Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations

BACKGROUND: Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter gamma-secretase activity to promote accumulation of toxic Abeta42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase. In addition, the levels of Abeta40/42 peptides were quantified by ELISA. RESULTS: We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Abeta40 over Abeta42. The AbetaPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations. CONCLUSION: These observations imply that missense mutations in PSEN genes can alter a range of key gamma-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.Fil: Maarouf, Chera L.. Sun Health Research Institute; Estados UnidosFil: Daugs, Ian D.. Sun Health Research Institute; Estados UnidosFil: Spina, Salvatore. Universita Degli Studi Di Siena; Italia. Indiana University; Estados UnidosFil: Vidal, Ruben. Indiana University; Estados UnidosFil: Kokjohn, Tyler A.. Sun Health Research Institute; Estados Unidos. Midwestern University; Estados UnidosFil: Patton, R. Lyle. Sun Health Research Institute; Estados UnidosFil: Kalback, Walter M.. Sun Health Research Institute; Estados UnidosFil: Luehrs, Dean C.. Sun Health Research Institute; Estados UnidosFil: Walker, Douglas G.. Sun Health Research Institute; Estados UnidosFil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Beach, Thomas G.. Sun Health Research Institute; Estados UnidosFil: Ghetti, Bernardino. Indiana University; Estados UnidosFil: Roher, Alex E.. Sun Health Research Institute; Estados Unido

The Tarantula Massive Binary Monitoring

We present the first SB2 orbital solution and disentanglement of the massive Wolf-Rayet binary R145 (P = 159d) located in the Large Magellanic Cloud. The primary was claimed to have a stellar mass greater than 300Msun, making it a candidate for the most massive star known. While the primary is a known late type, H-rich Wolf-Rayet star (WN6h), the secondary could not be so far unambiguously detected. Using moderate resolution spectra, we are able to derive accurate radial velocities for both components. By performing simultaneous orbital and polarimetric analyses, we derive the complete set of orbital parameters, including the inclination. The spectra are disentangled and spectroscopically analyzed, and an analysis of the wind-wind collision zone is conducted. The disentangled spectra and our models are consistent with a WN6h type for the primary, and suggest that the secondary is an O3.5 If*/WN7 type star. We derive a high eccentricity of e = 0.78 and minimum masses of M1 sin^3 i ~ M2 sin^3 i ~ 13 +- 2 Msun, with q = M2 / M1 = 1.01 +- 0.07. An analysis of emission excess stemming from a wind-wind collision yields a similar inclination to that obtained from polarimetry (i = 39 +- 6deg). Our analysis thus implies M1 = 53^{+40}_{-20} and M2 = 54^{+40}_{-20} Msun, excluding M1 > 300Msun. A detailed comparison with evolution tracks calculated for single and binary stars, as well as the high eccentricity, suggest that the components of the system underwent quasi-homogeneous evolution and avoided mass-transfer. This scenario would suggest current masses of ~ 80 Msun and initial masses of Mi,1 ~ 105 and Mi,2 ~ 90Msun, consistent with the upper limits of our derived orbital masses, and would imply an age of ~2.2 Myr.Comment: Accepted for Publication in A&A, 16 pages, 17 figures and 4 table

Neurofeedback training for alcohol dependence versus treatment as usual: study protocol for a randomized controlled trial

Background Real-time functional magnetic resonance imaging (rtfMRI) is used for neurofeedback training (NFT). Preliminary results suggest that it can help patients to control their symptoms. This study uses rtfMRI NFT for relapse prevention in alcohol dependence. Methods/design Participants are alcohol-dependent patients who have completed a detoxification programme within the past 6 months and have remained abstinent. Potential participants are screened for eligibility, and those who are eligible are randomly assigned to the treatment group (receiving rtfMRI NFT in addition to treatment as usual) or the control group (receiving only treatment as usual). Participants in both groups are administered baseline assessments to measure their alcohol consumption and severity of dependence and a variety of psychological and behavioural characteristics that are hypothesised to predict success with rtfMRI NFT. During the following 4 months, experimental participants are given six NFT sessions, and before and after each session various alcohol-related measures are taken. Participants in the control group are given the same measures to coincide with their timing in the experimental group. Eight and 12 months after the baseline assessment, both groups are followed up with a battery of measures. The primary research questions are whether NFT can be used to teach participants to down-regulate their brain activation in the presence of alcohol stimuli or to up-regulate their brain activation in response to pictures related to healthy goal pursuits, and, if so, whether this translates into reductions in alcohol consumption. The primary outcome measures will be those derived from the functional brain imaging data. We are interested in improvements (i.e., reductions) in participants’ alcohol consumption from pretreatment levels, as indicated by three continuous variables, not simply whether or not the person has remained abstinent. The indices of interest are percentage of days abstinent, drinks per drinking day, and percentage of days of heavy drinking. General linear models will be used to compare the NFT group and the control group on these measures. Discussion Relapse in alcohol dependence is a recurring problem, and the present evaluation of the role of rtfMRI in its treatment holds promise for identifying a way to prevent relapse. Trial registration ClinicalTrials.gov Identifier: NCT02486900, registered on 26 June 2015

Chemical characterization of pro-inflammatory amyloid-beta peptides in human atherosclerotic lesions and platelets

Amyloid-β (Aβ) peptides are intimately involved in the inflammatory pathology of atherosclerotic vascular disease (AVD) and Alzheimer's disease (AD). Although substantial amounts of these peptides are produced in the periphery, their role and significance to vascular disease outside the brain requires further investigation. Amyloid-β peptides present in the walls of human aorta atherosclerotic lesions as well as activated and non-activated human platelets were isolated using sequential size-exclusion columns and HPLC reverse-phase methods. The Aβ peptide isolates were quantified by ELISA and structurally analyzed using MALDI-TOF mass spectrometry procedures. Our experiments revealed that both aorta and platelets contained Aβ peptides, predominately Aβ40. The source of the Aβ pool in aortic atherosclerosis lesions is probably the activated platelets and/or vascular wall cells expressing APP/PN2. Significant levels of Aβ42 are present in the plasma, suggesting that this reservoir makes a minor contribution to atherosclerotic plaques. Our data reveal that although aortic atherosclerosis and AD cerebrovascular amyloidosis exhibit clearly divergent end-stage manifestations, both vascular diseases share some key pathophysiological promoting elements and pathways. Whether they happen to be deposited in vessels of the central nervous system or atherosclerotic plaques in the periphery, Aβ peptides may promote and perhaps synergize chronic inflammatory processes which culminate in the degeneration, malfunction and ultimate destruction of arterial walls.Fil: Kokjohn, Tyler A.. Banner Sun Health Research Institute; Estados Unidos. Midwestern University; Estados UnidosFil: Van Vickle, Gregory D.. Banner Sun Health Research Institute; Estados UnidosFil: Maarouf, Chera L.. Banner Sun Health Research Institute; Estados UnidosFil: Kalback, Walter M.. Banner Sun Health Research Institute; Estados UnidosFil: Hunter, Jesse M.. Banner Sun Health Research Institute; Estados UnidosFil: Daugs, Ian D.. Banner Sun Health Research Institute; Estados UnidosFil: Luehrs, Dean C.. Banner Sun Health Research Institute; Estados UnidosFil: Lopez, John. Arizona State University; Estados UnidosFil: Brune, Daniel. Arizona State University; Estados UnidosFil: Sue, Lucia I.. Banner Sun Health Research Institute; Estados UnidosFil: Beach, Thomas G.. Banner Sun Health Research Institute; Estados UnidosFil: Castaño, Eduardo Miguel. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Roher, Alex E.. Banner Sun Health Research Institute; Estados Unido

The biochemical aftermath of anti-amyloid immunotherapy

Immunotherapy responses were characterized by extreme variability. Considering the broad range of biological variation that characterizes aging and complicates the recognition of reliable AD biomarkers, such disparities will make the interpretation of outcomes derived from epidemiologic and therapeutic investigations challenging. Although in some cases the apparent removal of amyloid plaques by AN-1792 was impressive, proportionate alterations in the clinical progression of AD were not evident. The fact that plaque elimination did not alter the trajectory of decline into dementia suggests the likelihood that these deposits alone are not the underlying cause of dementia