Blood-Cerebrospinal Fluid Barrier Gradients in Mild Cognitive Impairment and Alzheimer's Disease: Relationship to Inflammatory Cytokines and Chemokines

Background: The pathophysiology underlying altered blood-cerebrospinal fluid barrier (BCSFB) function in Alzheimer's disease (AD) is unknown but may relate to endothelial cell activation and cytokine mediated inflammation.Methods: Cerebrospinal fluid (CSF) and peripheral blood were concurrently collected from cognitively healthy controls (N = 21) and patients with mild cognitive impairment (MCI) (N = 8) or AD (N = 11). The paired serum and CSF samples were assayed for a panel of cytokines, chemokines, and related trophic factors using multiplex ELISAs. Dominance analysis models were conducted to determine the relative importance of the inflammatory factors in relationship to BCSFB permeability, as measured by CSF/serum ratios for urea, creatinine, and albumin.Results: BCSFB disruption to urea, a small molecule distributed by passive diffusion, had a full model coefficient of determination (r2) = 0.35, and large standardized dominance weights (>0.1) for monocyte chemoattractant protein-1, interleukin (IL)-15, IL-1rα, and IL-2 in serum. BCSFB disruption to creatinine, a larger molecule governed by active transport, had a full model r2 = 0.78, and large standardized dominance weights for monocyte inhibitor protein-1b in CSF and tumor necrosis factor-α in serum. BCSFB disruption to albumin, a much larger molecule, had a full model r2 = 0.62, and large standardized dominance weights for IL-17a, interferon-gamma, IL-2, and VEGF in CSF, as well IL-4 in serum.Conclusions: Inflammatory proteins have been widely documented in the AD brain. The results of the current study suggest that changes in BCSFB function resulting in altered permeability and transport are related to expression of specific inflammatory proteins, and that the shifting distribution of these proteins from serum to CSF in AD and MCI is correlated with more severe perturbations in BCSFB function

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images

Neuroimaging measurements derived from magnetic resonance imaging provide important information required for detecting changes related to the progression of mild cognitive impairment (MCI). Cortical features and changes play a crucial role in revealing unique anatomical patterns of brain regions, and further differentiate MCI patients from normal states. Four cortical features, namely, gray matter volume, cortical thickness, surface area, and mean curvature, were explored for discriminative analysis among three groups including the stable MCI (sMCI), the converted MCI (cMCI), and the normal control (NC) groups. In this study, 158 subjects (72 NC, 46 sMCI, and 40 cMCI) were selected from the Alzheimer's Disease Neuroimaging Initiative. A sparse-constrained regression model based on the l2-1-norm was introduced to reduce the feature dimensionality and retrieve essential features for the discrimination of the three groups by using a support vector machine (SVM). An optimized strategy of feature addition based on the weight of each feature was adopted for the SVM classifier in order to achieve the best classification performance. The baseline cortical features combined with the longitudinal measurements for 2 years of follow-up data yielded prominent classification results. In particular, the cortical thickness produced a classification with 98.84% accuracy, 97.5% sensitivity, and 100% specificity for the sMCI–cMCI comparison; 92.37% accuracy, 84.78% sensitivity, and 97.22% specificity for the cMCI–NC comparison; and 93.75% accuracy, 92.5% sensitivity, and 94.44% specificity for the sMCI–NC comparison. The best performances obtained by the SVM classifier using the essential features were 5–40% more than those using all of the retained features. The feasibility of the cortical features for the recognition of anatomical patterns was certified; thus, the proposed method has the potential to improve the clinical diagnosis of sub-types of MCI and predict the risk of its conversion to Alzheimer's disease

Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients

Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results:18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification

University of Miami Division of Clinical Pharmacology Therapeutic Rounds: medications used to treat anorexia in the frail elderly

Weight loss and anorexia are common problems that are associated with increased morbidity and mortality in the growing frail elderly population. Orexigenic agents are often prescribed in an attempt to improve appetite and lean muscle mass. Much of the data regarding their benefit comes from studies involving younger patients with illnesses such as acquired immunodeficiency syndrome or cancer. This article reviews the use and potential adverse events associated with these medications in frail elderly patients. This article also discusses the effects of the different antidepressants and antipsychotics on weight gain and appetite

Effect of a pharmacist-led multicomponent intervention focussing on the medication monitoring phase to prevent potential adverse drug events in nursing homes

OBJECTIVES: To determine the extent to which the use of a clinical informatics tool that implements prospective monitoring plans reduces the incidence of potential delirium, falls, hospitalizations potentially due to adverse drug events, and mortality. DESIGN: Randomized cluster trial. SETTING: Twenty-five nursing homes serviced by two long-term care pharmacies. PARTICIPANTS: Residents living in nursing homes during 2003 (1,711 in 12 intervention; 1,491 in 13 usual care) and 2004 (1,769 in 12 intervention; 1,552 in 13 usual care). INTERVENTION: The pharmacy automatically generated Geriatric Risk Assessment MedGuide (GRAM) reports and automated monitoring plans for falls and delirium within 24 hours of admission or as part of the normal time frame of federally mandated drug regimen review. MEASUREMENTS: Incidence of potential delirium, falls, hospitalizations potentially due to adverse drug events, and mortality. RESULTS: GRAM triggered monitoring plans for 491 residents. Newly admitted residents in the intervention homes experienced a lower rate of potential delirium onset than those in usual care homes (adjusted hazard ratio (HR) = 0.42, 95% confidence interval (CI) = 0.35–0.52), overall hospitalization (adjusted HR = 0.89, 95% CI = 0.72–1.09), and mortality (adjusted HR = 0.88, 95% CI = 0.66–1.16). In longer stay residents, the effects of the intervention were attenuated, and all estimates included unity. CONCLUSION: Using health information technology in long-term care pharmacies to identify residents who might benefit from the implementation of prospective medication monitoring care plans when complex medication regimens carry potential risks for falls and delirium may reduce adverse effects associated with appropriate medication use

Pilot study of an Alzheimer's disease risk assessment program in a primary care setting.

IntroductionThe goal of this study was to pilot a referral-based cognitive screening and genetic testing program for Alzheimer's disease (AD) risk assessment in a primary care setting.MethodsPrimary care providers (PCPs; N = 6) referred patients (N = 94; M = 63 years) to the Rhode Island Alzheimer's Disease Prevention Registry for apolipoprotein E (APOE) genotyping and cognitive screening. PCPs disclosed test results to patients and counseled them about risk factor modification.ResultsCompared to the Registry as a whole, participants were younger, more likely to be non-White, and had lower cognitive screening scores. Mild cognitive impairment participants correctly reported a higher perceived risk of developing AD. Patients who recalled being counseled about modifiable risk factors were more likely to report positive health behavior changes.DiscussionA referral-based program for cognitive and genetic AD risk assessment in a primary care setting is feasible, acceptable to patients, and yielded a more demographically diverse sample than an AD prevention registry

Trends in antipsychotic prescribing among long‐term care residents receiving hospice care

ImportanceThe Centers for Medicare & Medicaid Services’ (CMS) National Partnership to Improve Dementia Care in Nursing Homes (“CMS National Partnership”) focuses on reducing antipsychotic prescribing to long‐term care residents. Hospice enrollment is not an exclusionary condition for the antipsychotic quality measure reported by CMS. It is unclear how prescribing in hospice may have been impacted by the initiative.ObjectiveEstimate the association of the CMS National Partnership with trends in antipsychotic prescribing among long‐term care residents in hospice.DesignInterrupted time‐series analysis of a 100% Minimum Data Set sample with linked hospice claims from 2011 to 2017.SettingLong‐term care nursing facilities.ParticipantsOlder adults ≥65 residing in long‐term care (n = 3,741,379) and limited to those enrolled in hospice (n = 821,610).Main outcomeQuarterly prevalence of antipsychotic and other psychotropic (antianxiety, hypnotic, antidepressant) use among long‐term care residents; overall and among residents with dementia, stratified by hospice enrollment.ResultsFrom 2011 to 2017, parallel declines in antipsychotic prescribing were observed among long‐term care residents enrolled and not enrolled in hospice (hospice: decline from 26.8% to 18.7%; non‐hospice: decline from 23.0% to 14.4%). Following the 2012 CMS National Partnership, quarterly rates of antipsychotic prescribing declined significantly for both residents enrolled and not enrolled in hospice care. Declines in antipsychotic prescribing were greater for residents with dementia, with similar rates among residents enrolled and not enrolled in hospice. Among residents with dementia enrolled in hospice, use of other psychotropic medication classes including antianxiety, antidepressant, and hypnotic use remained relatively stable over time.Conclusions and relevanceDeclines in antipsychotic prescribing during the CMS National Partnership occurred among long‐term care residents in hospice, where use may be deemed clinically appropriate. Nursing homes are an important location for the provision of dementia end‐of‐life care and the drivers of potentially unintended reductions in antipsychotic use merits further investigation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/169272/1/jgs17172_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169272/2/jgs17172.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169272/3/jgs17172-sup-0001-supinfo.pd