Showing papers by "Richard Lathe published in 2018"

The antimicrobial protection hypothesis of Alzheimer's disease.

Abstract: Objective We explore here a novel model for amyloidogenesis in Alzheimer's disease (AD). This new perspective on AD amyloidosis seeks to provide a rational framework for incorporating recent and seemingly independent findings on the antimicrobial role of β-amyloid and emerging experimental, genetic, and epidemiological data, suggesting innate immune-mediated inflammation propagates AD neurodegeneration. Background AD pathology is characterized by cerebral deposition of amyloid-β protein (Aβ) as β-amyloid. Genetic studies have confirmed the key role of Aβ in AD, revealing that mutation-mediated shifts in the peptides generation lead to early onset familial Alzheimer's disease. However, Aβ generation appears normal for the majority of AD patients, who lack early onset familial Alzheimer's disease mutations. In prevailing models of nonfamilial AD, individual genetics and age-associated changes in brain milieu promote an intrinsically abnormal propensity of Aβ for self-association. However, emerging findings are increasingly inconsistent with characterization of Aβ oligomerization as a nonphysiological and exclusively pathological activity. Recent studies suggest Aβ is an ancient, highly conserved effector molecule of innate immunity. Moreover, Aβ oligomerization and β-amyloid generation appear to be important innate immune pathways that mediate pathogen entrapment and protect against infection. New AD amyloidogenesis model Recent findings on inflammation-mediated neurodegeneration and the role of Aβ in immunity have led to emergence of the "Antimicrobial Protection Hypothesis" of AD. In this model, β-amyloid deposition is an early innate immune response to genuine, or mistakenly perceived, immunochallenge. Aβ first entraps and neutralizes invading pathogens in β-amyloid. Aβ fibrillization drives neuroinflammatory pathways that help fight the infection and clear β-amyloid/pathogen deposits. In AD, chronic activation of this pathway leads to sustained inflammation and neurodegeneration. Mounting data link elevated brain microbe levels with AD. The Antimicrobial Protection Hypothesis reveals how increased brain microbial burden may directly exacerbate β-amyloid deposition, inflammation, and AD progression. Amyloid cascade hypothesis In the antimicrobial protection model, the modality of Aβ's pathophysiology is shifted from abnormal stochastic behavior toward dysregulated innate immune response. However, β-amyloid deposition in AD still leads to neurodegeneration. Thus, the new model extends but remains broadly consistent with the Amyloid Cascade Hypothesis and overwhelming data showing the primacy of Aβ in AD pathology.

Herpes Viruses and Senile Dementia: First Population Evidence for a Causal Link.

Abstract: Three articles have very recently appeared that are of especial relevance to the causes of dementia and its potential treatment. The first two (Tsai et al., published in PLoS One in November 2017; Chen et al., published in the January/February 2018 issue of Journal of Clinical Psychiatry) demonstrate an increased risk of subsequent senile dementia (SD) development in patients with acute varicella zoster (herpes zoster) infection. These articles present data highly relevant to the third, and most important, paper-by Tzeng et al., published online in the journal Neurotherapeutics at the end of February 2018. These authors report that infection with a different herpes virus, herpes simplex virus type 1 (HSV1), leads to a similarly increased risk of later developing SD. Further, when the authors looked at patients treated aggressively with antiherpetic medications at the time, the relative risk of SD was reduced by a factor of 10. It should be stressed that no investigations were made on subjects already suffering from SD, and that those treated were the few rare cases severely affected by HSV. Nonetheless, antiherpetic medication prevented later SD development in 90% of their study group. These articles provide the first population evidence for a causal link between herpes virus infection and senile dementia.

Mechanism Underlying Tissue Cryotherapy to Combat Obesity/Overweight: Triggering Thermogenesis

Abstract: Background. Local adipose tissue (AT) cooling is used to manage obesity and overweight, but the mechanism is unclear. The current view is that acute local cooling of AT induces adipocyte cell disruption and inflammation (“cryolipolysis”) that lead to adipocyte cell death, with loss of subcutaneous fat being recorded over a prolonged period of weeks/months. A contrasting view is that AT loss via targeted cryotherapy might be mediated by thermogenic fat metabolism without cell disruption. Methods. In this retrospective study of individuals presenting for cryotherapy to the Clinic BioEsthetic, Paris, France, we recorded waist circumference, body weight, and body mass index (BMI) by direct measurement and by whole-body dual-energy X-ray absorptiometric scanning. In select individuals, blood analysis of markers of inflammation and fat mobilization was performed before and after the procedure. Results. We report that (i) single sessions of tissue cryotherapy lead to significant loss of tissue volume in the time frame of hours and (ii) multiple daily procedures lead to a cumulative decline in AT, as assessed by waist circumference, body weight, and BMI, confirmed by whole-body dual-energy X-ray absorptiometric scanning. In addition, (iii) blood analysis following tissue cryotherapy found no significant changes in biochemical parameters including markers of inflammation. Moreover, (iv) calculations of heat extracted and of compensatory weight loss taking place through thermogenesis are substantially consistent with the observed loss of AT. Conclusions. These findings argue that cold-induced thermogenesis (“cryothermogenesis”) rather than adipocyte disruption underlies the reduction in AT volume, raising the prospect that more intensive cryotherapy may be a viable option for combating obesity and overweight.