Using magnetic resonance imaging to measure head muscles: An innovative method to opportunistically determine muscle mass and detect sarcopenia.

BACKGROUND: Sarcopenia is associated with multiple adverse outcomes. Traditional methods to determine low muscle mass for the diagnosis of sarcopenia are mainly based on dual-energy X-ray absorptiometry (DXA), whole-body magnetic resonance imaging (MRI) and bioelectrical impedance analysis. These tests are not always available and are rather time consuming and expensive. However, many brain and head diseases require a head MRI. In this study, we aim to provide a more accessible way to detect sarcopenia by comparing the traditional method of DXA lean mass estimation versus the tongue and masseter muscle mass assessed in a standard brain MRI. METHODS: The H70 study is a longitudinal study of older people living in Gothenburg, Sweden. In this cross-sectional analysis, from 1203 participants aged 70 years at baseline, we included 495 with clinical data and MRI images available. We used the appendicular lean soft tissue index (ALSTI) in DXA images as our reference measure of lean mass. Images from the masseter and tongue were analysed and segmented using 3D Slicer. For the statistical analysis, the Spearman correlation coefficient was used, and concordance was estimated with the Kappa coefficient. RESULTS: The final sample consisted of 495 participants, of which 52.3% were females. We found a significant correlation coefficient between both tongue (0.26) and masseter (0.33) with ALSTI (P < 0.001). The sarcopenia prevalence confirmed using the alternative muscle measure in MRI was calculated using the ALSTI (tongue = 2.0%, masseter = 2.2%, ALSTI = 2.4%). Concordance between sarcopenia with masseter and tongue versus sarcopenia with ALSTI as reference has a Kappa of 0.989 (P < 0.001) for masseter and a Kappa of 1 for the tongue muscle (P < 0.001). Comorbidities evaluated with the Cumulative Illness Rating Scale were significantly associated with all the muscle measurements: ALSTI (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.07-1.26, P < 0.001), masseter (OR 1.16, 95% CI 1.07-1.26, P < 0.001) and tongue (OR 1.13, 95% CI 1.04-1.22, P = 0.002); the higher the comorbidities, the higher the probability of having abnormal muscle mass. CONCLUSIONS: ALSTI was significantly correlated with tongue and masseter muscle mass. When performing the sarcopenia diagnostic algorithm, the prevalence of sarcopenia calculated with head muscles did not differ from sarcopenia calculated using DXA, and almost all participants were correctly classified using both methods.

A review of decision aids to assess cardiovascular risk.

PURPOSE OF REVIEW: Cardiovascular disease remains one of the leading causes of morbidity and mortality today. The major risk factors for cardiovascular disease include type 2 diabetes mellitus, hypertension, tobacco smoking, elevated body mass index, and hyperlipidemia. The decision to use medication treatment for hyperlipidemia can be assisted using computerized decision tools. RECENT FINDINGS: The treatment of hyperlipidemia with 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has become widely recommended even though most people treated with them do not get clinical benefit, and the magnitude of their effect is dependent upon prior clinical risk. This article reviews recent research about the effectiveness of HMG-CoA reductase inhibitors, and the use of decision-making tools to assist the clinician in advising patients about the use of these medications. SUMMARY: On-line decision tools are available to estimate cardiovascular risk and to assist clinicians in helping their patients make their own decision about whether to take HMG-CoA reductase inhibitor medication to reduce cardiovascular risk.

Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals.

BACKGROUND AND OBJECTIVES: Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals. METHODS: The contribution of amyloid and tau pathology was assessed through CSF levels of the Aß42/40 ratio and phosphorylated tau (p-tau). CSF Aß38 levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis as variables of interest. RESULTS: We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of Aß38 and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The Aß42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE ε4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T201 = -1.55; p = 0.123). DISCUSSION: In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.

Competing paradigms of obesity pathogenesis: energy balance versus carbohydrate-insulin models.

The obesity pandemic continues unabated despite a persistent public health campaign to decrease energy intake ("eat less") and increase energy expenditure ("move more"). One explanation for this failure is that the current approach, based on the notion of energy balance, has not been adequately embraced by the public. Another possibility is that this approach rests on an erroneous paradigm. A new formulation of the energy balance model (EBM), like prior versions, considers overeating (energy intake > expenditure) the primary cause of obesity, incorporating an emphasis on "complex endocrine, metabolic, and nervous system signals" that control food intake below conscious level. This model attributes rising obesity prevalence to inexpensive, convenient, energy-dense, "ultra-processed" foods high in fat and sugar. An alternative view, the carbohydrate-insulin model (CIM), proposes that hormonal responses to highly processed carbohydrates shift energy partitioning toward deposition in adipose tissue, leaving fewer calories available for the body's metabolic needs. Thus, increasing adiposity causes overeating to compensate for the sequestered calories. Here, we highlight robust contrasts in how the EBM and CIM view obesity pathophysiology and consider deficiencies in the EBM that impede paradigm testing and refinement. Rectifying these deficiencies should assume priority, as a constructive paradigm clash is needed to resolve long-standing scientific controversies and inform the design of new models to guide prevention and treatment. Nevertheless, public health action need not await resolution of this debate, as both models target processed carbohydrates as major drivers of obesity.

Cognitive dedifferentiation as a function of cognitive impairment in the ADNI and MemClin cohorts.

The cause of cognitive dedifferentiation has been suggested as specific to late-life abnormal cognitive decline rather than a general feature of aging. This hypothesis was tested in two large cohorts with different characteristics. Individuals (n = 2710) were identified in the Alzheimer's Disease Neuroimaging Initiative (ADNI) research database (n = 1282) in North America, and in the naturalistic multi-site MemClin Project database (n = 1223), the latter recruiting from 9 out of 10 memory clinics in the greater Stockholm catchment area in Sweden. Comprehensive neuropsychological testing informed diagnosis of dementia, mild cognitive impairment (MCI), or subjective cognitive impairment (SCI). Diagnosis was further collapsed into cognitive impairment (CI: MCI or dementia) vs no cognitive impairment (NCI). After matching, loadings on the first principal component were higher in the CI vs NCI group in both ADNI (53.1% versus 38.3%) and MemClin (33.3% vs 30.8%). Correlations of all paired combinations of individual tests by diagnostic group were also stronger in the CI group in both ADNI (mean inter-test r = 0.51 vs r = 0.33, p < 0.001) and MemClin (r = 0.31 vs r = 0.27, p = 0.042). Dedifferentiation was explained by cognitive impairment when controlling for age, sex, and education. This finding replicated across two separate, large cohorts of older individuals. Knowledge that the structure of human cognition becomes less diversified and more dependent on general intelligence as a function of cognitive impairment should inform clinical assessment and care for these patients as their neurodegeneration progresses.

Longitudinal deterioration of white-matter integrity: heterogeneity in the ageing population.

Deterioration in white-matter health plays a role in cognitive ageing. Our goal was to discern heterogeneity of white-matter tract vulnerability in ageing using longitudinal imaging data (two to five imaging and cognitive assessments per participant) from a population-based sample of 553 elderly participants (age ≥60 years). We found that different clusters (healthy white matter, fast white-matter decliners and intermediate white-matter group) were heterogeneous in the spatial distribution of white-matter integrity, systemic health and cognitive trajectories. White-matter health of specific tracts (genu of corpus callosum, posterior corona radiata and anterior internal capsule) informed about cluster assignments. Not surprisingly, brain amyloidosis was not significantly different between clusters. Clusters had differential white-matter tract vulnerability to ageing (commissural fibres > association/brainstem fibres). Identification of vulnerable white-matter tracts is a valuable approach to assessing risk for cognitive decline.

The cholinergic system in subtypes of Alzheimer's disease: an in vivo longitudinal MRI study.

BACKGROUND: The heterogeneity within Alzheimer's disease (AD) seriously challenges the development of disease-modifying treatments. We investigated volume of the basal forebrain, hippocampus, and precuneus in atrophy subtypes of AD and explored the relevance of subtype stratification in a small clinical trial on encapsulated cell biodelivery (ECB) of nerve growth factor (NGF) to the basal forebrain. METHODS: Structural MRI data was collected for 90 amyloid-positive patients and 69 amyloid-negative healthy controls at baseline, 6-, 12-, and 24-month follow-up. The effect of the NGF treatment was investigated in 10 biopsy-verified AD patients with structural MRI data at baseline and at 6- or 12-month follow-up. Patients were classified as typical, limbic-predominant, hippocampal-sparing, or minimal atrophy AD, using a validated visual assessment method. Volumetric analyses were performed using a region-of-interest approach. RESULTS: All AD subtypes showed reduced basal forebrain volume as compared with the healthy controls. The limbic-predominant subtype showed the fastest basal forebrain atrophy rate, whereas the minimal atrophy subtype did not show any significant volume decline over time. Atrophy rates of the hippocampus and precuneus also differed across subtypes. Our preliminary data from the small NGF cohort suggest that the NGF treatment seemed to slow the rate of atrophy in the precuneus and hippocampus in some hippocampal-sparing AD patients and in one typical AD patient. CONCLUSIONS: The cholinergic system is differentially affected in distinct atrophy subtypes of AD. Larger studies in the future should confirm that this differential involvement of the cholinergic system may contribute to subtype-specific response to cholinergic treatment. Our preliminary findings suggest that future clinical trials should target specific subtypes of AD, or at least report treatment effects stratified by subtype. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01163825. Registered 14 July 2010.

Brain Atrophy Subtypes and the ATN Classification Scheme in Alzheimer's Disease.

INTRODUCTION: We investigated the association between atrophy subtypes of Alzheimer's disease (AD), the ATN classification scheme, and key demographic and clinical factors in 2 cohorts with different source characteristics (a highly selective research-oriented cohort, the Alzheimer's Disease Neuroimaging Initiative [ADNI]; and a naturalistic heterogeneous clinically oriented cohort, Karolinska Imaging Dementia Study [KIDS]). METHODS: A total of 382 AD patients were included. Factorial analysis of mixed data was used to investigate associations between AD subtypes based on brain atrophy patterns, ATN profiles based on cerebrospinal fluid biomarkers, and age, sex, Mini Mental State Examination (MMSE), cerebrovascular disease (burden of white matter signal abnormalities, WMSAs), and APOE genotype. RESULTS: Older patients with high WMSA burden, belonging to the typical AD subtype and showing A+T+N+ or A+T+N- profiles clustered together and were mainly from ADNI. Younger patients with low WMSA burden, limbic-predominant or minimal atrophy AD subtypes, and A+T-N- or A+T-N+ profiles clustered together and were mainly from KIDS. APOE ε4 carriers more frequently showed the A+T-N- and A+T+N- profiles. CONCLUSIONS: Our findings align with the recent framework for biological subtypes of AD: the combination of risk factors, protective factors, and brain pathologies determines belonging of AD patients to distinct subtypes.

The MOPEAD project: Advancing patient engagement for the detection of "hidden" undiagnosed cases of Alzheimer's disease in the community.

In most, if not all health systems, dementia is underdiagnosed, and when diagnosis occurs, it is typically at a relatively late stage in the disease process despite mounting evidence showing that a timely diagnosis would result in numerous benefits for patients, families, and society. Moving toward earlier diagnoses in Alzheimer's disease (AD) requires a conscientious and collective effort to implement a global strategy addressing the multiple causes hindering patient engagement at different levels of society. This article describes the design of the Models of Patient Engagement for Alzheimer's Disease project, an ongoing EU-funded public-private multinational initiative that will compare four innovative patient engagement strategies across five European countries regarding their ability to identify individuals with prodromal AD and mild AD dementia, which are "hidden" in their communities and traditionally not found in the typical memory clinic setting. The strategies include an online AD citizen science platform, an open house initiative at the memory clinics, and patient engagement at primary care and diabetologist clinics.

A lifestyle intervention of weight loss via a low-carbohydrate diet plus walking to reduce metabolic disturbances caused by androgen deprivation therapy among prostate cancer patients: carbohydrate and prostate study 1 (CAPS1) randomized controlled trial.

PURPOSE: The objective of this study was to test a low-carbohydrate diet (LCD) plus walking to reduce androgen deprivation therapy (ADT)-induced metabolic disturbances. MATERIALS AND METHODS: This randomized multi-center trial of prostate cancer (PCa) patients initiating ADT was designed to compare an LCD (≤20g carbohydrate/day) plus walking (≥30 min for ≥5 days/week) intervention vs. control advised to maintain usual diet and exercise patterns. Primary outcome was change in insulin resistance by homeostatic model assessment at 6 months. To detect 20% reduction in insulin resistance, 100 men were required. The study was stopped early after randomizing 42 men due to slow accrual. Secondary outcomes included weight, body composition, lipids, and prostate-specific antigen (PSA). Changes from baseline were compared between arms using rank-sum tests. RESULTS: At 6 months, LCD/walking reduced insulin resistance by 4% vs. 36% increase in control (p = 0.13). At 3 months, vs. control, LCD/walking arm significantly lost weight (7.8kg; p<0.001), improved insulin resistance (↑36%; p = 0.015), hemoglobin A1c (↓3.3%; p = 0.01), high-density lipoprotein (HDL) (↑13%; p = 0.004), and triglyceride (↓37%; p = 0.036). At 6 months, weight loss (10.6kg; p<0.001) and HDL (↑27%; p = 0.003) remained significant. LCD/walking preserved total body bone mineral count (p = 0.025), reduced fat mass (p = 0.002), lean mass (p = 0.036), and percent body fat (p = 0.004). There were no differences in PSA. Limitations include the effect of LCD, weight loss vs. walking instruction are indistinguishable, and small sample size. CONCLUSIONS: In an underpowered study, LCD/walking did not improve insulin sensitivity at 6 months. Given most secondary outcomes were improved at 3 months with some remaining improved at 6 months and a secondary analysis showed that LCD/walking reduced insulin resistance over the study, supporting future larger studies of LCD/walking intervention to reduce ADT-induced disturbances.

American Society of Clinical Oncology Summit on Addressing Obesity Through Multidisciplinary Provider Collaboration: Key Findings and Recommendations for Action.

OBJECTIVE: Given the increasing evidence that obesity increases the risk of developing and dying from malignancy, the American Society of Clinical Oncology (ASCO) launched an Obesity Initiative in 2013 that was designed to increase awareness among oncology providers and the general public of the relationship between obesity and cancer and to promote research in this area. Recognizing that the type of societal change required to impact the obesity epidemic will require a broad-based effort, ASCO hosted the "Summit on Addressing Obesity through Multidisciplinary Collaboration" in 2016. METHODS: This meeting was held to review current challenges in addressing obesity within the respective health care provider communities and to identify priorities that would most benefit from a collective and cross-disciplinary approach. RESULTS: Efforts focused on four key areas: provider education and training; public education and activation; research; and policy and advocacy. Summit attendees discussed current challenges in addressing obesity within their provider communities and identified priorities that would most benefit from multidisciplinary collaboration. CONCLUSIONS: A synopsis of recommendations to facilitate future collaboration, as well as examples of ongoing cooperative efforts, provides a blueprint for multidisciplinary provider collaboration focused on obesity prevention and treatment.

27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation.

Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory. Furthermore, patients exhibiting higher 27-OH levels had reduced 18F-fluorodeoxyglucose uptake. This interplay between 27-OH and glucose uptake revealed the engagement of the insulin-regulated aminopeptidase (IRAP). 27-OH increased the levels and activity of IRAP, countered the IRAP antagonist angiotensin IV (AngIV)-mediated glucose uptake, and enhanced the levels of the AngIV-degrading enzyme aminopeptidase N (AP-N). These effects were mediated by liver X receptors. Our results reveal a molecular link between cholesterol, brain glucose, and the brain renin-angiotensin system, all of which are affected in some neurodegenerative diseases. Thus, reducing 27-OH levels or inhibiting AP-N maybe a useful strategy in the prevention of the altered glucose metabolism and memory decline in these disorders.

Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer's disease patients: application of a second-generation encapsulated cell biodelivery device.

BACKGROUND: Targeted delivery of nerve growth factor (NGF) has emerged as a potential therapy for Alzheimer's disease (AD) due to its regenerative effects on basal forebrain cholinergic neurons. This hypothesis has been tested in patients with AD using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-human study. We report our results from a third-dose cohort of patients receiving second-generation NGF-ECB implants with improved NGF secretion. METHODS: Four patients with mild to moderate AD were recruited to participate in an open-label, phase Ib dose escalation study with a 6-month duration. Each patient underwent stereotactic implant surgery with four NGF-ECB implants targeted at the cholinergic basal forebrain. The NGF secretion of the second-generation implants was improved by using the Sleeping Beauty transposon gene expression technology and an improved three-dimensional internal scaffolding, resulting in production of about 10 ng NGF/device/day. RESULTS: All patients underwent successful implant procedures without complications, and all patients completed the study, including implant removal after 6 months. Upon removal, 13 of 16 implants released NGF, 8 implants released NGF at the same rate or higher than before the implant procedure, and 3 implants failed to release detectable amounts of NGF. Of 16 adverse events, none was NGF-, or implant-related. Changes from baseline values of cholinergic markers in cerebrospinal fluid (CSF) correlated with cortical nicotinic receptor expression and Mini Mental State Examination score. Levels of neurofilament light chain (NFL) protein increased in CSF after NGF-ECB implant, while glial fibrillary acidic protein (GFAP) remained stable. CONCLUSIONS: The data derived from this patient cohort demonstrate the safety and tolerability of sustained NGF release by a second-generation NGF-ECB implant to the basal forebrain, with uneventful surgical implant and removal of NGF-ECB implants in a new dosing cohort of four patients with AD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01163825 . Registered on 14 Jul 2010.

Lipids and bariatric procedures Part 2 of 2: scientific statement from the American Society for Metabolic and Bariatric Surgery (ASMBS), the National Lipid Association (NLA), and Obesity Medicine Association (OMA).

Bariatric procedures generally improve dyslipidemia, sometimes substantially so. Bariatric procedures also improve other major cardiovascular risk factors. This 2-part Scientific Statement examines the lipid effects of bariatric procedures and reflects contributions from authors representing the American Society for Metabolic and Bariatric Surgery (ASMBS), the National Lipid Association (NLA), and the Obesity Medicine Association (OMA). Part 1 was published in the Journal of Clinical Lipidology, and reviewed the impact of bariatric procedures upon adipose tissue endocrine and immune factors, adipose tissue lipid metabolism, as well as the lipid effects of bariatric procedures relative to bile acids and intestinal microbiota. This Part 2 reviews: (1) the importance of nutrients (fats, carbohydrates, and proteins) and their absorption on lipid levels; (2) the effects of bariatric procedures on gut hormones and lipid levels; (3) the effects of bariatric procedures on nonlipid cardiovascular disease (CVD) risk factors; (4) the effects of bariatric procedures on lipid levels; (5) effects of bariatric procedures on CVD; and finally, (6) the potential lipid effects of vitamin, mineral, and trace element deficiencies, that may occur after bariatric procedures.

Lipids and bariatric procedures part 1 of 2: Scientific statement from the National Lipid Association, American Society for Metabolic and Bariatric Surgery, and Obesity Medicine Association: EXECUTIVE SUMMARY.

Bariatric procedures often improve lipid levels in patients with obesity. This 2-part scientific statement examines the potential lipid benefits of bariatric procedures and represents contributions from authors representing the National Lipid Association, American Society for Metabolic and Bariatric Surgery, and the Obesity Medicine Association. The foundation for this scientific statement was based on data published through June 2015. Part 1 of this 2-part scientific statement provides an overview of: (1) adipose tissue, cholesterol metabolism, and lipids; (2) bariatric procedures, cholesterol metabolism, and lipids; (3) endocrine factors relevant to lipid influx, synthesis, metabolism, and efflux; (4) immune factors relevant to lipid influx, synthesis, metabolism, and efflux; (5) bariatric procedures, bile acid metabolism, and lipids; and (6) bariatric procedures, intestinal microbiota, and lipids, with specific emphasis on how the alterations in the microbiome by bariatric procedures influence obesity, bile acids, and inflammation, which in turn, may all affect lipid levels. Included in part 2 of this comprehensive scientific statement will be a review of: (1) the importance of nutrients (fats, carbohydrates, and proteins) and their absorption on lipid levels; (2) the effects of bariatric procedures on gut hormones and lipid levels; (3) the effects of bariatric procedures on nonlipid cardiovascular disease risk factors; (4) the effects of bariatric procedures on lipid levels; (5) effects of bariatric procedures on cardiovascular disease; and finally (6) the potential lipid effects of vitamin, mineral, and trace element deficiencies that may occur after bariatric procedures. This document represents the executive summary of part 1.

Lipids and bariatric procedures part 1 of 2: Scientific statement from the National Lipid Association, American Society for Metabolic and Bariatric Surgery, and Obesity Medicine Association: FULL REPORT.

Bariatric procedures often improve lipid levels in patients with obesity. This 2 part scientific statement examines the potential lipid benefits of bariatric procedures and represents the contributions from authors representing the National Lipid Association, American Society for Metabolic and Bariatric Surgery, and the Obesity Medicine Association. The foundation for this scientific statement was based on published data through June 2015. Part 1 of this 2 part scientific statement provides an overview of: (1) adipose tissue, cholesterol metabolism, and lipids; (2) bariatric procedures, cholesterol metabolism, and lipids; (3) endocrine factors relevant to lipid influx, synthesis, metabolism, and efflux; (4) immune factors relevant to lipid influx, synthesis, metabolism, and efflux; (5) bariatric procedures, bile acid metabolism, and lipids; and (6) bariatric procedures, intestinal microbiota, and lipids, with specific emphasis on how the alterations in the microbiome by bariatric procedures influence obesity, bile acids, and inflammation, which in turn, may all affect lipid levels. Included in part 2 of this comprehensive scientific statement will be a review of (1) the importance of nutrients (fats, carbohydrates, and proteins) and their absorption on lipid levels; (2) the effects of bariatric procedures on gut hormones and lipid levels; (3) the effects of bariatric procedures on nonlipid cardiovascular disease (CVD) risk factors; (4) the effects of bariatric procedures on lipid levels; (5) effects of bariatric procedures on CVD; and finally, (6) the potential lipid effects of vitamin, mineral, and trace element deficiencies that may occur after bariatric procedures. This document represents the full report of part 1.

The effects of nicotine and non-nicotine smoking factors on working memory and associated brain function.

Smoking abstinence impairs executive function, which may promote continued smoking behavior and relapse. The differential influence of nicotine and non-nicotine (i.e. sensory, motor) smoking factors and related neural substrates is not known. In a fully factorial, within-subjects design, 33 smokers underwent fMRI scanning following 24 hours of wearing a nicotine or placebo patch while smoking very low nicotine content cigarettes or remaining abstinent from smoking. During scanning, blood oxygenation level-dependent (BOLD) signal was acquired while participants performed a verbal N-back task. Following 24-hour placebo (versus nicotine) administration, accuracy on the N-back task was significantly worse and task-related BOLD signal lower in dorsomedial frontal cortex. These effects were observed irrespective of smoking. Our data provide novel evidence that abstinence-induced deficits in working memory and changes in underlying brain function are due in large part to abstinence from nicotine compared with non-nicotine factors. This work has implications both for designing interventions that target abstinence-induced cognitive deficits and for nicotine-reduction policy.

Automated CT-based segmentation and quantification of total intracranial volume.

OBJECTIVES: To develop an algorithm to segment and obtain an estimate of total intracranial volume (tICV) from computed tomography (CT) images. MATERIALS AND METHODS: Thirty-six CT examinations from 18 patients were included. Ten patients were examined twice the same day and eight patients twice six months apart (these patients also underwent MRI). The algorithm combines morphological operations, intensity thresholding and mixture modelling. The method was validated against manual delineation and its robustness assessed from repeated imaging examinations. Using automated MRI software, the comparability with MRI was investigated. Volumes were compared based on average relative volume differences and their magnitudes; agreement was shown by a Bland-Altman analysis graph. RESULTS: We observed good agreement between our algorithm and manual delineation of a trained radiologist: the Pearson's correlation coefficient was r = 0.94, tICVml[manual] = 1.05 × tICVml[automated] - 33.78 (R(2) = 0.88). Bland-Altman analysis showed a bias of 31 mL and a standard deviation of 30 mL over a range of 1265 to 1526 mL. CONCLUSIONS: tICV measurements derived from CT using our proposed algorithm have shown to be reliable and consistent compared to manual delineation. However, it appears difficult to directly compare tICV measures between CT and MRI. KEY POINTS: • Automated estimation of tICV is in good agreement with manual tracing. • Consistent tICV estimations from repeated measurements demonstrate the robustness of the algorithm. • Automatically segmented volumes seem less variable than those from manual tracing. • Unbiased and automated tlCV estimation is possible from CT.

Nicotine and non-nicotine smoking factors differentially modulate craving, withdrawal and cerebral blood flow as measured with arterial spin labeling.

Smoking cessation results in withdrawal symptoms such as craving and negative mood that may contribute to lapse and relapse. Little is known regarding whether these symptoms are associated with the nicotine or non-nicotine components of cigarette smoke. Using arterial spin labeling, we measured resting-state cerebral blood flow (CBF) in 29 adult smokers across four conditions: (1) nicotine patch+denicotinized cigarette smoking, (2) nicotine patch+abstinence from smoking, (3) placebo patch+denicotinized cigarette smoking, and (4) placebo patch+abstinence from smoking. We found that changes in self-reported craving positively correlated with changes in CBF from the denicotinized cigarette smoking conditions to the abstinent conditions. These correlations were found in several regions throughout the brain. Self-reported craving also increased from the nicotine to the placebo conditions, but had a minimal relationship with changes in CBF. The results of this study suggest that the non-nicotine components of cigarette smoke significantly impact withdrawal symptoms and associated brain areas, independently of the effects of nicotine. As such, the effects of non-nicotine factors are important to consider in the design and development of smoking cessation interventions and tobacco regulation.

Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology.

Blood proteins and their complexes have become the focus of a great deal of interest in the context of their potential as biomarkers of Alzheimer's disease (AD). We used a SOMAscan assay for quantifying 1001 proteins in blood samples from 331 AD, 211 controls, and 149 mild cognitive impaired (MCI) subjects. The strongest associations of protein levels with AD outcomes were prostate-specific antigen complexed to α1-antichymotrypsin (AD diagnosis), pancreatic prohormone (AD diagnosis, left entorhinal cortex atrophy, and left hippocampus atrophy), clusterin (rate of cognitive decline), and fetuin B (left entorhinal atrophy). Multivariate analysis found that a subset of 13 proteins predicted AD with an accuracy of area under the curve of 0.70. Our replication of previous findings provides further evidence that levels of these proteins in plasma are truly associated with AD. The newly identified proteins could be potential biomarkers and are worthy of further investigation.