Neuroimaging measures and chemical biomarkers may be important indices of clinical progression in normal aging and mild cognitive impairment (MCI) and need to be evaluated longitudinally.
To ...characterize cross-sectionally and longitudinally clinical measures in normal controls, subjects with MCI, and subjects with mild Alzheimer disease (AD) to enable the assessment of the utility of neuroimaging and chemical biomarker measures.
A total of 819 subjects (229 cognitively normal, 398 with MCI, and 192 with AD) were enrolled at baseline and followed for 12 months using standard cognitive and functional measures typical of clinical trials.
The subjects with MCI were more memory impaired than the cognitively normal subjects but not as impaired as the subjects with AD. Nonmemory cognitive measures were only minimally impaired in the subjects with MCI. The subjects with MCI progressed to dementia in 12 months at a rate of 16.5% per year. Approximately 50% of the subjects with MCI were on antidementia therapies. There was minimal movement on the Alzheimer's Disease Assessment Scale-Cognitive Subscale for the normal control subjects, slight movement for the subjects with MCI of 1.1, and a modest change for the subjects with AD of 4.3. Baseline CSF measures of Abeta-42 separated the 3 groups as expected and successfully predicted the 12-month change in cognitive measures.
The Alzheimer's Disease Neuroimaging Initiative has successfully recruited cohorts of cognitively normal subjects, subjects with mild cognitive impairment (MCI), and subjects with Alzheimer disease with anticipated baseline characteristics. The 12-month progression rate of MCI was as predicted, and the CSF measures heralded progression of clinical measures over 12 months.
To investigate the neurocognitive measures that best predict progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD).
We evaluated 539 participants with aMCI from the ...Alzheimer's Disease Cooperative Study clinical drug trial of donepezil, vitamin E, or placebo. During the study period of 36 months, 212 aMCI participants progressed to AD. Using progression from aMCI to AD within 36 months as the dependent variable, a generalized linear model was fit to the data using the least absolute shrinkage and selection operator. Independent variables included in this analysis were age, sex, education, APOE-e4 (APOE4) status, family history of dementia, Mini-Mental State Examination score, Digits Backwards (Wechsler Memory Scale), Maze Time and Errors, Number Cancellation, Delayed Recall of Alzheimer's Disease Assessment Scale Word List, New York University Paragraph Recall Test (Immediate and Delayed), Boston Naming Test, Category Fluency, Clock Drawing Test, and the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog).
The model that best predicted progression from aMCI to AD over 36 months included APOE4 status, the Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), and the ADAS-cog total score. When APOE4 was removed from the analysis the resulting model had a similar estimated predictive accuracy as the full model. As determined by cross-validation, the estimated predictive accuracy of the final model was 80%.
Progression from amnestic mild cognitive impairment to Alzheimer disease in this cohort was best determined by combining four common, easily administered, cognitive measures.
To compare volumetric MRI of whole brain and medial temporal lobe structures to clinical measures for predicting progression from amnestic mild cognitive impairment (MCI) to Alzheimer disease (AD).
...Baseline MRI scans from 129 subjects with amnestic MCI were obtained from participants in the Alzheimer's Disease Cooperative Study group's randomized, placebo-controlled clinical drug trial of donepezil, vitamin E, or placebo. Measures of whole brain, ventricular, hippocampal, and entorhinal cortex volumes were acquired. Participants were followed with clinical and cognitive evaluations until formal criteria for AD were met, or completion of 36 months of follow-up. Logistic regression modeling was done to assess the predictive value of all MRI measures, risk factors such as APOE genotype, age, family history of AD, education, sex, and cognitive test scores for progression to AD. Least angle regression modeling was used to determine which variables would produce an optimal predictive model, and whether adding MRI measures to a model with only clinical measures would improve predictive accuracy.
Of the four MRI measures evaluated, only ventricular volumes and hippocampal volumes were predictive of progression to AD. Maximal predictive accuracy using only MRI measures was obtained by hippocampal volumes by themselves (60.4%). When clinical variables were added to the model, the predictive accuracy increased to 78.8%. Use of MRI measures did not improve predictive accuracy beyond that obtained by cognitive measures alone. APOE status, MRI, or demographic variables were not necessary for the optimal predictive model. This optimal model included the Delayed 10-word list recall, New York University Delayed Paragraph Recall, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale total score.
In moderate stages of amnestic mild cognitive impairment, common cognitive tests provide better predictive accuracy than measures of whole brain, ventricular, entorhinal cortex, or hippocampal volumes for assessing progression to Alzheimer disease.
We consider the Bayesian analysis of a few complex, highdimensional models and show that intuitive priors, which are not tailored to the fine details of the model and the estimated parameters, ...produce estimators which perform poorly in situations in which good, simple frequentisi estimators exist. The models we consider are: stratified sampling, the partial linear model, linear and quadratic functionals of white noise and estimation with stopping times. We present a strong version of Doob's consistency theorem which demonstrates that the existence of a uniformly $\sqrt n $-consistent estimator ensures that the Bayes posterior is $\sqrt n $-oensistent for values of the parameter in subsets of prior probability 1. We also demonstrate that it is, at least, in principle, possible to construct Bayes priors giving both global and local minimax rates, using a suitable combination of loss functions. We argue that there is no contradiction in these apparently conflicting findings.
To determine the safety and efficacy of 2 dose formulations of melatonin for the treatment of insomnia in patients with Alzheimer's disease.
A multicenter, randomized, placebo-controlled clinical ...trial of 2 dose formulations of oral melatonin coordinated by the National Institute of Aging-funded Alzheimer's Disease Cooperative Study. Subjects with Alzheimer's disease and nighttime sleep disturbance were randomly assigned to 1 of 3 treatment groups: placebo, 2.5-mg slow-release melatonin, or 10-mg melatonin.
Private homes and long-term care facilities.
157 individuals were recruited by 36 Alzheimer's disease research centers. Subjects with a diagnosis of Alzheimer's disease were eligible if they averaged less than 7 hours of sleep per night (as documented by wrist actigraphy) and had 2 or more episodes per week of nighttime awakenings reported by the caregiver.
Nocturnal total sleep time, sleep efficiency, wake-time after sleep onset, and day-night sleep ratio during 2- to 3-week baseline and 2-month treatment periods. Sleep was defined by an automated algorithmic analysis of wrist actigraph data.
No statistically significant differences in objective sleep measures were seen between baseline and treatment periods for the any of the 3 groups. Nonsignificant trends for increased nocturnal total sleep time and decreased wake after sleep onset were observed in the melatonin groups relative to placebo. Trends for a greater percentage of subjects having more than a 30-minute increase in nocturnal total sleep time in the 10-mg melatonin group and for a decline in the day-night sleep ratio in the 2.5-mg sustained-release melatonin group, compared to placebo, were also seen. On subjective measures, caregiver ratings of sleep quality showed improvement in the 2.5-mg sustained-release melatonin group relative to placebo. There were no significant differences in the number or seriousness of adverse events between the placebo and melatonin groups.
Based on actigraphy as an objective measure of sleep time, melatonin is not an effective soporific agent in people with Alzheimer's disease.
To investigate the regional pattern of white matter and cerebellar changes, as well as subcortical and cortical changes, in Huntington disease (HD) using morphometric analyses of structural MRI.
...Fifteen individuals with HD and 22 controls were studied; groups were similar in age and education. Primary analyses defined six subcortical regions, the gray and white matter of primary cortical lobes and cerebellum, and abnormal signal in the cerebral white matter.
As expected, basal ganglia and cerebral cortical gray matter volumes were significantly smaller in HD. The HD group also demonstrated significant cerebral white matter loss and an increase in the amount of abnormal signal in the white matter; occipital white matter appeared more affected than other cerebral white matter regions. Cortical gray and white matter measures were significantly related to caudate volume. Cerebellar gray and white matter volumes were both smaller in HD.
The cerebellum and the integrity of cerebral white matter may play a more significant role in the symptomatology of HD than previously thought. Furthermore, changes in cortical gray and cerebral white matter were related to caudate atrophy, supporting a similar mechanism of degeneration.
To identify the sources of HIV virions in CSF by modeling treatment-associated HIV dynamics.
We postulated a model in which cell-free CSF virions originate from two major sources, namely, systemic ...non-CNS and CNS tissues, the latter including brain parenchyma and meninges. The model predicted that with initiation of antiretroviral therapy, the acute-phase decline in CSF HIV RNA levels would be controlled by the kinetics of the dominant virion source (systemic versus CNS). Based on prior observations, we hypothesized that the dominant source of CSF virions would shift from systemic to CNS in more advanced disease.
Three patient groups were studied: Group 1 (n = 5): nondemented, with early HIV disease (CD4+ lymphocytes > or = 400/microL) or pleocytosis (CSF leukocytes > or = 4/microL); Group 2 (n = 5): nondemented, with advanced HIV disease (CD4+ < 400/microL) and no pleocytosis; Group 3 (n = 2): patients with HIV-associated dementia (HAD). All patients began a new, highly active antiretroviral treatment regimen and underwent serial lumbar punctures and phlebotomies.
For patients in Group 2, the rate of decline in CSF HIV RNA was slower than in plasma (p < 0.00001). For Group 1, the rate of decline in CSF was not different from plasma (p > 0.25). Patients with HAD showed high CSF HIV RNA after 5 to 6 weeks of treatment despite a 100-fold decrease in plasma HIV RNA.
CSF and plasma HIV dynamics became increasingly independent in advanced HIV disease, and the compartmental discrepancy was largest in HAD. Our findings suggest that viral replication in CNS tissues may constitute a major, independent source of CSF HIV RNA. In patients with HAD, brain parenchyma itself may be the principal CNS tissue source, and CNS-targeted treatment strategies may be required to eradicate this infection.
Aim To investigate the relationship between bone marrow fat content and hepatic fat content in children with known or suspected non-alcoholic fatty liver disease (NAFLD). Materials and methods This ...was an institutional review board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant, cross-sectional, prospective analysis of data collected between October 2010 to March 2013 in 125 children with known or suspected NAFLD. Written informed consent was obtained for same-day research magnetic resonance imaging (MRI) of the lumbar spine, liver, and abdominal adiposity. Lumbar spine bone marrow proton density fat fraction (PDFF) and hepatic PDFF were estimated using complex-based MRI (C-MRI) techniques and magnitude-based MRI (M-MRI), respectively. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SCAT) were quantified using high-resolution MRI. All images were acquired by two MRI technologists. Hepatic M-MRI images were analysed by an image analyst; all other images were analysed by a single investigator. The relationship between lumbar spine bone marrow PDFF and hepatic PDFF was assessed with and without adjusting for the presence of covariates using correlation and regression analysis. Results Lumbar spine bone marrow PDFF was positively associated with hepatic PDFF in children with known or suspected NAFLD prior to adjusting for covariates ( r =0.33, p =0.0002). Lumbar spine bone marrow PDFF was positively associated with hepatic PDFF in children with known or suspected NAFLD ( r =0.24, p =0.0079) after adjusting for age, sex, body mass index z -score, VAT, and SCAT in a multivariable regression analysis. Conclusion Bone marrow fat content is positively associated with hepatic fat content in children with known or suspected NAFLD. Further research is needed to confirm these results and understand their clinical and biological implications.
Normal volunteers, aged 30 to 99 years, were studied with MRI. Age was related to estimated volumes of: gray matter, white matter, and CSF of the cerebrum and cerebellum; gray matter, white matter, ...white matter abnormality, and CSF within each cerebral lobe; and gray matter of eight subcortical structures. The results were: 1) Age-related losses in the hippocampus were significantly accelerated relative to gray matter losses elsewhere in the brain. 2) Among the cerebral lobes, the frontal lobes were disproportionately affected by cortical volume loss and increased white matter abnormality. 3) Loss of cerebral and cerebellar white matter occurred later than, but was ultimately greater than, loss of gray matter. It is estimated that between the ages of 30 and 90 volume loss averages 14% in the cerebral cortex, 35% in the hippocampus, and 26% in the cerebral white matter. Separate analyses were conducted in which genetic risk associated with the Apolipoprotein E ϵ4 allele was either overrepresented or underrepresented among elderly participants. Accelerated loss of hippocampal volume was observed with both analyses and thus does not appear to be due to the presence of at-risk subjects. MR signal alterations in the tissues of older individuals pose challenges to the validity of current methods of tissue segmentation, and should be considered in the interpretation of the results.
Background:Swedish male smokers are more likely than female smokers to switch to smokeless tobacco (snus) and males’ smoking cessation rate is higher than that of females. These results have fuelled ...international debate over promoting smokeless tobacco for harm reduction. This study examines whether similar results emerge in the United States, one of few other western countries where smokeless tobacco has long been widely available.Methods:US data source: national sample in Tobacco Use Supplement to Current Population Survey, 2002, with 1-year follow-up in 2003. Analyses included adult self-respondents in this longitudinal sample (n = 15 056). Population-weighted rates of quitting smoking and switching to smokeless tobacco were computed for the 1-year period.Results:Among US men, few current smokers switched to smokeless tobacco (0.3% in 12 months). Few former smokers turned to smokeless tobacco (1.7%). Switching between cigarettes and smokeless tobacco, infrequent among current tobacco users (<4%), was more often from smokeless to smoking. Men quit smokeless tobacco at three times the rate of quitting cigarettes (38.8% vs 11.6%, p<0.001). Overall, US men have no advantage over women in quitting smoking (11.7% vs 12.4%, p = 0.65), even though men are far likelier to use smokeless tobacco.Conclusion:The Swedish results are not replicated in the United States. Both male and female US smokers appear to have higher quit rates for smoking than have their Swedish counterparts, despite greater use of smokeless tobacco in Sweden. Promoting smokeless tobacco for harm reduction in countries with ongoing tobacco control programmes may not result in any positive population effect on smoking cessation.
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