Sex-specific associations of matrix metalloproteinases in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) can be characterised in vivo by biomarkers reflecting amyloid-ß (Aß) and tau pathology. However, there is a need for biomarkers reflecting additional pathological pathways. Matrix metalloproteinases (MMPs) have recently been highlighted as candidate biomarkers for sex-specific mechanisms and progression in AD. METHODS: In this cross-sectional study, we investigated nine MMPs and four tissue inhibitors of metalloproteinases (TIMPs) in the cerebrospinal fluid of 256 memory clinic patients with mild cognitive impairment or dementia due to AD and 100 cognitively unimpaired age-matched controls. We studied group differences in MMP/TIMP levels and examined the associations with established markers of Aß and tau pathology as well as disease progression. Further, we studied sex-specific interactions. RESULTS: MMP-10 and TIMP-2 levels differed significantly between the memory clinic patients and the cognitively unimpaired controls. Furthermore, MMP- and TIMP-levels were generally strongly associated with tau biomarkers, whereas only MMP-3 and TIMP-4 were associated with Aß biomarkers; these associations were sex-specific. In terms of progression, we found a trend towards higher MMP-10 at baseline predicting more cognitive and functional decline over time exclusively in women. CONCLUSION: Our results support the use of MMPs/TIMPs as markers of sex differences and progression in AD. Our findings show sex-specific effects of MMP-3 and TIMP-4 on amyloid pathology. Further, this study highlights that the sex-specific effects of MMP-10 on cognitive and functional decline should be studied further if MMP-10 is to be used as a prognostic biomarker for AD.

Effects of nutritional intervention upon bone turnover in elderly hip fracture patients. Randomized controlled trial.

BACKGROUND AND AIM: Hip fracture patients are at great risk of malnutrition, but documentation of the effect of nutrition supplementation in this group is sparse and inconclusive. The aim of this study was to examine if personalized nutrition advice combined with vitamin K1, Ca and vitamin D could improve bone turnover 4 months after hip fracture. DESIGN: This is a preplanned sub study of a randomized controlled trial of orthogeriatric care. The intervention group received orthogeriatric care, including nutrition advice and supplementation. The control group received usual care at the orthopedic ward. Blood was drawn for measurements of a number of vitamins and of bone turnover markers upon admission and at four months follow up. RESULTS: 71 patients (31 in the intervention group and 40 controls) had available data at 4 months as well as at baseline. After four months, vitamin K1 and 25(OH)D were higher in the intervention group compared with controls; vitamin K1: 1.0 ± 1.2 vs 0.6 ± 0.6 ng/ml, p = 0.09, 25(OH)D: 60 ± 29 vs 43 ± 22 nmol/L, p = 0.01 when adjusted for baseline differences. In a secondary, unadjusted analysis, comprising all patients with available four months data (n = 136), the differences were statistically significant for vitamin K1 as well as 25(OH)D (p = 0.03 and p < 0.001, respectively). There was a non-significant increase in 25(OH)D in the intervention group from baseline to 4 months follow up, and a significant decrease in the control group. There was no difference in bone turnover markers between the two groups at 4 months follow up. A substantial loss of weight and physical function was found in both groups. CONCLUSIONS: The supplementation of 25(OH)D and vitamin K1 improved serum concentrations of these vitamins, but this did not translate into any improvement in the bone turnover markers. The RCT is registered in ClinicalTrials.govNCT01009268 and NCT01738776.

Delirium screening in an acute geriatric ward by nurses using 4AT: results from a quality improvement project.

METHODS: We conducted a retrospective chart-based analysis based on a quality improvement project in an acute geriatric ward. Delirium screening with the 4AT was performed by nurses within 24 h after hospital admission. Delirium according to DSM-5 criteria was diagnosed retrospectively based on review of patient records. RESULTS: In total, 59 patients (mean age 86 years) were included. The prevalence of delirium was 36%. Two out of three patients recovered from their delirium within four days after onset. The sensitivity and specificity of the single-point assessment with 4AT performed by nurses were 50.0% [95% confidence interval (CI) 27.2-72.8] and 86.2% (95% CI 68.3-96.1). CONCLUSION: Patients admitted to the acute geriatric ward had a high prevalence of delirium. The sensitivity of the 4AT performed by nurses for delirium was lower than in previous studies where it was undertaken by experienced geriatricians or delirium researchers.

CSF sodium at toxic levels precedes delirium in hip fracture patients.

Delirium is an acute state of confusion and a fluctuating level of consciousness. It is precipitated by physical illness or trauma, such as pneumonia, heart infarction, or hip fracture. Delirium is common among elderly hospitalized patients, and as many as 50% of hip fracture patients may develop delirium. Delirium may precipitate dementia, but recent studies indicate that delirium is caused by unknown neurotoxic mechanisms that are different from those that are associated with dementia. Experimental studies have shown that high extracellular levels of sodium are neurotoxic. We sampled lumbar cerebrospinal fluid (CSF) from hip fracture patients during hip surgery and analyzed metal ions that influence neuronal function. Eight patients who developed delirium after surgery had 21% higher CSF sodium than 17 patients who did not develop delirium (median value 175 mmol/L; range 154-188, vs. 145 mmol/L (112-204; p < 0.008) or 39 patients who underwent elective surgery under spinal anesthesia without developing delirium (145 mmol/L; 140-149; p = 0.0004). Seven patients who had developed delirium before CSF sampling had a median CSF sodium of 150 mmol/L (144-185; p = 0.3). CSF potassium was also 21% higher in patients who developed delirium (p = 0.024), but remained within the physiological range. Serum sodium and potassium were normal in all patient groups. This study, on a small sample of patients, confirms the neurotoxic potential and clinical importance of high extracellular levels of sodium in the brain. High CSF sodium would likely affect cerebral function and could precipitate delirium; further, it could interact with dementia-specific mechanisms to precipitate dementia development.

Micronutrients and the risk of hip fracture: Case-control study.

BACKGROUND: Vitamin D, and possibly vitamin K, has an established association to fracture risk. Other vitamins are, however, less studied. AIM: To determine whether specific micronutrients other than 25(OH)D and vitamin K play a role in risk of hip fracture and bone turnover. METHODS: In this case-control study, blood was drawn for measurements of vitamins A, B6, B12, C, E, and folic acid as well as the bone turnover markers osteocalcin and bone-specific alkaline phosphatase upon admission for hip fracture in 116 patients and in 73 home-dwelling non fractured controls. Results for vitamin K1 and 25(OH)D from the same populations have been reported previously. RESULTS: Low vitamin A, C, and E concentrations were independently associated with a risk of hip fracture. The adjusted odds ratio (95% confidence interval) per 10 µmol/L increase in vitamin A concentration was 0.74 (0.65-0.84); for 1 µmol/L vitamin C and E: 0.94 (0.92-0.97) and 0.81 (0.74-0.89) respectively. The results were principally unchanged when 25(OH)D, vitamin K1, Body Mass Index, and other potential confounders were adjusted for. All vitamins except B12 and folic acid correlated positively with total osteocalcin and negatively with bone-specific alkaline phosphatase. CONCLUSIONS: Low vitamin A, C, and E concentrations are associated with an increased risk of hip fracture, possibly mediated through bone turnover mechanisms. This case-control study is registered at: ClinicalTrials.gov. NCT01738776. The patient related outcome is also registered at: ClinicalTrials.gov. NCT01009268.

Vitamin K1 and 25(OH)D are independently and synergistically associated with a risk for hip fracture in an elderly population: a case control study.

BACKGROUND & AIMS: The incidence of hip fractures in Oslo is among the highest in the world. Vitamin D, as well as vitamin K, may play an important role in bone metabolism. We examined if vitamin K1 and 25(OH)D were associated with an increased risk of hip fracture, and whether the possible synergistic effect of these two micronutrients is mediated through bone turnover markers. METHODS: Blood was drawn for vitamin K1, 25(OH)D, and the bone turnover marker osteocalcin upon admission for hip fracture and in healthy controls. RESULTS: Vitamin K1 and 25(OH)D were independently associated with a risk of hip fracture. The adjusted odds ratio (95% CI) per ng/ml increase in vitamin K1 was 0.07 (0.02-0.32), and that per nmol/L increase in 25(OH)D was 0.96 (0.95-0.98). There was a significant interaction between 25(OH)D and vitamin K1 (p < 0.001), and a significant correlation between total osteocalcin and vitamin K1 and 25(OH)D (rho = 0.18, p = 0.01; rho = 0.20, p = 0.01, respectively). CONCLUSIONS: Vitamin K1 and 25(OH)D are lower in hip fracture patients compared with controls. Vitamin K1 and 25(OH)D are independently and synergistically associated with the risk of hip fracture when adjusting for confounders. Intervention studies should include both vitamins.