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Figure.
Hazard Ratio for Mortality Among 104 Patients With Amyotrophic Lateral Sclerosis by Serum RBP4 Concentration as a Continuous Measure
Hazard Ratio for Mortality Among 104 Patients With Amyotrophic Lateral Sclerosis by Serum RBP4 Concentration as a Continuous Measure

Adjusted for body mass index, diagnostic delay, Amyotrophic Lateral Sclerosis–Functional Rating Scale score, and site of onset. The odds ratios are for quartile midpoints (0.125, 0.375, 0.625, and 0.775 percentiles) indicated by dotted lines. RBP4 indicates retinol-binding protein 4.

Table 1.  
Association of Selected Sociodemographic and Clinical Variables With Serum RBP4 Concentration
Association of Selected Sociodemographic and Clinical Variables With Serum RBP4 Concentration
Table 2.  
Odds Ratio for Amyotrophic Lateral Sclerosis by Quartile of Serum RBP4 Concentrationa
Odds Ratio for Amyotrophic Lateral Sclerosis by Quartile of Serum RBP4 Concentrationa
Table 3.  
Characteristics of 279 Patients With Amyotrophic Lateral Sclerosis (ALS) With Mortality Follow-up by Survival Status
Characteristics of 279 Patients With Amyotrophic Lateral Sclerosis (ALS) With Mortality Follow-up by Survival Status
Table 4.  
Hazard Ratio for Mortality by Quartile of Serum RBP4 Concentration Among Patients With Amyotrophic Lateral Sclerosisa
Hazard Ratio for Mortality by Quartile of Serum RBP4 Concentration Among Patients With Amyotrophic Lateral Sclerosisa
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Original Investigation
May 2018

Association of Serum Retinol-Binding Protein 4 Concentration With Risk for and Prognosis of Amyotrophic Lateral Sclerosis

Author Affiliations
  • 1Department of Neurology, University of Ulm, Ulm, Germany
  • 2Institute for Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
  • 3Department of Internal Medicine II–Cardiology, University of Ulm Medical Center, Ulm, Germany
  • 4Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
  • 5German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich
  • 6Institut National de la Santé et de la Récherche Médicale Unité 1118, Université de Strasbourg, Strasbourg, France
JAMA Neurol. 2018;75(5):600-607. doi:10.1001/jamaneurol.2017.5129
Key Points

Question  Is retinol-binding protein 4 (a specific carrier for retinol but also expressed in adipose tissue and found to be causally associated with insulin resistance) associated with risk for and prognosis of amyotrophic lateral sclerosis?

Finding  Among 289 cases and 504 controls in this case-control cohort study, serum retinol-binding protein 4 concentration was inversely associated with risk for and prognosis of amyotrophic lateral sclerosis. Age, sex, and biomarkers for renal damage and fat mass (ie, leptin and adiponectin) did not substantially alter the association.

Meaning  If corroborated in prospective studies, interventions resulting in high retinol-binding protein 4 concentration may point to a relevant pathogenetic pathway and indicate a potential target for therapeutic intervention.

Abstract

Importance  Knowledge about the metabolic states of patients with amyotrophic lateral sclerosis (ALS) may provide a therapeutic approach.

Objective  To investigate the association between the onset and prognosis of ALS and serum retinol-binding protein 4 (RBP4) concentration as a biomarker for insulin resistance and vitamin A metabolism.

Design, Setting, and Participants  Case-control design for risk factors of ALS; cohort design for prognostic factors within ALS cases. Between October 1, 2010, and June 30, 2014, a population-based case-control study with randomly selected controls was established based on the ALS Registry Swabia in southern Germany, with a target population of 8.4 million inhabitants. Response rates were 64.8% among the cases and 18.7% among the controls. The dates of analysis were April 2016 to May 2017.

Main Outcomes and Measures  Serum samples were measured for RBP4. Information on covariates was assessed by an interview-based standardized questionnaire. Main outcomes and measures were adjusted odds ratios for risk of ALS associated with serum RBP4 concentration, as well as time to death associated with RBP4 concentration at baseline in ALS cases only. Conditional logistic regression was applied to calculate multivariable odds ratios for risk of ALS. Survival models were used in cases only to appraise their prognostic value.

Results  Data from 289 patients with ALS (mean [SD] age, 65.7 [10.5] years; 172 [59.5%] male) and 504 controls (mean [SD] age, 66.3 [9.8] years; 299 [59.3%] male) were included in the case-control study. Compared with controls, ALS cases were characterized by lower body mass index, less educational attainment, smoking, light occupational work intensity, and self-reported diabetes. The median serum RBP4 concentration was lower in ALS cases than in controls (54.0 vs 59.5 mg/L). In the multivariable model, increasing RBP4 concentration was associated with reduced odds for ALS (top vs bottom quartile odds ratio, 0.36; 95% CI, 0.22-0.59; P for trend <.001), which persisted after further adjustment for renal function and for leptin and adiponectin. Among 279 ALS cases during a median follow-up of 14.5 months, 104 died (mean [SD] age, 68.9 [10.3] years; 56 [53.9%] male). In this ALS cohort, an inverse association was found between serum RBP4 concentration as a continuous measure and survival.

Conclusions and Relevance  RBP4 was inversely related to risk for and prognosis of ALS, suggesting that vitamin A metabolism or impaired insulin signaling could be involved. Further research, including a prospective design and other biological markers, is necessary to clarify the role of insulin resistance in the pathogenesis of ALS.

Introduction

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons, leading to death within 3 to 4 years after diagnosis.1 The pathogenesis of ALS is still largely unknown.2,3

Retinoic acid and its derivatives, such as vitamin A, have been directly or indirectly associated with ALS.4 As shown in several studies,5-7 retinoic acid is a critical factor in motor neuron development and specification. Retinoic acid also stimulates neurite outgrowth in the peripheral nervous system and is beneficial for nerve regeneration.8 Furthermore, retinoic acid is required for maintaining high expression of the choline acetyltransferase gene in cholinergic neurons, like motor neurons.9 The expression of retinoic acid receptors is modified during disease progression in mice10 and patients11 with ALS. Notably, a complete absence of retinoic acid in adult rats leads to motor neuron disease.12 Epidemiological evidence also indirectly suggests a role of retinoic acid in ALS risk because a case-control study13 from Japan revealed that increased intake of fruits and vegetables was associated with decreased risk for ALS. However, only small differences were found for serum vitamin A levels among patients with ALS and controls.14,15

Vitamin A is obtained from animal sources or from plants containing carotenoids and circulates bound to retinol-binding protein 4 (RBP4), its only specific transport protein.16 Retinol-binding protein 4 not only is a carrier of retinol but also acts as an adipokine. Retinol-binding protein 4 is expressed in adipose tissue, and elevated RBP4 concentration was found to be causally associated with insulin resistance in animal models.17 It has been shown that RBP4 can impair insulin signaling, especially in the muscle and liver.18 In humans, adipose tissue–derived RBP4 was found to be correlated with insulin resistance and was associated with established cardiovascular risk markers, such as body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), waist to hip ratio, and serum triglyceride levels.19 Circulating RBP4 is increased in individuals with diabetes or impaired glucose tolerance.19 Impaired insulin signaling is also observed in patients with ALS,20 who demonstrate abnormal adipose tissue distribution that correlates with survival.21,22 Together, circulating RBP4 concentration appears to constitute a surrogate marker of retinoic acid metabolism and insulin signaling, with both pathways being potentially involved in ALS.

Therefore, the aim of our study was to analyze the associations of serum RBP4 concentration as a biomarker related to vitamin A metabolism and insulin signaling with risk for and prognosis of ALS. This population-based case-control study was conducted in southern Germany.

Methods
Ethics Statement

International, national, and state rules were followed in implementing the ALS Registry Swabia in southern Germany. We obtained full approval of the ethical committees of the University of Ulm, Ulm, Germany, and the regional medical associations (“Landesaerztekammer Baden-Wuerttemberg” and “Landesaerztekammer Bayern”). Patients included in the registry were asked to provide written informed consent for study participation.

Study Design and Study Population

The ALS Registry Swabia has been described previously in detail.23-25 In brief, it is a population-based clinical-epidemiological registry with the aim to collect data on all newly diagnosed ALS cases in Swabia, where approximately 8.4 million German citizens reside. The study aims were to provide estimates of epidemiological variables, such as incidence, to describe the natural history of ALS and to investigate risk factors in a registry-based case-control study in a defined geographic region.

Between October 1, 2010, and June 30, 2014, newly diagnosed ALS cases were prospectively registered. The dates of analysis were April 2016 to May 2017. The ALS cases were defined by the diagnosis of possible, probable, or definite ALS according to the revised El Escorial criteria.26 Depending on the onset of symptoms, the following locational criteria can be distinguished: bulbar, cervical, thoracic, and lumbosacral onset and signs of upper or lower motor neurons. All cases were reviewed by an experienced neurologist (A.R.) according to predefined standardized criteria. Notifications of patients with suspected ALS were tracked and evaluated during the clinical course by the registry.

Patients included in the registry were also asked to provide written informed consent to participate in a population-based case-control study to investigate risk factors of ALS. For each case (n = 289), 2 age and sex–matched control individuals (n = 504) were randomly selected from the general population as registered in the regional registry office (“Einwohnermeldeamt”) in the catchment area. The identified individuals were contacted by postal mail and invited to participate in the study. After written informed consent was obtained, study nurses visited the participants for a standardized interview, including specific neuropsychological tests and blood sampling. The standardized instruments and tests were performed identically in ALS cases and healthy controls. Response rates were 64.8% among the cases (19.9% refused, and 15.2% could not be contacted) and 18.7% among the controls (39.3% refused, and 42.0% did not respond after several attempts to get in contact by mail and telephone). The most frequent reason for refusal was “disinterest,” followed by “limitations due to ill health or age” and “lack of time.”

In addition, serum samples from cases and controls were collected and processed according to a standardized protocol. Serum samples were transported in cool containers to the Department of Neurology at the University of Ulm. Serum was obtained by centrifugation for 10 minutes at 2000g rpm and 4°C (Heraeus Multifuge 3 S-R; Thermo Fisher Scientific). Blood specimens were transferred into aliquots with screw tops (0.5-1.0 mL) on the same day and were stored at −80°C until further analysis. For the present study, all consecutively registered cases until June 30, 2014 (n = 289) and matched controls (n = 504) with available serum samples were selected.

In addition, patients with ALS were actively followed up and interviewed. Record linkage with the central registration office in Baden-Württemberg, Germany, and the local registration offices in Bavaria was performed to update vital status in April 2014. In case of death, the date of death was obtained from the local registration offices.

Biomarker Measurement

Retinol-binding protein 4 (in milograms per liter) was measured in serum by immunonephelometry (BN II System; Siemens). The lower detection limit of RBP4 in this assay was approximately 12.0 mg/L. The interassay coefficient of variation was 5.4%. Serum leptin (in nanograms per milliliter) was measured by enzyme-linked immunosorbent assay (ELISA) (Quantikine, Human Leptin Immunoassay; R&D Systems). Serum levels of adiponectin (in micrograms per milliliter) were also determined by a commercial immunoassay (Human Total Adiponectin/Acrp30 Quantikine ELISA Kit; R&D Systems). Further details can be found elsewhere.22 All laboratory analyses were performed masked at the Biomarker Laboratory of the Department of Internal Medicine II–Cardiology, University of Ulm Medical Center.

Statistical Analysis

Demographic and medical characteristics were compared descriptively. Generalized linear models were used to test associations of selected sociodemographic and clinical variables with serum RBP4 concentration when controlled for case-control status, age, sex, and region of residence. Conditional logistic regression was used to calculate multivariable odds ratios (ORs) and 95% CIs for the association of ALS with quartiles of serum RBP4 concentration. Quartile cut points were calculated based on controls. Models were stratified for sex and age groups and, based on the current literature,2 were adjusted for potential confounders, such as BMI, educational attainment, smoking (ever), occupational work intensity, self-reported diabetes, and family history of ALS. The models are based on data with a full set of covariates (271 cases for the adjusted model and 264 cases for the additionally adjusted models). Estimated glomerular filtration rate (eGFR) was calculated based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation27 and was included as a potential confounder because renal function influences serum RBP4 concentration. In addition, we also adjusted for leptin (in quartiles) and adiponectin (in quartiles).

To investigate the prognostic value of serum RBP4 concentration in patients with ALS, we used Cox proportional hazards regression models to calculate hazard ratios (HRs). Survival times were censored at the date of the last systematic mortality update (April 30, 2014). Cox proportional hazards regression models were adjusted and centered for age, diagnostic delay, site of onset, and ALS–Functional Rating Scale (ALS-FRS) score. Sensitivity analyses excluding the El Escorial categories “clinically suspected” and “clinically possible” were performed in the adjusted model. All provided P values are 2 sided, and P = .05 denotes statistical significance. A statistical software package (SAS, release 9.4; SAS Institute Inc) was used.

Results

The case-control study comprised 289 ALS cases (172 [59.5%] male), with a mean (SD) age of 65.7 (10.5) years, and 504 controls (299 [59.3%] male), with a mean (SD) age of 66.3 (9.8) years (eTable 1 in the Supplement). Most ALS cases showed lumbar (97 [33.6%]), bulbar (91 [31.5%]), or cervical (73 [25.3%]) onset. According to the revised El Escorial criteria, more than 70% of ALS cases had a probable or definite diagnosis. Compared with controls, ALS cases were characterized by lower BMI, less educational attainment, smoking, light occupational work intensity, and self-reported diabetes, which was reported by 9.3% (26 of 281) of ALS cases and 11.0% (54 of 492) of controls. The median serum RBP4 concentration was lower in ALS cases than in controls (54.0 vs 59.5 mg/L).

As summarized in Table 1, the comparison between various sociodemographic and clinical variables and biomarkers revealed no association of RBP4 with age, BMI, educational attainment, smoking, or occupational work intensity. However, it showed statistically significant higher concentration of RBP4 in men than in women (geometric mean, 60.8 vs 53.9 mg/L; P < .001).

In analyses adjusted for age and stratified by sex (Table 2), serum RBP4 concentration was inversely associated with risk of ALS (top vs bottom quartile OR, 0.40; 95% CI, 0.26-0.62; P for trend <.001). After further adjustment for educational attainment, smoking, occupational work intensity, and family history of ALS, the inverse associations remained (top vs bottom quartile OR, 0.44; 95% CI, 0.28-0.68; P for trend <.001). Additional adjustment for BMI, self-reported diabetes, and renal function did not substantially change the estimates (top vs bottom quartile OR, 0.36; 95% CI, 0.22-0.59; P for trend <.001). Sensitivity analyses excluding the El Escorial categories “clinically suspected” and “clinically possible” showed similar risk estimates (top vs bottom quartile OR, 0.47; 95% CI, 0.29-0.77; P for trend <.001) (eTable 2 in the Supplement). Further adjustment for renal function and for leptin and adiponectin did not change the estimates substantially (eTable 3 in the Supplement). The evaluation of the prognostic value of serum RBP4 concentration as a continuous measure by using restricted cubic splines (resulting in a more powerful analytic approach) revealed an inverse association with ALS onset (eFigure in the Supplement). The OR corresponding to the top vs bottom quartile was 0.48 (95% CI, 0.35-0.66).

In the follow-up part of the study, 104 deaths were identified in the 279 patients with ALS with follow-up information during a median follow-up of 14.5 months (Table 3). The median RBP4 concentration was 52.0 mg/L in patients with ALS who died during follow-up compared with 55.0 mg/L in patients who survived.

As summarized in Table 4 in the adjusted model, increased RBP4 concentration was associated with decreased mortality (top vs bottom quartile HR, 0.72; 95% CI, 0.38-1.34), which was not statistically significant. This estimate changed only marginally after additional adjustment for renal function and for leptin and adiponectin (eTable 4 in the Supplement). The sensitivity analyses excluding the El Escorial categories “clinically suspected” and “clinically possible” revealed a statistically significant inverse association (HR, 0.48; 95% CI, 0.23-0.98; P for trend = .02) (eTable 5 in the Supplement).

However, the evaluation of the prognostic value of serum RBP4 concentration as a continuous measure by using restricted cubic splines (Figure) showed that serum RBP4 concentration was inversely associated with the survival of patients with ALS. The HR for the top vs bottom quartile was 0.67 (95% CI, 0.48-0.94).

Discussion

In this population-based case-control study in southern Germany, serum RBP4 concentration was inversely associated with relative risk of ALS. The association showed a statistically significant dose-response relationship. Further adjustment for potential confounders, such as BMI, self-reported diabetes, renal function, and leptin and adiponectin, did not substantially alter the association. In addition, among patients with ALS, we found evidence for an inverse association between serum RBP4 concentration and survival if RBP4 was analyzed as a continuous measure, suggesting also a potential role of RBP4 in the prognosis of ALS. Notably, the primary function of RBP4 to deliver retinol to peripheral tissues may be related to its preventive function and, if corroborated in prospective studies, may represent a possible target toward prevention and treatment of ALS.

One possibility to explain the protective association of RBP4 would be that it represents a validated surrogate marker for serum retinol.28,29 An association between vitamin A (retinol) and its derivatives (retinoids) and ALS is biologically plausible because vitamin A, as an essential micronutrient, has an important role in normal brain development, and vitamin A excess leads to alterations of the central nervous system.30 More specifically related to ALS, retinoic acid is known to have critical roles in motor neuron development, as well as in nerve regeneration after injury or motor neuron survival in adults.4-7,12 The protection offered by increasing RBP4 concentration suggests that retinol levels might be associated with better prognosis in patients with ALS. Early studies have shown that dietary administration of retinoic acid worsened symptoms in an ALS mouse model.31 However, more recent studies using high-affinity retinoid agonists showed a protective potential in the same mouse model.4 Therefore, it is possible that the metabolism of retinol is a modifier of ALS, and our study is consistent with this hypothesis.

An alternative hypothesis, not mutually exclusive from the previous one, would be that RBP4 is a surrogate marker of energy metabolism in patients with ALS.32,33 Indeed, circulating RBP4 is elevated in patients with obesity, metabolic syndrome, and insulin resistance.34 Elevations of RBP4 detected in diabetes stem largely from adipose tissue.19 Our observation of an inverse association between RBP4 concentration and ALS onset is consistent with the findings showing an inverse association between BMI and ALS.35,36 Also, recent findings from the ALS Registry Swabia demonstrating that serum concentrations of leptin and adiponectin were related to ALS onset fits in this picture.22 In those previous analyses, no indication was found that high-sensitivity C-reactive protein is associated with ALS onset or progression.22 The inverse association between RBP4 and ALS onset remained almost unchanged after adjustment for serum leptin and adiponectin, suggesting the involvement of other variables. There is also evidence showing an inverse association between diabetes and ALS.37,38 However, in our study, further adjustment for BMI and self-reported diagnosis of diabetes did not substantially change the risk estimates. Retinol-binding protein 4 is elevated in insulin resistance17 and obesity.39 Experimental research has shown that mice with ALS were hypermetabolic and lean40 and demonstrated a shift from glucose to lipid metabolism.40,41 Indeed, increasing calorie intake was protective in mice with ALS,40 and pilot studies42,43 in gastrostomized patients with ALS yielded similar results. Therefore, our finding that serum RBP4 concentration was inversely associated with the onset and survival of ALS might suggest that RBP4 is a surrogate marker of a protective metabolic status in patients with ALS. The 2 mechanisms potentially explaining our results are not mutually exclusive because at least part of the effects of RBP4 on insulin resistance are mediated by retinoids.17,44

Strengths and Limitations

Among the strengths of our study are its large sample size and the almost complete follow-up of all patients with ALS.25 In addition, we carefully matched for age, sex, and region of residence and used multivariable analysis to further adjust for potential confounders. In our analyses, we considered relevant covariates, such as educational attainment, occupational work intensity, and renal function, using cystatin C–based eGFR measurements, which are independent of age and muscle mass and thus represent a fairly accurate and reliable renal function marker.45 Sensitivity analyses corroborated the inverse associations of RBP4 with ALS risk and mortality. All biomarkers were measured in the Biomarker Laboratory of the Department of Internal Medicine II–Cardiology, University of Ulm Medical Center according to a standard protocol under masked conditions.

Our study also has limitations that need to be considered. Residual confounding due to medications cannot be ruled out. Yet, adjustment for BMI and self-reported diabetes did not substantially change the risk estimates. Furthermore, renal damage may have influenced RBP4 concentration. By study design, we controlled for age, which is positively correlated with serum creatinine levels and negatively correlated with eGFR. When generalizing the results from the case-control study, the low participation rate among the controls should be considered. Finally, our case-control design limits the causal interpretation of the results; notably, the temporal sequence of the associations cannot be assessed. Therefore, prospective data are necessary to further evaluate the potential causal association of serum RBP4 concentration with ALS risk. Our analyses of RPB4 as a prognostic factor are based on the cohort design that included patients with ALS who are representative of the ALS Registry Swabia.25 Research from exome sequence or genome-wide association study data sets46-48 showed no association between genetic RBP4 variants and ALS; however, this finding does not preclude a functional role of RBP4 or retinol in this disease. More research is necessary to corroborate our findings and further disentangle the association between RPB4 and ALS.

Conclusions

In summary, our study showed that serum RBP4 concentration was inversely associated with risk for and prognosis of ALS, suggesting that biological mechanisms influencing RPB4 concentration may be related to the pathogenesis of ALS. Further research, including a prospective design and additional metabolites of retinoid metabolism, is necessary to delineate the effects of vitamin A on the onset and prognosis of ALS.

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Article Information

Accepted for Publication: December 1, 2017.

Corresponding Author: Dietrich Rothenbacher, MD, Institute for Epidemiology and Medical Biometry, University of Ulm, Helmholtzstrasse 22, 89081 Ulm, Germany (dietrich.rothenbacher@uni-ulm.de).

Published Online: February 26, 2018. doi:10.1001/jamaneurol.2017.5129

Author Contributions: Drs Rosenbohm and Nagel contributed equally to this work. Drs Nagel and Rothenbacher had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Rosenbohm, Nagel, Dupuis, Rothenbacher, Ludolph.

Acquisition, analysis, or interpretation of data: Rosenbohm, Nagel, Peter, Brehme, Koenig, Rothenbacher, Ludolph.

Drafting of the manuscript: Rosenbohm, Nagel, Rothenbacher.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Peter, Brehme, Rothenbacher.

Obtained funding: Nagel, Koenig, Rothenbacher, Ludolph.

Administrative, technical, or material support: Nagel, Koenig, Rothenbacher, Ludolph.

Study supervision: Rosenbohm, Nagel, Koenig, Rothenbacher, Ludolph.

Conflict of Interest Disclosures: None reported.

Funding/Support: The ALS Registry Swabia and this study were supported by the German Research Council (DFG) (Drs Nagel, Rothenbacher, and Ludolph).

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The following cooperative partners provided data for the ALS Registry Swabia and comprise the ALS Registry Study Group: B. Alber, Klinikum Günzburg, Department of Neurology; F. Andres, Kreiskliniken Reutlingen Department of Neurology; G. Arnold, Klinikum Sindelfingen-Böblingen Department of Neurology; I. Asshauer, Klinikum Friedrichshafen Department of Psychiatry and Psychotherapy; H. Baezner, Bürgerhospital Stuttgart Department of Neurology; H. Baier, ZFP Südwürttemberg Weissenau Department of Epileptology; J. Beattie, Ostalb-Klinikum Aalen Department of Neurology; T. Becker, University of Ulm Department of Psychiatry and Psychotherapy II; F. Behne, ZFP Südwürttemberg Weissenau Department of Epileptology; D. Bengel, Oberschwabenklinik Ravensburg Department of Neurology; A. Boertlein, Bürgerhospital Stuttgart Department of Neurology; V. Bracknies, Klinik Dietenbronn Department of Neurology; R. Broer, Klinikum am Weissenhof, Weinsberg, Department of Psychiatry and Psychotherapy; B. Connemann, University of Ulm Department of Psychiatry and Psychotherapy III; S. Dempewolf, Klinikum Ludwigsburg Department of Neurology; C. Dettmers, Schmieder Kliniken Konstanz Department of Neurology; M. Dieterich, LMU München Department of Neurology; E. Etzersdorfer, Furtbachkrankenhaus Stuttgart Department of Psychiatry and Psychotherapy; W. Freund, Biberach; T. Gersner, ZFP Zwiefalten Department of Psychiatry and Psychotherapy; H.-J. Gold, Klinikum am Gesundbrunnen Heilbronn Department of Neurology; W. Hacke, University of Heidelberg Department of Neurology; G. Hamann, Klinikum Günzburg Department of Neurology; M. Hecht, Bezirkskrankenhaus Kaufbeuren Department of Neurology; B. Heimbach, University of Freiburg Department of Neurology; B. Hemmer, TU München Department of Neurology; C. Hendrich, Klinikum Friedrichshafen Department of Neurology; B. Herting, Diakonie-Klinikum Schwäbisch Hall Department of Neurology; R. Huber, Klinikum Friedrichshafen Department of Neurology; K. Huber-Hartmann, Kliniken Landkreis Heidenheim Department of Neurology; P.-J. Hülser, Fachklinik Wangen Department of Neurology; E. Jüttler, Ostalb-Klinikum Aalen Department of Neurology; J. Kammerer-Ciernioch, Klinikum am Weissenhof, Weinsberg, Department of Psychiatry and Psychotherapy; A. Kaspar, Oberschwabenklinik Ravensburg Department of Neurology; R. Kern, Klinikum Kempten Department of Neurology; H. Kimmig, Kliniken Schwenningen Department of Neurology; S. Klebe, University of Würzburg Department of Neurology; C. Kloetzsch, Schmieder Kliniken Allensbach Department of Neurology; T. Klopstock, LMU München Department of Neurology; A. Kohler, Klinikum am Gesundbrunnen Heilbronn Department of Neurology; A. Kuethmann, Bezirkskrankenhaus Memmingen Department of Psychiatry and Psychotherapy; D. Lewis, Marienhospital Stuttgart Department of Neurology; C. Lichy, Klinikum Memmingen Department of Neurology; A. Lindner, Marienhospital Stuttgart Department of Neurology; D. Lulé, University of Ulm Department of Neurology; M. Mäurer, Caritas Krankenhaus Bad Mergentheim Department of Neurology; W. Maier-Janson, Ravensburg; J. Metrikat, Bundeswehrkrankenhaus Ulm Department of Neurology; O. Meudt, Klinikum Memmingen Department of Neurology; A. Meyer, Weissenau Department of Neurology; J. Müller vom Hagen, University of Tübingen Department of Neurology; A. Naegele, Christophsbad Göppingen Department of Neurology; M. Naumann, Klinikum Augsburg Department of Neurology; K.-D. Neher, Vinzenz von Paul Hospital, Rottweil, Department of Neurology; O. Neuhaus, Kliniken Landkreis Sigmaringen Department of Neurology; C. Neusch, EMSA Singen; L. Niehaus, Klinikum Winnenden Department of Neurology; C. Opherk, Klinikum am Gesundbrunnen Heilbronn Department of Neurology; J. Raape, ZFP Südwürttemberg Weissenau Department of Neurology; P. Ratzka, Klinikum Augsburg Department of Neurology; C. Rettenmayr, Klinikum Esslingen Department of Neurology; M. W. Riepe, Klinikum Günzburg Department of Gerontopsychiatry; J. Rothmeier, ZFP Südwürttemberg Weissenau Department of Neurology; M. Sabolek, Klinik Biberach Department of Neurology; M. Schabet, Klinikum Ludwigsburg Department of Neurology; C. Schell, Kreiskliniken Reutlingen Department of Neurology; T. Schlipf, Klinikum Winnenden Department of Psychiatry and Psychotherapy; M. Schmauss, Bezirkskrankenhaus Augsburg Department of Psychiatry and Psychotherapy; L. Schoels, University of Tübingen Department of Neurology; K. Schuetz, Kliniken Schwenningen Department of Neurology; B. Schweigert, Caritas Krankenhaus Bad Mergentheim Department of Neurology; N. Sommer, Christophsbad Göppingen Department of Neurology; W. Sperber, Kliniken Esslingen Department of Neurology; C. Steber, Bezirkskrankenhaus Augsburg Department of Psychiatry and Psychotherapy; R. Steber, Bezirkskrankenhaus Memmingen Department of Psychiatry and Psychotherapy; M. Stroick, Klinikum Memmingen Department of Neurology; M. Synofzik, University of Tübingen Department of Neurology; T. Trottenberg, Klinikum Winnenden Department of Neurology; H. Tumani, Klinikum Dietenbronn Department of Neurology; C. Wahl, Klinikum Kempten Department of Neurology; F. Weber, Bundeswehrkrankenhaus Ulm Department of Neurology; M. Weiler, University of Heidelberg Department of Neurology; C. Weiller, University of Freiburg Department of Neurology; C. Wessig, University of Würzburg Department of Neurology; and A. Winkler, TU München Department of Neurology.

Additional Contributions: Ilonka Kraft-Overbeck, Ines Dobias, and Nicola Lämmle performed excellent fieldwork. Gerlinde Trischler provided expert technical assistance. Gertrud Feike, Sarah Enderle, and Birgit Och contributed excellent data management and technical support.

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