Patient-perceived progression in multiple system atrophy: natural history of quality of life.

BACKGROUND: Health-related quality of life (Hr-QoL) scales provide crucial information on neurodegenerative disease progression, help improve patient care and constitute a meaningful endpoint for therapeutic research. However, Hr-QoL progression is usually poorly documented, as for multiple system atrophy (MSA), a rare and rapidly progressing alpha-synucleinopathy. This work aimed to describe Hr-QoL progression during the natural course of MSA, explore disparities between patients and identify informative items using a four-step statistical strategy. METHODS: We leveraged the data of the French MSA cohort comprising annual assessments with the MSA-QoL questionnaire for more than 500 patients over up to 11 years. A four-step strategy (1) determined the subdimensions of Hr-QoL, (2) modelled the subdimension trajectories over time, (3) mapped item impairments with disease stages and (4) identified most informative items. RESULTS: Four dimensions were identified. In addition to the original motor, non-motor and emotional domains, an oropharyngeal component was highlighted. While the motor and oropharyngeal domains deteriorated rapidly, the non-motor and emotional aspects were already impaired at cohort entry and deteriorated slowly over the disease course. Impairments were associated with sex, diagnosis subtype and delay since symptom onset. Except for the emotional domain, each dimension was driven by key identified items. CONCLUSION: The multidimensional Hr-QoL deteriorates progressively over the course of MSA and brings essential knowledge for improving patient care. As exemplified with MSA, the thorough description of Hr-QoL over time using the four-step strategy can provide perspectives on neurodegenerative diseases' management to ultimately deliver better support focused on the patient's perspective.

DeepAlienorNet: A deep learning model to extract clinical features from colour fundus photography in age-related macular degeneration.

OBJECTIVE: This study aimed to develop a deep learning (DL) model, named 'DeepAlienorNet', to automatically extract clinical signs of age-related macular degeneration (AMD) from colour fundus photography (CFP). METHODS AND ANALYSIS: The ALIENOR Study is a cohort of French individuals 77 years of age or older. A multi-label DL model was developed to grade the presence of 7 clinical signs: large soft drusen (>125 µm), intermediate soft (63-125 µm), large area of soft drusen (total area >500 µm), presence of central soft drusen (large or intermediate), hyperpigmentation, hypopigmentation, and advanced AMD (defined as neovascular or atrophic AMD). Prediction performances were evaluated using cross-validation and the expert human interpretation of the clinical signs as the ground truth. RESULTS: A total of 1178 images were included in the study. Averaging the 7 clinical signs' detection performances, DeepAlienorNet achieved an overall sensitivity, specificity, and AUROC of 0.77, 0.83, and 0.87, respectively. The model demonstrated particularly strong performance in predicting advanced AMD and large areas of soft drusen. It can also generate heatmaps, highlighting the relevant image areas for interpretation. CONCLUSION: DeepAlienorNet demonstrates promising performance in automatically identifying clinical signs of AMD from CFP, offering several notable advantages. Its high interpretability reduces the black box effect, addressing ethical concerns. Additionally, the model can be easily integrated to automate well-established and validated AMD progression scores, and the user-friendly interface further enhances its usability. The main value of DeepAlienorNet lies in its ability to assist in precise severity scoring for further adapted AMD management, all while preserving interpretability.

Associations of drusen location with risk factors and incidence of late age-related macular degeneration in the Alienor study.

PURPOSE: To test the hypothesis that central drusen location is strongly linked with known Age-related Macular Degeneration (AMD) risk factors and risk of incident late AMD. METHODS: The Alienor study is a prospective population-based cohort study of residents of Bordeaux, France, followed from 2009 to 2017. On retinal photographs, we defined central drusen as at least one soft drusen (>63 µm) within 500 µm from fovea and pericentral drusen as at least one drusen 500-3000 µm from fovea, in the absence of any central drusen. Late AMD (atrophic and/or neovascular) was diagnosed using multimodal imaging. In total, 481 eyes were included in the analysis: 160 central and 321 pericentral. We investigated associations with systemic (age, sex, smoking, medical prescriptions, plasma concentrations of lipids and nutrients, UV exposure, blood pressure), ocular (retinal thickness, cataract extraction) and genetic risk scores (GRS). RESULTS: In multivariate logistic regression central drusen were associated with smoking (OR, 2.95 for smoking more than 20 pack-years, p = 0.02), HDL-cholesterol (OR, 1.57 for 1 standard deviation (SD) increase, p = 0.0048), pulse pressure (OR, 0.77 for 1 SD increase, p = 0.04), Age-Related Maculopathy Susceptibility 2 (ARMS2) GRS (OR, 1.42; 95% CI, 1.11-1.83) and complement GRS (OR, 1.55; 95% CI, 1.15-2.10). In Cox modelling, the central location of drusen (at baseline or during the follow-up) was associated with a 4.41-fold increased risk (95% CI,1.98-9.81) for an incident late AMD. CONCLUSION: Central drusen were strongly associated with AMD risk factors and incident late AMD, suggesting that it represents a key marker for AMD progression.

Omega-3 Blood Levels and Stroke Risk: A Pooled and Harmonized Analysis of 183 291 Participants From 29 Prospective Studies.

BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P<0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.

Skin autofluorescence of Advanced Glycation End-products and mortality in older adults: The roles of chronic kidney disease and diabetes.

BACKGROUND AND AIM: Advanced glycation end products are involved in age-related multisystem decline. They accumulate in body tissues with age, diabetes and chronic kidney disease (CKD), and can be measured non-invasively by the skin autofluorescence (SAF). We studied the relation between SAF and later mortality in old adults. METHODS AND RESULTS: The SAF was measured using an AGE-Reader in 451 individuals from the general population aged over 75 years, and all-cause mortality was assessed during an average follow-up of 6.4 years. The association between SAF and mortality was analyzed using a multivariate Cox survival model, adjusted for age and gender. Analyses were further adjusted for diabetes and stratified on the presence of CKD due to its interaction with SAF for the risk of mortality. Participants were 82 years old on average (SD 4.1). Their mean SAF was 2.8 AU (SD 0.6). One hundred and forty-four individuals (31.9%) died during the follow-up. Adjusted for age and gender, SAF was associated with an increased risk of all-cause mortality (HR 1.44, 95%CI: 1.14-1.82 for a one-AU increase of SAF). The association was no longer significant after adjustment for diabetes. However, after stratification for the presence of CKD, higher SAF was associated with an increased risk of all-cause mortality in the participants with CKD at baseline (HR 1.68, 95%CI: 1.11-2.55), whereas there was no association among participants without CKD (HR 0.95, 95%CI: 0.63-1.44). CONCLUSION: Skin autofluorescence is associated with increased all-cause mortality in older adults already suffering from CKD.

Characterization of the Achromobacter xylosoxidans Type VI Secretion System and Its Implication in Cystic Fibrosis.

Bacteria of the genus Achromobacter are environmental germs, with an unknown reservoir. It can become opportunistic pathogens in immunocompromised patients, causing bacteremia, meningitis, pneumonia, or peritonitis. In recent years, Achromobacter xylosoxidans has emerged with increasing incidence in patients with cystic fibrosis (CF). Recent studies showed that A. xylosoxidans is involved in the degradation of the respiratory function of patients with CF. The respiratory ecosystem of patients with CF is colonized by bacterial species that constantly fight for space and access to nutrients. The type VI secretion system (T6SS) empowers this constant bacterial antagonism, and it is used as a virulence factor in several pathogenic bacteria. This study aimed to investigate the prevalence of the T6SS genes in A. xylosoxidans isolated in patients with CF. We also evaluated clinical and molecular characteristics of T6SS-positive A. xylosoxidans strains. We showed that A. xylosoxidans possesses a T6SS gene cluster and that some environmental and clinical isolates assemble a functional T6SS nanomachine. A. xylosoxidans T6SS is used to target competing bacteria, including other CF-specific pathogens. Finally, we demonstrated the importance of the T6SS in the internalization of A. xylosoxidans in lung epithelial cells and that the T6SS protein Hcp is detected in the sputum of patients with CF. Altogether, these results suggest for the first time a role of T6SS in CF-lung colonization by A. xylosoxidans and opens promising perspective to target this virulence determinant as innovative theranostic options for CF management.

An Item Response Theory analysis of the Unified Multiple System Atrophy Rating Scale.

INTRODUCTION: The Unified Multiple System Atrophy Rating Scale (UMSARS) has four subscales that have been specifically designed for the clinical assessment of MSA patients. UMSARS I (activities of daily living) and II (motor examination) subscales are regularly used as primary endpoints in treatment trials. The main objective of this study was to identify UMSARS I and II subscale items that best describe progression over time. METHODS: All MSA patients seen at the French Reference Centre for MSA from 2007 to 2020 were included in a prospective cohort with an annual follow-up assessment including UMSARS. The repeated measures of the 26 UMSARS I and II items were analyzed using a longitudinal Item Response Theory model to identify the most informative items for each of the five UMSARS IV disease stages. Sample size estimates were further calculated for the most informative items as a group. RESULTS: A total of 557 MSA patients were included with a mean follow-up of 2.3 years. The majority of items progressed with disease duration or across the different UMSARS IV disability stages, with the exception of those related to dysautonomia. Roughly 70% of the scale information was carried by only 11/26 items, many reflecting the patient perspective. These yielded similar sample size estimates than UMSARS I + II items. CONCLUSION: This study provides important information about the progression of UMSARS I and II subscale items. Improvements seem particularly necessary regarding those assessing dysautonomia. A shortened scale may be useful as outcome for future clinical trials.

Self-Rated Health and Frailty in Older Adults from the Population-Based Three-City Bordeaux Cohort.

INTRODUCTION: This study aimed to investigate whether self-rated health (SRH) predict frailty and its components among community dwellers aged 75 years and older. METHODS: We ran a cross-sectional and prospective analysis from 643 and 379 participants of the Bordeaux Center (France) of the Three-City Study, respectively. We assessed SRH using a single question with 5 response options. We defined frailty as having at least 3 out of the following 5 criteria: weight loss, exhaustion, slowness, weakness, and low energy expenditure. We used multivariate logistic regression and Cox proportional hazard models. RESULTS: At baseline, poor SRH was significantly associated with frailty (odds ratio = 5.2; 95% confidence interval [CI]: 2.9-9.5) and its components except for weakness. In the prospective analysis on nonfrail participants, poor SRH was associated with the 4-year risk of slowness (hazard ratio [HR] = 1.7; 95% CI: 1.1-2.6) but not with that of frailty (HR = 1.6; 95% CI: 0.9-2.9) or the other components. CONCLUSIONS: In a French cohort of community dwellers aged 75 years or older, poorer SRH was associated with concomitant frailty and 70% higher risk of slowness over 4 years.

Quantitative Analysis of Radial Peripapillary Capillary Network in Patients With Papilledema Compared with Healthy Subjects Using Optical Coherence Tomography Angiography.

BACKGROUND: To quantitatively compare the peripapillary microvascular network between patients with papilledema and healthy subjects using swept source optical coherence tomography angiography. METHODS: In this retrospective observational study, patients with papilledema secondary to idiopathic intracranial hypertension and healthy controls were imaged with swept source optical coherence tomography angiography (PLEX Elite 9000; Carl Zeiss Meditec, Dublin, CA) using a 6 × 6 mm scan pattern centered on the optic disc. The capillary perfusion density (CPD) and capillary flux index (CFI) of the radial peripapillary capillaries in the retinal nerve fiber layer (RNFL) were calculated using Zeiss algorithm. RESULTS: Thirty-nine eyes of 20 patients with papilledema and 66 eyes of 33 healthy subjects were imaged. The mean (P < 0.01), superior (P < 0.01), inferior (P < 0.01), and temporal (P = 0.02) CPD significantly differed between both groups. No significant difference was found between both groups for the CFI. The mean (P < 0.01), superior (P < 0.01), inferior (P = 0.01), temporal (P < 0.01), and nasal (P < 0.01) quadrants of the RNFL were positively associated with the CFI. The mean (P < 0.01), superior (P = 0.01), inferior (P = 0.01), temporal (P < 0.01), and nasal (P = 0.01) quadrants of the RNFL were negatively associated with the CPD. CONCLUSION: Our study showed a decreased peripapillary capillary density without changes in flux intensity in eyes with papilledema. There were a positive association between the CFI and the RNFL and a negative association between the CPD and the RNFL. It confirmed the discriminatory ability of OCTA in differentiating a papilledema secondary to IIH from a normal optic disc, while providing complementary information for understanding papilledema pathophysiology.

INCIDENCE, PROGRESSION, AND RISK FACTORS OF EPIRETINAL MEMBRANES IN THE ELDERLY.

PURPOSE: To determine the incidence, progression rate, and risk factors for epiretinal membranes (ERMs) in a population of French elderly subjects. METHODS: Seven hundred and thirty-five eyes of 413 participants of the population-based ALIENOR study were included between 2009 and 2010. Participants were re-evaluated every 2 years between 2011 and 2017 (i.e., three follow-up visits). The mean duration of follow-up was 5.09 years (SD, 1.8; range, 0.99-7.85). Epiretinal membranes were graded from spectral-domain optical coherence tomography images according to a standardized classification. RESULTS: The incidence rate of ERMs was 9.42 per 100 eye-years (95% confidence interval, 7.36-12.05), corresponding to a 5-year cumulative incidence of 37.6%. In the final multivariable model, ERM incidence was significantly associated with vitreomacular or vitreopapillary adhesion at baseline (hazard ratio, 2.15; P = 0.02), choroidal thinning (hazard ratio, 1.04 per 10 µm decrease; P = 0.02), ERM in the contralateral eye (P = 0.02), and smoking after 85 years (hazard ratio, 6.01; P = 0.003). The 5-year cumulative progression rate was 6.9%. CONCLUSION: Incidence of ERMs was higher in our population than that previously reported, most probably because of the use of spectral-domain optical coherence tomography images. Incident ERMs were found to be associated with vitreous adhesion at baseline, choroidal thinning, ERM in the contralateral eye, and smoking after 85 years.

OCT angiography analysis in acute non-arteritic anterior ischemic optic neuropathy: The importance of segmentation.

BACKGROUND: In non-arteritic anterior ischemic optic neuropathy (NAION), optical coherence tomography angiography (OCTA) shows changes in peripapillary vascularization. However, the presence of an optic disc edema may induce artifacts that prevent visualizing the peripapillary network. The aim of this study was to evaluate the peripapillary vascularization in acute NAION using swept-source OCTA algorithms allowing segmenting only the retinal nerve fiber layer (RNFL). METHODS: Retrospective analysis of 15 eyes with acute NAION of 15 patients. The optic nerve head was imaged using swept-source OCTA. Morphological and quantitative analyzes were performed. The capillary flux index (CFI), defined as the total weighted area of perfused vasculature per unit area, and the capillary perfusion density (CPD), defined as the total area of perfused microvasculature per unit area, were quantified. Each NAION eye was compared to the unaffected fellow eye using a Wilcoxon test for matched samples. RESULTS: After segmentation at the RNFL, the morphological analysis showed less vascular dropout and more vascular tortuosity than the analysis of a larger segmentation. The quantitative analysis showed that the mean CFI and the CFI in the four quadrants were significantly higher in NAION eyes compared to healthy eyes (p = 0.0002 and p < 0.01). The mean CPD and the CFD in the inferior quadrant were lower in NAION eyes (p = 0.03 and p = 0.0054, respectively). DISCUSSION: The RNFL segmentation allowed better visualizing the peripapillary network because the edema related darkening was reduced. The increased CFI suggests an autoregulatory phenomenon to compensate the ischemic process at the ciliary vasculature.

Cognitive and functional changes in prediagnostic phase of Parkinson disease: A population-based study.

INTRODUCTION: Prodromal non-motor symptoms precede, often by decades, motor signs and diagnosis of Parkinson's disease. It is however still uncertain if cognitive changes belong to the spectrum of non-motor prodromal Parkinson's disease. Thanks to the very long-term follow-up of the PAQUID population-based cohort, we assessed trajectories of cognitive complaints and functioning over a 13-year period before the diagnosis of late onset Parkinson's disease. METHODS: This study relies on a matched nested case-control sample selected from the cohort. Of the 3777 initial subjects of the cohort, 43 developed incident Parkinson's disease over the follow-up. The mean age at diagnosis was 78.0 (standard deviation = 5.8) years and 46.5% were men. These cases were matched to 86 elderly control subjects. Scores of different cognitive domains, daily function, and depressive symptoms were described throughout the follow-up using mixed-effects models. RESULTS: No significant global cognitive decline preceded the diagnosis of late onset Parkinson's disease. However, psychomotor speed appeared significantly slower 2 years before the diagnosis and depressive symptoms 12 years before. Global score of instrumental activities of daily living became altered 2-3 years preceding the diagnosis of late onset Parkinson's disease, including the use of public transportation that was altered ten years before the diagnosis. CONCLUSION: In late onset Parkinson's disease, while global cognitive functions seem preserved, psychomotor speed starts to decline 2 years before the diagnosis and activities of daily living are also impacted. Depressive symptoms appear very early in the prediagnosic phase.

Prevalence of epiretinal membranes in the ageing population using retinal colour images and SD-OCT: the Alienor Study.

PURPOSE: To analyse and compare the prevalence of epiretinal membranes (ERMs) obtained using either standard retinal colour images or spectral-domain optical coherence tomography (SD-OCT) in a population-based setting of French elderly subjects. METHODS: Six hundred twenty-four subjects of the Alienor cohort aged 75 years or older underwent both colour fundus imaging and SD-OCT examinations. The ERMs were graded from retinal images and SD-OCT macular scans in a masked fashion. On SD-OCT images, the early ERMs, mature contractile ERMs without foveal modifications and mature contractile ERMs with foveal alterations were distinguished. RESULTS: 610 (97.8%) subjects had gradable SD-OCT examinations, and 511 (81.9%) had gradable fundus images in at least one eye. According to colour photographs, 11.6% of participants had definite ERMs. From SD-OCT images, 52.8% of the subjects had early ERMs, 7.4% had mature ERMs without foveal involvement, and 9.7% had mature ERMs with foveal alterations. Regardless of the imaging method used, the ERMs were more often observed in pseudophakic eyes than in phakic eyes. Comparison of ERM assessment using fundus photographs versus SD-OCT images demonstrated that the specificity of retinal colour images was good (>89.3%), whereas the sensitivity remained low even though it increased with ERM severity on SD-OCT images. CONCLUSIONS: Spectral-domain optical coherence tomography (SD-OCT) examinations have high feasibility in this elderly population and are much more sensitive than standard colour images for ERM assessments, especially in the early stages of the disease. Our results further highlight the need to use SD-OCT instead of colour retinal photographs for the classification of ERMs in epidemiological studies.

Gait speed and body mass index: Results from the AMI study.

BACKGROUND: While physical frailty and malnutrition/obesity (parameters easily measured by a nurse) are not the same, older persons who are malnourished/obese are more likely to be frail and there is a potential overlap between these conditions. The objective was to examine the relationship between gait speed (GS) and body mass index (BMI) in men and women aged 75 years and older. DESIGN: Cross-sectional analysis. SETTING, PARTICIPANTS: Data from the Aging Multidisciplinary Investigation (AMI), a French prospective cohort study with participants randomly selected from the farmer Health Insurance rolls. MEASUREMENTS: Usual GS was measured over a 4 meters-track. BMI was categorized using clinical cut-points for European populations: (e.g, <20.0 kg/m2; 20.0-24.9 kg/m2; 25.0-29.9 kg/m2; 30.0-34.9 kg/m2; ≥35.0 kg/m2). RESULTS: The current analyses were performed in 449 participants. Mean age was 81 years. Being malnourished/obese was significantly associated with slow GS. Unadjusted and age-adjusted models showed that underweight, overweight and obesity statuses were significantly associated with slow GS for both women (0.83m/s [0.61; 1.04], 0.87m/s [0.72; 1.02], 0.70 m/s [0.41; 0.98], respectively) and men (0.83m/s [0.61; 1.04], 1.11m/s [1.03; 1.20], 0.97m/s [0.75; 1.19], respectively). CONCLUSION: Malnourished/obese are associated with slow GS in older persons. These variables could be contributed at comprehensively and complementarily assessing the older person.

Incidence and Risk Factors of Reticular Pseudodrusen Using Multimodal Imaging.

Importance: Although retinal multimodal imaging is needed for diagnosing reticular pseudodrusen (RPD), the incidence of RPD in the general population typically has been assessed only using fundus photographs, which may underestimate their incidence. Objectives: To describe the incidence of RPD using retinal color photographs, spectral-domain optical coherence tomography scans, fundus autofluorescence, and near-infrared reflectance images among individuals 77 years of age or older and to analyze the associated risk factors of RPD. Design, Setting, and Participants: The ALIENOR (Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires) Study is a cohort of French individuals 77 years of age or older. Data for this study were collected between February 22, 2011, and February 15, 2017, with a mean (SD) follow-up of 3.7 (1.0) years (range, 1.2-5.6 years). At baseline, 501 individuals were eligible to participate. Of 1002 eyes, 197 had prevalent RPD, advanced age-related macular degeneration, or ungradable images. Of the remaining 805 eyes, 333 were missing follow-up data; therefore, the statistical analyses included data from 472 eyes. Data management and statistical analyses were performed between March 15, 2017, and April 5, 2019. Main Outcomes and Measures: Reticular pseudodrusen were considered as present if detected by at least 2 of the following imaging methods: color fundus photographs, fundus autofluorescence, near-infrared reflectance, and spectral-domain optical coherence tomography images. Results: Of the 472 eyes analyzed, 263 (55.7%) were from female participants, and the mean (SD) age was 81.9 (3.2) years. Forty-three eyes developed RPD, corresponding to an annual incidence rate of 2.9% (95% CI, 1.9%-4.4%) per participant and an estimated 5-year risk of 13.5%. In multivariable analysis, 4 risk factors of incident RPD were identified: subfoveal choroidal thinning (hazard ratio [HR], 0.99; 95% CI, 0.99-1.00 per 10-µm decrease in thickness; P = .02) and the presence of the minor allelic variants rs10490924 for ARMS2 (HR, 3.57; 95% CI, 1.80-7.10; P < .001), rs1061170 for CFH (HR, 2.12; 95% CI, 1.02-4.41; P = .04), and rs10468017 for LIPC (HR, 2.57; 95% CI, 1.37-4.82; P = .003). Lipophilic statin therapy was associated with a lower incidence of RPD (HR, 0.13; 95% CI, 0.02-0.74; P = .02). Conclusions and Relevance: With the use of multimodal imaging, the RPD incidence rate was higher than previously reported in other population-based studies using fundus color images. Individuals with subfoveal choroidal thinning or carrying minor allelic variants for ARMS2, CFH, or LIPC had an increased risk for RPD, whereas lipophilic statin therapy was associated with a lower incidence.

Disease progression and prognostic factors in multiple system atrophy: A prospective cohort study.

Multiple system atrophy (MSA) is a rare neurodegenerative disease, with limited understanding of disease progression and prognostic factors. We leveraged the data of a large prospective cohort of MSA to study both clinical progression and survival and assess their determinants. All consecutive patients seen at the French Reference Centre for MSA since 2007 were included in a prospective cohort with an annual follow-up including the Unified MSA Rating Scale (UMSARS). We used joint models to evaluate the risk of death, the mean trajectory of each UMSARS subscale and to determine the potential factors. Investigated factors included gender, age at baseline, MSA subtype, diagnosis certainty, type of first symptoms and the duration between symptom onset and the first visit. Among the 261 MSA patients included in our cohort, the median duration of clinical follow-up was 2.1 years (up to 10.3 years) and the median survival was 4.0 years since the first visit. Main factors for poor survival were the progression over time of UMSARS score (I + II and IV) and the severity of orthostatic hypotension. MSA subtype had no effect on progression or survival. The UMSARS I + II score progressed faster over time in subjects with autonomic dysfunction as the initial feature and in women. Despite a faster progression, women and men had similar survival. From this large MSA cohort, we confirm the rapid progression and poor prognosis of MSA. We provide additional evidence for a negative impact of early autonomic dysfunction and the severity of orthostatic hypotension on both disease progression and survival.

Distinct Requirements for Tail-Anchored Membrane Protein Biogenesis in Escherichia coli.

Tail-anchored membrane proteins (TAMPs) are a distinct subset of inner membrane proteins (IMPs) characterized by a single C-terminal transmembrane domain (TMD) that is responsible for both targeting and anchoring. Little is known about the routing of TAMPs in bacteria. Here, we have investigated the role of TMD hydrophobicity in tail-anchor function in Escherichia coli and its influence on the choice of targeting/insertion pathway. We created a set of synthetic, fluorescent TAMPs that vary in the hydrophobicity of their TMDs and corresponding control polypeptides that are extended at their C terminus to create regular type II IMPs. Surprisingly, we observed that TAMPs have a much lower TMD hydrophobicity threshold for efficient targeting and membrane insertion than their type II counterparts. Using strains conditional for the expression of known membrane-targeting and insertion factors, we show that TAMPs with strongly hydrophobic TMDs require the signal recognition particle (SRP) for targeting. Neither the SecYEG translocon nor YidC appears to be essential for the membrane insertion of any of the TAMPs studied. In contrast, corresponding type II IMPs with a TMD of sufficient hydrophobicity to promote membrane insertion followed an SRP- and SecYEG translocon-dependent pathway. Together, these data indicate that the capacity of a TMD to promote the biogenesis of E. coli IMPs is strongly dependent upon the polypeptide context in which it is presented.IMPORTANCE A subset of membrane proteins is targeted to and inserted into the membrane via a hydrophobic transmembrane domain (TMD) that is positioned at the very C terminus of the protein. The biogenesis of these so-called tail-anchored proteins (TAMPs) has been studied in detail in eukaryotic cells. Various partly redundant pathways were identified, the choice for which depends in part on the hydrophobicity of the TMD. Much less is known about bacterial TAMPs. The significance of our research is in identifying the role of TMD hydrophobicity in the routing of E. coli TAMPs. Our data suggest that both the nature of the TMD and its role in routing can be very different for TAMPs versus "regular" membrane proteins. Elucidating these position-specific effects of TMDs will increase our understanding of how prokaryotic cells face the challenge of producing a wide variety of membrane proteins.

Evolution of brain atrophy subtypes during aging predicts long-term cognitive decline and future Alzheimer's clinical syndrome.

It is currently unknown whether brain atrophy subtypes defined in Alzheimer's disease are clinically relevant during aging. We investigated participants (n = 368) from a population-based cohort of nondemented older adults who received longitudinal neuropsychological assessments during 12 years. Magnetic resonance imaging scans at baseline and 4 years later were used to define participants with "hippocampal predominant atrophy," "cortical predominant atrophy," "homogenous atrophy," and "no evidence of brain subtype atrophy" based on the dynamics of hippocampal-to-cortical volume ratio evolution. After adjustment on age, gender, educational level, and ApoE4 genotype, participants with "hippocampal predominant atrophy" declined faster regarding global cognition, verbal fluency, and verbal episodic memory. In Cox proportional-hazards models, "hippocampal predominant atrophy" was associated with an increased risk of developing Alzheimer's clinical syndrome over time (hazard ratio = 5.73; 95% CI 2.71-12.15), independently of age and ApoE4 genotype, the 2 other significant predictive factors. As a possible surrogate of confined tauopathy and early Alzheimer's disease pathology, future studies should consider the definition of "hippocampal predominant atrophy" based on hippocampal-to-cortical volume ratio evolution rather than hippocampal volume alone.

CHOROIDAL THICKNESS, VASCULAR FACTORS, AND AGE-RELATED MACULAR DEGENERATION: The ALIENOR Study.

PURPOSE: To study the associations of subfoveal choroidal thickness with vascular risk factors and age-related macular degeneration. METHODS: Two hundred sixty-one participants of the Alienor study had gradable enhanced-depth imaging optical coherence tomography scans of the macula and available data on vascular and genetic risk factors (assessed through face-to-face interview and fasting blood samples) and age-related macular degeneration status (assessed from retinal photographs and optical coherence tomography). Subfoveal choroidal thickness was measured manually on one horizontal scan passing through the fovea. RESULTS: In a multivariate mixed linear model, subfoveal choroidal thickness was independently associated with age greater than 80 years (-21.77 µm, P = 0.02), axial length (-21.77 µm, P < 0.0001), heavy smoking (≥20 pack-years: -24.89 µm, P = 0.05), fasting blood glucose higher than 7 mmol/L (-53.17 µm, P = 0.02), and lipid-lowering treatment (+18.23, P = 0.047). After multivariate adjustment for age, sex, axial length, and vascular and genetic risk factors, subfoveal choroidal thickness was thinner in eyes with central hyperpigmentation (-45.39 µm, P = 0.006), central hypopigmentation (-44.99 µm, P = 0.001), and central pigmentary abnormalities (-44.50 µm, P = 0.001), but not in eyes with late age-related macular degeneration (-18.05 µm, P = 0.33) or soft drusen. CONCLUSION: These findings indicate a relationship between vascular risk factors and choroidal thinning and suggest an early involvement of the choroid in the pathogenesis of age-related macular degeneration.