life and in which areas such restrictions can be found. Results The parents of children with FSH (frequent or severe headaches) reported that the children had difficulties with emotions, concentration, behaviour, and were unable to get along with others. Children with FSH were significantly more likely to be upset or distressed by their difficulties, while experiencing disappointments, and to have these difficulties interfere with home life, friendships and classroom learning (Strine et al., 2006). Moreover, mothers described children with migraine as evidencing higher levels of internalizing behaviour and symptoms of anxiety and depression. Children with migraine indicated more negative self-perceptions of their physical appearance (Vannatta et al., 2008). Children with migraine lost school activity and performance, household tasks and leisure. Furthermore, it was observed that children with migraine went to school but didn't show a good performance because of physical or mental health problems (Ferracini, Dach & Speciali, 2013). Conclusion Compared to children without migraine, children and adolescents with migraine have generally poorer qualities of life in different areas.

Prevalence and burden of gait disorders in elderly men and women aged 60-97 years: a population-based study.

BACKGROUND: Although gait disorders are common in the elderly, the prevalence and overall burden of these disorders in the general community is not well defined. METHODS: In a cross-sectional investigation of the population-based Bruneck Study cohort, 488 community-residing elderly aged 60-97 years underwent a thorough neurological assessment including a standardized gait evaluation. Gait disorders were classified according to an accepted scheme and their associations to falls, neuropsychological measures, and quality of life were explored. RESULTS: Overall, 32.2% (95% confidence interval [CI] 28.2%-36.4%) of participants presented with impaired gait. Prevalence increased with age (p<0.001), but 38.3% (95%CI 30.1%-47.3%) of the subjects aged 80 years or older still had a normally preserved gait. A total of 24.0% (95%CI 20.4%-28.0%) manifested neurological gait disorders, 17.4% (14.3%-21.0%) non-neurological gait problems, and 9.2% (6.9%-12.1%) a combination of both. While there was no association of neurological gait disorders with gender, non-neurological gait disorders were more frequent in women (p = 0.012). Within the group of neurological gait disorders 69.2% (95%CI 60.3%-76.9%) had a single distinct entity and 30.8% (23.1%-39.7%) had multiple neurological causes for gait impairment. Gait disorders had a significant negative impact on quantitative gait measures, but only neurological gait disorders were associated with recurrent falls (odds ratio 3.3; 95%CI 1.4-7.5; p = 0.005 for single and 7.1; 2.7-18.7; p<0.001 for multiple neurological gait disorders). Finally, we detected a significant association of gait disorders, in particular neurological gait disorders, with depressed mood, cognitive dysfunction, and compromised quality of life. CONCLUSIONS: Gait disorders are common in the general elderly population and are associated with reduced mobility. Neurological gait disorders in particular are associated with recurrent falls, lower cognitive function, depressed mood, and diminished quality of life.

Substantia nigra hyperechogenicity as a marker for Parkinson's disease: a population-based study.

BACKGROUND: The clinical diagnosis of Parkinson's disease (PD) is currently anchored in its cardinal motor symptoms. According to hospital-based studies, an enlarged echogenicity in the area of the substantia nigra (SN) assessed with transcranial sonography (TCS) may represent a useful biomarker in the diagnosis of PD. OBJECTIVE: To evaluate SN hyperechogenicity as a marker for PD in the Bruneck Study cohort, which is representative of the general elderly community. METHODS: The diagnostic accuracy of TCS in distinguishing clinically diagnosed PD from nonparkinsonian subjects was assessed in 574 subjects from this cohort. RESULTS: There was a good diagnostic accuracy of TCS in distinguishing PD subjects from nonparkinsonian subjects with an area under the curve value of 0.82. At a receiver-operating characteristic curve analysis-based cutoff value for SN hyperechogenicity of 0.18 cm(2), TCS had a sensitivity of 88.2% (95% confidence interval, CI, 64.4-98.0), a specificity of 77.0% (95% CI 72.8-80.6), a positive predictive value of 12.7% (95% CI 7.8-20.0) and a negative predictive value of 99.4% (95% CI 97.8-100.0) for subjects with clinically definite PD at baseline. When analyzing the same population after 5 years with regard to the presence of known and newly diagnosed PD cases, baseline TCS yielded very similar diagnostic accuracy values. CONCLUSION: SN hyperechogenicity may represent a useful biomarker for PD not only in a hospital-based setting but also in the general community.