A Scoping Review of Alzheimers Disease Hypotheses: An Array of Uni- and Multi-Factorial Theories.

Background: There is a common agreement that Alzheimers disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed. Objective: To perform a scoping review of original manuscripts describing hypotheses and theories of AD published in the past decades. Results: We reviewed 131 original manuscripts that fulfilled our inclusion criteria out of more than 13,807 references extracted from open databases. Each entry was characterized as having a single or multifactorial focus and assigned to one of 15 theoretical groupings. Impact was tracked using open citation tools. Results: Three stages can be discerned in terms of hypotheses generation, with three quarter of studies proposing a hypothesis characterized as being single-focus. The most important theoretical groupings were the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Infections and Cerebrovascular. Lately, evidence towards Genetics and especially Gut/Brain interactions came to the fore. Conclusions: When viewed together, these multi-faceted reports reinforce the notion that AD affects multiple sub-cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. The challenge of providing a comprehensive view of all systems and their interactions remains, alongside ways to manage this inherent complexity.

Longitudinal association between ß-amyloid accumulation and cognitive decline in cognitively healthy older adults: A systematic review.

This systematic review examined the longitudinal association between amyloid-ß (Aß) accumulation and cognitive decline in cognitively healthy adults. It was conducted using the PubMed, Embase, PsycInfo, and Web of Science databases. The methodological quality of the selected articles was assessed. In fine, seventeen longitudinal clinical studies were included in this review. A minority (seven out of 17) of studies reported a statistically significant association or prediction of cognitive decline with Aß change, measured by positron emission tomography (PET; n = 6) and lumbar puncture (n = 1), with a mean follow-up duration of 3.17 years for cognition and 2.99 years for Aß. The studies reporting significant results with PET found differences in the frontal, posterior cingular, lateral parietal and global (whole brain) cortices as well as in the precuneus. Significant associations were found with episodic memory (n = 6) and global cognition (n = 1). Five of the seven studies using a composite cognitive score found significant results. A quality assessment revealed widespread methodological biases, such as failure to report or account for loss-to follow up and missing data, and failure to report p-values and effect sizes of non-significant results. Overall, the longitudinal association between Aß accumulation and cognitive decline in preclinical Alzheimer's disease remains unclear. The discrepancy in results between studies may be explained in part by the choice of neuroimaging technique used to measure Aß change, the duration of longitudinal studies, the heterogeneity of the healthy preclinical population, and importantly, the use of a composite score to capture cognitive changes with increased sensitivity. More longitudinal studies with larger sample sizes are needed to elucidate this relationship.

The neural correlates of referential communication: Taking advantage of sparse-sampling fMRI to study verbal communication with a real interaction partner.

This paper introduces an innovative functional magnetic resonance imaging (fMRI) protocol to study real verbal interactions while limiting the impact of speech-related movement artefacts. This protocol is based on a sparse sampling acquisition technique and allowed participants to complete a referential communication task with a real interaction partner. During verbal interactions, speakers adjust their verbal productions depending on their interlocutors' knowledge of the referents being mentioned. These adjustments have been linked to theory of mind (ToM), the ability to infer other's mental states. We thus sought to determine if the brain regions supporting ToM would also be activated during a referential communication task in which participants have to present movie characters that vary in their likelihood of being known by their interlocutor. This pilot study establishes that the sparse sampling strategy is a viable option to study the neural correlates of referential communication while minimizing movement artefacts. In addition, the brain regions supporting ToM were recruited during the task, though specifically for the conditions where participants could adjust their verbal productions to the interlocutor's likely knowledge of the referent. This study therefore demonstrates the feasibility and relevance of a sparse-sampling approach to study verbal interactions with fMRI, including referential communication.

S100A9 potentiates the activation of neutrophils by the etiological agent of gout, monosodium urate crystals.

Gout is one of the most painful types of arthritis that arises when the body mounts an acute inflammatory reaction against a crystallized form of uric acid known as monosodium urate crystals (MSUs). Although MSUs are known to activate neutrophils, the most abundant leukocyte in the synovial fluid of patients with gout, few studies have investigated the effect on neutrophils of the simultaneous stimulation with MSU and proinflammatory mediators in the inflamed joint. Herein, we focused on a protein that is highly expressed in the synovium in gout, S100A9. The predominant expression of S100A9 in and around blood vessels suggests it may prime neutrophils during their migration toward the inflamed joint. Using a combination of functional and signaling assays, we found that S100A9 enhances the production of radical oxygen species as well as IL-1 and IL-8 release by human neutrophils activated with MSU. Moreover, upstream and downstream signaling events activated by MSUs in human neutrophils were also potentiated by S100A9, including the mobilization of intracellular calcium stores, tyrosine phosphorylation, the serine phosphorylation of PKC substrates, Akt, and p38. We also show that S100A9 alone increases glycolysis in human neutrophils, which is suggestive of an additional mechanism through which neutrophils can be primed. Together, our observations indicate a novel way in which S100A9 may contribute to the pathogenesis of gout, by priming neutrophils to respond to MSUs.

The different effects of LPS and poly I:C prenatal immune challenges on the behavior, development and inflammatory responses in pregnant mice and their offspring.

In recent years, in vivo animal models of prenatal infection have been developed in an attempt to recreate behavioral and neuropathological features associated to a number of neurological and neuropsychiatric disorders. However, these models are still in their emerging phase and a better understanding of how these types of infections relate to adult-onset of brain-related disorders is needed. Here, we undertook an extensive behavioral characterization of both pregnant females and their pups following late gestational exposure (from gestational days (GD) 15-17) to either lipopolysaccharide (LPS; 120µg/kg i.p.) or polyinosinic:polycytidylic acid (poly I:C; 5mg/kg i.v.). We observed that both LPS and poly I:C treatments produced anxiety-like behaviors in treated pregnant females, although to a lesser extent with LPS. LPS injections, but not poly I:C, led to reduced food intake and consequently decreased weight gain in pregnant dams. In pups, poly I:C treatments triggered a delay in growth and sensorimotor development, as evaluated by righting, geotaxis and grasping reflexes. At the cellular level, both toxins induced an initial inflammatory response while only LPS reduced the expression of brain cell markers in foetuses (GFAP and NeuN), which was no longer observable at postnatal day (PnD) 10. Higher levels of IL-2, IL-5 and IL-6 in plasma and an upregulation of the metabotropic receptor 5 (mGluR5) in foetal brains of 10-day-old offspring prenatally exposed to poly I:C was also observed. Interestingly, the increased mGluR5 expression correlated with impairments of the righting reflex. This study is the first to directly compare reflex development following LPS and poly I:C prenatal immune challenges in mice and sheds light onto the different patterns of behavior and pathology in dams and their offspring.