[Pelvic fracture and urogenital dysfunction in women: A literature review]. / Fracture du pelvis et conséquences urogénitales chez la femme : revue de la littérature.

INTRODUCTION: The consequences of a pelvic fracture on pelvic statics and sexuality in women are often overlooked and relegated to secondary care. OBJECTIVE: To carry out a state of knowledge on disorders of pelvic statics and sexuality in patients with a history of pelvic fracture: incidence, risk factors, management. METHODS: Literature review on the Pubmed, Medline, Embase and Cochrane database using the following keywords and MeSH terms: pelvis floor dysfunction, urinary dysfunction, sexual dysfunction, pelvic organ prolapse, in association with the terms pelvic fracture, pelvic trauma. RESULTS: Among the 270 initial articles, 21 were selected. Finally, one retrospective cohort study has evaluated the impact of pelvic fracture on the onset of a genital prolapse, 2 comparative retrospective studies and one prospective study focused on the impact of pelvic fracture on lower urinary tract symptoms. One comprehensive review studied pelvic fracture and sexuality outcomes. The incidence of prolapse following pelvic fracture could not be identified. The incidence of lower urinary tract symptoms varies between 21 and 67% with a significant difference for urinary urgency without leakage (P=0.016) and SUI (P=0.004). The incidence of sexual disorders varies between 21 and 62% with a predominance of dyspareunia. The mechanism of the trauma is thought to be a contributing factor, as well as the damage of the pubic symphysis (RR 4.8 95% CI 2.0-11.2). CONCLUSION: The evaluation of urogenital, sexual and anorectal dysfunctions following trauma to the pelvis has so far been little explored in the literature. Future prospective studies are to be carried out to improve patient care.

Utility of enhanced CT for patients with suspected uncomplicated renal colic and no acute findings on non-enhanced CT.

AIM: To evaluate the utility of contrast-enhanced computed tomography (CECT) for patients with suspected uncomplicated renal colic (URC) and no abnormalities on non-enhanced computed tomography (NECT). MATERIALS AND METHODS: The hospital institutional review board and ethics committee approved this retrospective study with a waiver of informed consent. Between January 2016 and April 2017, all consecutive adult patients who consulted at the adult Emergency Department (ED) with suspected URC and who had undergone both NECT and CECT were included retrospectively. The primary endpoint was prevalence of CECT-only diagnosis without acute findings on NECT. The risk factors for an acute finding were identified by logistic regression analysis. RESULTS: Among 126 patients with suspected URC, 12 were excluded. Among the 76 patients with no acute findings on NECT, CECT led to find acute lesions in 14/76 (18%) cases, but only 2/76 (3%) resulted in a change of management. Predictive factors of abnormal finding on CECT were: low renal clearance and high leukocyte count with OR 0.96 (95% confidence interval [CI]: 0.93-0.99), p=0.0189 and OR 5.79 (95% CI: 1.55-21.64), p=0.0091, respectively. CONCLUSIONS: In most cases, NECT is sufficient for screening patients with suspected URC. If leucocytosis and low renal function are present, stronger consideration may be given to CECT.

Quantification of brain cholinergic denervation in Alzheimer's disease using PET imaging with [18F]-FEOBV.

18F-fluoroethoxybenzovesamicol (FEOBV) is a new PET radiotracer that binds to the vesicular acetylcholine transporter. In both animals and healthy humans, FEOBV was found sensitive and reliable to characterize presynaptic cholinergic nerve terminals in the brain. It has been used here for we believe the first time in patients with Alzheimer's disease (AD) to quantify brain cholinergic losses. The sample included 12 participants evenly divided in healthy subjects and patients with AD, all assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) cognitive scales. Every participant underwent three consecutive PET imaging sessions with (1) the FEOBV as a tracer of the cholinergic terminals, (2) the 18F-NAV4694 (NAV) as an amyloid-beta tracer, and (3) the 18F-Fluorodeoxyglucose (FDG) as a brain metabolism agent. Standardized uptake value ratios (SUVRs) were computed for each tracer, and compared between the two groups using voxel wise t-tests. Correlations were also computed between each tracer and the cognitive scales, as well as between FEOBV and the two other radiotracers. Results showed major reductions of FEOBV uptake in multiple cortical areas that were evident in each AD subject, and in the AD group as a whole when compared to the control group. FDG and NAV were also able to distinguish the two groups, but with lower sensitivity than FEOBV. FEOBV uptake values were positively correlated with FDG in numerous cortical areas, and negatively correlated with NAV in some restricted areas. The MMSE and MoCA cognitive scales were found to correlate significantly with FEOBV and with FDG, but not with NAV. We concluded that PET imaging with FEOBV is more sensitive than either FDG or NAV to distinguish AD patients from control subjects, and may be useful to quantify disease severity. FEOBV can be used to assess cholinergic degeneration in human, and may represent an excellent biomarker for AD.

Amyloid-ß and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer's disease.

This study was designed to test the interaction between amyloid-ß and tau proteins as a determinant of metabolic decline in preclinical Alzheimer's disease (AD). We assessed 120 cognitively normal individuals with [18F]florbetapir positron emission tomography (PET) and cerebrospinal fluid (CSF) measurements at baseline, as well as [18F]fluorodeoxyglucose ([18F]FDG) PET at baseline and at 24 months. A voxel-based interaction model was built to test the associations between continuous measurements of CSF biomarkers, [18F]florbetapir and [18F]FDG standardized uptake value ratios (SUVR). We found that the synergistic interaction between [18F]florbetapir SUVR and CSF phosphorylated tau (p-tau) measurements, rather than the sum of their independent effects, was associated with a 24-month metabolic decline in basal and mesial temporal, orbitofrontal, and anterior and posterior cingulate cortices (P<0.001). In contrast, interactions using CSF amyloid-ß1-42 and total tau biomarkers did not associate with metabolic decline over a time frame of 24 months. The interaction found in this study further support the framework that amyloid-ß and hyperphosphorylated tau aggregates synergistically interact to cause downstream AD neurodegeneration. In fact, the regions displaying the metabolic decline reported here were confined to brain networks affected early by amyloid-ß plaques and neurofibrillary tangles. Preventive clinical trials may benefit from using a combination of amyloid-ß PET and p-tau biomarkers to enrich study populations of cognitively normal subjects with a high probability of disease progression in studies, using [18F]FDG as a biomarker of efficacy.

Surface manipulation of a curved polycyclic aromatic hydrocarbon-based nano-vehicle molecule equipped with triptycene wheels.

With a central curved chassis, a four-wheeled molecule-vehicle was deposited on a Au(111) surface and imaged at low temperature using a scanning tunneling microscope. The curved conformation of the chassis and the consequent moderate interactions of the four wheels with the surface were observed. The dI/dV constant current maps of the tunneling electronic resonances close to the Au(111) Fermi level were recorded to identify the potential energy entry port on the molecular skeleton to trigger and control the driving of the molecule. A lateral pushing mode of molecular manipulation and the consequent recording of the manipulation signals confirm how the wheels can step-by-step rotate while passing over the Au(111) surface native herringbone reconstructions. Switching a phenyl holding a wheel to the chassis was not observed for triggering a lateral molecular motion inelastically and without any mechanic push by the tip apex. This points out the necessity to encode the sequence of the required wheels action on the profile of the potential energy surface of the excited states to be able to drive a molecule-vehicle.

Influence of Cu adatoms on the molecular assembly of 4,4'-bipyridine on Cu(111).

The formation of highly organized structures based on two ligands with pyridyl functionalities, 4,4'-bipyridine (BPY) and 1,4-di(4,4''-pyridyl) benzene (BPYB), and Cu adatoms on the Cu(111) surface has been studied with low temperature and variable temperature scanning tunneling microscopy (STM) and first-principles calculations. We show that the formation of a highly organized adlayer built from adatom-molecule and molecule-molecule units strongly depends on the number of mobile Cu atoms on the surface. While a high concentration of Cu adatoms (high adatom/BPY ratio, ≥1) leads systematically to the formation of organometallic nanolines, their absence (low adatom/BPY ratio, ≈0) gives a compact self-assembled molecular network, and more specifically hydrogen-bond networks (HBN) with BPY molecules organized in a T-shaped fashion. Alternatively, an intermediate concentration of Cu adatoms (0 < adatom/BPY < 1) allows the formation of a well-organized and compact structure where both organometallic and HBN components coexist. Although STM images cannot clearly reveal the presence of Cu adatoms within the organometallic moiety, the bonding of BPY to a single or two Cu adatoms can be clearly identified by scanning tunneling spectroscopy (STS), and is supported by Density Functional Theory (DFT) results. Additional STM simulations suggest that the relative position of the Cu adatom with respect to the organic ligands just above has a significant impact on its detection by STM. This study exemplifies the prominent role of metallic adatoms on the formation of a complex organometallic network and should open more rational practices to optimize the formation of these supramolecular networks.

Suicide and assisted dying in dementia: what we know and what we need to know. A narrative literature review.

BACKGROUND: Evidence-based data on prevalence and risk factors of suicidal intentions and behavior in dementia are as scarce as the data on assisted dying. The present literature review aimed on summarizing the current knowledge and provides a critical discussion of the results. METHODS: A systematic narrative literature review was performed using Medline, Cochrane Library, EMBASE, PSYNDEX, PSYCINFO, Sowiport, and Social Sciences Citation Index literature. RESULTS: Dementia as a whole does not appear to be a risk factor for suicide completion. Nonetheless some subgroups of patients with dementia apparently have an increased risk for suicidal behavior, such as patients with psychiatric comorbidities (particularly depression) and of younger age. Furthermore, a recent diagnosis of dementia, semantic dementia, and previous suicide attempts most probably elevate the risk for suicidal intentions and behavior. The impact of other potential risk factors, such as patient's cognitive impairment profile, behavioral disturbances, social isolation, or a biomarker based presymptomatic diagnosis has not yet been investigated. Assisted dying in dementia is rare but numbers seem to increase in regions where it is legally permitted. CONCLUSION: Most studies that had investigated the prevalence and risk factors for suicide in dementia had significant methodological limitations. Large prospective studies need to be conducted in order to evaluate risk factors for suicide and assisted suicide in patients with dementia and persons with very early or presymptomatic diagnoses of dementia. In clinical practice, known risk factors for suicide should be assessed in a standardized way so that appropriate action can be taken when necessary.

Canadian Consensus Guidelines on Use of Amyloid Imaging in Canada: Update and Future Directions from the Specialized Task Force on Amyloid imaging in Canada.

Positron emission tomography (PET) imaging of brain amyloid beta is now clinically available in several countries including the United States and the United Kingdom, but not Canada. It has become an established technique in the field of neuroimaging of aging and dementia, with data incorporated in the new consensus guidelines for the diagnosis of Alzheimer disease and predementia Alzheimer's disease-related conditions. At this point, there are three US Food and Drug Administration- and European Union-approved tracers. Guided by appropriate use criteria developed in 2013 by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging, the utility of amyloid imaging in medical practice is now supported by a growing body of research. In this paper, we aimed to provide an update on the 2012 Canadian consensus guidelines to dementia care practitioners on proper use of amyloid imaging. We also wished to generate momentum for the industry to submit a new drug proposal to Health Canada. A group of local, national, and international dementia experts and imaging specialists met to discuss scenarios in which amyloid PET could be used appropriately. Peer-reviewed and published literature between January 2004 and May 2015 was searched. Technical and regulatory considerations pertaining to Canada were considered. The results of a survey of current practices in Canadian dementia centers were considered. A set of specific clinical and research guidelines was agreed on that defines the types of patients and clinical circumstances in which amyloid PET could be used in Canada. Future research directions were also outlined, notably the importance of studies that would assess the pharmaco-economics of amyloid imaging.

Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes.

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.

Colostrum whey down-regulates the expression of early and late inflammatory response genes induced by Escherichia coli and Salmonella enterica Typhimurium components in intestinal epithelial cells.

Pathogenic invasion by Escherichia coli and Salmonellae remains a constant threat to the integrity of the intestinal epithelium and can rapidly induce inflammatory responses. At birth, colostrum consumption exerts numerous beneficial effects on the properties of intestinal epithelial cells and protects the gastrointestinal tract of newborns from pathogenic invasion. The present study aimed to investigate the effect of colostrum on the early and late inflammatory responses induced by pathogens. The short-term (2 h) and long-term (24 h) effects of exposure to heat-killed (HK) E. coli and Salmonella enterica Typhimurium on gene expression in the porcine intestinal epithelial cell (IPEC-J2) model were first evaluated by microarray and quantitative PCR analyses. Luciferase assays were performed using a NF-κB-luc reporter construct to investigate the effect of colostrum whey treatment on the activation of NF-κB induced by HK bacteria. Luciferase assays were also performed using NF-κB-luc, IL-8-luc and IL-6-luc reporter constructs in human colon adenocarcinoma Caco-2/15 cells exposed to dose-response stimulations with HK bacteria and colostrum whey. Bovine colostrum whey treatment decreased the expression of early and late inflammatory genes induced by HK bacteria in IPEC-J2, as well as the transcriptional activation of NF-κB-luc induced by HK bacteria. Unlike that with colostrum whey, treatment with other milk fractions failed to decrease the activation of NF-κB-luc induced by HK bacteria. Lastly, the reduction of the HK bacteria-induced activation of NF-κB-luc, IL-8-luc and IL-6-luc by colostrum whey was dose dependent. The results of the present study indicate that bovine colostrum may protect and preserve the integrity of the intestinal mucosal barrier in the host by controlling the expression levels of early and late inflammatory genes following invasion by enteric pathogens.

Mild cognitive impairment: a concept in evolution.

The construct of mild cognitive impairment (MCI) has evolved over the past 10 years since the publication of the new MCI definition at the Key Symposium in 2003, but the core criteria have remained unchanged. The construct has been extensively used worldwide, both in clinical and in research settings, to define the grey area between intact cognitive functioning and clinical dementia. A rich set of data regarding occurrence, risk factors and progression of MCI has been generated. Discrepancies between studies can be mostly explained by differences in the operationalization of the criteria, differences in the setting where the criteria have been applied, selection of subjects and length of follow-up in longitudinal studies. Major controversial issues that remain to be further explored are algorithmic versus clinical classification, reliability of clinical judgment, temporal changes in cognitive performances and predictivity of putative biomarkers. Some suggestions to further develop the MCI construct include the tailoring of the clinical criteria to specific populations and to specific contexts. The addition of biomarkers to the clinical phenotypes is promising but requires deeper investigation. Translation of findings from the specialty clinic to the population setting, although challenging, will enhance uniformity of outcomes. More longitudinal population-based studies on cognitive ageing and MCI need to be performed to clarify all these issues.

Health economic evaluation of treatments for Alzheimer's disease: impact of new diagnostic criteria.

The socio-economic impact of Alzheimer's disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from a cost-effectiveness viewpoint. The diagnostic criteria for preclinical AD suggested by the National Institute on Aging and Alzheimer's Association workgroups in combination with the goal of effective disease-modifying treatment (DMT) are, however, a challenge for clinical practice and for the design of clinical trials. Key issues for future cost-effectiveness studies include the following: (i) the consequences for patients if diagnosis is shifted from AD-dementia to predementia states, (ii) bridging the gap between clinical trial populations and patients treated in clinical practice, (iii) translation of clinical trial end-points into measures that are meaningful to patients and policymakers/payers and (iv) how to measure long-term effects. To improve cost-effectiveness studies, long-term population-based data on disease progression, costs and outcomes in clinical practice are needed not only in dementia but also in predementia states. Reliable surrogate end-points in clinical trials that are sensitive to detect effects even in predementia states are also essential as well as robust and validated modelling methods from predementia states that also take into account comorbidities and age. Finally, the ethical consequences of early diagnosis should be considered.

How can we improve transfer of outcomes from randomized clinical trials to clinical practice with disease-modifying drugs in Alzheimer's disease?

BACKGROUND: Randomized clinical trials (RCTs) for putative disease-modifying drugs in Alzheimer's disease (AD) are using cognitive outcomes, such as the Alzheimer's Disease Assessment Scale--cognitive subscale, activities of daily living scales, such as the Alzheimer's Disease Cooperative Study Activities of Daily Living, and time from mild cognitive impairment to AD dementia. OBJECTIVE: It was the aim of this study to build clinically relevant outcomes for future use in clinical practice into RCT designs and help third-party payers to measure benefit. METHODS: We used a literature review for analysis. RESULTS: The Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) appears to be the most reliable primary outcome for RCT at different stages of AD, with the Relevant Outcome Scale for Alzheimer's Disease (ROSA) as a suitable alternative. The importance of current AD biomarkers vis-à- vis determination of efficacy of disease-modifying drugs has yet to be established; however, it is likely that at least one amyloid-specific test will be required prior to treatment with a drug acting predominantly on ß-amyloid (Aß42). Furthermore, serial MRI may be required to monitor adverse side effects associated with such drugs. CONCLUSIONS: Global clinical scales such as CDR-SB and ROSA should be considered for use with treatments aiming at slowing disease progression.

CTAD Task Force Paper: Neuropsychiatric Symptoms in AD: Clinical Trials Targeting Mild Behavioral Impairment: A Report from the International CTAD Task Force.

The International CTAD Task Force (TF) addressed challenges related to designing clinical trials for agitation in dementia, presenting accomplishments from the two previous TFs on neuropsychiatric symptoms (NPS). In addition, this TF proposed a paradigm shift in NPS assessment and management, presenting Mild Behavioral Impairment (MBI) as a clinical syndrome. MBI is marked by later-life emergent and persistent NPS in dementia-free older persons (ranging from cognitively unimpaired to subjective cognitive decline to mild cognitive impairment), which facilitates earlier detection and better prognostication of Alzheimer's disease (AD). The TF has made the following recommendations for incorporation of NPS into AD preventative trials: (1) clinical trials targeting improvement in MBI symptoms should be undertaken; (2) treatment trials for MBI should be disease specific and confirm the diagnosis of participants using biomarkers; trials should include measures sensitive to cognitive changes in preclinical AD, which can serve as outcome measures, in addition to changes in biomarker levels; (3) as a first step, pharmacotherapeutic trials should address the full MBI complex as well as the specific symptoms/domains that constitute MBI; (4) clinical trials using problem-adaptation psychotherapy to target affective MBI should be considered; and (5) MBI should be considered in AD trials of disease modifying therapies. The well-validated and widely-used MBI Checklist (MBI-C) is an appropriate symptom rating scale for these studies, as it was developed specifically to identify and measure MBI in dementia-free persons. Other scales such as the Neuropsychiatric Inventory (NPI) may be used, although administration at two timepoints may be necessary to operationalize the MBI criterion of symptom persistence.

Clinical Correlates of the PET-based Braak Staging Framework in Alzheimer's Disease.

In vivo Alzheimer's disease diagnosis and staging is traditionally based on clinical features. However, the agreement between clinical and pathological Alzheimer's disease diagnosis, whose diagnosis assessment includes amyloid and Braak histopathological tau staging, is not completely convergent. The development of positron emission tomography (PET) tracers targeting neurofibrillary tangles offers prospects for advancing the staging of Alzheimer's disease from both biological and clinical perspectives. Recent advances in radiochemistry made it possible to apply the postmortem Braak staging framework to tau-PET images obtained in vivo. Here, our aim is to provide a narrative review of the current literature on the relationship between Alzheimer's disease clinical features and the PET-based Braak staging framework. Overall, the available studies support the stepwise increase in disease severity following the advance of PET-based Braak stages, with later stages being associated with worse cognitive and clinical symptoms. In line with this, there is a trend for unimpaired cognition, mild cognitive impairment, and Alzheimer's disease dementia to be compatible with early, intermediate, and late patterns of tau deposition based on PET-based Braak stages. Moreover, neuropsychiatric symptom severity seems to be linked to the extent of tau-PET signal across Braak areas. In sum, this framework seems to correspond well with the clinical progression of Alzheimer's disease, which is an indication of its potential utility in research and clinical practice, especially for detecting preclinical tau levels in individuals without symptoms. However, further research is needed to improve the generalizability of these findings and to better understand the applications of this staging framework.

Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials.

BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.

Impact of buttermilk consumption on plasma lipids and surrogate markers of cholesterol homeostasis in men and women.

BACKGROUND AND AIMS: Sphingolipids (SL) are important components of the milk fat globule membrane (MFGM) found in buttermilk. While studies in animal models suggest that dietary SL may have cholesterol-lowering properties, data in human are lacking. The aim of this study was to investigate the impact of buttermilk consumption on plasma lipids and surrogate markers of cholesterol (C) homeostasis in humans. METHODS AND RESULTS: Men and women (n = 34) with serum LDL-C <5.0 mmol/L at screening (mean LDL-C = 3.8 mmol/L) were recruited in this double-blinded randomized crossover placebo controlled study. Their diets were supplemented with 45 g/d of buttermilk and with 45 g/d of a macro/micronutrient matched placebo (4 weeks each in random order). Serum lipid concentrations and surrogate markers of cholesterol homeostasis were measured post diet and compared using mixed models for repeated measures. Consumption of buttermilk led to reduction in serum cholesterol (-3.1%, P = 0.019), LDL-C (-3.1%, P = 0.057) and triacylglycerol (-10.7%, P = 0.007). Buttermilk consumption increased plasma lathosterol concentrations (+12.1%, P = 0.001), but multiple regression analysis indicated that variations in ß-sitosterol concentrations (P = 0.002) were the only significant predictor of the LDL-C response to buttermilk consumption. CONCLUSION: Buttermilk consumption may be associated with reduced cholesterol concentrations in men and women, primarily through inhibition of intestinal absorption of cholesterol. REGISTRATION NUMBER: This trial is registered at clinicaltrials.gov as NCT01248026.

Adding the Topographical Information from Tau-PET to the A/T/(N) Framework: Steps Towards Staging AD in Vivo.

Biomarkers have revolutionized the study and clinical diagnosis of Alzheimer's disease (AD). While amyloid-ß accumulation begins decades before the onset of clinical dementia in AD, tau pathology is more closely associated in both space and time to neurodegeneration and to clinical dysfunction. Correspondingly, tau-PET may prove useful in determining the severity of AD. Building on the biological research framework for AD, we review here methods and rationale to stage the severity of AD in vivo using the topographical distribution of tau-PET. We discuss how tau-PET can be used to detect early and subthreshold tau accumulation in medial temporal cortices prior to the onset of cognitive symptoms. Furthermore, tau-PET can be used to monitor the severity of AD as tau-PET spreads to association cortices and finally primary sensory cortices. We discuss the utility of tau-PET to monitor the progression of AD, the flexibility of potential approaches, and applications for clinical trials. In this regard, topographical information from tau-PET is a useful addition to the A/T/(N) framework.

Viewpoint: Clinicians' Perspectives on How Disease Modifying Drugs for Alzheimer's Disease Impact Specialty Care.

Clinicians specialized in the diagnosis and management of persons living with early-stage Alzheimer's disease need to enable access, for those meeting criteria, to the new class of disease modifying drugs (DMDs). These drugs act on amyloid ß42 and delay progression of symptoms. Thus, there will be interest from patients and families. Over the short term, the use of antibodies administered intravenously with serial MRIs to detect amyloid-related imaging abnormalities (ARIA) may require participation in structured phase 4 studies or in registries with third party funding for support staff and MRI scans. In the mid term, the availability of oral anti-amyloid therapy, likely with lower risk of ARIA, may transform clinical practice to a model of screening suitable patients using plasma biomarkers, with a subsequent rapid referral to a specialized memory clinic. Eventually, the biological profile of patients for amyloid, tau, and inflammation will determine which type of DMD to use. We are optimistic that clinicians will gain confidence with the use DMDs and answer the increasing needs of our aging population.

White Matter Hyperintensity as a Vascular Contribution to the AT(N) Framework.

The AT(N) framework enables the classification of an individual within the biological Alzheimer's disease (AD) continuum by pairing the cognitive stage with the biomarker status of amyloid-beta (Aß, A), tau (T) and neurodegeneration (N). AD is a multifactorial disease that may involve different pathogenic mechanisms such as cerebrovascular disease (CVD). Therefore, biomarkers of these mechanisms can be added to the AT(N) framework to enhance the biomarker characterization of individuals within the AD continuum. In AD, white matter hyperintensities (WMH) which are postulated to develop as a result of chronic ischemia from small vessel CVD are shown to play a role in the aetiology. However, the interplay of WMH with Aß and tau pathophysiology in AD remains unclear. In this review, we summarized the studies that evaluated the associations between WMH and AD pathophysiology (Aß and tau). We found that the evidence supporting the association of WMH with Aß was mixed, and this may be explained by the relative contributions of WMH due to its differential load and anatomical distribution. More studies are also needed to determine the association of WMH with tau pathology. Future longitudinal studies with harmonized methodologies to quantify WMH and account for the anatomical differences of WMH are required to validate the relationship between WMH and AT(N) biomarkers. This will allow a clearer understanding of the utility of WMH as a vascular biomarker in the AT(N) framework. Novel CVD biomarkers will also have the potential to further elucidate the contributions of CVD to the AD pathophysiology.