Plasma 5-HIAA activity indicative of serotonergic disturbances in cognitively impaired, elderly patients experiencing postoperative delirium.

OBJECTIVES: Delirium frequently arises in older demented and non-demented patients in postoperative, clinical settings. To date, the underlying pathophysiological mechanisms remain poorly understood. Monoamine neurotransmitter alterations have been linked to delirium and cognitive impairment. Our aim was to investigate if this holds true in cognitively normal and impaired patients experiencing delirium following hip surgery. METHODS: Monoamines and metabolites were measured in plasma samples of 181 individuals by means of reversed-phase ultra-high-performance liquid chromatography with electrochemical detection. Delirium and delirium severity were scored with the Confusion Assessment Method and Delirium Rating Scale-Revised-1998. Cognitive function was assessed using the Informant Questionnaire on Cognitive Decline and the Mini-Mental State Examination, multimorbidity with the Charlson Comorbidity Index. RESULTS: Plasma 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (5-HT), was significantly higher in delirious and non-delirious cognitively impaired subjects as compared to control individuals without delirium and cognitive impairment (p < 0.001 and p = 0.007), which remained highly significant after excluding patients taking psychotropic medication (p < 0.0001 and p = 0.003). No significant differences were found for cognitively normal delirious patients, although serotonergic levels were numerically higher compared to control counterparts. CONCLUSIONS: Our findings indicate a general serotonergic disturbance in delirious and non-delirious postoperative patients suffering from cognitive impairment. We observed a similar, but less pronounced difference in delirious patients, which suggests serotonergic disturbances may be further aggravated by the co-occurrence of delirium and cognitive impairment.

A complete pupillometry toolbox for real-time monitoring of locus coeruleus activity in rodents.

The locus coeruleus (LC) is a region in the brainstem that produces noradrenaline and is involved in both normal and pathological brain function. Pupillometry, the measurement of pupil diameter, provides a powerful readout of LC activity in rodents, primates and humans. The protocol detailed here describes a miniaturized setup that can screen LC activity in rodents in real-time and can be established within 1-2 d. Using low-cost Raspberry Pi computers and cameras, the complete custom-built system costs only ~300 euros, is compatible with stereotaxic surgery frames and seamlessly integrates into complex experimental setups. Tools for pupil tracking and a user-friendly Pupillometry App allow quantification, analysis and visualization of pupil size. Pupillometry can discriminate between different, physiologically relevant firing patterns of the LC and can accurately report LC activation as measured by noradrenaline turnover. Pupillometry provides a rapid, non-invasive readout that can be used to verify accurate placement of electrodes/fibers in vivo, thus allowing decisions about the inclusion/exclusion of individual animals before experiments begin.

Pre-analytical stability of novel cerebrospinal fluid biomarkers.

Stability of the cerebrospinal fluid (CSF) composition under different pre-analytical conditions is relevant for the diagnostic potential of biomarkers. Our aim was to examine the pre-analytical stability of promising CSF biomarkers that are currently evaluated for their discriminative use in various neurological diseases. Pooled CSF was aliquoted and experimentally exposed to delayed storage: 0, 1, 2, 4, 24, 72, or 168 h at 4 °C or room temperature (RT), or 1-4 months at -20 °C; or up to 7 freeze/thaw (f/t) cycles, before final storage at -80 °C. Eleven CSF biomarkers were screened using immunoassays, liquid chromatography, or enzymatic methods. Levels of neurogranin (truncP75), chitinase-3-like protein (YKL-40), beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), acetylcholinesterase (AChE) enzymatic activity, theobromine, secreted protein acidic and rich in cysteine-like 1 (SPARCL-1) and homovanillic acid (HVA) levels were not affected by the applied storage conditions. 3-Methoxy-4-hydroxyphenylglycol (MHPG) levels linearly and strongly decreased after 4 h at RT (-10%) or 24 h at 4 °C (-27%), and with 6% after every f/t cycle. 5-Methyltetrahydrofolate (5-MTHF) (-29% after 1 week at RT) and 5-hydroxyindoleacetic acid levels (5-HIAA) (-16% after 1 week at RT) were reduced and 3,4-dihydroxyphenylacetic acid (DOPAC) levels (+22% after 1 week at RT) increased, but only after >24 h at RT. Ten out of eleven potential CSF novel biomarkers showed very limited change under common storage and f/t conditions, suggesting that these CSF biomarkers can be trustfully tested under the pre-analytical conditions present across different cohorts.

Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation.

The locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain and regulates many fundamental brain functions. Studies in humans have suggested that strong LC activation might shift network connectivity to favor salience processing. To causally test this hypothesis, we use a mouse model to study the effect of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term "chemo-connectomics." We show that LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. Functional connectivity changes strongly correlate with transcript levels of alpha-1 and beta-1 adrenergic receptors across the brain, and functional network connectivity correlates with NE turnover within select brain regions. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection.

Neutrophil Gelatinase-Associated Lipocalin and its Receptors in Alzheimer's Disease (AD) Brain Regions: Differential Findings in AD with and without Depression.

Co-existing depression worsens Alzheimer's disease (AD) pathology. Neutrophil gelatinase-associated lipocalin (NGAL) is a newly identified (neuro)inflammatory mediator in the pathophysiologies of both AD and depression. This study aimed to compare NGAL levels in healthy controls, AD without depression (AD-D), and AD with co-existing depression (AD+D) patients. Protein levels of NGAL and its receptors, 24p3R and megalin, were assessed in nine brain regions from healthy controls (n = 19), AD-D (n = 19), and AD+D (n = 21) patients. NGAL levels in AD-D patients were significantly increased in brain regions commonly associated with AD. In the hippocampus, NGAL levels were even further increased in AD+D subjects. Unexpectedly, NGAL levels in the prefrontal cortex of AD+D patients were comparable to those in controls. Megalin levels were increased in BA11 and amygdala of AD+D patients, while no changes in 24p3R were detected. These findings indicate significant differences in neuroimmunological regulation between AD patients with and without co-existing depression. Considering its known effects, elevated NGAL levels might actively promote neuropathological processes in AD with and without depression.

Serum NGAL is Associated with Distinct Plasma Amyloid-ß Peptides According to the Clinical Diagnosis of Dementia in Down Syndrome.

BACKGROUND: The majority of people with Down syndrome (DS) develop dementia due to Alzheimer's disease (AD). Neuropathological features are characterized by an accumulation of amyloid-ß (Aß) deposits and the presence of an activated immune response. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a newly identified (neuro)inflammatory constituent in AD. OBJECTIVE: This study examines NGAL as an inflammatory marker in DS and its associations with plasma Aß peptides according to the follow-up clinical diagnosis of dementia. METHODS: Baseline serum NGAL and plasma Aß40, Aß42, Aß(n40), and Aß(n42) were quantified in 204 people with DS. The diagnosis of dementia in DS was established by follow-up clinical assessments. The following study groups were characterized: DS with AD at baseline (n = 67), DS without AD (n = 53), and non-demented DS individuals that converted to AD (n = 84). Serum NGAL was analyzed in 55 elderly non-DS, non-demented people. RESULTS: Serum NGAL levels were significantly increased in DS subjects compared to non-DS people. Serum NGAL levels were not associated with clinical dementia symptoms in DS. However, NGAL was positively associated with Aß42 and Aß(n42) in demented DS individuals and with Aß40 and Aß(n40) in the non-demented DS group. NGAL was negatively associated with Aß42/Aß40 and Aß(n42)/Aß(n40) ratios in converted DS subjects. These associations persisted for Aß(n40), Aß42/Aß40, and Aß(n42)/Aß(n40) after adjusting for demographics measures, apolipoprotein E ε4 allele, platelets, and anti-inflammatory medication. CONCLUSION: Serum NGAL levels are increased in DS and associated with distinct species of Aß depending on the progression of dementia as diagnosed by baseline and follow-up clinical assessments.