Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer’s Disease: A Pragmatic Review for Clinicians

\ua9 The Author(s) 2024.This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer’s disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)—parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners

Sex differences in brain atrophy in dementia with Lewy bodies

\ua9 2023 The Authors. Alzheimer\u27s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer\u27s Association.INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n = 327; 73 \ub1 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 \ub1 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. Highlights: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age

Administration of M. leprae Hsp65 Interferes with the Murine Lupus Progression

The heat shock protein [Hsp] family guides several steps during protein synthesis, are abundant in prokaryotic and eukaryotic cells, and are highly conserved during evolution. The Hsp60 family is involved in assembly and transport of proteins, and is expressed at very high levels during autoimmunity or autoinflammatory phenomena. Here, the pathophysiological role of the wild type [WT] and the point mutated K409A recombinant Hsp65 of M. leprae in an animal model of Systemic Lupus Erythematosus [SLE] was evaluated in vivo using the genetically homogeneous [NZBxNZW]F1 mice. Anti-DNA and anti-Hsp65 antibodies responsiveness was individually measured during the animal's life span, and the mean survival time [MST] was determined. The treatment with WT abbreviates the MST in 46%, when compared to non-treated mice [p<0.001]. An increase in the IgG2a/IgG1 anti-DNA antibodies ratio was also observed in animals injected with the WT Hsp65. Incubation of BALB/c macrophages with F1 serum from WT treated mice resulted in acute cell necrosis; treatment of these cells with serum from K409A treated mice did not cause any toxic effect. Moreover, the involvement of WT correlates with age and is dose-dependent. Our data suggest that Hsp65 may be a central molecule intervening in the progression of the SLE, and that the point mutated K409A recombinant immunogenic molecule, that counteracts the deleterious effect of WT, may act mitigating and delaying the development of SLE in treated mice. This study gives new insights into the general biological role of Hsp and the significant impact of environmental factors during the pathogenesis of this autoimmune process

Homocysteinylated Albumin Promotes Increased Monocyte-Endothelial Cell Adhesion and Up-Regulation of MCP1, Hsp60 and ADAM17

RATIONALE:The cardiovascular risk factor homocysteine is mainly bound to proteins in human plasma, and it has been hypothesized that homocysteinylated proteins are important mediators of the toxic effects of hyperhomocysteinemia. It has been recently demonstrated that homocysteinylated proteins are elevated in hemodialysis patients, a high cardiovascular risk population, and that homocysteinylated albumin shows altered properties. OBJECTIVE:Aim of this work was to investigate the effects of homocysteinylated albumin - the circulating form of this amino acid, utilized at the concentration present in uremia - on monocyte adhesion to a human endothelial cell culture monolayer and the relevant molecular changes induced at both cell levels. METHODS AND RESULTS:Treated endothelial cells showed a significant increase in monocyte adhesion. Endothelial cells showed after treatment a significant, specific and time-dependent increase in ICAM1 and VCAM1. Expression profiling and real time PCR, as well as protein analysis, showed an increase in the expression of genes encoding for chemokines/cytokines regulating the adhesion process and mediators of vascular remodeling (ADAM17, MCP1, and Hsp60). The mature form of ADAM17 was also increased as well as Tnf-α released in the cell medium. At monocyte level, treatment induced up-regulation of ICAM1, MCP1 and its receptor CCR2. CONCLUSIONS:Treatment with homocysteinylated albumin specifically increases monocyte adhesion to endothelial cells through up-regulation of effectors involved in vascular remodeling

A Mycobacterium leprae Hsp65 Mutant as a Candidate for Mitigating Lupus Aggravation in Mice

Hsp60 is an abundant and highly conserved family of intracellular molecules. Increased levels of this family of proteins have been observed in the extracellular compartment in chronic inflammation. Administration of M. leprae Hsp65 [WT] in [NZBxNZW]F1 mice accelerates the Systemic Lupus Erythematosus [SLE] progression whereas the point mutated K409A Hsp65 protein delays the disease. Here, the biological effects of M. leprae Hsp65 Leader pep and K409A pep synthetic peptides, which cover residues 352–371, are presented. Peptides had immunomodulatory effects similar to that observed with their respective proteins on survival and the combined administration of K409A+Leader pep or K409A pep+WT showed that the mutant forms were able to inhibit the deleterious effect of WT on mortality, indicating the neutralizing potential of the mutant molecules in SLE progression. Molecular modeling showed that replacing Lysine by Alanine affects the electrostatic potential of the 352–371 region. The number of interactions observed for WT is much higher than for Hsp65 K409A and mouse Hsp60. The immunomodulatory effects of the point-mutated protein and peptide occurred regardless of the catalytic activity. These findings may be related to the lack of effect on survival when F1 mice were inoculated with Hsp60 or K409A pep. Our findings indicate the use of point-mutated Hsp65 molecules, such as the K409A protein and its corresponding peptide, that may minimize or delay the onset of SLE, representing a new approach to the treatment of autoimmune diseases

A Possible Alignment between the Orbits of Planetary Systems and their Visual Binary Companions

Astronomers do not have a complete picture of the effects of wide-binary companions (semimajor axes greater than 100 au) on the formation and evolution of exoplanets. We investigate these effects using new data from Gaia Early Data Release 3 and the Transiting Exoplanet Survey Satellite mission to characterize wide-binary systems with transiting exoplanets. We identify a sample of 67 systems of transiting exoplanet candidates (with well-determined, edge-on orbital inclinations) that reside in wide visual binary systems. We derive limits on orbital parameters for the wide-binary systems and measure the minimum difference in orbital inclination between the binary and planet orbits. We determine that there is statistically significant difference in the inclination distribution of wide-binary systems with transiting planets compared to a control sample, with the probability that the two distributions are the same being 0.0037. This implies that there is an overabundance of planets in binary systems whose orbits are aligned with those of the binary. The overabundance of aligned systems appears to primarily have semimajor axes less than 700 au. We investigate some effects that could cause the alignment and conclude that a torque caused by a misaligned binary companion on the protoplanetary disk is the most promising explanation. © 2022. The Author(s). Published by the American Astronomical Society.AB022006; ANR-15-IDEX-01; 80NSSC19K1727; National Science Foundation, NSF; National Aeronautics and Space Administration, NASA: 18-2XRP18_2-0136; New York Community Trust, NYCT; Australian Research Council, ARC; National Research Foundation, NRF; Japan Society for the Promotion of Science, KAKEN: 15H02063, 18H05442, 20K14521, 22000005, JP17H04574, JP18H05439, JP20J21872, JP20K14518, JP21K13955; Ministry of Education, Culture, Sports, Science and Technology, MEXT; Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF; Fonds De La Recherche Scientifique - FNRS, FNRS: FRFC 2.5.594.09; Ministry of Science, ICT and Future Planning, MSIP; Nagoya University, NU: 10147207, 10147214; Université de Liège, ULg; Universidad Católica de la Santísima Concepción, UCSC: DI-FIAI 03/2021; National Astronomical Observatory of Japan, NAOJ; Precursory Research for Embryonic Science and Technology, PRESTO: JPMJPR1775; Instituto de Astrofísica de Andalucía, IAA: SEV-2017-0709This paper includes data collected by the TESS mission, which are publicly available from the Mikulski Archive for Space Telescopes (MAST). Funding for the TESS mission is provided by NASA’s Science Mission directorate.K.K.M. acknowledges support from the New York Community Trust's Fund for Astrophysical Research.The research leading to these results has received funding from the ARC grant for Concerted Research Actions, financed by the Wallonia-Brussels Federation. TRAPPIST is funded by the Belgian Fund for Scientific Research (Fond National de la Recherche Scientifique, FNRS) under the grant FRFC 2.5.594.09.F. TRAPPIST-North is a project funded by the University of Liège (Belgium), in collaboration with Cadi Ayyad University of Marrakech (Morocco).This work is partly supported by JSPS KAKENHI grant No. JP20K14518, and by Astrobiology Center SATELLITE Research project AB022006.This work is partly supported by JSPS KAKENHI grant No. JP21K13955.This work is partly supported by JSPS KAKENHI grant No. 20K14521.This paper is based on observations made with the MuSCAT3 instrument, developed by the Astrobiology Center and under financial supports by JSPS KAKENHI (JP18H05439) and JST PRESTO (JPMJPR1775), at Faulkes Telescope North on Maui, HI, operated by the Las Cumbres Observatory.The IRSF project is a collaboration between Nagoya University and the South African Astronomical Observatory (SAAO) supported by the Grants-in-Aid for Scientific Research on Priority Areas (A) (grant Nos. 10147207 and 10147214) and Optical & Near-Infrared Astronomy Inter-University Cooperation Program, from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and the National Research Foundation (NRF) of South Africa.C.R.-L. acknowledges financial support from the State Agency for Research of the Spanish MCIU through the Center of Excellence Severo Ochoa award for the Instituto de Astrofísica de Andalucía (SEV-2017-0709).M.T. is supported by MEXT/JSPS KAKENHI grant Nos. 18H05442, 15H02063, and 22000005.This work is partly supported by JSPS KAKENHI grant No. JP18H05439, and JST PRESTO grant No. JPMJPR1775, and a University Research Support Grant from the National Astronomical Observatory of Japan (NAOJ).P.J.A. acknowledges support from grant AYA2016-79425-C3-3-P of the Spanish Ministry of Economy and Competitiveness (MINECO) and the Centre of Excellence “Severo Ochoa” award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709)

Building Their Own Waldos Emerson's First Biographers and the Politics of Life-Writing in the Gilded Age

By the end of the nineteenth century, Ralph Waldo Emerson was well on his way to becoming the "Wisest American" and the "Sage of Concord," a literary celebrity and a national icon. With that fame came what Robert Habich describes as a blandly sanctified version of Emerson held widely by the reading public. Building Their Own Waldos sets out to understand the dilemma faced by Emerson's early biographers: how to represent a figure whose subversive individualism had been eclipsed by his celebrity, making him less a representative of his age than a caricature of it.   Drawing on never-before-published letters, diaries, drafts, business records, and private documents, Habich explores the making of a cultural hero through the stories of Emerson's first biographers- George Willis Cooke, a minister most recently from Indianapolis who considered himself a disciple; the English reformer and newspaper mogul Alexander Ireland, a friend for half a century; Moncure D. Conway, a Southern abolitionist then residing in London, who called Emerson his "spiritual father and intellectual teacher"; the poet and medical professor Oliver Wendell Holmes, with Emerson a member of Boston's gathering of literary elite, the Saturday Club; James Elliot Cabot, the family's authorized biographer, an architect and amateur philosopher with unlimited access to Emerson's unpublished papers; and Emerson's son Edward, a physician and painter whose father had passed over him as literary executor in favor of Cabot.   Just as their biographies reveal a complex, socially engaged Emerson, so too do the biographers' own stories illustrate the real-world perils, challenges, and motives of life-writing in the late nineteenth century, when biographers were routinely vilified as ghoulish and disreputable and biography as a genre underwent a profound redefinition. Building Their Own Waldos isat once a revealing look at Emerson's constructed reputation, a case study in the rewards and dangers of Victorian life-writing, and the story of six authors struggling amidst personal misfortunes and shifting expectations to capture the elusive character of America's "representative man," as they knew him and as they needed him to be.Intro -- Contents -- Acknowledgments -- Introduction -- Abbreviations -- One: A Genre in Transition: Biography in the 1880s -- Two: An Act of Wholesome and Pure-hearted Admiration: Emerson's First Biographer, George Willis Cooke -- Three: Biographers and the Pornographer: Conway, Ireland, and "Emerson and His Friends" -- Four: Diagnosing the Gentle Iconoclast: Dr. Holmes on Emerson -- Five: Authorizing Emerson's Biography: Cabot and/or Edward Emerson -- Six: Shelf Life: The Legacy of Emerson's First Biographies -- Notes -- Bibliography -- IndexBy the end of the nineteenth century, Ralph Waldo Emerson was well on his way to becoming the "Wisest American" and the "Sage of Concord," a literary celebrity and a national icon. With that fame came what Robert Habich describes as a blandly sanctified version of Emerson held widely by the reading public. Building Their Own Waldos sets out to understand the dilemma faced by Emerson's early biographers: how to represent a figure whose subversive individualism had been eclipsed by his celebrity, making him less a representative of his age than a caricature of it.   Drawing on never-before-published letters, diaries, drafts, business records, and private documents, Habich explores the making of a cultural hero through the stories of Emerson's first biographers- George Willis Cooke, a minister most recently from Indianapolis who considered himself a disciple; the English reformer and newspaper mogul Alexander Ireland, a friend for half a century; Moncure D. Conway, a Southern abolitionist then residing in London, who called Emerson his "spiritual father and intellectual teacher"; the poet and medical professor Oliver Wendell Holmes, with Emerson a member of Boston's gathering of literary elite, the Saturday Club; James Elliot Cabot, the family's authorized biographer, an architect and amateur philosopher with unlimited access to Emerson's unpublished papers; and Emerson's son Edward, a physician and painter whose father had passed over him as literary executor in favor of Cabot.   Just as their biographies reveal a complex, socially engaged Emerson, so too do the biographers' own stories illustrate the real-world perils, challenges, and motives of life-writing in the late nineteenth century, when biographers were routinely vilified as ghoulish and disreputable and biography as a genre underwent a profound redefinition. Building Their Own Waldos isat once a revealing look at Emerson's constructed reputation, a case study in the rewards and dangers of Victorian life-writing, and the story of six authors struggling amidst personal misfortunes and shifting expectations to capture the elusive character of America's "representative man," as they knew him and as they needed him to be.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries