Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium.

BACKGROUND: The aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration. METHODS: Using a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer's disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium. RESULTS: Here we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status. CONCLUSIONS: Several CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.

Delirium is a syndrome in which there are substantial changes in a person's ability to focus, understand, or pay attention to events. Delirium often occurs in response to sudden trauma and is more common in persons with pre-existing cognitive impairment. What happens in the brain during delirium is not well understood. To learn more, we have studied whether markers in the cerebrospinal fluid were altered in people with delirium compared to people without delirium. To understand differences specifically caused by delirium, we included two control groups without acute trauma, one with cognitively healthy participants and one with dementia patients. We found several markers altered in people with delirium, with most of the markers similarly altered in people with cognitive impairment due to dementia. One marker was directly linked to delirium and could potentially shed light on the brain processes that cause the syndrome.

Longitudinal patterns of systolic blood pressure, diastolic blood pressure, cardiorespiratory fitness, and their association with dementia risk: The HUNT study.

BACKGROUND: High blood pressure and poor cardiorespiratory fitness are independent risk factors for dementia. However, few studies have examined if combined longitudinal patterns of these modifiable risk factors are associated with dementia risk. METHODS: In this prospective cohort study, we used data from the population-based HUNT Study, Norway. We applied group-based multidimensional trajectory modeling to identify age-specific multidimensional trajectories of SBP, DBP and estimated cardiorespiratory fitness across three surveys (HUNT1, 1984-86 - HUNT3, 2006-08). Dementia was diagnosed in the HUNT4 70+ substudy in 2017-19. We used multivariate logistic regression to estimate odds ratios (ORs) and risk differences (RDs) of dementia. RESULTS: In total, 7594 participants (54.9% women) were included, with a mean age of 44.7 (SD 6.3) years at HUNT1. Dementia was diagnosed in 1062 (14.0%) participants. We identified two multidimensional trajectories throughout adulthood within three age groups: one with higher SBP and DBP, and lower estimated cardiorespiratory fitness (the poorer group), and one with lower SBP and DBP, and higher cardiorespiratory fitness (the better group). After adjustment for sex, APOE ε4 status, education, marital status and diabetes, the better group had consistently lower risk of dementia in all age groups with the lowest OR in the middle-aged group of 0.63 (95% CI 0.51, 0.78) with corresponding RD of -0.07 (95% CI -0.10, -0.04). CONCLUSIONS: Having a beneficial multidimensional trajectory of SBP, DBP and cardiorespiratory fitness in adulthood was associated with reduced dementia risk. Aiming for optimal SBP, DBP and estimated cardiorespiratory fitness throughout adulthood may reduce dementia risk.

Change in physical activity and systolic blood pressure trajectories throughout mid-life and the development of dementia in older age: the HUNT study.

BACKGROUND: There is lack of research on combinations of possible modifiable risk factors for dementia in a life-time perspective. Dementia has currently no cure, and therefore new knowledge of preventive factors is important. The purpose of this study is to investigate if changes in physical activity (PA) in combinations with systolic blood pressure (SBP) trajectories in mid to late life are related to development of dementia in older age. METHODS: This prospective cohort study uses data from four consecutive surveys of the HUNT Study, Norway. Dementia was assessed in the HUNT4 70 + sub-study (2017-19). Group-based trajectory modelling identified three SBP trajectories from HUNT1 (1984-86) to HUNT3 (2006-2008): low, middle, and high. Change in PA was categorized into four groups based on high or low PA level at HUNT1 and HUNT3 and were combined with the SBP trajectories resulting in 12 distinct categories. Logistic regression was used to estimate odds ratios (ORs) of dementia. RESULTS: A total of 8487 participants (55% women, mean age (SD) 44.8 (6.5) years at HUNT1) were included. At HUNT4 70 + , 15.2% had dementia. We observed an overall decrease in OR of dementia across the PA/SBP categories when ranked from low to high PA (OR, 0.96; 95% CI, 0.93 to 1.00, P = 0.04). Within PA groups, a low SBP trajectory was associated with lower OR for dementia, apart from those with decreasing PA. The strongest association was observed for people with stable high PA and low SBP trajectory (OR, 0.38; 95% confidence interval (CI), 0.13 to 1.10 and adjusted risk difference, -8.34 percentage points; 95% CI, -15.32 to -1.36). CONCLUSION: Our findings illustrate the clinical importance of PA and SBP for dementia prevention and that favorable levels of both are associated with reduced occurrence of dementia.

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.

The Association Between Circulating Inflammatory Markers and the Progression of Alzheimer Disease in Norwegian Memory Clinic Patients With Mild Cognitive Impairment or Dementia.

OBJECTIVE: Neuroinflammation may play an important role in the pathogenesis and progression of Alzheimer disease (AD). The aim of the present study was to detect whether increased inflammatory activity at baseline could predict cognitive and functional decline in patients with amnestic mild cognitive impairment (aMCI) or AD dementia after 2 years. METHODS: Serum samples from 242 memory clinic patients with an aMCI (n=88) or AD dementia (n=154) were analyzed for C-reactive protein and for 14 other inflammatory markers [interleukin (IL)-1ß, interleukin-1 receptor antagonist, IL-6, IL-10, IL-12p40, IL-17a, IL-18, IL-22, IL-33, tumor necrosis factor, cluster of differentiation 40 ligand, interferon-γ, chemokine ligand (CCL) 2, and CCL4] by bead-based multiplex immunoassay. Disease progression was measured by the annual increase in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and annual decrease in the score on the Mini-Mental State Examination (MMSE). RESULTS: No association between increased levels of the inflammatory markers and change on the CDR-SB or MMSE score was found, but there was a significant difference in baseline IL-6 and interleukin-1 receptor antagonist levels between aMCI and AD dementia groups. CONCLUSION: Increased levels of inflammatory markers were not associated with faster progression as measured by the annual change on the CDR-SB or MMSE score.

Cortisol levels among older people with and without depression and dementia.

Cortisol dysregulation has been reported in dementia and depression. Cortisol levels and its associates were investigated among older people living at home and in nursing homes, in a cross-sectional study. A sample of 650 older people, from the community (home and nursing homes) and specialized care (memory clinics and old age psychiatry wards), mean age 76.8 (SD = 10.3) (dementia n = 319, depression, n = 154, dementia plus depression n = 53, and reference group n = 124), was included. Assessment included the Mini Mental State Examination (MMSE), Cornell scale for depression in dementia, activities of daily living scales, and salivary cortisol. Number of drugs was registered. The results showed that the cortisol ratio was highest among patients with dementia and co-morbid depression in comparison to those with either depression or dementia and the reference group. Characteristics significantly associated with cortisol levels were higher MMSE score (in patients with dementia and co-morbid depression), male gender (in people with dementia), and number of medications (in the reference group). We conclude that the cortisol ratio was highest among patients with dementia and co-morbid depression in comparison to those with either depression or dementia and the reference group. The association of cortisol level with MMSE score among patients with dementia and depression could further indicate that increased stress is related to cognitive function.