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Background and Objectives: Proteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity.
Methods: Patients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.
Results: Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.
Discussion: D-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS.
Classification of Evidence: This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.
Objectives The aims of our study were to examine the anticholinergic drug use and to assess the association between anticholinergic burden and cognitive function in the multimorbid elderly patients of the MultiCare cohort.
Setting MultiCare was conducted as a longitudinal cohort study in primary care, located in eight different study centres in Germany.
Participants 3189 patients (59.3% female).
Primary and secondary outcome measures Baseline data were used for the following analyses. Drugs were classified according to the well-established anticholinergic drug scale (ADS) and the recently published German anticholinergic burden (German ACB). Cognitive function was measured using a letter digit substitution test (LDST) and a mixed-effect multivariate linear regression was performed to calculate the influence of anticholinergic burden on the cognitive function.
Results Patients used 1764 anticholinergic drugs according to ADS and 2750 anticholinergics according to the German ACB score (prevalence 38.4% and 53.7%, respectively). The mean ADS score was 0.8 (±1.3), and the mean German ACB score was 1.2 (±1.6) per patient. The most common ADS anticholinergic was furosemide (5.8%) and the most common ACB anticholinergic was metformin (13.7%). The majority of the identified anticholinergics were drugs with low anticholinergic potential: 80.2% (ADS) and 73.4% (ACB), respectively. An increasing ADS and German ACB score was associated with reduced cognitive function according to the LDST (−0.26; p=0.008 and −0.24; p=0.003, respectively).
Conclusion Multimorbid elderly patients are in a high risk for using anticholinergic drugs according to ADS and German ACB score. We especially need to gain greater awareness for the contribution of drugs with low anticholinergic potential from the cardiovascular system. As anticholinergic drug use is associated with reduced cognitive function in multimorbid elderly patients, the importance of rational prescribing and also deprescribing needs to be further evaluated.
Trial registration number ISRCTN89818205.
Introduction: In this article three research questions are addressed: (1) Is there an association between socioeconomic status (SES) and patient-reported outcomes in a cohort of multimorbid patients? (2) Does the association vary according to SES indicator used (income, education, occupational position)? (3) Can the association between SES and patient-reported outcomes (self-rated health, health-related quality of life and functional status) be (partly) explained by burden of disease?
Methods: Analyses are based on the MultiCare Cohort Study, a German multicentre, prospective, observational cohort study of multimorbid patients from general practice. We analysed baseline data and data from the first follow-up after 15 months (N = 2,729). To assess burden of disease we used the patients’ morbidity data from standardized general practitioner (GP) interviews based on a list of 46 groups of chronic conditions including the GP’s severity rating of each chronic condition ranging from marginal to very severe.
Results: In the cross-sectional analyses SES was significantly associated with the patient-reported outcomes at baseline. Associations with income were more consistent and stronger than with education and occupational position. Associations were partly explained (17% to 44%) by burden of disease. In the longitudinal analyses only income (but not education and occupational position) was significantly related to the patient-reported outcomes at follow-up. Associations between income and the outcomes were reduced by 18% to 27% after adjustment for burden of disease.
Conclusions: Results indicate social inequalities in self-rated health, functional status and health related quality of life among older multimorbid patients. As associations with education and occupational position were inconsistent, these inequalities were mainly due to income. Inequalities were partly explained by burden of disease. However, even among patients with a similar disease burden, those with a low income were worse off in terms of the three patient-reported outcomes under study.
Objective: The objective of this study was to describe and analyze the effects of depression on health care utilization and costs in a sample of multimorbid elderly patients.
Method: This cross-sectional analysis used data of a prospective cohort study, consisting of 1,050 randomly selected multimorbid primary care patients aged 65 to 85 years. Depression was defined as a score of six points or more on the Geriatric Depression Scale (GDS-15). Subjects passed a geriatric assessment, including a questionnaire for health care utilization. The impact of depression on health care costs was analyzed using multiple linear regression models. A societal perspective was adopted.
Results: Prevalence of depression was 10.7%. Mean total costs per six-month period were €8,144 (95% CI: €6,199-€10,090) in patients with depression as compared to €3,137 (95% CI: €2,735-€3,538; p<0.001) in patients without depression. The positive association between depression and total costs persisted after controlling for socio-economic variables, functional status and level of multimorbidity. In particular, multiple regression analyses showed a significant positive association between depression and pharmaceutical costs.
Conclusion: Among multimorbid elderly patients, depression was associated with significantly higher health care utilization and costs. The effect of depression on costs was even greater than reported by previous studies conducted in less morbid patients.
Objectives Our study aimed to assess the frequency of potentially inappropriate medication (PIM) use (according to three PIM lists) and to examine the association between PIM use and cognitive function among participants in the MultiCare cohort. Design MultiCare is conducted as a longitudinal, multicentre, observational cohort study. Setting The MultiCare study is located in eight different study centres in Germany. Participants 3189 patients (59.3% female). Primary and secondary outcome measures The study had a cross-sectional design using baseline data from the German MultiCare study. Prescribed and over-the-counter drugs were classified using FORTA (Fit fOR The Aged), PRISCUS (Latin for ‘time-honoured’) and EU(7)-PIM lists. A mixed-effect multivariate linear regression was performed to calculate the association between PIM use patients’ cognitive function (measured with (LDST)). Results Patients (3189) used 2152 FORTA PIM (mean 0.9±1.03 per patient), 936 PRISCUS PIM (0.3±0.58) and 4311 EU(7)-PIM (1.4±1.29). The most common FORTA PIM was phenprocoumon (13.8%); the most prevalent PRISCUS PIM was amitriptyline (2.8%); the most common EU(7)-PIM was omeprazole (14.0%). The lists rate PIM differently, with an overall overlap of 6.6%. Increasing use of PIM is significantly associated with reduced cognitive function that was detected with a correlation coefficient of −0.60 for FORTA PIM (p=0.002), −0.72 for PRISCUS PIM (p=0.025) and −0.44 for EU(7)-PIM (p=0.005). Conclusion We identified PIM using FORTA, PRISCUS and EU(7)-PIM lists differently and found that PIM use is associated with cognitive impairment according to LDST, whereby the FORTA list best explained cognitive decline for the German population. These findings are consistent with a negative impact of PIM use on multimorbid elderly patient outcomes.