The frequency of non-motor symptoms in SCA3 and their association with disease severity and lifestyle factors.

BACKGROUND: Non-motor symptoms (NMS) are a substantial burden for patients with SCA3. There are limited data on their frequency, and their relation with disease severity and activities of daily living is not clear. In addition, lifestyle may either influence or be affected by the occurrence of NMS. OBJECTIVE: To characterize NMS in SCA3 and investigate possible associations with disease severity and lifestyle factors. METHODS: In a prospective cohort study, we performed a cross-sectional analysis of NMS in 227 SCA3 patients, 42 pre-ataxic mutation carriers, and 112 controls and tested for associations with SARA score, activities of daily living, and the lifestyle factors alcohol consumption, smoking and physical activity. RESULTS: Sleep disturbance, restless legs syndrome, mild cognitive impairment, depression, bladder dysfunction and pallhypesthesia were frequent among SCA3 patients, while mainly absent in pre-ataxic mutation carriers. Except for restless legs syndrome, NMS correlated significantly with disease severity and activities of daily living. Alcohol abstinence was associated with bladder dysfunction. Patients with higher physical activity showed less cognitive impairment and fewer depressive symptoms, but these differences were not significant. CONCLUSION: This study revealed a clear association between disease severity and NMS, likely driven by the progression of the widespread neurodegenerative process. Associations between lifestyle and NMS can probably be attributed to the influence of NMS on lifestyle.

Characterization of Lifestyle in Spinocerebellar Ataxia Type 3 and Association with Disease Severity.

BACKGROUND: Lifestyle could influence the course of hereditary ataxias, but representative data are missing. OBJECTIVE: The objective of this study was to characterize lifestyle in spinocerebellar ataxia type 3 (SCA3) and investigate possible associations with disease parameters. METHODS: In a prospective cohort study, data on smoking, alcohol consumption, physical activity, physiotherapy, and body mass index (BMI) were collected from 243 patients with SCA3 and 119 controls and tested for associations with age of onset, disease severity, and progression. RESULTS: Compared with controls, patients with SCA3 were less active and consumed less alcohol. Less physical activity and alcohol abstinence were associated with more severe disease, but not with progression rates or age of onset. Smoking, BMI, or physiotherapy did not correlate with disease parameters. CONCLUSION: Differences in lifestyle factors of patients with SCA3 and controls as well as associations of lifestyle factors with disease severity are likely driven by the influence of symptoms on behavior. No association between lifestyle and disease progression was detected. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A physically active lifestyle is related to a lower level of skin autofluorescence in a large population with chronic-disease (LifeLines cohort).

BACKGROUND: Physical activity (PA) has substantial health benefits and is important in combatting chronic diseases, which have been associated with elevated levels of advanced glycation endproducts (AGEs). AGEs play a role in the aging process, and an association between PA and AGEs has been reported. We aimed to investigate the relationship between PA and AGE accumulation in a general population and in a population with chronic diseases. METHODS: This large cross-sectional population study used data from adult participants in the LifeLines project, with participant information drawn from the LifeLines database as well data from patients with diabetes mellitus or renal and/or cardiovascular diseases. Tissue AGE accumulation was assessed non-invasively by skin-autofluorescence (SAF) using an AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). PA was assessed using the short questionnaire to assess health-enhancing physical activity (SQUASH). Multivariate linear regression analyses were adjusted for age, body mass index, sex, and smoking status. RESULTS: Data from 63,452 participants (general population n = 59,177, chronic disease n = 4275) were analyzed. The general population was significantly younger (43.58 ± 11.77 years, mean ± SD) and had significantly lower SAF (1.90 ± 0.42 arbitrary units (AU)) compared to the population with chronic disease (age: 55.51 ± 12.07 years; SAF: 2.27 ± 0.51 AU). In the group with chronic disease, more hours of moderate to vigorous physical activities per week were associated with lower SAF (ß = -0.002, 95% confidence interval (95%CI): -0.002 to -0.001). For the general population, there was no association between hours of moderate to vigorous activity and SAF (ß = 3.2 â€¯× 10-5, 95%CI: 0.000-0.001, p = 0.742). However, there was an association in the general population between total hours of PA per week and SAF (ß = 4.2 × 10-4, 95%CI: 0.000-0.001, p < 0.001), but this association was not found in the chronic disease population (ß = -3.2 × 10-4, 95%CI: -0.001 to 0.000, p = 0.347). CONCLUSION: Our study demonstrates that an inverse relationship exists between PA and AGE accumulation in the population with chronic disease. More hours of moderate to vigorous activity is associated with a significantly decreased SAF. More PA is associated with a lower SAF, even after adjusting for the established predictors (age, body mass index, smoking status, and sex). Our findings could help to promote health and prolong longevity.

Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood.

BACKGROUND: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. OBJECTIVE: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). METHODS: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. RESULTS: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases. CONCLUSIONS: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Non-LDL dyslipidemia is prevalent in the young and determined by lifestyle factors and age: The LifeLines cohort.

BACKGROUND AND AIMS: Non-LDL dyslipidemia (NLD) confers cardiovascular risk, and prevalence rates appear to be high in elderly populations. Small cohorts have identified several lifestyle, anthropometric, and medical factors associated with NLD. We aimed to assess sex- and age-specific prevalence of NLD in a contemporary population cohort (n = 167 729), and to identify independent determinants of NLD, focusing on lifestyle, anthropometric, and medical factors. METHODS: The prevalence of NLD was assessed per 10-year age intervals in adults without cardiovascular disease not using lipid-modifying drugs from the Dutch LifeLines cohort. NLD was defined as low HDL-cholesterol or high triglycerides or high remnant cholesterol as per guideline cut-off values. Multivariable regression was used to identify factors independently associated with NLD. Determinants included age, smoking, alcohol use, physical activity, diet, BMI, diabetes mellitus (DM), chronic kidney disease, and in women, menopausal state and oral contraceptive use. RESULTS: NLD occurred in 15-19% of women and 13-30% of men in this cohort, with the highest prevalence of 30% in 35-55 year old men. In most age groups, the prevalence in women was lower than in men. Obesity (both sexes: Odds ratio (OR) 5.3, 95% confidence interval (95%CI) 5.0-5.7), current smoking (men: OR 1.8, 95%CI 1.7-1.9; women OR 2.2, 95%CI 2.1-2.3), and DM (men: OR 2.2, 95%CI 1.8-2.6; women: OR 2.7, 95%CI 2.3-3.1) were strongly associated with NLD. CONCLUSIONS: NLD already occurs frequently at an early age. Modifiable lifestyle choices, obesity, and DM were strong determinants of NLD. Public health efforts could substantially contribute to decrease NLD.

Time to improve statin prescription guidelines in low-risk patients?

Background The challenge of the primary prevention of cardiovascular disease (CVD) is to identify patients who would benefit from treatment with statins. Statins are currently prescribed to many patients, even those at a low 10-year risk of CVD. These latter patients may not be eligible for statins according to current guidelines. Design This study investigated the prescription of guideline-consistent (according to guidelines) and guideline-inconsistent (not according to guidelines) lipid-lowering treatment in primary prevention in a large contemporary Dutch cohort study (Lifelines). Methods Lifelines is a large cohort study from the Netherlands. Participants were recruited between 2006 and 2013. They completed questionnaires and underwent a physical examination. Participants with previous CVD were excluded. Statins and ezetimibe were grouped as statin treatment. The Dutch guideline on cardiovascular management was used to assess eligibility for statins. Results Of 147,785 participants, 7092 (4.8%) reported statin treatment. In 4667 (66%) participants, statin treatment was inconsistent with the Dutch guideline. A total of 78% of these participants had a low 10-year predicted CVD risk. Multivariable logistic regression analysis showed that female sex and smoking were strongly associated with guideline-inconsistent treatment. Interestingly, 65% of the these participants had low-density lipoprotein cholesterol levels above the 95th percentile, adjusted for age and sex, two or more major risk factors of CVD or a positive family history of premature CVD. Therefore treatment might be reasonable. Conclusions There is a large inconsistency between guideline recommendations and the prescription of statins in clinical practice in the Netherlands. This is especially true for patients with low CVD risk. Many of these patients probably had risk-increasing circumstances justifying treatment.

Impact of tumour invasion on seminal vesicles mobility in radiotherapy of prostate cancer.

PURPOSE: Mobility of the seminal vesicles relative to the prostate challenges adequate dose coverage. The aim of this study was to assess the impact of tumour invasion on SV mobility. METHODS AND MATERIALS: Three groups of 30 prostate cancer patients with (1) no invasion on MR, (2) minimal invasion (<5mm), and (3) extensive invasion (>5mm) were studied. Translations and rotations of the SV were measured with CBCT and compared between the three groups. RESULTS: In the extensive group the random SV translations were significantly lower in comparison with the no invasion group in the LR: 0.15 vs 0.16 cm (p=0.015), CC: 0.17 vs 0.23 cm (p=0.004) and AP direction: 0.19 vs 0.26 cm (p=0.002). Also the random SV rotation on the LR axis was significantly lower: 5.2 vs 6.3° (p=0.035). In comparison with the minimal invasion group the random SV translations were significantly lower in the extensive group in the CC: 0.17 vs 0.24 cm (p=0.001) and AP direction 0.19 vs 0.31 cm (p=0.007) and for the rotation on the LR axis: 5.2 vs 6.5° (p=0.043). CONCLUSION: Increasing tumour invasion in the SV reduces the mobility of the SV, however the mobility remains considerable.

Tomato Pto encodes a functional N-myristoylation motif that is required for signal transduction in Nicotiana benthamiana.

Pto kinase of tomato (Lycopersicon esculentum) confers resistance to bacterial speck disease caused by Pseudomonas syringae pv. tomato expressing avrPto or avrPtoB. Pto interacts directly with these type-III secreted effectors, leading to induction of defence responses including the hypersensitive response (HR). Signalling by Pto requires the nucleotide-binding site-leucine-rich repeat (NBS-LRR) protein Prf. Little is known of how Pto is controlled prior to or during stimulation, although kinase activity is required for Avr-dependent activation. Here we demonstrate a role for the N-terminus in signalling by Pto. N-terminal residues outside the kinase domain were required for induction of the HR in Nicotiana benthamiana. The N-terminus also contributed to both AvrPto-binding and phosphorylation abilities. Pto residues 1-10 comprise a consensus motif for covalent attachment of myristate, a hydrophobic 14-carbon saturated fatty acid, to the Gly-2 residue. Several lines of evidence indicate that this motif is important for Pto function. A heterologous N-myristoylation motif complemented N-terminal deletion mutants of Pto for Prf-dependent signalling. Signalling by wild-type and mutant forms of Pto was strictly dependent on the Gly-2 residue. The N-myristoylation motif of Pto complemented the cognate motif of AvrPto for avirulence function and membrane association. Furthermore, Pto was myristoylated in vivo dependent on the presence of Gly-2. The subcellular localization of Pto was independent of N-myristoylation, indicating that N-myristoylation is required for some function other than membrane affinity. Consistent with this idea, AvrPtoB was also found to be a soluble protein. The data indicate an important role(s) for the myristoylated N-terminus in Pto signalling.