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 ¼ 99, 64e93 years) with different profiles of the cerebrospinal fluid biomarkers beta amyloid 1e42 (Ab42), 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 6.8 years. Clustering revealed one group (39%) with more pathological concentrations of all biomarkers, which could further be divided into one group (20%) characterized by tauopathy and high FABP3 and one (19%) by brain b-amyloidosis, high NFL, and slightly higher YKL-40. The clustering approach clearly outperformed classification based on Ab42 and P-tau alone in prediction of memory decline, with the individuals with most tauopathy and FABP3 showing more memory decline, but not more hippocampal volume change. The results demonstrate that older adults can be classified based on biomarkers beyond amyloid and tau, with improved prediction of memory decline

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). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aβ-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology

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-β42 and phosphorylated tau181. Low baseline levels of MMP-3 predicted larger ventricle volumes and more entorhinal cortex thinning. Increased CSF MMP-2 levels over time predicted more entorhinal thinning, hippocampal atrophy, and ventricular expansion, while increased TIMP-123 over time predicted ventricular expansion. No MMP/TIMPs predicted changes in CSF AD biomarkers. Notably, we show for the first time that longitudinal increases in MMP-2 and TIMP-123 levels may predict age-associated brain atrophy. In conclusion, MMPs and TIMPs may play a role in brain atrophy in cognitively unimpaired aging

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

Introduction: The apolipoprotein E (APOE) 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 Lifebrain consortium. Results: The change-change association for hippocampal volume and memory was significant only in ε4 carriers (N = 173, r = 0.21, P = .007; non-carriers: N = 467, r = 0.073, P = .117). The linear relationship was significantly steeper for the carriers [t(629) = 2.4, P = .013]. A similar trend toward a stronger change-change relation for carriers was seen in a subsample with more than two assessments. Discussion: These findings provide evidence for a difference in hippocampus-memory association between ε4 carriers and non-carriers, thus highlighting how genetic factors modulate the translation of the AD-related pathophysiological cascade into cognitive deficits

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. METHODS: Self-reported sleep measures and MRI-derived hippocampal volumes were obtained from 3105 cognitively normal participants (18-90 years) from major European brain studies in the Lifebrain consortium. Hippocampal volume change was estimated from 5116 MRIs from 1299 participants for whom longitudinal MRIs were available, followed up to 11 years with a mean interval of 3.3 years. Cross-sectional analyses were repeated in a sample of 21,390 participants from the UK Biobank. RESULTS: No cross-sectional sleep-hippocampal volume relationships were found. However, worse sleep quality, efficiency, problems, and daytime tiredness were related to greater hippocampal volume loss over time, with high scorers showing 0.22% greater annual loss than low scorers. The relationship between sleep and hippocampal atrophy did not vary across age. Simulations showed that the observed longitudinal effects were too small to be detected as age-interactions in the cross-sectional analyses. CONCLUSIONS: Worse self-reported sleep is associated with higher rates of hippocampal volume decline across the adult lifespan. This suggests that sleep is relevant to understand individual differences in hippocampal atrophy, but limited effect sizes call for cautious interpretation

Increased CSF levels of aromatic amino acids in hip fracture patients with delirium suggests higher monoaminergic activity

textabstractBackground: To examine whether delirium in hip fracture patients was associated with changes in the levels of amino acids and/or monoamine metabolites in cerebrospinal fluid (CSF) and serum. Methods: In this prospective cohort study, 77 patients admitted with an acute hip fracture to Oslo University Hospital, Norway, were studied. The concentrations of amino acids in CSF and serum were determined by high performance liquid chromatography. The patients were assessed daily for delirium by the Confusion Assessment Method (pre-operatively and post-operative day 1-5 (all) or until discharge (delirious patients)). Pre-fracture dementia status was decided by an expert panel. Serum was collected pre-operatively and CSF immediately before spinal anesthesia. Results: Fifty-three (71 %) hip fracture patients developed delirium. In hip fracture patients without dementia (n = 39), those with delirium had significantly higher CSF levels of tryptophan (40 % higher), tyrosine (60 % higher), phenylalanine (59 % higher) and the monoamine metabolite 5-hydroxyindoleacetate (23 % higher) compared to those without delirium. The same amino acids were also higher in CSF in delirious patients with dementia (n = 38). The correlations between serum and CSF amino acid levels were poor. Conclusion: Higher CSF levels of monoamine precursors in hip fracture patients with delirium suggest a higher monoaminergic activity in the central nervous system during delirium in this patient group

Cerebrospinal fluid levels of neopterin are elevated in delirium after hip fracture

Background The inflammatory cell product neopterin is elevated in serum before and during delirium. This suggests a role for disordered cell-mediated immunity or oxidative stress. Cerebrospinal fluid (CSF) neopterin levels reflect brain neopterin levels more closely than serum levels. Here we hypothesized that CSF neopterin levels would be higher in delirium. Methods In this prospective cohort study, 139 elderly patients with acute hip fracture were recruited in Oslo and Edinburgh. Delirium was diagnosed with the confusion assessment method performed daily pre-operatively and on the first 5 days post-operatively. Paired CSF and blood samples were collected at the onset of spinal anaesthesia. Neopterin levels were measured using high-performance liquid chromatography. Results Sixty-four (46 %) of 139 hip fracture patients developed delirium perioperatively. CSF neopterin levels were higher in delirium compared to controls (median 29.6 vs 24.7 nmol/mL, p = 0.003), with highest levels in patients who developed delirium post-operatively. Serum neopterin levels were also higher in delirium (median 37.0 vs 27.1 nmol/mL, p = 0.003). CSF neopterin remained significantly associated with delirium after controlling for relevant risk factors. Higher neopterin levels were associated with poorer outcomes (death or new institutionalization) 1 year after surgery (p = 0.02 for CSF and p = 0.03 for serum). Conclusions This study is the first to examine neopterin in CSF from patients with delirium. Our findings suggest potential roles for activation of cell-mediated immune responses or oxidative stress in the delirium process. High levels of serum or CSF neopterin in hip fracture patients may also be useful in predicting poor outcomes

Alzheimer's disease-associated biomarkers in delirium and cognitively normal older adults

Background: Higher age comes with a multitude of changes in the brain, but the role of different neuropathological processes in cognitively normal older adults is far from fully understood. A substantial number of cognitively normal older adults show biomarker evidence of brain pathologies often associated with Alzheimer’s disease (AD), but the implications are not fully established. Furthermore, cognitively normal older adults often show hippocampal atrophy and memory decline, which are hallmarks of AD dementia. Older age is also a risk factor for delirium, a condition characterized by an acute disturbance in attention, awareness, and cognition. Delirium has epidemiologically been strongly linked to dementia, however the neuropathological processes underlying this relationship are not understood. Aims: The overall aim was to increase knowledge about the role of different neuropathological processes in delirium and in cognitively normal older adults using AD-associated cerebrospinal fluid (CSF) biomarkers reflecting core AD pathology (Aβ42 reflecting Aβ deposition, T-tau reflecting neurodegeneration, P-tau reflecting tauopathy) and novel biomarkers (NFL reflecting axonal damage, YKL-40 reflecting neuroinflammation, and FABP3 reflecting neuronal damage). More specifically, we wanted to assess relationships between biomarkers, test whether subgroups of individuals with similar biomarker profiles could be identified using clustering analyses, and examine the relationship between biomarkers and longitudinal hippocampal atrophy and relationships between biomarker-based subgroups and longitudinal hippocampal atrophy and memory change, respectively, in cognitively normal older adults. We also wanted to examine whether the core AD biomarkers are related to delirium. Methods: CSF from cognitively normal older adults (n=99) was assessed for CSF Aβ42, Ttau, P-tau, NFL, YKL-40, and FABP3, and CSF from hip fracture patients (n=129) was assessed for CSF Aβ42, T-tau, and P-tau. Delirium was assessed pre- and postoperatively in hip fracture patients, and the diagnosis of dementia at admission was based upon clinical consensus. Hippocampal volume and memory in cognitively normal adults was assessed across multiple follow-up examinations over up to 6 years. Main results: The novel biomarkers NFL, YKL-40, and FABP3 were linked to T-tau and Ptau, but not to Aβ42. Concentrations of NFL, YKL-40, and FABP3 differed between at least two biomarker subgroups identified by clustering analyses with a relatively large effect size. High NFL levels predicted higher hippocampal atrophy rate in cognitively normal older adults, independently of core AD biomarkers, and also in subgroups unlikely to have preclinical AD. A clustering-based subgroup characterized by high concentrations of T-tau, P-tau, and FABP3 showed more memory decline than biomarkers groups with less abnormal biomarker levels, whereas biomarker groups based on only Aβ42 and P-tau showed no differences in memory trajectories. The core AD biomarkers (low CSF Aβ42, high CSF T-tau, low Aβ42/T-tau, low Aβ42/P-tau) were significantly associated with delirium in patients without dementia. Conclusion: We have shown that CSF biomarkers previously associated with AD are also associated with delirium, hippocampal atrophy, and memory decline in individuals without dementia. Our findings suggest that neuronal damage, axonal damage, and neuroinflammation are accompanying tauopathy and neurodegeneration, but not Aβ deposition, in this group. Our results further suggest that it is meaningful to use the three novel biomarkers for characterization of brain states in cognitively normal older adults, and that addition of novel biomarkers improve prediction of memory decline compared to classification based on biomarkers of Aβ deposition and tauopathy only. Moreover, our findings suggest that a high degree of neurodegeneration and tauopathy is associated with more hippocampal atrophy and greater memory decline in cognitively normal adults. Lastly, our findings in the hip fracture cohort suggests that AD pathologies may underlie the interrelationship between delirium and dementia, and raises the question of whether delirium is an early symptom of AD

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). Objective: To examine the relationship between CSF FABP3 concentration and delirium in hip fracture patients compared to a group of cognitively normal controls. Methods: CFS FABP3 concentration was measured in 128 hip fracture patients with (n = 71) and without (n = 57) delirium, and in cognitively unimpaired adults ≥64 years (n = 124) undergoing elective surgery. Results: CSF FABP3 (pg/ml) concentration (median (IQR)) was higher in hip-fracture patients compared to cognitively normal controls (5.7 (4.2–7.7) versus 4.5 (3.4–6.1), p < 0.001). There was a significant weak correlation between age and CSF FABP3 (ρ= 0.3, p < 0.001). After adjustment for age, the association between CSF FABP3 and hip-fracture was no longer statistically significant (β= 0.05, p = 0.5). There were no significant differences in CSF FABP3 concentration between hip fracture patients with (5.4 (4.1–8.2)) and without (5.8 (4.2–7.2)) delirium. CSF FABP3 concentration correlated positively with CSF AD biomarkers p-tau (ρ= 0.7, p < 0.01) and t-tau (ρ= 0.7, p < 0.01). Conclusion: CSF FABP3 concentrations were higher in hip fracture patients compared with cognitively normal older adults, indicating ongoing age-related neurodegeneration in these patients. There were no differences of CSF FABP3 concentrations across delirium groups, suggesting that neuronal damage or degeneration reflected by FABP3 may not be directly linked to delirium pathophysiology