A Two-Study Comparison of Clinical and MRI Markers of Transition from Mild Cognitive Impairment to Alzheimer's Disease

A published predictor model in a single-site cohort study (questionable dementia, QD) that contained episodic verbal memory (SRT total recall), informant report of function (FAQ), and MRI measures was tested using logistic regression and ROC analyses with comparable measures in a second multisite cohort study (Alzheimer's Disease Neuroimaging Initiative, ADNI). There were 126 patients in QD and 282 patients in ADNI with MCI followed for 3 years. Within each sample, the differences in AUCs between the statistical models were very similar. Adding hippocampal and entorhinal cortex volumes to the model containing AVLT/SRT, FAQ, age and MMSE increased the area under the curve (AUC) in ADNI but not QD, with sensitivity increasing by 2% in ADNI and 2% in QD for a fixed specificity of 80%. Conversely, adding episodic verbal memory (SRT/AVLT) and FAQ to the model containing age, Mini Mental State Exam (MMSE), hippocampal and entorhinal cortex volumes increased the AUC in ADNI and QD, with sensitivity increasing by 17% in ADNI and 10% in QD for 80% specificity. The predictor models showed similar differences from each other in both studies, supporting independent validation. MRI hippocampal and entorhinal cortex volumes showed limited added predictive utility to memory and function measures

Sertraline Treatment of Elderly Patients with Depression and Cognitive Impairment

Background There is little information on the efficacy and side effects of antidepressant treatment in elderly patients with combined depression and cognitive impairment without dementia (DEP-MCI), and it is unclear if cognitive performance improves with antidepressant response in these patients. Methods In 39 elderly DEP-MCI patients, changes in depression and cognitive impairment were evaluated with open sertraline treatment up to 200 mg/day for 12 weeks. Results Of the 26 completers, 17 were responders and nine were non-responders. Diagnostic subtype of depression was unrelated to response. ANCOVA on WAIS-R digit symbol percent change scores revealed a significant effect for responder status (F = 5.59, p < 0.03), and age (F = 0.24, p < 0.64) and education (F = 1.64, p < 0.22) were not significant covariates. From pre-trial to post-trial, responders improved in WAIS-R digit symbol percent change scores (Mean −10% SD 24) while non-responders declined (Mean 14% SD 18; t = 2.60, p < 0.02). Other neuropsychological measures were unrelated to response. Percent change in HRSD scores showed significant inverse correlations with percent change in several cognitive measures. Conclusions DEP-MCI patients showed moderate clinical response to sertraline treatment. When responders were compared to non-responders, cognitive improvement was limited to one measure of attention and executive function. Overall, there was little cognitive improvement with antidepressant treatment. The findings indirectly suggest that lack of improvement in cognition following treatment of depression in DEP-MCI patients may be associated with increased risk of meeting diagnostic criteria for dementia during follow-up

Functional Deficits in Patients with Mild Cognitive Impairment: Prediction of Ad

Objective: To evaluate the predictive utility of self-reported and informant-reported functional deficits in patients with mild cognitive impairment (MCI) for the follow-up diagnosis of probable AD. Methods: The Pfeffer Functional Activities Questionnaire (FAQ) and Lawton Instrumental Activities of Daily Living (IADL) Scale were administered at baseline. Patients were followed at 6-month intervals, and matched normal control subjects (NC) were followed annually. Results: Self-reported deficits were higher for patients with MCI than for NC. At baseline, self- and informant-reported functional deficits were significantly greater for patients who converted to AD on follow-up evaluation than for patients who did not convert, even after controlling for age, education, and modified Mini-Mental State Examination scores. While converters showed significantly more informant- than self-reported deficits at baseline, nonconverters showed the reverse pattern. Survival analyses further revealed that informant-reported deficits (but not self-reported deficits) and a discrepancy score indicating greater informant- than self-reported functional deficits significantly predicted the development of AD. The discrepancy index showed high specificity and sensitivity for progression to AD within 2 years. Conclusions: These findings indicate that in patients with MCI, the patient's lack of awareness of functional deficits identified by informants strongly predicts a future diagnosis of AD. If replicated, these findings suggest that clinicians evaluating MCI patients should obtain both self-reports and informant reports of functional deficits to help in prediction of long-term outcome

Cost-Effectiveness Analysis of Tdap in the Prevention of Pertussis in the Elderly

Objectives: Health benefits and costs of combined reduced-antigen-content tetanus, diphtheria, and pertussis (Tdap) immunization among adults ≥65 years have not been evaluated. In February 2012, the Advisory Committee on Immunization Practices (ACIP) recommended expanding Tdap vaccination (one single dose) to include adults ≥65 years not previously vaccinated with Tdap. Our study estimated the health and economic outcomes of one-time replacement of the decennial tetanus and diphtheria (Td) booster with Tdap in the 10% of individuals aged 65 years assumed eligible each year compared with a baseline scenario of continued Td vaccination. Methods: We constructed a model evaluating the cost-effectiveness of vaccinating a cohort of adults aged 65 with Tdap, by calculating pertussis cases averted due to direct vaccine effects only. Results are presented from societal and payer perspectives for a range of pertussis incidences (25–200 cases per 100,000), due to the uncertainty in estimating true annual incidence. Cases averted were accrued throughout the patient 's lifetime, and a probability tree used to estimate the clinical outcomes and costs (US$2010) for each case. Quality-adjusted life-years (QALYs) lost to acute disease were calculated by multiplying cases of mild/moderate/severe pertussis by the associated health-state disutility; QALY losses due to death and long-term sequelae were also considered. Incremental costs and QALYs were summed over the cohort to derive incremental cost-effectiveness ratios. Scenario analyses evaluated the effect of alternative plausible parameter estimates on results. Results: At incidence levels of 25, 100, 200 cases/100,000, vaccinating adults aged 65 years costs an additional$336,000, $63,000 and$17,000/QALY gained, respectively. Vaccination has a cost-effectiveness ratio less than $50,000/QALY if pertussis incidence is >116 cases/100,000 from societal and payer perspectives. Results were robust to scenario analyses. Conclusions: Tdap immunization of adults aged 65 years according to current ACIP recommendations is a cost-effective health-care intervention at plausible incidence assumptions

Cost-Effectiveness of Tdap Vaccination of Adults Aged ≥65 Years in the Prevention of Pertussis in the US: A Dynamic Model of Disease Transmission

Objectives: In February 2012, the Advisory Committee on Immunization Practices (ACIP) advised that all adults aged ≥65 years receive a single dose of reduced-antigen-content tetanus, diphtheria, and acellular pertussis (Tdap), expanding on a 2010 recommendation for adults >65 that was limited to those with close contact with infants. We evaluated clinical and economic outcomes of adding Tdap booster of adults aged ≥65 to “baseline” practice [full-strength DTaP administered from 2 months to 4–6 years, and one dose of Tdap at 11–64 years replacing decennial Td booster], using a dynamic model. Methods: We constructed a population-level disease transmission model to evaluate the cost-effectiveness of supplementing baseline practice by vaccinating 10% of eligible adults aged ≥65 with Tdap replacing the decennial Td booster. US population effects, including indirect benefits accrued by unvaccinated persons, were estimated during a 1-year period after disease incidence reached a new steady state, with consequences of deaths and long-term pertussis sequelae projected over remaining lifetimes. Model outputs include: cases by severity, encephalopathy, deaths, costs (of vaccination and pertussis care) and quality-adjusted life-years (QALYs) associated with each strategy. Results in terms of incremental cost/QALY gained are presented from payer and societal perspectives. Sensitivity analyses vary key parameters within plausible ranges. Results: For the US population, the intervention is expected to prevent >97,000 cases (>4,000 severe and >5,000 among infants) of pertussis annually at steady state. Additional vaccination costs are $4.7 million. Net cost savings, including vaccination costs, are$47.7 million (societal perspective) and $44.8 million (payer perspective). From both perspectives, the intervention strategy is dominant (less costly, and more effective by >3,000 QALYs) versus baseline. Results are robust to sensitivity analyses and alternative scenarios. Conclusions: Immunization of eligible adults aged ≥65, consistent with the current ACIP recommendation, is cost saving from both payer and societal perspectives

PET Network Abnormalities and Cognitive Decline in Patients with Mild Cognitive Impairment

Temporoparietal and posterior cingulate metabolism deficits characterize patients with Alzheimer's disease (AD). A H(2)(15)O resting PET scan covariance pattern, derived by using multivariate techniques, was previously shown to discriminate 17 mild AD patients from 16 healthy controls. This AD covariance pattern revealed hypoperfusion in bilateral inferior parietal lobule and cingulate; and left middle frontal, inferior frontal, precentral, and supramarginal gyri. The AD pattern also revealed hyperperfusion in bilateral insula, lingual gyri, and cuneus; left fusiform and superior occipital gyri; and right parahippocampal gyrus and pulvinar. In an independent sample of 23 outpatients with mild cognitive impairment (MCI) followed at 6-month intervals, the AD pattern score was evaluated as a predictor of cognitive decline. In this MCI sample, an H2(15)O resting PET scan was carried out at baseline. Mean duration of follow-up was 48.8 (SD 15.5) months, during which time six of 23 MCI patients converted to AD. In generalized estimating equations (GEE) analyses, controlling for age, sex, education, and baseline neuropsychological scores, increased AD pattern score was associated with greater decline in each neuropsychological test score over time (Mini Mental State Exam, Selective Reminding Test delayed recall, Animal Naming, WAIS-R digit symbol; Ps<0.01-0.001). In summary, a resting PET covariance pattern previously reported to discriminate AD patients from control subjects was applied prospectively to an independent sample of MCI patients and found to predict cognitive decline. Independent replication in larger samples is needed before clinical application can be considere

Covariance PET Patterns in Early Alzheimer's Disease and Subjects with Cognitive Impairment but No Dementia: Utility in Group Discrimination and Correlations with Functional Performance

Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimer's disease (AD) or cognitive impairment. Nonquantitative H2(15)O PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Noxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, P = 0.002), delayed recall (r = -0.351, P = 0.008) and mMMS scores (r = -0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes

Association of Obstructive Sleep Apnea with Episodic Memory and Cerebral Microvascular Pathology: A Preliminary Study

Objectives: To evaluate the impact of obstructive sleep apnea (OSA) on neurocognitive function and brain morphology in older adults with depression and cognitive impairment. Methods: We prospectively screened OSA with the STOP-Bang questionnaire in the last 25 patients enrolled into the Donepezil Treatment of Cognitive Impairment and Depression (DOTCODE) trial. High and low probability of OSA were defined as a STOP-Bang score of ≥5 (h-OSA) and of <5 (l-OSA), respectively. Baseline magnetic resonance imaging (MRI) was used to evaluate brain morphology. The initial 16 weeks of antidepressant treatment were part of the DOTCODE trial. Results: After 16 weeks of antidepressant treatment, the h-OSA group performed significantly worse on the Selective Reminding Test delayed recall task than the l-OSA group, controlling for baseline performance (F = 19.1, df = 1,22, p < 0.001). In 19 of 25 participants who underwent brain MRI, the h-OSA group had significantly greater volumes of MRI hyperintensities in deep white matter, periventricular white matter, and subcortical gray matter compared with the l-OSA group. There was no significant association between OSA and hippocampal or entorhinal cortex volumes in our sample, even after controlling for intracranial volume. Conclusions: OSA is associated with impaired verbal episodic memory and microvascular damage in older adults with depression and cognitive impairment. One possibility is that by contributing to cerebral microvascular damage, OSA may exacerbate progressive memory decline

Ultrafast Structural Dynamics of BlsA, a Photoreceptor from the Pathogenic Bacterium Acinetobacter baumannii

Acinetobacter baumannii is an important human pathogen that can form biofilms and persist under harsh environmental conditions. Biofilm formation and virulence are modulated by blue light, which is thought to be regulated by a BLUF protein, BlsA. To understand the molecular mechanism of light sensing, we have used steady-state and ultrafast vibrational spectroscopy to compare the photoactivation mechanism of BlsA to the BLUF photosensor AppA from Rhodobacter sphaeroides. Although similar photocycles are observed, vibrational data together with homology modeling identify significant differences in the β5 strand in BlsA caused by photoactivation, which are proposed to be directly linked to downstream signaling

A 10-item smell identification scale related to risk for Alzheimer's disease

University of Pennsylvania Smell Identification Test data from control subjects (n = 63), patients with mild cognitive impairment (n = 147), and patients with Alzheimer's disease (n = 100) were analyzed to derive an optimal subset of items related to risk for Alzheimer's disease (ie, healthy through mild cognitive impairment to early and moderate disease stages). The derived 10-item scale performed comparably with the University of Pennsylvania Smell Identification Test in classifying subjects, and it strongly predicted conversion to Alzheimer's disease on follow-up evaluation in patients with mild cognitive impairment. Independent replication is needed to validate these findings