Differential effects of neurodegeneration biomarkers on subclinical cognitive decline

Introduction: Neurodegeneration appears to be the biological mechanism most proximate to cognitive decline in Alzheimer's disease. We test whether t-tau and alternative biomarkers of neurodegeneration—neurogranin and neurofilament light protein (NFL)—add value in predicting subclinical cognitive decline. Methods: One hundred fifty cognitively unimpaired participants received a lumbar puncture for cerebrospinal fluid and at least two neuropsychological examinations (mean age at first visit = 59.3 ± 6.3 years; 67% female). Linear mixed effects models were used with cognitive composite scores as outcomes. Neurodegeneration interactions terms were the primary predictors of interest: age × NFL or age × neurogranin or age × t-tau. Models were compared using likelihood ratio tests. Results: Age × NFL accounted for a significant amount of variation in longitudinal change on preclinical Alzheimer's cognitive composite scores, memory composite scores, and learning scores, whereas age × neurogranin and age × t-tau did not. Discussion: These data suggest that NFL may be more sensitive to subclinical cognitive decline compared to other proposed biomarkers for neurodegeneration

Ageing and brain white matter structure in 3513 UK Biobank participants

Quantifying the microstructural properties of the human brain's connections is necessary for understanding normal ageing and disease. Here we examine brain white matter magnetic resonance imaging (MRI) data in 3,513 generally healthy people aged 44.64–77.12 years from the UK Biobank. Using conventional water diffusion measures and newer, rarely studied indices from neurite orientation dispersion and density imaging, we document large age associations with white matter microstructure. Mean diffusivity is the most age-sensitive measure, with negative age associations strongest in the thalamic radiation and association fibres. White matter microstructure across brain tracts becomes increasingly correlated in older age. This may reflect an age-related aggregation of systemic detrimental effects. We report several other novel results, including age associations with hemisphere and sex, and comparative volumetric MRI analyses. Results from this unusually large, single-scanner sample provide one of the most extensive characterizations of age associations with major white matter tracts in the human brain

Neurodegeneration, synaptic dysfunction, and gliosis are phenotypic of Alzheimer dementia

Objective: To test the hypothesis that cognitively unimpaired individuals with Alzheimer disease (AD) neuropathology differ from individuals with AD dementia on biomarkers of neurodegeneration, synaptic dysfunction, and glial activation. Methods: In a cross-sectional study, adult participants >70 years old (n = 79, age 77.1 ± 5.3 years) underwent comprehensive cognitive evaluation and CSF collection, which was assayed for markers of amyloid, phosphorylated tau (p-tau), neurodegeneration (neurofilament light protein [NFL] and total tau), synaptic dysfunction (neurogranin), and glial activation (chitinase-3–like protein 1 [YKL-40]). Participants were divided into 3 groups based on diagnosis and p-tau/β-amyloid42 (Aβ42): those with low p-tau/Aβ42 and unimpaired cognition were classified as controls (n = 25); those with high p-tau/Aβ42 diagnosed with AD-dementia or AD–mild cognitive impairment were classified as AD-Dementia (n = 40); and those with high p-tau/Aβ42 but unimpaired cognition were classified as mismatches (n = 14). A similar, secondary analysis was performed with no age exclusion criteria (n = 411). Results: In both the primary and secondary analyses, biomarker levels between groups were compared with the use of analysis of covariance while controlling for age and demographic variables. Despite p-tau/Aβ42 and Aβ42/Aβ40 levels comparable to those of the AD-Dementia group, mismatches had significantly lower levels of NFL and total tau. While not significantly lower than the AD-Dementia group on YKL-40 and neurogranin, mismatches were also not significantly different from controls. Conclusions: These results provide evidence that, in the absence of significant neurodegenerative processes, individuals who harbor AD neuropathology may remain cognitively unimpaired. This finding provides insight into the biological processes phenotypic of dementia and supports monitoring multiple biomarkers in individuals positive for AD neuropathology

The phylogenetic profile of mast cells

Mast cells (MCs) are tissue-based immune cells that participate to both innate and adaptive immunities as well as to tissue-remodelling processes. Their evolutionary history appears as a fascinating process, whose outline we can only partly reconstruct according to current remnant evidence. MCs have been identified in all vertebrate classes, and a cell population with the overall characteristics of higher vertebrate MCs is identifiable even in the most evolutionarily advanced fish species. In invertebrates, cells related to vertebrate MCs have been recognized in ascidians, a class of urochordates which appeared approximately 500 million years ago. These comprise the granular hemocyte with intermediate characteristics of basophils and MCs and the \u201ctest cell\u201d (see below). Both types of cells contain histamine and heparin, and provide defensive functions. The test cell releases tryptase after stimulation with compound 48/80. A leukocyte ancestor operating in the context of a primitive local innate immunity probably represents the MC phylogenetic progenitor. This cell was likely involved in phagocytic and killing activity against pathogens and operated as a general inducer of inflammation. This early type of defensive cell possibly expressed concomitant tissue- reparative functions. With the advent of recombinase activating gene (RAG)-mediated adaptive immunity in the Cambrian era, some 550 million years ago, and the emergence of early vertebrates, MC progenitors differentiated towards a more complex cellular entity. Early MCs probably appeared in the last common ancestor we shared with hagfish, lamprey, and sharks about 450-500 million years ago