Association of glial and neuronal degeneration markers with Alzheimer's disease cerebrospinal fluid profile and cognitive functions.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBackground: Neuroinflammation has gained increasing attention as a potential contributing factor in the onset and progression of Alzheimer's disease (AD). The objective of this study was to examine the association of selected cerebrospinal fluid (CSF) inflammatory and neuronal degeneration markers with signature CSF AD profile and cognitive functions among subjects at the symptomatic pre- and early dementia stages. Methods: In this cross-sectional study, 52 subjects were selected from an Icelandic memory clinic cohort. Subjects were classified as having AD (n = 28, age = 70, 39% female, Mini-Mental State Examination [MMSE] = 27) or non-AD (n = 24, age = 67, 33% female, MMSE = 28) profile based on the ratio between CSF total-tau (T-tau) and amyloid-β1-42 (Aβ42) values (cut-off point chosen as 0.52). Novel CSF biomarkers included neurofilament light (NFL), YKL-40, S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP), measured with enzyme-linked immunosorbent assays (ELISAs). Subjects underwent neuropsychological assessment for evaluation of different cognitive domains, including verbal episodic memory, non-verbal episodic memory, language, processing speed, and executive functions. Results: Accuracy coefficient for distinguishing between the two CSF profiles was calculated for each CSF marker and test. Novel CSF markers performed poorly (area under curve [AUC] coefficients ranging from 0.61 to 0.64) compared to tests reflecting verbal episodic memory, which all performed fair (AUC > 70). LASSO regression with a stability approach was applied for the selection of CSF markers and demographic variables predicting performance on each cognitive domain, both among all subjects and only those with a CSF AD profile. Relationships between CSF markers and cognitive domains, where the CSF marker reached stability selection criteria of > 75%, were visualized with scatter plots. Before calculations of corresponding Pearson's correlations coefficients, composite scores for cognitive domains were adjusted for age and education. GFAP correlated with executive functions (r = - 0.37, p = 0.01) overall, while GFAP correlated with processing speed (r = - 0.68, p < 0.001) and NFL with verbal episodic memory (r = - 0.43, p = 0.02) among subjects with a CSF AD profile. Conclusions: The novel CSF markers NFL and GFAP show potential as markers for cognitive decline among individuals with core AD pathology at the symptomatic pre- and early stages of dementia. Keywords: AD biomarker profile; Alzheimer’s disease; Cerebrospinal fluid; Cognitive domains; Glial fibrillary acidic protein; Neurofilament light; S100 calcium-binding protein B; YKL-40.St. Josef's Hospital Fund, Reykjavik, Iceland Landspitali University Hospital Research Fund Icelandic Research Fund of the Icelandic Centre for Researc

Phenotypic Displays of Cholinergic Enzymes Associate With Markers of Inflammation, Neurofibrillary Tangles, and Neurodegeneration in Pre- and Early Symptomatic Dementia Subjects

Funding Information: This study was supported by the St. Josef’s Hospital Fund, Reykjavik, Iceland, the Landspitali University Hospital Research Fund, and the Icelandic Research Fund of the Icelandic Centre for Research (163172-051). Publisher Copyright: Copyright © 2022 Teitsdottir, Darreh-Shori, Lund, Jonsdottir, Snaedal and Petersen.Background: Cholinergic drugs are the most commonly used drugs for the treatment of Alzheimer’s disease (AD). Therefore, a better understanding of the cholinergic system and its relation to both AD-related biomarkers and cognitive functions is of high importance. Objectives: To evaluate the relationships of cerebrospinal fluid (CSF) cholinergic enzymes with markers of amyloidosis, neurodegeneration, neurofibrillary tangles, inflammation and performance on verbal episodic memory in a memory clinic cohort. Methods: In this cross-sectional study, 46 cholinergic drug-free subjects (median age = 71, 54% female, median MMSE = 28) were recruited from an Icelandic memory clinic cohort targeting early stages of cognitive impairment. Enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was measured in CSF as well as levels of amyloid-β1–42 (Aβ42), phosphorylated tau (P-tau), total-tau (T-tau), neurofilament light (NFL), YKL-40, S100 calcium-binding protein B (S100B), and glial fibrillary acidic protein (GFAP). Verbal episodic memory was assessed with the Rey Auditory Verbal Learning (RAVLT) and Story tests. Results: No significant relationships were found between CSF Aβ42 levels and AChE or BuChE activity (p > 0.05). In contrast, T-tau (r = 0.46, p = 0.001) and P-tau (r = 0.45, p = 0.002) levels correlated significantly with AChE activity. Although neurodegeneration markers T-tau and NFL did correlate with each other (r = 0.59, p < 0.001), NFL did not correlate with AChE (r = 0.25, p = 0.09) or BuChE (r = 0.27, p = 0.06). Inflammation markers S100B and YKL-40 both correlated significantly with AChE (S100B: r = 0.43, p = 0.003; YKL-40: r = 0.32, p = 0.03) and BuChE (S100B: r = 0.47, p < 0.001; YKL-40: r = 0.38, p = 0.009) activity. A weak correlation was detected between AChE activity and the composite score reflecting verbal episodic memory (r = −0.34, p = 0.02). LASSO regression analyses with a stability approach were performed for the selection of a set of measures best predicting cholinergic activity and verbal episodic memory score. S100B was the predictor with the highest model selection frequency for both AChE (68%) and BuChE (73%) activity. Age (91%) was the most reliable predictor for verbal episodic memory, with selection frequency of both cholinergic enzymes below 10%. Conclusions: Results indicate a relationship between higher activity of the ACh-degrading cholinergic enzymes with increased neurodegeneration, neurofibrillary tangles and inflammation in the stages of pre- and early symptomatic dementia, independent of CSF Aβ42 levels.Peer reviewe

Plasma Apolipoprotein Levels Are Associated with Cognitive Status and Decline in a Community Cohort of Older Individuals

<div><h3>Objectives</h3><p>Apolipoproteins have recently been implicated in the etiology of Alzheimer’s disease (AD). In particular, Apolipoprotein J (ApoJ or clusterin) has been proposed as a biomarker of the disease at the pre-dementia stage. We examined a group of apolipoproteins, including ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH and ApoJ, in the plasma of a longitudinal community based cohort.</p> <h3>Methods</h3><p>664 subjects (257 with Mild Cognitive Impairment [MCI] and 407 with normal cognition), mean age 78 years, from the Sydney Memory and Aging Study (MAS) were followed up over two years. Plasma apolipoprotein levels at baseline (Wave 1) were measured using a multiplex bead fluorescence immunoassay technique.</p> <h3>Results</h3><p>At Wave 1, MCI subjects had lower levels of ApoA1, ApoA2 and ApoH, and higher levels of ApoE and ApoJ, and a higher ApoB/ApoA1 ratio. Carriers of the apolipoprotein E ε4 allele had significantly lower levels of plasma ApoE, ApoC3 and ApoH and a significantly higher level of ApoB. Global cognitive scores were correlated positively with ApoH and negatively with ApoJ levels. ApoJ and ApoE levels were correlated negatively with grey matter volume and positively with cerebrospinal fluid (CSF) volume on MRI. Lower ApoA1, ApoA2 and ApoH levels, and higher ApoB/ApoA1 ratio, increased the risk of cognitive decline over two years in cognitively normal individuals. ApoA1 was the most significant predictor of decline. These associations remained after statistically controlling for lipid profile. Higher ApoJ levels predicted white matter atrophy over two years.</p> <h3>Conclusions</h3><p>Elderly individuals with MCI have abnormal apolipoprotein levels, which are related to cognitive function and volumetric MRI measures cross-sectionally and are predictive of cognitive impairment in cognitively normal subjects. ApoA1, ApoH and ApoJ are potential plasma biomarkers of cognitive decline in non-demented elderly individuals.</p> </div

Histo-Blood Group Gene Polymorphisms as Potential Genetic Modifiers of Infection and Cystic Fibrosis Lung Disease Severity

The pulmonary phenotype in cystic fibrosis (CF) is variable; thus, environmental and genetic factors likely contribute to clinical heterogeneity. We hypothesized that genetically determined ABO histo-blood group antigen (ABH) differences in glycosylation may lead to differences in microbial binding by airway mucus, and thus predispose to early lung infection and more severe lung disease in a subset of patients with CF. infection in the severe or mild groups. Multivariate analyses of other clinical phenotypes, including gender, asthma, and meconium ileus demonstrated no differences between groups based on ABH type. infection, nor was there any association with other clinical phenotypes in a group of 808 patients homozygous for the ΔF508 mutation

Dynamics of protein and fluid secretion from the major salivary glands of rat: Relevance of research findings to clinically observed defective secretion in cystic fibrosis

Although there are indications of a defect in secretion of protein from exocrine cells in cystic fibrosis (CF), this remains an aspect of CF research that has not been adequately addressed. Using salivary glands of rat as model systems, and following the effects of parasympathetic and sympathetic autonomic nerve stimulation on these glands, we demonstrate the existence of three separate pathways through which secretion of protein can be evoked from serous and mucous exocrine cells. These pathways allow the secretion of proteins from the intracellular compartments in a constitutive, intermediate or regulated manner. The primary aspects of secretory profile including concentration and the degree of hydration of secreted material differ greatly between the pathways, are cell type specific, and presumably are a direct consequence of controlled changes in the levels of second messengers induced upon stimulation of these cells. As previously published reports suggest that only the beta-adrenergic regulated pathway is affected by CF, differences between the pathways in their secretory profiles may influence the development of lung disease, through disparate disturbances in the secretion of protein and fluid from serous and mucous cells of the submucosal glands that line the bronchiolar tree in humans. We gratefully acknowledge support from The Wellcome Trust and from The European Union Biomed II Programme

Glial activation mediates phenotypic effects of APOEε4 and sex in Alzheimer’s disease

ABSTRACT INTRODUCTION This study examined the impact of apolipoprotein ɛ4 ( APOEɛ4 ) allele frequency and sex on the phenotype of Alzheimer’s disease (AD). METHODS The baseline characteristics, CSF, and neuroimaging biomarkers, and cognition scores collected from 45 patients aged 50-74 years with confirmed early AD from clinical trial NCT03186989 were evaluated in a post-hoc study. RESULTS A phenotypic spectrum was observed from a predominant amyloid and limbic-amnestic phenotype in male APOEɛ4 homozygotes to a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype in female APOEɛ4 noncarriers. Amyloid pathology inversely correlated with tau pathophysiology, glial activation, and synaptic injury, with the strongest correlations observed in male APOEɛ4 carriers. Tau pathophysiology was correlated with glial activation, synaptic injury, and neuroaxonal damage, with the strongest correlation observed in female APOEɛ4 noncarriers. DISCUSSION Glial activation is influenced by apoE isoform and sex, which explains much of the phenotypic heterogeneity in early AD below age 75 years. HIGHLIGHTS APOEɛ4 homozygotes displayed a predominantly amyloid and limbic-amnestic phenotype. Female APOEɛ4 noncarriers displayed a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype. In male APOEɛ4 carriers, amyloid pathology was inversely correlated with tau pathophysiology, synaptic injury, and glial activation Females displayed a non- APOEɛ4 allele frequency-dependent increase in glial activation and synaptic injury In female APOEɛ4 noncarriers, tau pathophysiology was strongly correlated with glial activation, synaptic injury, and neuroaxonal damage RESEARCH IN CONTEXT Systematic review The impact of APOEɛ4 alleles and sex on phenotypic features was examined in 45 patients, aged 50-74 years, with early AD. Interpretation Findings were consistent with prior reports and suggest that glial activation, influenced by apoE isoform and sex, explains much of the phenotypic heterogeneity in early AD below age 75 years. Lower glial activation in APOEɛ4 homozygotes associated with the highest levels of amyloid and the lowest levels of tau pathology, and a limbic-amnestic phenotype, suggesting degeneration of basal forebrain cholinergic neurons. Higher glial activation in female APOEɛ4 noncarriers was associated with the highest tau pathology and synaptic injury, the lowest amyloid pathology, greater ventricular expansion, and multi-domain cognitive deficits. Future directions This work defined a combined sex, genotype, and age framework that delineates multiple pathways to end-stage AD. Confirmation is required, followed by optimization of therapeutic approaches to amyloid, tau, and glial activation pathologies along the disease stage continuum