Subtypes of brain change in aging and their associations with cognition and Alzheimer's disease biomarkers.

Structural brain changes underlie cognitive changes and interindividual variability in cognition in older age. By using structural MRI data-driven clustering, we aimed to identify subgroups of cognitively unimpaired older adults based on brain change patterns and assess how changes in cortical thickness, surface area, and subcortical volume relate to cognitive change. We tested (1) which brain structural changes predict cognitive change (2) whether these are associated with core cerebrospinal fluid (CSF) Alzheimer's disease biomarkers, and (3) the degree of overlap between clusters derived from different structural modalities in 1899 cognitively healthy older adults followed up to 16 years.

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.

Subtypes of brain change in aging and their associations with cognition and Alzheimer's disease biomarkers.

Structural brain changes underly cognitive changes in older age and contribute to inter-individual variability in cognition. Here, we assessed how changes in cortical thickness, surface area, and subcortical volume, are related to cognitive change in cognitively unimpaired older adults using structural magnetic resonance imaging (MRI) data-driven clustering. Specifically, we tested (1) which brain structural changes over time predict cognitive change in older age (2) whether these are associated with core cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers phosphorylated tau (p-tau) and amyloid-β (Aβ42), and (3) the degree of overlap between clusters derived from different structural features.

Matrix metalloproteinases are associated with brain atrophy in cognitively unimpaired individuals.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been linked to age-related neurodegeneration and Alzheimer's disease (AD), but their role in normal aging is poorly understood. We used linear mixed models to determine if baseline or rate of yearly change in cerebrospinal fluid (CSF) levels of MMP-2; MMP-3; MMP-10; TIMP-123 (composite of TIMP-1, TIMP-2, and TIMP-3); or TIMP-4 predicted changes in bilateral entorhinal cortex thickness, hippocampal volume, or lateral ventricle volume in cognitively unimpaired individuals. We also assessed effects on the CSF AD biomarkers amyloid-β and phosphorylated tau.

Associations of neuroinflammatory IL-6 and IL-8 with brain atrophy, memory decline, and core AD biomarkers - in cognitively unimpaired older adults.

Concentrations of pro-inflammatory cytokines -interleukin-6 (IL-6) and interleukin-8 (IL-8) - are increased with age and in Alzheimer's disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62-91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time - up to 9 years - with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-β (Aβ-42) concentrations (for a subsample).

Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients.

BACKGROUNDThe kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanisms underlying delirium, particularly in relation to the KP, remain elusive.

Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging.

The kynurenine pathway is implicated in aging, longevity, and immune regulation, but longitudinal studies and assessment of the cerebrospinal fluid (CSF) are lacking. We investigated tryptophan (Trp) and downstream kynurenine metabolites and their associations with age and change over time in four cohorts using comprehensive, targeted metabolomics. The study included 1574 participants in two cohorts with repeated metabolite measurements (mean age at baseline 58 years ± 8 SD and 62 ± 10 SD), 3161 community-dwelling older adults (age range 71-74 years), and 109 CSF donors (mean age 73 years ± 7 SD).

Relationship between cerebrospinal fluid neurodegeneration biomarkers and temporal brain atrophy in cognitively healthy older adults.

It is unclear whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration predict brain atrophy in cognitively healthy older adults, whether these associations can be explained by phosphorylated tau181 (p-tau) and the 42 amino acid form of amyloid-β (Aβ42) biomarkers, and which neural substrates may drive these associations. We addressed these questions in 2 samples of cognitively healthy older adults who underwent longitudinal structural MRI up to 7 years and had baseline CSF levels of heart-type fatty-acid binding protein (FABP3)=, total-tau, neurogranin, and neurofilament light (NFL) (n = 189, scans = 721). The results showed that NFL, total-tau, and FABP3 predicted entorhinal thinning and hippocampal atrophy.

Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer's disease in healthy samples across the lifespan.

The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer's disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan.

Cerebrospinal fluid catecholamines in delirium and dementia.

Dopamine and noradrenaline are functionally connected to delirium and have been targets for pharmacological interventions but the biochemical evidence to support this notion is limited. To study the CSF levels of dopamine, noradrenaline and the third catecholamine adrenaline in delirium and dementia, these were quantified in three patient cohorts: (i) cognitively normal elderly patients ( = 122); (ii) hip fracture patients with or without delirium and dementia ( = 118); and (iii) patients with delirium precipitated by another medical condition (medical delirium,  = 26). Delirium was assessed by the Confusion Assessment Method.

Cerebrospinal Fluid Concentration of Neurogranin in Hip Fracture Patients with Delirium.

Background: Delirium is associated with an increased risk of incident dementia and accelerated progression of existing cognitive symptoms. Reciprocally, dementia increases the risk of delirium. Cerebrospinal fluid (CSF) concentration of the dendritic protein neurogranin has been shown to increase in early Alzheimer's disease (AD), likely reflecting synaptic dysfunction and/or degeneration.

Poor Self-Reported Sleep is Related to Regional Cortical Thinning in Aging but not Memory Decline-Results From the Lifebrain Consortium.

We examined whether sleep quality and quantity are associated with cortical and memory changes in cognitively healthy participants across the adult lifespan. Associations between self-reported sleep parameters (Pittsburgh Sleep Quality Index, PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n = 2205, 4363 MRIs, 18-92 years). In additional analyses, we tested coherence with cell-specific gene expression maps from the Allen Human Brain Atlas, and relations to changes in memory performance.

Genetic risk for Alzheimer disease predicts hippocampal volume through the human lifespan.

Objective: To test the hypothesis that genetic risk for Alzheimer disease (AD) may represent a stable influence on the brain from early in life, rather than being primarily age dependent, we investigated in a lifespan sample of 1,181 persons with a total of 2,690 brain scans, whether higher polygenic risk score (PGS) for AD and presence of ε4 was associated with lower hippocampal volumes to begin with, as an offset effect, or possibly faster decline in older age.

Methods: Using general additive mixed models, we assessed the relations of PGS for AD, including variants in with hippocampal volume and its change in a cognitively healthy longitudinal lifespan sample (age range: 4-95 years, mean visit age 39.7 years, SD 26.

Longitudinal association between hippocampus atrophy and episodic-memory decline in non-demented ε4 carriers.

Introduction: The apolipoprotein E () ε4 allele is the main genetic risk factor for Alzheimer's disease (AD), accelerated cognitive aging, and hippocampal atrophy, but its influence on the association between hippocampus atrophy and episodic-memory decline in non-demented individuals remains unclear.

Methods: We analyzed longitudinal (two to six observations) magnetic resonance imaging (MRI)-derived hippocampal volumes and episodic memory from 748 individuals (55 to 90 years at baseline, 50% female) from the European consortium.

Results: The change-change association for hippocampal volume and memory was significant only in ε4 carriers (N = 173, r = 0.

Cerebrospinal fluid sTREM2 in Alzheimer's disease: comparisons between clinical presentation and AT classification.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia. Its cleaved fragments, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF). Previous studies indicate higher CSF sTREM2 in symptomatic AD; however most of these studies have included biomarker positive AD cases and biomarker negative controls.

Fatty Acid-Binding Protein 3 in Cerebrospinal Fluid of Hip Fracture Patients with Delirium.

Background: Delirium is associated with dementia and thus biomarkers reflecting neurodegeneration are of interest. Fatty acid-binding protein 3 (FABP3) is a cytoplasmic neuronal protein that has been isolated from the brain. It is released following brain injury and concentrations in cerebrospinal fluid (CSF) are also higher in neurodegenerative disorders such as Alzheimer's disease (AD).

Biomarker profiling beyond amyloid and tau: cerebrospinal fluid markers, hippocampal atrophy, and memory change in cognitively unimpaired older adults.

Brain changes occurring in aging can be indexed by biomarkers. We used cluster analysis to identify subgroups of cognitively unimpaired individuals (n = 99, 64-93 years) with different profiles of the cerebrospinal fluid biomarkers beta amyloid 1-42 (Aβ42), phosphorylated tau (P-tau), total tau, chitinase-3-like protein 1 (YKL-40), fatty acid binding protein 3 (FABP3), and neurofilament light (NFL). Hippocampal volume and memory were assessed across multiple follow-up examinations covering up to 6.

Self-reported Sleep Problems Related to Amyloid Deposition in Cortical Regions with High HOMER1 Gene Expression.

Sleep problems are related to the elevated levels of the Alzheimer's disease (AD) biomarker β-amyloid (Aβ). Hypotheses about the causes of this relationship can be generated from molecular markers of sleep problems identified in rodents. A major marker of sleep deprivation is Homer1a, a neural protein coded by the HOMER1 gene, which has also been implicated in brain Aβ accumulation.

Cerebrospinal Fluid Levels of Interleukin-8 in Delirium, Dementia, and Cognitively Healthy Patients.

Background: Delirium is a common and serious complication in geriatric patients. The pathophysiology of delirium is not known.

Objective: The objective of the current study was to test the hypothesis that cerebrospinal fluid (CSF) levels of inflammatory markers at the time of spinal anesthesia for hip surgery are associated with delirium.

CSF sTREM2 and Tau Work Together in Predicting Increased Temporal Lobe Atrophy in Older Adults.

Neuroinflammation may be a key factor in brain atrophy in aging and age-related neurodegenerative disease. The objective of this study was to test the association between microglial expression of soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2), as a measure of neuroinflammation, and brain atrophy in cognitively unimpaired older adults. Brain magnetic resonance imagings (MRIs) and cerebrospinal fluid (CSF) sTREM2, total tau (t-tau), phosphorylated181 tau (p-tau), and Aβ42 were analyzed in 115 cognitively unimpaired older adults, classified according to the A/T/(N)-framework.

Self-reported sleep relates to hippocampal atrophy across the adult lifespan: results from the Lifebrain consortium.

Objectives: Poor sleep is associated with multiple age-related neurodegenerative and neuropsychiatric conditions. The hippocampus plays a special role in sleep and sleep-dependent cognition, and accelerated hippocampal atrophy is typically seen with higher age. Hence, it is critical to establish how the relationship between sleep and hippocampal volume loss unfolds across the adult lifespan.

Author Correction: GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study.

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample.

Neurofilament Light in Serum and Cerebrospinal Fluid of Hip Fracture Patients with Delirium.

Background: Delirium is associated with new-onset dementia, suggesting that delirium pathophysiology involves neuronal injury. Neurofilament light (NFL) is a sensitive biomarker for neuroaxonal injury.

Methods: NFL was measured in cerebrospinal fluid (CSF) (n = 130), preoperative serum (n = 192), and postoperative serum (n = 280) in hip fracture patients, and in CSF (n = 123) and preoperative serum (n = 134) in cognitively normal older adults undergoing elective surgery.

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.