Children of Alzheimer's Disease (AD) patients are at heightened risk of developing AD due to genetic influences, including the apolipoprotein E4 (ApoE4) allele. In this study, we assessed the earliest cortical changes associated with AD in 71 cognitively healthy, adult children of AD patients (AD offspring) as compared with 69 with no family history of AD (non-AD offspring). Cortical thickness measures were obtained using FreeSurfer from 1.5T magnetic resonance (MR) scans. ApoE genotyping was obtained. Primary analyses examined family history and ApoeE4 effects on cortical thickness. Secondary analyses examined age effects within groups. All comparisons were adjusted using False Discovery Rate at a significance threshold of p < 0.05. There were no statistically significant differences between family history and ApoE4 groups. Within AD offspring, increasing age was related to reduced cortical thickness (atrophy) over large areas of the precuneus, superior frontal and superior temporal gyri, starting at around age 60. Further, these patterns existed within female and maternal AD offspring, but were absent in male and paternal AD offspring. Within non-AD offspring, negative correlations existed over small regions of the superior temporal, insula and lingual cortices. These results suggest that as AD offspring age, cortical atrophy is more prominent, particularly if the parent with AD is mother or if the AD offspring is female.
Antecedent biomarker; Familial risk; Alzheimer’s Disease; Dementia; Adult Children Study; Cortical thickness; Maternal risk
Population studies strive to determine the prevalence of Alzheimer dementia but prevalence estimates vary widely. The challenges faced by several noted population studies for Alzheimer dementia in operationalizing current clinical diagnostic criteria for Alzheimer’s disease (AD) are reviewed. Differences in case ascertainment, methodological biases, cultural and educational influences on test performance, inclusion of special populations such as underrepresented minorities and the oldest old, and detection of the earliest symptomatic stages of underlying AD are considered. Classification of Alzheimer dementia may be improved by the incorporation of biomarkers for AD if the sensitivity, specificity, and predictive value of the biomarkers are established and if they are appropriate for epidemiological studies as may occur should a plasma biomarker be developed. Biomarkers for AD also could facilitate studies of the interactions of various forms of neurodegenerative disorders with cerebrovascular disease, resulting in “mixed dementia”.
The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 × 10−4) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aβ42 levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aβ42 levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aβ42 levels was independent of the APOE ɛ4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ɛ4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10−13). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE ɛ4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value <10−6. Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10−9).
In this article, we use longitudinal morphometry (shape and size) measures of hippocampus in subjects with mild dementia of Alzheimer type (DAT) and nondemented controls in logistic discrimination. The morphometric measures we use are volume and metric distance measures at baseline and follow-up (two years apart from baseline). Morphometric differences with respect to a template hippocampus were measured by the metric distance obtained from the large deformation diffeomorphic metric mapping (LDDMM) algorithm. LDDMM assigns metric distances on the space of anatomical images, thereby allowing for the direct comparison and quantization of morphometric changes. We also apply principal component analysis (PCA) on volume and metric distance measures to obtain principal components that capture some salient aspect of morphometry. We construct classifiers based on logistic regression to distinguish diseased and healthy hippocampi (hence potentially diagnose the mild form of DAT). We consider logistic classifiers based on volume and metric distance change over time (from baseline to follow-up), on the raw volumes and metric distances, and on principal components from various types of PCA analysis. We provide a detailed comparison of the performance of these classifiers and guidelines for their practical use. Moreover, combining the information conveyed by volume and metric distance measures by PCA can provide a better biomarker for detection of dementia compared to volume, metric distance, or both.
computational anatomy; dementia of Alzheimer Type; hippocampus; large deformation diffeomorphic metric mapping (LDDMM); logistic discrimination; morphometry; principal component analysis
Biomarkers are needed to improve the sensitivity and accuracy of diagnosis as well as prognosis in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau protein levels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of the Alzheimer type.
A single CSF sample and longitudinal MR scans were collected. The CSF samples were assayed for tau, p-tau181, Aβ1–42 and Aβ1–40 by ELISA. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference.
Patients or Other Participants
13 participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0).
Main Outcome Measures
Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum and CA2-4+DG cellular subfields. Their correlations with initial CSF measures.
Lower CSF Aβ1–42 levels and higher tau/Aβ1–42 and p-tau181/Aβ1–42 ratios were strongly correlated with decreases in hippocampal volume and measure of progressive inward deformations of the CA1 subfield in participants with early AD, but not cognitively normal participants.
Despite small sample size, we found that Aβ1–42 and tau-related CSF measures were related to hippocampal degeneration in individuals with clinically diagnosed early AD, and may reflect an association with a common underlying disease mechanism.
Magnetic Resonance Imaging (MRI); Hippocampal subfields; β-Amyloid; Tau; P-Tau; biomarkers
Relations among antecedant biomarkers of AD were evaluated using causal modeling; although correlation cannot be equated to causation, causation does require correlation. Individuals aged 43 to 89 years (N = 220) enrolled as cognitively normal controls in longitudinal studies had clinical and psychometric assessment, structural magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarkers, and brain amyloid imaging via positron emission tomography with Pittsburgh Compound B (PIB) obtained within 1 year. CSF levels of Aβ42 and tau were minimally correlated, indicating they represent independent processes. Aβ42, tau, and their interaction explained 60% of the variance in PIB. Effects of APOE genotype and age on PIB were indirect, operating through CSF markers. Only spurious relations via their common relation with age were found between the biomarkers and regional brain volumes or cognition. Hence, at least two independent hypothesized processes, one reflected by CSF Aβ42 and one by CSF tau, contribute to the development of fibrillar amyloid plaques preclinically. The lack of correlation between these two processes and brain volume in the regions most often affected in AD suggests the operation of a third process related to brain atrophy.
preclinical Alzheimer disease; amyloid-β; tau; PIB; amyloid plaque; APOE; brain volumetry; memory; biomarkers; cerebrospinal fluid
The Dominantly Inherited Alzheimer Network (DIAN) is a collaborative effort of international Alzheimer disease (AD) centers that are conducting a multifaceted prospective biomarker study in individuals at-risk for autosomal dominant AD (ADAD). DIAN collects comprehensive information and tissue in accordance with standard protocols from asymptomatic and symptomatic ADAD mutation carriers and their non-carrier family members to determine the pathochronology of clinical, cognitive, neuroimaging, and fluid biomarkers of AD. This article describes the structure, implementation, and underlying principles of DIAN, as well as the demographic features of the initial DIAN cohort.
Alzheimer disease; autosomal dominant; biomarkers of Alzheimer disease; PSEN1; PSEN2; APP; amyloid-beta; preclinical Alzheimer disease
Offspring whose parents have Alzheimer’s disease (AD) are at increased risk for developing dementia. Patients with AD typically exhibit disruptions in the default mode network (DMN). The aim of this study was to investigate the effect of a family history of late-onset AD on DMN integrity in cognitively normal individuals. In particular, we determined whether a family history effect is detectable in apolipoprotein E (APOE) ε4 allele non-carriers.
We studied a cohort of 348 cognitively normal participants with or without family history of late-onset AD. DMN integrity was assessed by resting state functional connectivity magnetic resonance imaging.
A family history of late-onset AD was associated with reduced resting state functional connectivity between particular nodes of the DMN, namely the posterior cingulate and medial temporal cortex. The observed functional connectivity reduction was not attributable to medial temporal structural atrophy. Importantly, we detected a family history effect on DMN functional connectivity in APOE ε4 allele non-carriers.
Unknown genetic factors, embodied in a family history of late-onset AD, may affect DMN integrity prior to cognitive impairment.
To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a Workgroup sponsored by the National Institute on Aging and the Alzheimer’s Association, on the diagnosis of very mild and mild Alzheimer disease (AD) dementia.
Retrospective review of ratings of functional impairment across diagnostic categories. Participants: The functional ratings of individuals (N = 17,535) with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer’s Disease Centers and submitted to the National Alzheimer’s Coordinating Center were assessed in accordance with the definition of “functional independence” allowed by the revised criteria.
Pairwise demographic differences between the 3 diagnostic groups were tested using t-tests for continuous variables and chi-square for categorical variables.
Almost all (99.8%) of individuals currently diagnosed with very mild AD dementia and the large majority (92.7%) of those diagnosed with mild AD dementia could be reclassified as MCI with the revised criteria, based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home. Large percentages of these AD dementia individuals also meet the revised “functional independence” criterion for MCI as measured by the Functional Assessment Questionnaire.
The categorical distinction between MCI and milder stages of Alzheimer dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that “MCI due to AD” represents the earliest symptomatic stage of AD.
Dementia Diagnosis; Alzheimer disease; MCI
The sodium iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. We have extended the use of NIS-mediated radioiodine therapy to prostate cancer. We have developed a prostate tumor specific conditionally replicating adenovirus (CRAd) that expresses hNIS (Ad5PB_RSV-NIS). For radiovirotherapy to be effective in humans, the radioiodine dose administered in the pre-clinical animal model should scale to the range of acceptable doses in humans. We performed 131I dose-response experiments aiming to determine the dose required in mice to achieve efficient radiovirotherapy. Efficacy was determined by measuring tumor growth and survival times. We observed that individual tumors display disparate growth rates which preclude averaging within a treatment modality indicating heterogeneity of growth rate. We further show that a statistic and stochastic approach must be used when comparing the effect of an anti-cancer therapy on a cohort of tumors. Radiovirotherapy improves therapeutic value over virotherapy alone by slowing the rate of tumor growth in a more substantial manner leading to an increase in survival time. We also show that the radioiodine doses needed to achieve this increase scaled well within the current doses used for treatment of thyroid cancer in humans.
prostate cancer; probasin; adenovirus; sodium iodide symporter; virotherapy; gene therapy; allometry
Prostate cancer (PCa) is the second most commonly diagnosed and sixth leading cause of cancer death in American men and one for which no curative therapy exists after metastasis. To meet this need for novel therapies, our laboratory has previously generated conditionally replicating adenovirus (CRAd) vectors expressing the sodium iodide symporter (hNIS). This virus transduced PCa cells and induced functional NIS expression, allowing for noninvasive tumor imaging and combination therapy with radioiodide, referred to as radiovirotherapy. We have now generated two new modified vectors to further improve efficacy. Ad5/3PB-ADP-hNIS and Ad5/3PB-hNIS include a hybrid Ad5/3 fiber knob to improve transduction efficiency, and express NIS from the endogenous major late promoter to restrict NIS expression to target cells. Additionally, Ad5/3PB-ADP-hNIS includes the adenovirus death protein (ADP), which hastens the release of viral particles after assembly. These two vectors specifically induce radioisotope uptake, cytopathic effect, and viral replication in androgen receptor–expressing PCa cell lines with Ad5/3PB-ADP-hNIS showing earlier 131I uptake and cytolysis at low multiplicity of infection. SPECT-CT imaging of xenograft tumors infected with Ad5/3PB-hNIS showed steady uptake, whereas infection with Ad5/3PB-ADP-hNIS led to increasing uptake, indicating viral spread. Radiovirotherapy of xenograft LNCaP tumors with Ad5/3PB-ADP-hNIS showed the most significant survival extension versus control tumors (p=0.001), but the benefit of radiovirotherapy was not statistically significant compared with virotherapy alone in this model. These results show the potential of Ad5/3PB-ADP-hNIS as a vector for treatment of prostate cancer.
Oneal and colleagues report on two novel conditionally replicating adenoviral vectors that combine 131I therapy with conventional virotherapy, a treatment termed radiovirotherapy. They show that these vectors can specifically induce radioisotope uptake, cytopathic effect, and viral replication in androgen receptor-expressing prostate cancer cell lines. In vivo efficacy studies show that treatment of tumor-bearing xenograft mice with these vectors results in a significant oncolytic effect.
The volume of parcellated cortical regions is a composite measure related to both thickness and surface area. It is not clear whether volumetric decreases in medial temporal lobe (MTL) cortical regions in aging and Alzheimer's disease (AD) are due to thinning, loss of surface area, or both, nor is it clear whether aging and AD differ in their effects on these properties. Participants included 28 Younger Normals, 47 Older Normals, and 29 patients with mild AD. T1-weighted MRI data were analyzed using a novel semi-automated protocol (presented in a companion article) to delineate the boundaries of entorhinal (ERC), perirhinal (PRC), and posterior parahippocampal (PPHC) cortical regions and calculate their mean thickness, surface area, and volume. Compared to Younger Normals, Older Normals demonstrated moderately reduced ERC and PPHC volumes, which were due primarily to reduced surface area. In contrast, the expected AD-related reduction in ERC volume was produced by a large reduction in thickness with minimal additional effect (beyond that of aging) on surface area. PRC and PPHC also showed large AD-related reductions in thickness. Of all these MTL morphometric measures, ERC and PRC thinning were the best predictors of poorer episodic memory performance in AD. Although the volumes of MTL cortical regions may decrease with both aging and AD, thickness is relatively preserved in normal aging, while even in its mild clinical stage, AD is associated with a large degree of thinning of MTL cortex. These differential morphometric effects of aging and AD may reflect distinct biologic processes and ultimately may provide insights into the anatomic substrates of change in memory-related functions of MTL cortex.
Entorhinal cortex; Perirhinal cortex; Parahippocampal cortex; Magnetic resonance imaging; Alzheimer's disease; Aging
A dementia diagnosis is challenging to deliver and to hear, yet agreement about a diagnosis is essential for effective dementia care. We examined consensus about the results of a dementia evaluation in 90 patients assessed at an Alzheimer’s Disease Research Center. Diagnostic impressions were obtained from five sources: 1) the physician’s chart diagnosis, 2) the patient who was evaluated, 3) a companion present at the evaluation, 4) a diagnostic summary written by a nurse present during the evaluation, and 5) raters who watched a video of the diagnostic disclosure conversation. Overall, diagnostic consensus was only moderate. Patients and companions exhibited just fair agreement with one another. Agreement was better between physicians and companions compared to physicians and patients, though imperfect between the physician and video raters and the written summary. Agreement among sources varied by dementia severity, with lowest agreement occurring in instances of very mild dementia. This study documents discrepancies that can arise in diagnostic communication, which could influence adjustment to a dementia diagnosis and decisions regarding future planning and care.
Alzheimer’s disease; dementia; diagnostic disclosure; doctor-patient communication; patient education
The goal of this study was to define the natural progression of driving impairment in persons who initially have very mild to mild dementia.
We studied 128 older drivers, including 84 with early Alzheimer’s disease (AD) and 44 age-matched control subjects without cognitive impairment. Subjects underwent repeated assessments of their cognitive, neurological, visual and physical function over three years. Self-reports of driving accidents and traffic violations were supplemented by reports from family informants and state records. Within two weeks of the office evaluation, subjects were examined by a professional driving instructor on a standardized road test.
At baseline, AD subjects had experienced more accidents and performed more poorly on the road test, compared to controls. Over time, both groups declined in driving performance on the road test, with AD subjects declining more than controls. Survival analysis indicated that while the majority of subjects with AD passed the examination at baseline, greater severity of dementia, increased age, and lower education were associated with higher rates of failure and marginal performance.
This study confirms previous reports of potentially hazardous driving in persons with early AD, but also indicates that some individuals with very mild dementia can continue to drive safely for extended periods of time. Regular followup assessments, however, are warranted in those individuals.
The purpose of this study was to evaluate the utility of a noninvasive ultrasound-based method, vibro-acoustography (VA), for thyroid imaging and determine the feasibility and challenges of VA in detecting nodules in thyroid.
Our study included two parts. First, in an in vitro study, experiments were conducted on a number of excised thyroid specimens randomly taken from autopsy. Three types of images were acquired from most of the specimens: X-ray, B-mode ultrasound, and vibro-acoustography. The second and main part of the study includes results from performing VA and B-mode ultrasound imaging on 24 human subjects with thyroid nodules. The results were evaluated and compared qualitatively.
In vitro vibro-acoustography images displayed soft tissue structures, microcalcifications, cysts and nodules with high contrast and no speckle. In this group, all of US proven nodules and all of X-ray proven calcifications of thyroid tissues were detected by VA. In vivo results showed 100% of US proven calcifications and 91% of the US detected nodules were identified by VA, however, some artifacts were present in some cases.
In vitro and in vivo VA images show promising results for delineating the detailed structure of the thyroid, finding nodules and in particular calcifications with greater clarity compare to US. Our findings suggest that, with further development, VA may be a suitable imaging modality for clinical thyroid imaging.
Elasticity imaging techniques; Vibro-acoustography; Thyroid neoplasm; Thyroid nodule; Ultrasound; Imaging
APOE ε4 status has been associated with greater cortical amyloid deposition whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults.
APOE genotyping and a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with PET-PIB. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association.
201 cognitively normal adults (135 females) aged 45–88 were recruited from the Knight Alzheimer Disease Research Center at Washington University. CSF samples were collected from 165 participants. Amyloid imaging was performed on 163 participants.
APOE ε4 carriers evidenced higher PIB binding (p<.001) and lower CSF Aβ42 levels (p<.001) than non-carriers. Our previous findings of higher PIB binding (p=.005) and lower CSF Aβ42 levels (p=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for PIB binding (p=.008) such that a more sedentary lifestyle was significantly associated with higher PIB binding for ε4 carriers (p=.013) but not for ε4 non-carriers (p=.208). All findings remained significant after controlling for age, gender, education, hypertension, body mass index, diabetes, heart problems, history of depression and interval between assessments.
Collectively, these results suggest that cognitively normal sedentary APOE ε4+ individuals may be at augmented risk for cerebral amyloid deposition.
The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic and biochemical biomarkers for the early detection and tracking of Alzheimer’s disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD and 200 normal controls and $67 million funding was provided by both the public and private sectors including the National Institutes on Aging, thirteen pharmaceutical companies and two Foundations that provided support through the Foundation for NIH (FNIH). This article reviews all papers published since the inception of the initiative and summarizes the results as of February, 2011. The major accomplishments of ADNI have been 1) the development of standardized methods for clinical, magnetic resonance imaging (MRI) and positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in a multi-center setting; 2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control, MCI and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β amyloid (Aβ) cascade  and tau mediated neurodegeneration hypotheses for AD while brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; 3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities including MRI, FDG-PET, CSF biomarkers and clinical tests; 4) the development of methods for the early detection of AD. CSF biomarkers, Aβ42 and tau as well as amyloid PET may reflect the earliest steps in AD pathology in mildly or even non-symptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; 5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities whereas MRI measures of change were shown to be the most efficient outcome measures; 6) the confirmation of the AD risk loci CLU, CR1 and PICALM and the identification of novel candidate risk loci; 7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia and Australia; 8) understanding the biology and pathobiology of normal aging, MCI and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD thereby advancing efforts to find disease modifying drugs for AD; and 9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a two year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI2) in October, 2010 through to 2016, with enrollment of an additional 550 participants.
Lung cancer is a major public health problem causing more deaths than any other cancer. A better understanding of the biology of this disease and improvements in treatment are greatly needed. Increasing evidence supports the concept that a rare and specialized population of cancer cells, so-called cancer-initiating cells with stem cell-like characteristics, is responsible for tumor growth, maintenance, and recurrence. Cancer-initiating cells also exhibit characteristics that render them resistant to both radiation and chemotherapy, and therefore they are believed to play a role in treatment failure. This has led to the hypothesis that traditional therapies that indiscriminately kill tumor cells will not be as effective as therapies that selectively target cancer-initiating cells. Investigating putative cancer-initiating cells in lung cancer will greatly benefit the understanding of the origins of this disease and may lead to novel approaches to therapy by suggesting markers for use in either further isolating this population for study or for selectively targeting these cells. This review will discuss (1) lung cancer, (2) stem cells, and the role of cancer-initiating cells in tumorigenesis; (3) markers and functional characteristics associated with lung cancer-initiating cells; and (4) the potential to selectively target this subpopulation of tumor cells.
Lung; Cancer; Cancer-initiating cells; Stem cells; Self-renewal; Targeted therapy; Immunotherapy
The amyloid hypothesis predicts that increased production or decreased clearance of amyloid beta (Aβ) leads to amyloidosis, ultimately culminating in Alzheimer’s disease (AD). Dynamic changes in human CNS Aβ levels may be altered by aging or AD pathology and contribute to the risk of AD.
In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, PIB PET amyloid status and electroencephalography (EEG) and video recording data.
Linear increases of CSF Aβ concentrations over time were observed in younger control participants and older Amyloid- participants, but not in older Amyloid+ participants. Significant CSF Aβ circadian patterns were observed in younger control participants; however circadian amplitudes were decreased in both Amyloid- and Amyloid+ older participants. Aβ diurnal concentrations were correlated to the amount of sleep, but not various awake activities.
Decreased linear rise of CSF Aβ levels associated with amyloid deposition, and decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics, and may contribute to AD.
Primary care providers routinely evaluate older adults and are thus in a position to first detect symptoms and signs of Alzheimer’s disease. In urban areas, diagnostic or management difficulties may be referred to specialists; however, in rural areas, specialists may not be available. The Clinician Partners Program (CPP) was initiated to enhance rural health providers’ ability in dementia diagnosis and care, and to increase research recruitment into dementia research studies of participants from rural communities.
The CPP is a 3-day “mini-residency” of didactic, observational and skill-based teaching techniques. Participants completed pre- and post-tests evaluating dementia knowledge, confidence in providing care, and practice behaviors.
Between 2000–2009, 146 healthcare professionals with a mean age of 45.7±10.8y attended the CPP; 79.2% were Caucasian, 58.2% were female, and 58% of participants had been in practice for more than 10y. Post-tests showed improvements in knowledge and confidence to diagnose and treat and increased use of dementia screening tools. Rural research participation in an urban Alzheimer Disease Research Center increased 52% over the pre-CPP period.
Primary goals were accomplished: increased knowledge and confidence, changed practice habits, and enhanced research recruitment. Educational programs such as the CPP may be beneficial for increasing access to accurate diagnoses and appropriate treatment of Alzheimer’s disease while also enhancing research participation.
Alzheimer’s disease; physician education; research recruitment; dementia
Cancer immunotherapy is designed to stimulate the immune system to reject and destroy tumors. Recently, interleukin-15 (IL-15), a member of the 4-alpha-helix bundle family of cytokines, has emerged as a candidate immunomodulator for the treatment of cancer. IL-15 acts through its specific receptor, IL-15Rα, which is expressed on antigen-presenting dendritic cells, monocytes and macrophages. IL-15 exhibits broad activity and induces the differentiation and proliferation of T, B and natural killer (NK) cells. It also enhances cytolytic activity of CD8+ T cells and induces long-lasting antigen-experienced CD8+CD44hi memory T cells. IL-15 stimulates differentiation and immunoglobulin synthesis by B cells and induces maturation of dendritic cells. It does not stimulate immunosuppressive T regulatory cells (Tregs). Thus, boosting IL-15 activity could enhance innate and specific immunity and fight tumors. Here we review aspects of IL-15 biology that make it a promising agent for anticancer therapy. We also discuss preclinical models in which IL-15 has demonstrated antitumor activity and highlight ongoing clinical trials of IL-15 in patients with cancer and HIV infection.
Alzheimer’s disease (AD) is the most common cause of dementia. Much is known concerning AD pathophysiology but our understanding of the disease at the systems level remains incomplete. Previous AD research has used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to assess the integrity of functional networks within the brain. Most studies have focused on the default-mode network (DMN), a primary locus of AD pathology. However, other brain regions are inevitably affected with disease progression. We studied rs-fcMRI in five functionally defined brain networks within a large cohort of human participants of either gender (n=510) that ranged in AD severity from unaffected (clinical dementia rating, CDR 0) to very mild (CDR 0.5) to mild AD (CDR 1). We observed loss of correlations within not only the DMN but other networks at CDR 0.5. Within the salience network (SAL), increases were seen between CDR 0 and CDR 0.5. However, at CDR 1, all networks, including SAL, exhibited reduced correlations. Specific networks were preferentially affected at certain CDR stages. In addition, cross-network relations were consistently lost with increasing AD severity. Our results demonstrate that AD is associated with widespread loss of both intra- and inter-network correlations. These results provide insight into AD pathophysiology and reinforce an integrative view of the brain’s functional organization.
Alzheimer’s disease; fMRI; resting state functional connectivity; BOLD; default mode network; salience network
The clinical diagnosis of Alzheimer's disease is often based, at least in part, on poor cognitive test performance compared with normative values. The presence and extent of an ascertainment bias (omission of affected individuals) produced by such criteria when applied as early as possible in the course of the disease was examined.
Longitudinal study from 1979 to 2008.
Washington University in St. Louis Alzheimer Disease Research Center.
Of 78 individuals aged 65 to 101 years enrolled as healthy controls 55 later developed autopsy-confirmed AD; 23 remained cognitively healthy and did not have neuropathologic AD.
Main Outcome Measures:
Criteria for diagnosis of Alzheimer disease based on various cut-points (1.5, 1.0, and 0.5 standard deviations below the mean for robust test norms) for two standard psychometric measures from each of three cognitive domains (episodic memory, visusospatial ability, working memory) were applied to data from the first assessment associated with an independent clinical diagnosis of cognitive impairment for those who developed symptomatic AD and the last assessment for those who did not.
Areas under the curve from ROC analyses ranged from .71 to .49; sensitivities and specificities were unsatisfactory even after adjusting for age and education, using combinations of tests, or examining longitudinal decline prior to clinical diagnosis.
Reliance on divergence from group normative values to determine initial cognitive decline caused by Alzheimer disease results in failure to include people in the initial symptomatic stage of the illness.