Delirium in older patients with COVID-19: Prevalence, risk factors and clinical outcomes across the first three waves of the pandemic.

OBJECTIVES: Delirium is a serious condition, which poses treatment challenges during hospitalisation for COVID-19. Improvements in testing, vaccination and treatment might have changed patient characteristics and outcomes through the pandemic. We evaluated whether the prevalence and risk factors for delirium, and the association of delirium with in-hospital mortality changed through the pandemic. METHODS: This study was part of the COVID-OLD study in 19 Dutch hospitals including patients ≥70 years in the first (spring 2020), second (autumn 2020) and third wave (autumn 2021). Multivariable logistic regression models were used to study risk factors for delirium, and in-hospital mortality. Differences in effect sizes between waves were studied by including interaction terms between wave and risk factor in logistic regression models. RESULTS: 1540, 884 and 370 patients were included in the first, second and third wave, respectively. Prevalence of delirium in the third wave (12.7%) was significantly lower compared to the first (22.5%) and second wave (23.5%). In multivariable-adjusted analyses, pre-existing memory problems was a consistent risk factor for delirium across waves. Previous delirium was a risk factor for delirium in the first wave (OR 4.02), but not in the second (OR 1.61) and third wave (OR 2.59, p-value interaction-term 0.028). In multivariable-adjusted analyses, delirium was not associated with in-hospital mortality in all waves. CONCLUSION: Delirium prevalence declined in the third wave, which might be the result of vaccination and improved treatment strategies. Risk factors for delirium remained consistent across waves, although some attenuation was seen in the second wave.

New horizons in cognitive and functional impairment as a consequence of cerebral small vessel disease.

Cerebral small vessel disease (cSVD) is a frequent finding in imaging of the brain in older adults, especially in the concomitance of cardiovascular disease risk factors. Despite the well-established link between cSVD and (vascular) cognitive impairment (VCI), it remains uncertain how and when these vascular alterations lead to cognitive decline. The extent of acknowledged markers of cSVD is at best modestly associated with the severity of clinical symptoms, but technological advances increasingly allow to identify and quantify the extent and perhaps also the functional impact of cSVD more accurately. This will facilitate a more accurate diagnosis of VCI, against the backdrop of concomitant other neurodegenerative pathology, and help to identify persons with the greatest risk of cognitive and functional deterioration. In this study, we discuss how better assessment of cSVD using refined neuropsychological and comprehensive geriatric assessment as well as modern image analysis techniques may improve diagnosis and possibly the prognosis of VCI. Finally, we discuss new avenues in the treatment of cSVD and outline how these contemporary insights into cSVD can contribute to optimise screening and treatment strategies in older adults with cognitive impairment and multimorbidity.

Delirium in older COVID-19 patients: Evaluating risk factors and outcomes.

OBJECTIVES: A high incidence of delirium has been reported in older patients with Coronavirus disease 2019 (COVID-19). We aimed to identify determinants of delirium, including the Clinical Frailty Scale, in hospitalized older patients with COVID-19. Furthermore, we aimed to study the association of delirium independent of frailty with in-hospital outcomes in older COVID-19 patients. METHODS: This study was performed within the framework of the multi-center COVID-OLD cohort study and included patients aged ≥60 years who were admitted to the general ward because of COVID-19 in the Netherlands between February and May 2020. Data were collected on demographics, co-morbidity, disease severity, and geriatric parameters. Prevalence of delirium during hospital admission was recorded based on delirium screening using the Delirium Observation Screening Scale (DOSS) which was scored three times daily. A DOSS score ≥3 was followed by a delirium assessment by the ward physician In-hospital outcomes included length of stay, discharge destination, and mortality. RESULTS: A total of 412 patients were included (median age 76, 58% male). Delirium was present in 82 patients. In multivariable analysis, previous episode of delirium (Odds ratio [OR] 8.9 [95% CI 2.3-33.6] p = 0.001), and pre-existent memory problems (OR 7.6 [95% CI 3.1-22.5] p < 0.001) were associated with increased delirium risk. Clinical Frailty Scale was associated with increased delirium risk (OR 1.63 [95%CI 1.40-1.90] p < 0.001) in univariable analysis, but not in multivariable analysis. Patients who developed delirium had a shorter symptom duration and lower levels of C-reactive protein upon presentation, whereas vital parameters did not differ. Patients who developed a delirium had a longer hospital stay and were more often discharged to a nursing home. Delirium was associated with mortality (OR 2.84 [95% CI1.71-4.72] p < 0.001), but not in multivariable analyses. CONCLUSIONS: A previous delirium and pre-existent memory problems were associated with delirium risk in COVID-19. Delirium was not an independent predictor of mortality after adjustment for frailty.

Characteristics and outcomes of older patients hospitalised for COVID-19 in the first and second wave of the pandemic in The Netherlands: the COVID-OLD study.

BACKGROUND: as the coronavirus disease of 2019 (COVID-19) pandemic progressed diagnostics and treatment changed. OBJECTIVE: to investigate differences in characteristics, disease presentation and outcomes of older hospitalised COVID-19 patients between the first and second pandemic wave in The Netherlands. METHODS: this was a multicentre retrospective cohort study in 16 hospitals in The Netherlands including patients aged ≥ 70 years, hospitalised for COVID-19 in Spring 2020 (first wave) and Autumn 2020 (second wave). Data included Charlson comorbidity index (CCI), disease severity and Clinical Frailty Scale (CFS). Main outcome was in-hospital mortality. RESULTS: a total of 1,376 patients in the first wave (median age 78 years, 60% male) and 946 patients in the second wave (median age 79 years, 61% male) were included. There was no relevant difference in presence of comorbidity (median CCI 2) or frailty (median CFS 4). Patients in the second wave were admitted earlier in the disease course (median 6 versus 7 symptomatic days; P < 0.001). In-hospital mortality was lower in the second wave (38.1% first wave versus 27.0% second wave; P < 0.001). Mortality risk was 40% lower in the second wave compared with the first wave (95% confidence interval: 28-51%) after adjustment for differences in patient characteristics, comorbidity, symptomatic days until admission, disease severity and frailty. CONCLUSIONS: compared with older patients hospitalised in the first COVID-19 wave, patients in the second wave had lower in-hospital mortality, independent of risk factors for mortality.The better prognosis likely reflects earlier diagnosis, the effect of improvement in treatment and is relevant for future guidelines and treatment decisions.

A Systematic Review of Strategies for Preventing Delirium in Patients Undergoing Vascular Surgery.

BACKGROUND: Elderly patients undergoing vascular surgery are at a risk of developing postoperative delirium, which is associated with high mortality. Delirium prevention is difficult and is investigated in surgical patients from various specialisms, but little is known about delirium prevention in vascular surgery. For this reason we performed a systematic review on strategies for delirium prevention in patients undergoing elective surgery for peripheral arterial disease or for an aneurysm of the abdominal aorta. METHODS: This systematic review included studies describing strategies for preventing delirium in patients undergoing elective surgery for peripheral arterial disease or for an aneurysm of the abdominal aorta. The search was conducted using the keywords 'vascular surgery,' 'prevention,' and 'delirium' and was last run on October 21, 2021 in the electronic databases PubMed, MEDLINE, Embase, Web of Science, the Cochrane library, and Emcare. Risk of bias was assessed using the Cochrane risk of bias tool for randomized controlled trials and the ROBINS-1 tool for observational studies. RESULTS: Four studies including 565 patients were included in the systematic review. A significant decrease in the incidence of delirium was reported by a study investigating the effect of comprehensive geriatric assessments within patients undergoing surgery for an aneurysm of the abdominal aorta or lower limb bypass surgery (24% in the control group vs. 11% in the intervention group, P = 0.018) and in the total group of a study evaluating the effect of outpatient clinic multimodal prehabilitation for patients with an aneurysm of the abdominal aorta (11.7% in the control group vs. 8.2% in the intervention group, P = 0.043, Odds Ratio = 0.56). A nonsignificant decrease in delirium incidence was described for patients receiving a multidisciplinary quality improvement at the vascular surgical ward (21.4% in the control group vs. 14.6% in the intervention group, P = 0.17). The study concerning the impact of the type of anesthesia on delirium in 11 older vascular surgical patients, of which 3 developed delirium, did not differentiate between the different types of anesthesia the patients received. CONCLUSIONS: Despite the high and continuous increasing incidence of delirium in the growing elderly vascular population, little is known about effective preventive strategies. An approach to address multiple risk factors simultaneously seems to be promising in delirium prevention, whether through multimodal prehabilitation or comprehensive geriatric assessments. Several strategies including prehabilitation programs have been proven to be successful in other types of surgery and more research is required to evaluate effective preventive strategies and prehabilitation programs in vascular surgical patients.

The recognition and management of neuropsychiatric symptoms in early Alzheimer's disease: a qualitative study among Dutch memory clinic physicians.

BACKGROUND: Timely recognition and treatment of neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) dementia may improve quality of life, reduce caregiver burden, and delay disease progression. However, management of NPS in early AD dementia remains challenging. To date, little is known about the specific challenges for memory clinic-based physicians. The aims of this qualitative study were to obtain insights regarding the recognition and treatment of NPS in AD dementia in the memory clinic, to identify challenges experienced by physicians while managing NPS, and to examine the attitudes of memory clinic physicians on the role of the memory clinic in the care for NPS in early AD dementia. METHODS: Semi-structured interviews were conducted with 13 physicians working at a memory clinic in the Netherlands (n = 7 neurologist, n = 6 geriatrician, 46% female). The data were analyzed by two independent researchers using thematic analysis. RESULTS: We observed large variation among Dutch memory clinic physicians regarding care practices, expertise, and attitudes on the role of the memory clinic considering NPS in AD dementia. The most prominent challenges that memory clinic physicians experienced while managing NPS included that the outpatient setting complicates the recognition and treatment of NPS, a lack of experience, knowledge, and/or resources to adequately apply non-pharmacological interventions, and a lack of consensus among physicians on the role of the memory clinic in NPS recognition and management. CONCLUSIONS: We identified challenges that need to be addressed to improve the early recognition and adequate management of NPS in AD dementia at the memory clinic.

Orthostatic Hypotension: A Prodromal Marker of Parkinson's Disease?

BACKGROUND: Orthostatic hypotension is common in patients with Parkinson's disease (PD). However, it remains unknown whether orthostatic hypotension is a marker of prodromal PD or more advanced disease. The objectives of this study were to assess whether orthostatic hypotension is a prodromal marker of PD in the general population. METHODS: This study was embedded in the Rotterdam Study, a large prospective population-based cohort in the Netherlands. We measured orthostatic hypotension in 6910 participants. First, we determined the relation between prevalent PD and orthostatic hypotension using logistic regression. Second, we followed PD-free participants for the occurrence of PD until 2016 and studied the association between orthostatic hypotension and the risk of PD using Cox proportional hazards models. All models were adjusted for age and sex. RESULTS: At baseline, the mean age ± standard deviation of the study population was 69.0 ± 8.8 years, and 59.1% were women. Orthostatic hypotension was present in 1245 participants (19.8%), and 62 participants (1.0%) had PD at the time of orthostatic hypotension measurement. Participants with PD were significantly more likely to have orthostatic hypotension (odds ratio, 1.88; 95% confidence interval, 1.09-3.24). During a median (interquartile range) follow-up of 16.1 years (8.5-22.7 years), 122 participants were diagnosed with incident PD. Orthostatic hypotension at baseline was not associated with an increased risk of PD (hazard ratio, 0.97; 95% confidence interval, 0.59-1.58). CONCLUSIONS: Our study suggests that orthostatic hypotension is common in patients with PD, but that orthostatic hypotension is not associated with an increased risk of PD and thus is not a prodromal marker of PD in the general population. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Frailty is associated with in-hospital mortality in older hospitalised COVID-19 patients in the Netherlands: the COVID-OLD study.

BACKGROUND: During the first wave of the coronavirus disease 2019 (COVID-19) pandemic, older patients had an increased risk of hospitalisation and death. Reports on the association of frailty with poor outcome have been conflicting. OBJECTIVE: The aim of the present study was to investigate the independent association between frailty and in-hospital mortality in older hospitalised COVID-19 patients in the Netherlands. METHODS: This was a multicentre retrospective cohort study in 15 hospitals in the Netherlands, including all patients aged ≥70 years, who were hospitalised with clinically confirmed COVID-19 between February and May 2020. Data were collected on demographics, co-morbidity, disease severity and Clinical Frailty Scale (CFS). Primary outcome was in-hospital mortality. RESULTS: A total of 1,376 patients were included (median age 78 years (interquartile range 74-84), 60% male). In total, 499 (38%) patients died during hospital admission. Parameters indicating presence of frailty (CFS 6-9) were associated with more co-morbidities, shorter symptom duration upon presentation (median 4 versus 7 days), lower oxygen demand and lower levels of C-reactive protein. In multivariable analyses, the CFS was independently associated with in-hospital mortality: compared with patients with CFS 1-3, patients with CFS 4-5 had a two times higher risk (odds ratio (OR) 2.0 (95% confidence interval (CI) 1.3-3.0)) and patients with CFS 6-9 had a three times higher risk of in-hospital mortality (OR 2.8 (95% CI 1.8-4.3)). CONCLUSIONS: The in-hospital mortality of older hospitalised COVID-19 patients in the Netherlands was 38%. Frailty was independently associated with higher in-hospital mortality, even though COVID-19 patients with frailty presented earlier to the hospital with less severe symptoms.

Incidence, determinants and consequences of delirium in older patients after transcatheter aortic valve implantation.

BACKGROUND: delirium is an event leading to negative health outcomes and increased mortality in patients. The aim of this study is to investigate the incidence, determinants and consequences of post-operative delirium (POD) in older patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: The TAVI Care and Cure program is a prospective, observational registry in patients referred for TAVI at Erasmus University Medical Centre. The presence of delirium was evaluated by daily clinical assessment by a geriatrician pre- and up to 3 days post-TAVI. Mortality data were obtained from the Dutch Civil Registry. RESULTS: A total of 543 patients underwent TAVI between January 2014 and December 2017. Overall, the incidence of POD was 14% (75/543 patients) but declined from 18% in 2014 to 7% in 2017 (P = 0.009). Patients who developed POD were older (81.9 ± 5.8 versus 78.6 ± 8.3 years, P < 0.001), had higher prevalence of renal dysfunction and prior stroke (54% versus 40%, P = 0.02; 31% versus 18%, P = 0.01) and were more often frail (32% versus 25%, P = 0.02). From a procedural perspective, general anesthesia (odds ratios (OR), 2.31; 95% CI, 1.40-3.83; P = 0.001), non-transfemoral access (OR, 2.37; 95% CI, 1.20-4.70; P = 0.01) and longer procedural time (OR, 1.01; 95% CI, 1.01-1.02; P < 0.001) were significantly associated with POD. One-year survival rate was 68% among patients who had suffered a POD and was 85% in patients without a POD (hazard ratio's 1.8 (95% CI 1.01-3.10), P = 0.045). CONCLUSION: POD frequently occurs after TAVI and is associated with increased mortality. It might be speculated that patient selection and the minimalistic approach of TAVI may reduce the frequency of delirium.

Impact of frailty on health-related quality of life 1 year after transcatheter aortic valve implantation.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) brings symptom relief and improvement in health-related quality of life (HRQoL) in the majority of patients treated for symptomatic, severe aortic stenosis. However, there is a substantial group of patients that do not benefit from TAVI. The aim of this study is to investigate the impact of frailty on HRQoL 1 year after TAVI. METHODS: The TAVI Care & Cure Program is an ongoing, prospective, observational study including patients referred for TAVI to our institution. A comprehensive geriatric assessment was performed to evaluate existence of frailty using the Erasmus Frailty Score (EFS). HRQoL was assessed using the EQ-5D-5 L at baseline and 1 year after TAVI. RESULTS: 239 patients underwent TAVI and completed HRQoL assessment 1 year after TAVI. Seventy (29.3%) patients were classified as frail (EFS ≥ 3). In non-frail patients, the EQ-5D-5 L index did not change (0.71(± 0.22) to 0.68(± 0.33) points, P = 0.22); in frail patients, the EQ-5D-5 L index decreased from 0.55(±0.26) to 0.44 points (±0.33) (P = 0.022). Frailty was an independent predictor of deteriorated HRQoL 1 year after TAVI (OR 2.24, 95% CI 1.07-4.70, P = 0.003). In frail patients, the absence of peripheral artery disease (OR 0.17, 95% 0.05-0.50, P = 0.001) and renal dysfunction (OR 0.13, 95% CI 0.04-0.41, P = <0.001) at baseline was associated with improved HRQoL 1 year after TAVI. CONCLUSION: Frailty is associated with deterioration of HRQoL 1 year after TAVI. Notably, HRQoL did improve in frail patients with no peripheral arterial disease or renal impairment at baseline.

Thyroid function and life expectancy with and without noncommunicable diseases: A population-based study.

BACKGROUND: Variations in thyroid function within reference ranges are associated with increased risk of diseases and death. However, the impact of thyroid function on life expectancy (LE) with and without noncommunicable diseases (NCDs) remains unknown. We therefore aimed to investigate the association of thyroid function with total LE and LE with and without NCD among euthyroid individuals. METHODS AND FINDINGS: The study was embedded in the Rotterdam Study, a prospective population-based study carried out in the Netherlands. In total, 7,644 participants without known thyroid disease and with thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels within reference ranges were eligible. NCDs were defined as presence of cardiovascular disease, diabetes mellitus type 2, or cancer. We used the demographic tool of multistate life tables to calculate LE estimates at the age of 50 years, using prevalence, incidence rates, and hazard ratios for three transitions (healthy to NCD, healthy to death, and NCD to death). The total LE and LE with and without NCD among TSH and FT4 tertiles were calculated separately in men and women. Analyses were adjusted for sociodemographic and cardiovascular risk factors. The mean (standard deviation) age of the participants was 64.5 (9.7) years, and 52.3% were women. Over a median follow-up of 8 years (interquartile range 2.7-9.9 years), 1,396 incident NCD events and 1,422 deaths occurred. Compared with those in the lowest TSH tertile, men and women in the highest TSH tertile were expected to live 1.5 years (95% confidence interval [CI] 0.8-2.3, p < 0.001) and 1.5 years (CI 0.8-2.2, p < 0.001) longer, respectively, of which 1.4 years (CI 0.5-2.3, p = 0.002) and 1.3 years (CI 0.3-2.1, p = 0.004) with NCD. Compared with those in the lowest FT4 tertile, the difference in LE for men and women in the highest FT4 tertile was -3.7 years (CI -5.1 to -2.2, p < 0.001) and -3.3 years (CI -4.7 to -1.9, p < 0.001), respectively, of which -1.8 years (CI -3.1 to -0.7, p = 0.003) and -2.0 years (CI -3.4 to -0.7, p = 0.003) without NCD. A limitation of the study is the observational design. Thus, the possibility of residual confounding cannot be entirely ruled out. CONCLUSIONS: In this study, we found that people with low-normal thyroid function (i.e., highest tertile of TSH and lowest tertile of FT4 reference ranges) are expected to live more years with and without NCD than those with high-normal thyroid function (i.e., lowest tertile of TSH and highest tertile of FT4 reference ranges). These findings provide support for a re-evaluation of the current reference ranges of thyroid function.

Thyroid Function and the Risk of Atherosclerotic Cardiovascular Morbidity and Mortality: The Rotterdam Study.

RATIONALE: Thyroid hormones have been linked with various proatherogenic and antiatherogenic processes. However, the relationship of thyroid function with manifestations of atherosclerosis remains unclear. OBJECTIVE: To investigate the association of thyroid function with atherosclerosis throughout its spectrum; that is, subclinical atherosclerosis, incident atherosclerotic cardiovascular (ASCV) events, and ASCV mortality. METHODS AND RESULTS: This population-based study was embedded within the Rotterdam Study. The risk of atherosclerosis was evaluated by measuring (1) presence of subclinical atherosclerosis, assessed by coronary artery calcification score >100 AU; (2) ASCV events, defined as fatal and nonfatal myocardial infarction, other coronary heart disease mortality, or stroke; (3) ASCV mortality, defined as death because of coronary heart disease and cerebrovascular or other atherosclerotic diseases. Associations of thyroid-stimulating hormone and free thyroxine with the outcomes were assessed through logistic regression and Cox proportional hazard models, adjusted for potential confounders, including cardiovascular risk factors. A total of 9420 community-dwelling participants (mean age±SD, 64.8±9.7 years) were included. During a median follow-up of 8.8 years (interquartile range, 4.5-11.8 years), 934 incident ASCV events and 612 ASCV deaths occurred. Free thyroxine levels were positively associated with high coronary artery calcification score (odds ratio, 2.28; 95% confidence interval, 1.30-4.02) and incident ASCV events (hazard ratio, 1.87; confidence interval, 1.34-2.59). The risk of ASCV mortality increased in a linear manner with higher free thyroxine levels (hazard ratio, 2.41; confidence interval, 1.68-3.47 per 1 ng/dL) and lower thyroid-stimulating hormone levels (hazard ratio, 0.92; confidence interval, 0.84-1.00 per 1 logTSH). Results remained similar or became stronger among euthyroid participants. CONCLUSIONS: Free thyroxine levels in middle-aged and elderly subjects were positively associated with atherosclerosis throughout the whole disease spectrum, independent of cardiovascular risk factors.

Association of estimated glomerular filtration rate with muscle function in older persons who have fallen.

Background: studies suggest that estimated glomerular filtration rate (eGFR) is less reliable in older persons and that a low serum-creatinine might reflect reduced muscle mass rather than high kidney function. This study investigates the possible relationship between eGFR and multiple elements of physical performance in older fallers. Methods: baseline data of the IMPROveFALL-study were examined in participants ≥65 years. Serum-creatinine based eGFR was classified as normal (≥90 ml/min), mildly reduced (60-89 ml/min) or moderately-severely reduced (<60 ml/min). Timed-Up-and-Go-test and Five-Times-Sit-to-Stand-test were used to assess mobility; calf circumference and handgrip strength to assess muscle status. Ancova models adjusted for age, sex, Charlson comorbidity index and body mass index were performed. Results: a total of 578 participants were included. Participants with a normal eGFR had lower handgrip strength than those with a mildly reduced eGFR (-9.5%, P < 0.001) and those with a moderately-severely reduced eGFR (-6.3%, P = 0.033) with mean strengths of 23.4, 25.8 and 24.9 kg, respectively. Participants with a normal eGFR had a smaller calf circumference than those with a mildly reduced eGFR (35.5 versus 36.5 cm, P = 0.006). Mean time to complete the mobility tests did not differ. Conclusions: in this study we found that older fallers with an eGFR ≥ 90 ml/min had smaller calf circumference and up to 10% lower handgrip strength than those with a reduced eGFR. This lower muscle mass is likely to lead to an overestimation of kidney function. This outcome therefore supports the search for biomarkers independent of muscle mass to estimate kidney function in older persons.

Effectiveness of medication withdrawal in older fallers: results from the Improving Medication Prescribing to reduce Risk Of FALLs (IMPROveFALL) trial.

Objectives: To investigate the effect of withdrawal of fall-risk-increasing-drugs (FRIDs) versus 'care as usual' on reducing falls in community-dwelling older fallers. Design: Randomised multicentre trial Participants: Six hundred and twelve older adults who visited an Emergency Department (ED) because of a fall. Interventions: Withdrawal of FRIDs. Main Outcomes and Measures: Primary outcome was time to the first self-reported fall. Secondary outcomes were time to the second self-reported fall and to falls requiring a general practitioner (GP)-consultation or ED-visit. Intention-to-treat (primary) and a per-protocol (secondary) analysis were conducted. The hazard ratios (HRs) for time-to-fall were calculated using a Cox-regression model. Differences in cumulative incidence of falls were analysed using Poisson regression. Results: During 12 months follow-up, 91 (34%) control and 115 (37%) intervention participants experienced a fall; 35% of all attempted interventions were unsuccessful, either due to recurrence of the initial indication for prescribing, additional medication for newly diagnosed conditions or non-compliance. Compared to baseline, the overall percentage of users of ≥3 FRIDs at 12 months did not change in either the intervention or the control group. Our intervention did not have a significant effect on time to first fall (HR 1.17; 95% confidence interval 0.89­1.54), time to second fall (1.19; 0.78­1.82), time to first fall-related GP-consultation (0.66; 0.42­1.06) or time to first fall-related ED-visit (0.85; 0.43­1.68). Conclusion: In this population of complex multimorbid patients visiting an ED because of a fall, our single intervention of FRIDs-withdrawal was not effective in reducing falls. Trial Registration: Netherlands Trial Register NTR1593.

Kidney Function and Cerebral Blood Flow: The Rotterdam Study.

CKD is linked with various brain disorders. Whereas brain integrity is dependent on cerebral perfusion, the association between kidney function and cerebral blood flow has yet to be determined. This study was performed in the framework of the population-based Rotterdam Study and included 2645 participants with mean age of 56.6 years (45% men). We used eGFR and albumin-to-creatinine ratio to assess kidney function and performed phase-contrast magnetic resonance imaging of basilar and carotid arteries to measure cerebral blood flow. Participants had an average (SD) eGFR of 86.3 (13.4) ml/min per 1.73 m(2) and a median (interquartile range) albumin-to-creatinine ratio of 3.4 (2.2-6.1) mg/g. In age- and sex-adjusted models, a higher albumin-to-creatinine ratio was associated with lower cerebral blood flow level (difference in cerebral blood flow [milliliters per minute per 100 ml] per doubling of the albumin-to-creatinine ratio, -0.31; 95% confidence interval, -0.58 to -0.03). The association was not present after adjustment for cardiovascular risk factors (P=0.10). Each 1 SD lower eGFR was associated with 0.42 ml/min per 100 ml lower cerebral blood flow (95% confidence interval, 0.01 to 0.83) adjusted for cardiovascular risk factors. Thus, in this population-based study, we observed that lower eGFR is independently associated with lower cerebral blood flow.

Orthostatic Hypotension and the Long-Term Risk of Dementia: A Population-Based Study.

BACKGROUND: Orthostatic hypotension (OH) is a common cause of transient cerebral hypoperfusion in the population. Cerebral hypoperfusion is widely implicated in cognitive impairment, but whether OH contributes to cognitive decline and dementia is uncertain. We aimed to determine the association between OH and the risk of developing dementia in the general population. METHODS AND FINDINGS: Between 4 October 1989 and 17 June 1993, we assessed OH in non-demented, stroke-free participants of the population-based Rotterdam Study. OH was defined as a ≥20 mm Hg drop in systolic blood pressure (SBP) or ≥10 mm Hg drop in diastolic blood pressure (DBP) within 3 min from postural change. We furthermore calculated within participant variability in SBP related to postural change, expressed as coefficient of variation. Follow-up for dementia was conducted until 1 January 2014. We determined the risk of dementia in relation to OH and SBP variability, using a Cox regression model, adjusted for age; sex; smoking status; alcohol intake; SBP; DBP; cholesterol:high-density lipoprotein ratio; diabetes; body mass index; use of antihypertensive, lipid-lowering, or anticholinergic medication; and apolipoprotein E genotype. Finally, we explored whether associations varied according to compensatory increase in heart rate. Among 6,204 participants (mean ± standard deviation [SD] age 68.5 ± 8.6 y, 59.7% female) with a median follow-up of 15.3 y, 1,176 developed dementia, of whom 935 (79.5%) had Alzheimer disease and 95 (8.1%) had vascular dementia. OH was associated with an increased risk of dementia (adjusted hazard ratio [aHR] 1.15, 95% CI 1.00-1.34, p = 0.05), which was similar for Alzheimer disease and vascular dementia. Similarly, greater SBP variability with postural change was associated with an increased risk of dementia (aHR per SD increase 1.08, 95% CI 1.01-1.16, p = 0.02), which was similar when excluding those who fulfilled the formal criteria for OH (aHR 1.08, 95% CI 1.00-1.17, p = 0.06). The risk of dementia was particularly increased in those with OH who lacked a compensatory increase in heart rate (within lowest quartile of heart rate response: aHR 1.39, 95% CI 1.04-1.85, p-interaction = 0.05). Limitations of this study include potential residual confounding despite rigorous adjustments, and potentially limited generalisability to populations not of European descent. CONCLUSIONS: In this population predominantly of European descent, OH was associated with an increase in long-term risk of dementia.

Effect of vitamin B12 and folic acid supplementation on biomarkers of endothelial function and inflammation among elderly individuals with hyperhomocysteinemia.

B-vitamin trials failed to demonstrate beneficial effects on cardiovascular outcomes, but hyperhomocysteinemia still stands out as an independent cardiovascular risk factor, particularly in elderly individuals. B-vitamins may influence early vascular dysfunction, such as endothelial dysfunction, or may have adverse effects, for example on inflammation. We investigated the effect of B-vitamins on endothelial function and inflammation within an interventional study. This study was conducted within the framework of the B-PROOF trial, which included 2919 hyperhomocysteinemic elderly individuals, who received daily vitamin B12 (500 µg) and folic acid (400 µg) or placebo for 2 years. Using an electrochemiluminescence platform, we measured intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), serum amyloid A (SAA), vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) at baseline and follow-up in a subsample of 522 participants (271 intervention group; 251 placebo). Treatment effects were analyzed with ANCOVA. The participants had a mean age of 72 years, and 55% of them were male. At the 2-year follow-up, B-vitamins did not change the ICAM-1 (+36% change in the intervention group versus +32% change in the placebo group; p = 0.72), VCAM-1 (+27% vs +25%; p = 0.39), VEGF (-1% vs +4%; p = 0.40), SAA (+34% vs +38%; p = 0.85) or CRP levels (+26% vs +36%; p = 0.70) as compared to placebo. In conclusion, in elderly patients with hyperhomocysteinemia, vitamin B12 and folic acid are unlikely to influence either endothelial function or low-grade systemic inflammation. ClinicalTrials.gov Identifier: NCT00696514.

Cost-utility of medication withdrawal in older fallers: results from the improving medication prescribing to reduce risk of FALLs (IMPROveFALL) trial.

BACKGROUND: The use of Fall-Risk-Increasing-Drugs (FRIDs) has been associated with increased risk of falls and associated injuries. This study investigates the effect of withdrawal of FRIDs versus 'care as usual' on health-related quality of life (HRQoL), costs, and cost-utility in community-dwelling older fallers. METHODS: In a prospective multicenter randomized controlled trial FRIDs assessment combined with FRIDs-withdrawal or modification was compared with 'care as usual' in older persons, who visited the emergency department after experiencing a fall. For the calculation of costs the direct medical costs (intramural and extramural) and indirect costs (travel costs) were collected for a 12 month period. HRQoL was measured at baseline and at 12 months follow-up using the EuroQol-5D and Short Form-12 version 2. The change in EuroQol-5D and Short Form-12 scores over 12 months follow-up within the control and intervention groups was compared using the Wilcoxon Signed Rank test for continuous variables and the McNemar test for dichotomous variables. The change in scores between the control and intervention groups were compared using a two-way analysis of variance. RESULTS: We included 612 older persons who visited an emergency department because of a fall. The mean cost of the FRIDs intervention was €120 per patient. The total fall-related healthcare costs (without the intervention costs) did not differ significantly between the intervention group and the control group (€2204 versus €2285). However, the withdrawal of FRIDs reduced medication costs with a mean of €38 per participant. Furthermore, the control group had a greater decline in EuroQol-5D utility score during the 12-months follow-up than the intervention group (p = 0.02). The change in the Short Form-12 Physical Component Summary and Mental Component Summary scores did not differ significantly between the two groups. CONCLUSIONS: Withdrawal of FRID's in older persons who visited an emergency department due to a fall, did not lead to reduction of total health-care costs. However, the withdrawal of FRIDs reduced medication costs with a mean of €38 per participant in combination with less decline in HRQoL is an important result. TRIAL REGISTRATION: The trial is registered in the Netherlands Trial Register ( NTR1593 - October 1st 2008).

Neopterin: a potential biomarker for delirium in elderly patients.

BACKGROUND/AIMS: The diagnosis of delirium is not supported by specific biomarkers. In a previous study, high neopterin levels were found in patients with a postoperative delirium. In the present study, we investigated levels of neopterin, interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) in acutely ill admitted elderly patients with and without a delirium. METHODS: Plasma/serum levels of neopterin, IL-6 and IGF-1 were determined in patients aged ≥65 years admitted to the wards of Internal Medicine and Geriatrics. Differences in biomarker levels between patients with and without a delirium were investigated by the analysis of variance in models adjusted for age, gender, comorbidities and eGFR (when appropriate). RESULTS: Eighty-six patients were included; 23 of them with a delirium. In adjusted models, higher mean levels of neopterin (70.5 vs. 45.9 nmol/l, p = 0.009) and IL-6 (43.1 vs. 18.5 pg/ml, p = 0.034) and lower mean levels of IGF-1 (6.3 vs. 9.3 nmol/l, p = 0.007) were found in patients with a delirium compared to those without. CONCLUSIONS: The findings of this study suggest that neopterin might be a potential biomarker for delirium which, through oxidative stress and activation of the immune system, may play a role in the pathophysiology of delirium.