text:
Biochemical Markers of Alzheimer Disease
Effective Date November 20, 2014
Revision Date(s) 10/13/14; 10/14/13; 11/13/12; 07/12/11; 01/12/10; 01/13/09; 10/9/07; 05/09/06; 05/10/05; 06/08/04; 05/13/03; 12/21/00; 9/7/99
Measurement of cerebrospinal fluid (CSF) biomarkers of Alzheimer disease (AD) is considered investigational, including but not limited to tau protein, amyloid-ß (beta) peptides, or neural thread proteins.
Measurement of urinary biomarkers of Alzheimer disease (AD) is considered investigational, including but not limited to neural thread proteins.
There are no specific CPT codes for biochemical marker tests for AD and might be reported with the non-specific codes listed in the table above.
An example of a test for tau protein and beta peptides is the ADmark® CSF Analysis, which tests for phosphorylated-tau protein, total-tau protein, and AB42 peptide in cerebral spinal fluid (CSF). A laboratory website lists this test as being reported with 3 units of code 83520.
An example of a test for neural thread protein is the AlzheimAlert™ test. The manufacturer website notes CPT 81099 might be reported when testing is performed using urine and CPT 86849 when testing is performed using CSF.
Biochemical changes associated with the pathophysiology of Alzheimer's disease (AD) are being evaluated to aid in the diagnosis. Some of the most commonly studied biomarkers are amyloid beta peptide 1-42 (AB-42), and total or phosphorylated tau protein (T-tau or P-tau) in cerebrospinal fluid (CSF).
The diagnosis of AD is divided into 3 categories: possible, probable, and definite AD. A diagnosis of definite AD requires post-mortem confirmation of AD pathology, including the presence of extracellular beta amyloid plaques and intraneuronal neurofibrillary tangles in the cerebral cortex. (1) Probable AD dementia is diagnosed clinically when the patient meets core clinical criteria for dementia and has a typical clinical course for AD. A typical clinical course is defined as an insidious onset, with the initial and most prominent cognitive deficits being either amnestic or non-amnestic, (e.g., language, visuospatial, or executive function deficits), and a progressively worsening cognition over time. A diagnosis of possible AD dementia is made when the patient meets core clinical criteria for AD dementia but has an atypical course or an etiologically mixed presentation.
Mild cognitive impairment (MCI) may be diagnosed when there is a change in cognition but insufficient impairment for the diagnosis of dementia. (2) MCI is characterized by impairment in one or more cognitive domains but preserved functional independence. In some patients, MCI may be a predementia phase of AD. Patients with MCI or suspected AD may undergo ancillary testing (e.g., neuroimaging, laboratory tests, neuropsychological assessment) to rule out vascular, traumatic, and medical causes of cognitive decline and to evaluate genetic factors. Because clinical diagnosis can be difficult, particularly early in the course of disease, there has been considerable interest in developing an accurate laboratory test for AD. Several potential biomarkers of AD are associated with AD pathophysiology (i.e., ß-amyloid plaques and neurofibrillary tangles).
Elevated CSF levels of specific proteins have been found in patients with AD. These include tau protein, phosphorylated at AD-specific epitopes such as threonine 181 (P-tau) or total tau protein (T-tau), or an amyloid-ß peptide such as AB-42. Other potential CSF (3, 4) and serum (5) peptide markers also have been explored. tau protein is a microtubule-associated molecule found in neurofibrillary tangles that are typical of AD. Tau protein is thought to be related to degenerating and dying neurons, and high levels of tau protein in the CSF have been associated with AD. AB-42 is a subtype of amyloid-ß peptide that is produced from metabolism of amyloid precursor protein. AB-42 is the key peptide deposited in amyloid plaques characteristic of AD. Low levels of AB-42 in the CSF have been associated with AD, perhaps because AB-42 is deposited in amyloid plaques instead of remaining in fluid. Investigators have suggested that the Tau/AB-42 ratio may be a more accurate diagnostic marker than either alone. (6) A variety of kits are commercially available to measure AB-42 and tau proteins. between-laboratory variability in CSF biomarker measurement is large. (7,8)
Neural thread protein is associated with neurofibrillary tangles of AD. Both CSF and urine levels of this protein have been investigated as a potential marker of AD. Urine and CSF tests for neural thread protein may be referred to as the AD7C test.
Regulatory Status
No biochemical marker tests for AD are currently approved by the U.S. Food and Drug Administration (FDA). Commercially available tests include:
These are laboratory-developed tests (LDTs). Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; LDTs must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). AlzheimAlert™ and AdMark® CSF analysis are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, FDA has not chosen to require any regulatory review of these tests.
Nymox Pharmaceutical Corp. previously offered AD7C neural thread protein testing as an LDT but no longer lists the test on its website.
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The clinical purposes of testing for Alzheimer disease (AD) ‒ related biomarkers are to improve diagnostic accuracy or to predict conversion from mild cognitive impairment (MCI) to AD.
Evidence of health benefit or clinical utility from testing requires demonstrating:
A framework for evaluating evidence supporting health benefit from testing requires consideration of the following: appropriate reference standard; requirements for predicting conversion from MCI to AD; how better diagnostic accuracy or prediction of conversion would lead to improved health outcomes; appropriate data analysis, including assay cutoffs; patient sample composition (inclusion and exclusion criteria); and validation of accuracy or prediction in independent samples as evidence of generalizability.
Criterion Standard. Accuracy of clinical AD diagnostic criteria has been established by comparison with autopsy, the criterion standard. Therefore, comparison with autopsy is most appropriate to validly assess incremental diagnostic improvement of biomarkers.
Predicting Conversion from MCI to AD. Predicting conversion from MCI to AD may rely on clinical diagnosis, albeit with some attendant error and misclassification, because the prediction of interest is conversion and not the criterion standard diagnosis.
Incremental Diagnostic Improvement. Incremental diagnostic or prognostic improvement is best demonstrated by evidence that the proposed predictor can correctly reclassify patients with and without AD, or those with MCI who will and will not progress to AD. (9) Alternative approaches such as classical receiver operating characteristic (ROC) analyses, while providing insight, do not allow one to directly translate improvements in diagnostic or prognostic accuracy to changes in health outcomes. (10)
Test Cutoffs. Almost all studies employ optimal (data-driven) test cutoffs to define test accuracy (sensitivity and specificity). This approach is typically accompanied by a degree of optimism, in turn overstating test accuracy.
Sample Definition. Clear description of whether samples included consecutive patients or were selective is required to evaluate potential bias—including verification bias (exclusion of cases without postmortem autopsy) (11)—and generalizability.
Validation. Validation in independent samples is required to establish generalizability of markers.
Literature Review
Relevant evidence and guidelines were identified by a Medline search through July 2, 2014.
Diagnostic Accuracy of Cerebrospinal Fluid Markers Versus Clinical Diagnosis
Most studies have relied on clinically diagnosed AD as the criterion standard. These studies are described next, and results are summarized in Table 1.
Rosa et al. (2014) conducted a systematic review with meta-analysis of studies of cerebrospinal fluid (CSF) amyloid-ß peptide-1-42 (AB-42) in patients with clinically diagnosed AD. (12) Literature was searched to May 2013, and 41 prospective or retrospective, cohort, case-control, and cross-sectional studies were included (total N=5086; 2932 AD, 2154 nondemented controls). Patients with MCI were excluded. Seventy-six percent of studies satisfied all quality domains of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Publication bias was detected. A summary ROC curve was generated from all reported thresholds. Pooled sensitivity and specificity were 84% (95% confidence interval [CI], 81 to 85) and 79% (95% CI: 77 to 81), respectively. Positive and negative likelihood ratios were 4.5 (95% CI: 3.7 to 5.4) and 0.18 (95% CI: 0.14 to 0.22), respectively, and their ratio, the diagnostic odds ratio, was 29 (95% CI: 21 to 40). Statistical heterogeneity was substantial (I2=68%); studies varied in test cutoffs used and severity of AD across patient samples. Eleven studies (total N=1459; 830 AD, 629 controls) reported AB-42 CSF levels. Mean (SD) CSF AB-42 was 467 (189) pg/mL in patients with AD and 925 (414) pg/mL in controls (weighted mean difference, 450 pg/mL; 95% CI: -600 to -289; p<0.001). However, statistical heterogeneity was considerable (I2=99%).
Ferreira et al. (2014) published a meta-review of systematic reviews with meta-analyses to assess the use of CSF biomarker tests for AD after publication of revised AD diagnostic criteria (13) in 2011. (14) Literature was searched in September 2013, and 7 systematic reviews were included. None was published after introduction of the revised AD diagnostic criteria, so primary studies were searched. Twenty-six prospective or retrospective case-control, cross-sectional, or longitudinal studies were included. Most included studies used clinical criteria for AD diagnosis or did not specify. Results for both the systematic reviews and the individual studies are summarized in Table 1. For differentiating AD from nondemented controls, positive and negative likelihood ratios for all 3 biomarkers ranged from 4 to 8 and from 0.1 to 0.3, respectively. For differentiating AD from other dementias, 1 systematic review of 7 studies reported positive and negative likelihood ratios of 46 and 0.09, respectively, for differentiating AD (n=175) from Creutzfeldt-Jakob disease (n=110). (15) With this systematic review excluded, positive and negative likelihood ratios ranged from 2 to 7 and from 0.15 to 0.4, respectively.
A 2011 meta-analysis included 119 studies on biomarkers and diagnostic imaging in AD. (16) Sensitivity and specificity were calculated for distinguishing AD from non-demented controls, and for distinguishing AD from non-AD dementias with and without MCI, if available. Included studies of CSF biomarkers used a variety of thresholds, with clinical diagnosis or autopsy as the reference standard. Twenty studies of the AB-42 CSF marker were included; pooled analysis resulted in sensitivity of 76% and specificity of 77%. CSF total tau was evaluated in 30 studies with a resulting sensitivity of 79% and specificity of 85%. CSF P-tau was evaluated in 24 studies resulting in a pooled sensitivity of 78% and specificity of 81%. Six studies evaluated CSF P-tau as a biomarker to distinguish AD patients from patients with MCI, with a pooled sensitivity of 73% and specificity of 69%. The combination of total tau and AB-42 was evaluated in 12 studies with a pooled sensitivity of 80% and specificity of 76%. In a comparison of CSF biomarkers, area under the ROC curve was highest for P-tau alone (0.85). Study heterogeneity was due to use of different test thresholds and different assay kits. Sensitivity analysis including studies that used autopsy as the reference standard for P-tau resulted in slightly higher sensitivity (82%) and lower specificity (57%).
In a 2006 review of studies using clinical diagnosis as the criterion standard, Formichi et al. (17) identified studies examining diagnostic accuracy of the following CSF markers for AD: total tau protein (T-tau) (41 studies; 2287 AD patients, 1,384 controls; sensitivity, 52%-100%; specificity, 50%-100%), phosphorylated tau protein (P-tau) (12 studies; 760 AD patients, 396 controls; sensitivity, 37%-100%; specificity, 80%-100%), and amyloid-ß peptide 1 to 42 (AB-42) (14 studies; 688 AD patients, 477 controls; sensitivity, 55%-100%; specificity, 80%-100%). Although primarily a descriptive review, test accuracies varied widely and only 1 study included a majority of autopsy-confirmed AD diagnoses.
Table 1. CSF Biomarkers Performance for Distinguishing AD From Controls
Values in parentheses are 95% confidence intervals unless otherwise noted.
IS: individual studies; NR: not reported; P-tau: phosphorylated tau protein; SR: systematic review; T-tau: total tau protein.
a Or unspecified.
Section Summary
Several studies have examined the diagnostic performance of CSF biomarkers for distinguishing probable AD from non-demented controls and from patients with other types of dementia. The range of reported sensitivities and specificities is broad; in systematic reviews with meta-analyses, sensitivity and specificity were 80% to 82% and 82% to 90%, respectively, for differentiating AD from nondemented controls, and 73% and 67%, respectively, for differentiating AD from other dementias. Positive and negative likelihood ratios were 2 to 8 and 0.2 to 0.4, respectively, in either setting. This evidence does not indicate that CSF biomarkers improve the accuracy of clinical diagnostic criteria.
Diagnostic Accuracy of CSF Markers with AD Autopsy Confirmation
Engelborghs et al. (2008) assayed P-tau and AB-42 in banked CSF. (18) Samples were examined from 100 patients with and 100 without, dementing illness seen between 1992 and 2003. All dementia diagnoses were autopsy -proven (67 pure AD, 6 mixed, 27 non-AD dementias). Details of the sample selection were not provided; whether CSF testing was routine or selective was not indicated. Of those with dementia, 76 were evaluated in a memory clinic and the remainder in referring centers; all underwent clinical, neuropsychological, and imaging evaluations. The non-demented group was substantially younger (mean age, 47 years vs. 76 years). Laboratory technicians performing assays were blinded to clinical diagnoses. Samples from 52 patients required retesting due to unreliable results. Sensitivity and specificity of clinical evaluation for a pure AD diagnosis was 83% and 75%, respectively, and of P-tau and AB-42 in combination, 80% and 93%, respectively. In logistic regression models, CSF biomarkers did not provide incremental diagnostic accuracy over clinical diagnosis; as stated by the authors, "[a]lthough biomarkers did not perform significantly better comparing all unique clinical diagnoses, they were also not significantly worse, and could therefore add certainty to an established diagnosis." Four of 7 listed authors were employees of the test manufacturer (Innogenetics [now Fujirebio], Ghent, Belgium).
Clark et al. (2003) examined CSF from 106 patients with autopsy-confirmed dementia who were evaluated at 10 referral clinics, and 73 controls (4 pathologically examined). (19) Laboratory technicians were blinded to clinical diagnoses. An optimal cutoff of 234 pg/mL for total tau had sensitivity and specificity of 85% and 84%, respectively, for distinguishing those with AD (n=73) from cognitively normal people (n=74); AB-42 offered no incremental diagnostic value to total tau in ROC analyses. An optimal cutoff for total tau of 361 pg/mL had sensitivity and specificity of 72% and 69%, respectively, for distinguishing AD (n=74) from frontotemporal dementia (FTD) (n=3) and dementia with Lewy bodies (DLB) (n=10).
Bian et al. (2008) assembled from 2 institutions a sample of 30 patients with FTD (19 autopsy-proven, 11 with known causal genetic mutations) and autopsy -proven AD (n=19). (20) Using an optimal cutoff of 403 pg/mL, total tau had sensitivity and specificity of 68% and 90%, respectively, for distinguishing FTD from AD. A tau/AB-42 ratio of 1.06 had 97% specificity for distinguishing FTD from AD.
Cure et al. (2014) conducted a systematic review with meta-analysis of CSF and imaging studies for the diagnosis of definite AD (autopsy-confirmed). (21) Literature was searched in January 2012, and 3 studies of CSF markers (P-tau, T-tau, AB-42, AB-40) were identified (total N=337). Pooled sensitivity of all CSF tests was 82% (95% CI: 72 to 92), and pooled specificity was 75% (95% CI: 60 to 90). Statistical heterogeneity was not reported, but studies varied in AD definitions, controls (nondemented patients or patients with dementia due to other causes), and test thresholds. Area under the summary ROC curve constructed using multiple test thresholds was 0.84.
Section Summary
There is limited evidence examining incremental diagnostic accuracy of CSF biomarkers for AD diagnosis employing autopsy as a criterion standard. Current evidence does not demonstrate improvement over a clinical diagnosis, or whether diagnosis using CSF biomarkers would lead to improved health outcomes.
CSF Markers in Combination
As previously noted, for patients with clinically diagnosed AD, some have suggested that the tau/AB-42 ratio is a more accurate predictor, than either test alone. For example, using optimal cutoffs, de Jong et al. (2006) reported sensitivity and specificity of 95% and 90% in a sample with clinically diagnosed AD (n=61) and vascular dementia (VaD) (n=61). (22) In contrast, Le Bastard et al. (2007) found the P-tau/AB-42 ratio lacked specificity to distinguish AD from VaD in a sample of 85 patients (VaD [n=64], AD [n=21]; 76/85 autopsy-confirmed diagnoses); specificity was 52% and sensitivity ranged from 91% to 95%. (23)
CSF AB-42 level normalized to CSF AB-40 (i.e., the AB-42/AB-40 ratio) is being investigated as a marker for patients with uncertain clinical diagnosis. Because AB-40 is not incorporated into amyloid plaques, CSF levels are more stable than those of AB-42. Sauvee et al. (2014) examined the AB-42/AB-40 ratio in 122 patients with atypical dementia who had discordant CSF biomarker results (i.e., tau, P-tau, AB-42). (24) Using 0.05 as the ratio threshold, biological profiles were clarified in 72 (59%) of 122 patients with the addition of the AB-42/AB-40 ratio. However, of 35 patients diagnosed with AD by biological profile, 9 (26%) did not meet clinical criteria for AD or mixed dementia.
Section Summary
The clinical utility of CSF biomarkers used in combination has not been demonstrated.
Neural Thread Protein
Zhang et al. (2014) conducted a systematic review and meta-analysis of urinary AD‒associated neural thread protein for diagnosing AD in patients with suspected AD. (25) Nine studies were included (total N=841 patients with probable or possible AD, 37 patients with MCI, 992 non-AD demented or nondemented controls). For probable AD, pooled sensitivity and specificity were 89% (95% CI: 86 to 92) and 90% (95% CI: 88 to 92), respectively. Pooled positive and negative likelihood ratios were 8.9 (95% CI: 7.1 1 to 11.1) and 0.12 (95% CI: 0.09 to 0.16), respectively.
Kahle et al. (2000) reported on the diagnostic potential of CSF levels of total tau protein and neural thread protein in a group of 35 patients with dementia (30 with probable or definite AD), 5 patients with DLB, 29 patients with Parkinson disease, and 16 elderly healthy control patients. (26) Levels of both tau and neural thread protein were elevated in patients with AD compared with controls; sensitivity and specificity were 63% and 93%, respectively, for tau, and 70% and 80%, respectively, for neural thread protein.
In a prospective multicenter study conducted at 8 sites, Goodman et al. (2007) enrolled 168 patients with recent referrals to memory clinics. (27) The urinary neural thread Protein test was 91.4% sensitive for a diagnosis of probable AD (32/35) and 90.1% specific among healthy patients. However, it was unclear whether the marker changed management or what the potential consequences of a 9.9% false-positive rate might be.
Section Summary
Data on neural thread protein as a marker for AD are limited. In 2 studies and 1 meta-analysis, estimated sensitivity and specificity ranged from 70% to 91% and from 80% to 90%, respectively. The clinical utility of neural thread protein testing has not been demonstrated.
CSF Markers and Progression of MCI
Studies also have evaluated the prognostic value of markers for progression of MCI and conversion to clinically manifest AD.
Ritchie et al. (2014) published a Cochrane review of CSF amyloid-ß protein (primarily AB-42) for detecting which patients with MCI would progress to AD or other dementias. (28) Literature was searched in December 2012, and 14 prospective or retrospective cohort studies of AD, including one discussed next, 29 were included (total N=1,349 patients with MCI). Studies that enrolled patients younger than 50 years of age or with less than 2 years of follow-up were excluded. Risk of bias was moderate to high in most studies. AD, diagnosed by clinical criteria, developed in 436 (32%) of 1,349 patients. Sensitivity ranged from 36% to 100%, and specificity from 29% to 91%. Due to heterogeneity of thresholds used, summary sensitivity and specificity were not calculated. However, a summary ROC curve was generated using the median specificity of 64%; pooled sensitivity was 81% (95% CI: 72 to 87). Positive and negative likelihood ratios were 2.2 (95% CI: 2.0 to 2.5) and 0.31 (95% CI: 0.21 to 0.48), respectively. Analysis of the pre- and posttest probabilities of conversion to AD among patients with MCI in primary and secondary care settings showed little incremental value of AB-42 testing in either setting.
The 2014 meta-review of systematic reviews by Ferriera et al. (previously discussed) included studies of CSF biomarkers for differentiating patients with MCI who progress to AD from those who do not. (14) In systematic reviews with meta-analyses, sensitivity and specificity of AB-42 were 67% (95% CI: 59 to 75) and 71% (95% CI: 65 to 78), respectively; for T-tau, 82% (95% CI: 76 to 86) and 70% (95% CI: 65 to 85), respectively; and for P-tau, 81% (95% CI: 69% to 91%) and 65% to 76%, respectively. Positive and negative likelihood ratios for all three tests ranged from two to three and from 0.3 to 0.5, respectively.
Mattsson et al. (2009) recruited from 12 U.S. and European centers patients with MCI (n=750) or AD (n=529) and controls (n=304). (30) Those with MCI were followed a minimum of 2 years or to disease progression. Development of probable AD was associated with lower CSF AB-42 and higher T-tau and P-tau. Using cutoffs defined in the AD and control groups for a diagnostic sensitivity of 85%, combining AB-42/P-tau and T-tau yielded sensitivity for AD conversion of 83% (95% CI, 78 to 88); specificity, 72% (95% CI: 68 to 76); positive predictive value, 62%; and negative predictive value, 88%. Type of MCI (amnestic or nonamnestic) was not specified.
Herukka et al. (2007) reported on a sample of 106 patients evaluated at a university neurology department and 33 patients "from an ongoing prospective population-based study"; selection criteria other than agreeing to a lumbar puncture were not further described. (31) Seventy-nine patients were diagnosed with MCI, 47 with amnestic type, and 33 converting to dementia; 60 patients were included as controls. Average follow-up was 3.5 years (MCI converters), 3.9 years (controls), and 4.6 years (stable MCI). CSF AB-42, P-tau, and total tau were measured. Graphical representation of AB-42, P-tau, and total tau suggested considerable overlap between controls, those with stable MCI, and progressive MCI. Test accuracy was not reported.
Hansson et al. (2006) obtained 137 CSF samples from a larger group of 180 consecutive patients with MCI who were evaluated at a referral memory clinic between 1998 and 2001. (32) CSF also was obtained from 39 controls. In the analytical sample (n=137), patients were 50 to 86 years of age at baseline, and 55% were female. Median follow-up was 5.2 years; 57 (42%) progressed to AD. Using a predictor comprising T-tau and AB-42/P-tau with optimal cutoffs, sensitivity and specificity for progression to clinical AD were 95% (95% CI: 86 to 98) and 87% (95% CI: 78 to 93), respectively. Patients were not categorized by the presence of amnestic MCI conferring increased risk of conversion to AD. (33)
From 4 international clinical research centers, Ewers et al. (2007) retrospectively assembled a sample of 88 patients with amnestic MCI based on both the availability of CSF samples and at least one follow-up visit between 1 and 3 years after initial evaluation; 57 healthy controls with baseline evaluations only also were included. (34) Forty-three patients (49%) in the MCI group converted to AD over an average 1.5-year follow-up. Using a cutoff of 27.3 pg/mL, sensitivity and specificity of p-tau for conversion were 87% (95% CI: 73 to 93) and 73% (95% CI: 55 to 84), respectively. It should be noted that the conversion rate to AD in the sample was between two- and 3-fold higher than the typical 15% found in amnestic MCI.
Andreasen et al. (2005) studied 32 controls and 44 patients with MCI who, after a 1-year follow-up, had progressed to probable AD. (35) At the start of the study, investigators evaluated total and P-tau and AB-42 levels. At baseline, 79.5%, 70.4%, and 77.3% had abnormal levels of total tau, P-tau, and AB-42, respectively. These results would have been more informative if patients with MCI who did not progress to AD were included for comparison.
Bouwman et al. (2007) followed 59 patients with MCI for a mean of 19 months (range, 4-45), obtaining baseline CSF AB-42 and tau. (36) Abnormal AB-42 (<495 pg/mL) and total tau (>356 pg/mL) were accompanied by increased, but imprecise, relative risks for progression to AD (5.0 [95% CI: 1.4 to 18.0] and 5.3 [95% CI: 1.5 to 19.2], respectively).
Parnetti et al. (2006) examined 55 patients with MCI. (29) Baseline CSF AB-42, total tau, and P-tau were measured; 38% had abnormal values. After 1 year, 4 (12%) of 33 stable patients had abnormal markers. Of 11 patients who progressed to AD, DLB, or familial FTD, 10 (91%) had 2 or more abnormal markers. Although results from these studies are consistent with potential prognostic utility of markers, sample sizes were small. Additionally, the type of MCI (amnestic or nonamnestic) was not specified but has important predictive value for progression to dementia.
Section Summary
Evidence suggests that biomarker testing may identify increased risk of conversion from MCI to AD. Evidence that earlier diagnosis leads to improved health outcomes through delay of AD onset or improved quality of life is lacking.
Alzheimer Disease Neuroimaging Initiative
In 2003, the Alzheimer Disease Neuroimaging Initiative (ADNI) initiated a public-private effort designed to aid researchers and clinicians to develop new treatments and monitor their effectiveness, as well as to lessen the time and cost of clinical trials. Participants have been recruited across the U.S. and Canada with follow-up every 6 months for approximately 10 years. Participants undergo neuropsychological testing, imaging, and biomarker evaluations to determine whether these measures can be combined to monitor the progression of MCI and AD. Ongoing results from several studies span diagnostic and prognostic questions addressed here.
In a 2011 report, Gomar et al. evaluated the value of neuropsychological testing, neuroimaging, and biomarkers (CSF AB and tau) for diagnosing AD in all participants in the ADNI database who had a lumbar puncture. (37) This included 105 normal controls, 179 patients with MCI, and 91 patients with AD. Neuropsychological testing and magnetic resonance imaging (MRI) were found to be the most informative techniques, with 84% and 82% correct classification, respectively. CSF assessments had 73% correct classification and did not add diagnostic information when all techniques were combined. CSF assessments were less informative in patients aged 75 years and older (70% correct classification vs. 77% for patients ≤75 years).
Two reports from 2009 compared MRI scans and CSF biomarkers for diagnosis and prognosis among 399 participants undergoing both exams (109 normal, 192 amnestic MCI, 98 AD). (38,39) In ROC analyses, C statistics for MRI as diagnostic of probable AD compared with normal and for P-tau/AB-42 were 0.90 and 0.84, respectively. (38) In longitudinal evaluation, both MRI and biomarkers were associated with conversion to AD; c-indices were 0.69 for MRI and 0.62 for T-tau/AB-42.39 Reclassification measures were not reported. In these studies, MRI appeared to provide greater diagnostic (for probable AD) and prognostic information.
In a 2012 report, Schmand et al. evaluated the value of neuropsychological testing, neuroimaging, and biomarkers (AB and tau in CSF) for predicting conversion to AD in 175 patients with MCI. (40) With a mean follow-up of 2.7 years (range, 0.5-4.6), 81 patients (46%) converted to AD. Neuropsychological testing and MRI predicted conversion with 63% to 67% classification success both in patients younger and older than 75 years. CSF biomarkers correctly classified 64% of patients younger than 75 years and 60% of patients 75 years of age or older. Difference in prediction for markers in combination (70%) was not significantly better than for individual markers.
Landau et al. (2010) examined predictors of conversion to clinically diagnosed AD and cognitive decline in 85 patients with amnestic MCI in the ADNI. (41) Twenty-eight patients developed AD over a mean 1.9-year follow-up. In multivariate models, CSF markers (P-tau, T-tau, P-tau/AB-42, T-tau/AB-42) were not associated with conversion to AD.
De Meyer et al (2010) developed a model using biomarkers (CSF AB-42/P-tau) in the U.S.-ADNI sample (114 cognitively normal, 200 MCI, 102 AD patients). (42) Sensitivity and specificity in the development set were 90% and 64%, respectively; one-third of cognitively normal people had false -positive results. The model was then validated in a Belgian data set of 73 patients with autopsy-confirmed dementia and correctly identified 64 (94%) of 68 AD patients. In a separate data set of 57 patients with MCI, the model identified all patients who progressed to AD.
Ewers et al. (2012) evaluated CSF AB-42, amyloid PET, fluorodeoxyglucose-positron emission testing (FDG-PET), and MRI in 211 ADNI patients with at least one detected amyloid biomarker. (43) Using the most recent diagnostic criteria, in 92 patients undergoing all tests, AB-42 had 94% sensitivity for a positive FDG-PET or MRI. The authors concluded, "[m]ore correlation and validation studies of biomarkers in the AD population will be essential to understand biomarker performance and correlation with autopsy data."
In 181 ADNI patients with MCI, Richard et al. (2013) found neither MRI nor CSF biomarkers improved classification of patients who developed AD compared with a brief memory test. (44) Net reclassification improvement obtained by adding MRI results to the memory test was 1.1% and for CSF AB-42/P-tau, 2.2%.
Improved Health Outcomes (Clinical Utility)
Although not without controversy because of modest efficacy, cholinesterase inhibitors are used to treat mild-to-moderate AD. (45, 46) Memantine, an N-methyl-d-aspartate receptor antagonist, appears to provide a small benefit in those with moderate-to-advanced disease. (45,47) Given available therapies, in principle, more accurate diagnosis might allow targeting treatment to those most likely to benefit. However, clinical trial entry criteria and benefit have been based on clinical diagnosis. While the possibility that more accurate diagnosis may lead to improved outcomes is plausible, it is not based on current evidence. Pharmacologic interventions for MCI have not demonstrated benefit in reducing progression to AD. (48-51)
Summary of Evidence
Evidence that testing for Alzheimer disease (AD) ‒ related biomarkers in patients with dementia can improve health outcomes is lacking. Most studies derive from select patient samples and define optimal test cutoffs without validation; thus, generalizability of results is uncertain. For the diagnosis of AD, evidence does not demonstrate incremental improvement in diagnostic accuracy over clinical testing. For predicting conversion from mild cognitive impairment to AD, limited evidence, including that from the Alzheimer Disease Neuroimaging Initiative, suggests that testing may define increased risk. Whether earlier diagnosis leads to improved health outcomes through delay of AD onset or improved quality of life is unknown. Guidelines align with these conclusions. Therefore, biochemical testing for AD is considered investigational.
Practice Guidelines and Position Statements
National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association
In 1984, National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and Alzheimer Disease and Related Disorders Association (ADRDA) developed clinical criteria for the diagnosis of AD. (52) Although evidence to date has used NINCDS/ADRDA's AD classification, in 2011, the National Institute on Aging and the Alzheimer's Association workgroup revised diagnostic criteria for dementia due to AD. (13)
In the 1984 guidelines, diagnostic categories were defined as follows.
Possible Alzheimer Disease
Clinical diagnosis of possible AD:
Probable Alzheimer Disease
Criteria for the clinical diagnosis of probable AD included:
The diagnosis of probable AD is supported by:
Other clinical features consistent with the diagnosis of probable AD, after exclusion of causes of dementia other than AD, include
Features that make the diagnosis of probable AD uncertain or unlikely include:
Definite Alzheimer Disease
Criteria for diagnosis of definite AD are:
National Institute on Aging and the Alzheimer's Association
As of 2011, probable AD is defined by the National Institute on Aging and the Alzheimer's Association workgroup according to the following diagnostic criteria (13):
"Meets criteria for dementia…and in addition, has the following characteristics:
All probable AD by NINCDS-ADRDA criteria are subsumed in the revised probable AD criteria. Revised criteria include a category of "Probable AD dementia with increased level of certainty" due to documented decline or having a causative AD genetic mutation. Additionally, a category "Probable AD dementia with evidence of the AD pathophysiological process" has been added. Evidence of the AD pathophysiologic process is supported by detection of low cerebrospinal fluid (CSF) AB-42, positive positron emission tomography (PET) amyloid imaging, or elevated CSF tau, and decreased 18-F fluorodeoxyglucose uptake on PET in the temporoparietal cortex with accompanying atrophy by magnetic resonance imaging in relevant structures. Detection of the "pathophysiological process" is further divided according to when in the disease natural history markers are expected to be detectable.
Note on Revised AD Criteria and Biomarkers
The biomarkers reviewed in this policy are included in a category among revisions to the 2011 updated AD diagnostic criteria, "probable AD dementia with evidence of the AD pathophysiological process." (13) However, the diagnostic criteria workgroup noted that "we do not advocate the use of AD biomarker tests for routine diagnostic purposes at the present time. There are several reasons for this limitation:
Alzheimer's Association
In 2009, the Alzheimer's Association (AA) initiated a quality control program for CSF markers, noting that "Measurements of CSF AD biomarkers show large between laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers." (8) In 2012, the Alzheimer's Biomarkers Standardization Initiative published consensus recommendations for standardization of preanalytical aspects (e.g., fasting, tube types, centrifugation, storage time, temperature) of CSF biomarker testing. (53)
In 2013, AA published recommendations for operationalizing the detection of cognitive impairment during the Medicare annual wellness visit in primary care settings.54 The recommended algorithm for cognitive assessment was based on "current validated tools and commonly used rule-out assessments." Guideline authors noted that use of biomarkers (e.g., CSF tau and ß-amyloid proteins) "was not considered as these measures are not currently approved or widely available for clinical use."
The 4th Canadian Consensus Conference on Diagnosis and Treatment of Dementia
The 4th Canadian Consensus Conference on Diagnosis and Treatment of Dementia published updated evidence-based consensus recommendations in 2012. (55,56) There was consensus that plasma AB-42 measurement is unreliable and is not recommended for clinical practice. There was lack of consensus for measurement of CSF AB-42 and tau levels in patients with atypical dementia. Conference participants concluded that "for now, measurement of CSF AB1-42 and tau have no clinical utility in Canada, although they are part of research protocols in observational and therapeutic studies."
European Federation of Neurological Societies-European Neurological Society
In 2012, European Federation of Neurological Societies and European Neurological Society published updated evidence-based consensus guidelines on the diagnosis and management of disorders associated with dementia.57 A level B recommendation (probably effective based on class 3 [unblinded] evidence) that CSF AB-42/tau/p-tau assessment helps to differentiate AD was included.
U.S. Preventive Services Task Force Recommendations
Testing for biochemical markers is not a preventive service.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
Unlisted molecular pathology procedure
Immunoassay, analyte, quantitative; not otherwise specified (x2)
Type of Service
Place of Service
Physician's office
Add to Medicine Section - New Policy
Replace policy - Coding information added
Replace policy - Policy updated; references added, policy statement unchanged.
Replace policy - Policy updated; references added; policy statement unchanged.
Replace policy - Policy updated with literature search; no change in policy statement
Replace policy - Policy updated with literature search; references added; no change in policy statement.
Update Scope and Disclaimer - No other changes.
Replace policy - Policy updated with literature search; no change in policy statement. Reference added.
Replace policy - Policy updated with literature search; no change to the policy statement. Rationale and references extensively edited.
Replace policy - Policy updated with literature search; no change to the policy statement. References added.
Replace policy - Policy updated with literature search. References 2, 5, 11-14, 35, and 36 added. No change to policy statement. ICD-10 codes added to policy.
Update Coding Section - ICD-10 codes are now effective 10/01/2014; Add Related Policy 6.01.55.
Replace policy - Policy updated with literature search through July 2012; references 7, 12, 28, 31 and 42 added; policy statements unchanged.
Replace policy. Policy updated with literature search through July 2013; references 34 and 35 added; policy statements unchanged. CPT code 83912 removed from policy (deleted 1/13); code 81479 added.
Annual Review. Policy updated with literature review through July 2, 2014. References 5, 7, 12, 14-15, 21, 24-25, 28, 44-45, 48, 53-54, 56 added; references 1-2, 55, 57 updated; others renumbered/removed. Policy statements unchanged.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).


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Finish line is only a starting point
Updated: January 23, 2013, 12:06 PM ETBy Chris McCormack | Triathlete.com
Kona 2012 didn't go as planned. I had prepared perfectly for the race, I was in amazing form and had implemented new training techniques that I thought would take me to another title in Hawaii. My season in Europe was exceptional, and in mid-July I ran away with another world championship in Spain. That win gave me the confidence that my training was on track for success in October.
On race day I was empty, and the event was over before it began. I sat confused and flat in my house ...
Read full story
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Tom's of Maine Natural Deodorant Aluminum Free Original Unscented -- 2.25 oz
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The chemical name for SO4 is sulfate. Almost all natural bodies of water contain sulfates, and these generally come from the presence of shales, sulfite ore oxidation or industrial waste. When rain dissolves, sulfate is a primary component.Know More
The most common sulfate minerals include gypsum, barite and anhydrite. These form when SO4 groups combine with different metals. Sulfate-class minerals have the following characteristics: the density is average or above average, the hardness is average, a vitreous luster is present, and the minerals can be fluorescent and soluble. Initially, these minerals form in oxidation zones, evaporite deposits, veins and contact metamorphic zones.Learn more about Chemistry
The chemical name for P4O6 is "tetraphosphorus hexoxide." "Tetra" is a prefix that is used for naming four atoms of a formula's nonmetal element.Full Answer >
The water in the Fe + CuSO4 single displacement reaction facilitates the reaction by separating the Cu and SO4 ions and allowing ionized Fe to interact with SO4. This occurs because water is a polar solvent and dissociates ionic salts more readily than any other compound.Full Answer >
The chemical name for SO3 is sulfur trioxide. The compound contains one atom of sulfur, as indicated by the S, and three atoms of oxygen, as indicated by the O3.Full Answer >
Salts are a type of ionic compound that derives its chemical name from the anions and cations it contains. For example, the chemical name for table salt is sodium chloride, which is represented by the chemical formula NaCl.Full Answer >


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The TicketCity Event Guide for the 2014 World Cup in Brazil will be posted as the event nears. Check back later.
For archived information and the 2010 Event Guide, click here.
I received my tickets very quickly and the seats were great. I will definitely use TicketCity again!Kathleen - San Francisco, CA


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I have this core controller in my code igniter app and I want to pass a view variable's to all my views.
My view is loaded in my normal controllers, so I can't load the view again in my Core controller.
So, how am I gonna do that? I tried using $data['fromCoreVar'] and I tried $fromCoreVar. Neither of both does work which is incredibly well understandable. But, I want it to work.
Whats the solution?
Tnx in advance.


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Indiana Underground >> Dragon Leg Matee Jedeepitak Muay Thai Seminar
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Top Level Gym
Member Since: 10/14/11
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To be held Saturday, November 5th at Top Level Gym www.toplevelgym.com
Muay Thai Seminar featuring "Dragon Leg" Matee Jedeepitak
Matee is a former Lumpinee Stadium, World Muay Thai Council and IKF Champion.
This is your opportunity to learn REAL World Class Muay Thai from a REAL World Class instructor.
The Muay Thai seminar at Top Level Gym will be in two sessions:
11am-1:30pm and 4pm-6:30pm on Saturday, November 5th.
The sessions will cover different Muay Thai techniques, so don't miss either!
Pricing will be (One session/Both Sessions):
Now-Oct. 29th - $40/$75.
Oct. 31st-Nov. 4th - $50/$85
Day of the seminar Nov. 5th - $65/$100
See our website www.toplevelgym.com, www.facebook.com/toplevelgym or contact us at firstname.lastname@example.com for more details!
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Shipyard receives $1 million wind turbine grant
Vancouver, Wash.-based yacht builder Christensen Shipyards received a $1 million grant allowing its sister company to switch a portion of the boat manufacturing plant to small wind turbine production. The newly created sister business, Renewable Energy Composite Solutions LLC, is using the money to get into the wind turbine and hydrokinetic energy component manufacturing. According…more


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Paddle Fenwick fundraiser scheduled for June 29
FENWICK ISLAND - Paddle Fenwick is a weekend of stand-up paddleboard festivities, racing fun and fundraising for a worthy cause.
Operation Second Chance is a nonprofit group committed to serving wounded combat veterans and their families' recovery and transition back into civilian life.
The event kicks off Saturday, June 29, with an afternoon of "everything SUP." This will include clinics, demos, the latest in boards and equipment and will be capped off with a pre-race happy hour at Harpoon Hanna's.
Race Day will be Sunday, June 30, at Holts Landing State Park features the main event - a five-mile course for fast and furious paddlers and a 2.5-mile run for fun and festive paddlers. The day will wrap up with an awards ceremony following the Kids & Critters event for future two-legged and four-legged SUP future stars.
Delaware Sports Museum and Hall of Fame open for tours
WILMINGTON - It is spring and the Delaware Sports Museum and Hall of Fame is open for individual and group tours.
Attendees can view the state's history from the Native Americans to present day as well as view photos, memorabilia, models and displays. Volunteers to help guide tours, man the welcome desk and do minor maintenance of the building and exhibits is also being sought.
The Delaware Sports Museum and Hall of Fame is open Tuesday through Saturday from noon-5 p.m. and at other times by appointment. Call 302-425-3263 for additional information and appointments.
The Delaware Sports Museum and Hall of Fame will hold its annual Induction Banquet on Wednesday, May 15, at the Chase Center on the Wilmington Riverfront with a social hour at 5:30 p.m. and dinner at 6:45 p.m.
To purchase banquet tickets, email Sue Holloway at firstname.lastname@example.com or call 302-992-0550. Banquet tickets are $60 each. Tables for 10 are available.
Registration open for annual golf tournament
BETHANY BEACH - Registration has opened for the annual golf tournament to raise funds for Alzheimer's research sponsored by the Coastal Chapter, National Active and Retired Federal Employees Association.
It will be held at 9 a.m. Friday, May 17, at the Salt Pond Golf Club in Bethany Beach. Last year's tournament resulted in a contribution of $6,573 to the Alzheimer's Research Fund.
Greens fees are $65, including a cart and a luncheon at the Cottage Café in Bethany Beach following the tournament. The luncheon will also include door prizes, prizes for the top finishing foursomes and a live auction of items, including golf foursomes donated by area golf courses.
For a $50 contribution individuals and businesses can sponsor a hole at the tournament. Sponsors will have their name and business advertised on their respective tee boxes. All fees and donations go directly to Alzheimer's research.
Anyone interested in signing up for the tournament, donating gift certificates and goods, or serving as a tee box sponsor, should email Ron Weber at email@example.com or Dick Oliver at firstname.lastname@example.com.
Beach Breast Cancer Fun Run slated for May 11
BETHANY BEACH - The annual Bethany Beach Breast Cancer Fun Run and Walk is scheduled for 1-6 p.m. Saturday, May 11, rain or shine.
This year's theme is "Safari - It Takes a Village," because it takes a village to find a cure, to support loved ones, to care for families and caregivers, to make each other laugh on a difficult day and to offer each other hope.
The online registration is April 26 at http://bethanybeachbreastcancer.com.
The event is sponsored by the Beebe Breast Health Center in Lewes and Little Pink Houses of Hope. Organizers are in need of host houses for the June 1-8 Bethany Beach retreat for breast cancer patients and their families.
For more information, call Ann Raskauska at 302-537-9700.
Third junior mud run to benefit cancer research
MIDDLETOWN - The third annual Delaware Mud Run JR will take place Wednesday, June 19.
Children ages 6 to 13 are invited to participate in the event, which will benefit the Leukemia Research Foundation of Delaware. Participants can register in groups during any of the eight start times this year, with the last heat at 7:45 p.m., which will also accommodate runners needing assistance.
Individuals will race through mud, sludge, obstacles and muck that will require climbing, crawling and jumping towards the finish line. The deadline to register is midnight Friday, June 14. Find out all the details at www.delawaremudrunjr.com.
Applebee's hosted Dodgeball Madness Tournament
CAMDEN - On Saturday, March 23, the Rehoboth Applebee's participated in the Dodge Ball Madness Tournament in Camden.
Sponsored by the Delaware State Police, the tournament is held annually to raise money for the Delaware Special Olympics.
Though the teams three wins and four losses wasn't enough to win the whole tourney, they were able to raise more than $500 for the cause through a bake sale at the store.


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Boys' Ice Hockey - La Salle
Explorers coach Wally Muehlbronner has the same
problem every season — many of his best players end
up leaving early for prep schools in the hopes of getting
recognized by major colleges. The result is a rebuilding
of the team every season. Yet through it all,
Muehlbronner has managed to keep La Salle not only
afloat, but he's also kept them very competitive, and
last year's Class AAA state title proves it. This year, the
team's talent is just as evident, even if the players are
different from those on last year's roster. Senior Ross
Denczi is a quiet leader whose gritty style sets the tone
for this year's team. "He plays a tough, grind-it-out
style of hockey, but he can score as well,"
Muehlbronner says. "He's definitely one of the top forwards
in the area."He's paired on the wing with senior
Matt O'Brien, a speedy forward. "We're expecting a lot
of good things out of Matt," Muehlbronner says.
Defensively, Tom Krulikowski and Pat Gallagher
anchor an efficient defensive unit in front of junior
netminder Gabe Antoni. "He's been very solid for the
past two years, and this is his chance to shine,"
Muehlbronner says. "He's been to a few USA Hockey
Select games and festivals." Younger players will fill
out the team's roster, as they reinvent the style every
year. This year, it's blue collar. "We take pride in scoring
ugly," Muehlbronner says.
Girls' Cross Country - Emmaus
For the second consecutive year, Emmaus is the Class AAA state champion. The Green Hornets cruised
to the state crown on Nov. 8 after placing all five of their scoring runners in the Top 25, led by senior Lindsey
Graybill's fourth-place finish, third in team scoring. Juniors Amanda Faust, Brianna Faust and Christine
Faust also paced the team while senior Melissa Meade rounded out the scoring as the Green Hornets
topped Latrobe by 59 points.
Boys' Soccer - Downingtown West
The Whippets entered their season with the hope of avenging a tough overtime loss to South Park in
last year's Class AAA state championship. So nobody was more thrilled than senior defenseman Brian
Forgue and company when Downingtown West reached the final on Nov. 15, only to be paired against
the same team that ended its title hopes last year. This time around, the Whippets earned a 2-1 win on
goals from seniors Joe Sales and Travis Cantrell.
Field Hockey - Penn Manor
With a 5-0 win over Hershey on Nov. 15, the Comets finally earned the Class AAA state title they had
coveted. Penn Manor had been close several times before, but this time around, led by eight seniors, the
Comets were able to seal the deal. Lexy Adams, Cathryn Altdoerffer, Jenn Bradley, Maggie Brommer, Mariah
Farbo, Nicole Henderson, Haley Weaver and Kathi Weidman were the seniors who got to savor the
team's long-awaited title.
Junior Vince Perrozzi, ninth at state this year, will contend for the crown next season.
The Raiders will look to sophomore Kelsey Stevens to keep the PCL title streak intact.
Junior QB Mark McHugh will return to help the Jaguars get back to the state tourney.
One of the area's best liberos, junior Dana Markol, leads the Vikings.


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January 3, 2012
Stories this photo appears in:
Rams' Perfect Run
COVINGTON — The Newton County Recreation Department football 12-under Rams team was a once-in-a-lifetime group. While there have been other football teams that have won championships, no one has done it the way this group did.
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Paul Vincent Wiseman & The Wiseman GroupThis first book on the interior designs of San Francisco–based Paul Vincent Wiseman and The Wiseman Group showcases distinctive homes where clients find themselves at peace in a profound way. The hallmarks of Wiseman interiors are superb details executed in custom furniture and furnishings. The homes range from a Victorian update on San Francisco's Russian Hill to an Art Deco apartment on
From the Collection of Cavallini & Co.Cavallini is one of the best-known companies for high-quality gift and stationery products. They have been producing everything from calendars to wrapping papers for 25 years. Designs are based on ephemera from all walks of life—charming vintage post cards of the Eiffel Tower, centuries-old hand-colored engravings of birds and flowers, rare maps and prints, amusing early twentieth-century
$23.99Manufactured in Venice, Italy, textiles by Fortuny have borne the standard of quality and excellence for a hundred years. For walls, sofas, pillows, draperies, bed coverings, tablecloths, and even napkins, the sumptuous art of Fortuny textiles has been decorating old world and new world homes for generations. Not everyone can afford Fortuny, but some of those who can have opened their doors so we
$15.99Barry Dixon Inspirations takes the reader through eight homes transformed by renowned designer Barry Dixon. From a cottage and a chic chateau to a grand estate home, with a high-rise apartment and a row house in between, we see the broad range of Dixon's decorating style and learn what inspired his colors and materials for each location.Barry Dixon, named the "2010 Master of Design" by Veranda
$10.69Cottages travels from coast to coast, sharing delightful examples from the Catskills of New York to Georgia's Tybee Island to Southern California and beyond. The popularity of cottage homes has continued to thrive; cottages share charming details that capture the imagination and creativity of their owners, from a built-in window seat to a front porch swing to an outdoor shower for washing sandy
$15.99Preeminent designer Barry Dixon approaches each project with the design philosophy that the greatest quality ahome might possess is that of innate, soulful hospitality. His work features a masterful blend of traditional and contemporary décor that mixes color and texture in astounding ways. Barry Dixon Interiors exemplifies Dixon's belief that our homes reflect our past, emanate our present and
Liner Notes for Hip-Hop JunkiesA Tribe Called Quest • Beastie Boys • De La Soul • Eric B. & Rakim • The Fugees • KRS-One • Pete Rock & CL Smooth • Public Enemy • The Roots • Run-DMC • Wu-Tang Clan • and twenty-five more hip-hop immortalsIt's a sad fact: hip-hop album liners have always been reduced to a list of producer and sample credits, a publicity photo or two, and some hastily composed shout-outs. That's a damn shame,
An Inspiring and Practical HandbookIf you dream of decorating (or redecorating) your home but have no idea where to begin, this decorating workshop-in-a-book decodes an interior designer's thought process on creating a stylish home with vision and flow.The secret to those gorgeous interiors in the magazines lies not in the things that fill the rooms, but in the "decorating story" or point of view that the designer has applied to
The Ultimate Guide to Hip-Hop and R&BIn this fun, edgy, and essential guide, the editors of today's hottest music magazine give you the ultimate, all-access pass to the exciting world of hip-hop and contemporary R&B. From the megaselling songs to the biggest stars to the most outrageous scandals, RAP-UP gives you a comprehensive behind-the-scenes look at the revolutionary music that's transforming pop culture. Discover: HISTORY
The Story of Singing Sensation Britney SpearsPOP PRINCESSBritney Spears is putting girls back on the map in the pop music world. With the effervescent and intoxicating sounds of her first album, ...Baby One More Time, Britney shot straight to the top of the charts--in just the first week of the album's release. Her ripe style and smart lyrics have captured the hearts of millions of fans, young and old.But Britney didn't just come out of
21st Century Residential Landscape DesignThis beautifully illustrated book takes the reader on a journey through a number of outstanding gardens that have been landscaped by one of Australia's leading landscape designers, Dean Herald of 'Rolling Stone Landscapes'. 21st Century Residential Landscape Design showcases over 20 designs produced by Dean, who has achieved the pinnacle of the landscape design industry in winning a gold medal at
The World's Best Songwriters on Creating the Music that Moves UsThe secrets of songwriting from the legends of musicSong is an enthralling compilation of songwriting wisdom from 100 of the biggest names in music. From country to rock to folk to alternative, this genre-spanning collection of interviews captures the anecdotes, history, and wisdom of the best songwriters around - in their words. An entertaining read as well as an indispensable guide to the art


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IT environments continue to grow in complexity. Organizations today are using multiple database platforms, embracing cloud technologies, and generating enormous volumes of data, and users have increasingly high expectations for availability and performance. These trends increase the pressure on DBAs to proactively find and address performance issues, even as budgets tighten.
This paper outlines the resulting challenges for DBAs, and offers a solution to help.To read white paper, submit the form or sign in.


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Paul Dessau Easy Piano Sheet Music: 1 items found
Paul Dessau (1894-1979) - Easy Piano Pieces
(7 Pieces for Piano Solo). Composed by Paul Dessau (1894-1979). For Piano (Piano). Schott. 16 pages. Schott Music #ED9688. Published by Schott Music (HL.49013063)
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It can be easy to get wrapped-up in the fast pace of this day and age, especially as a college student where the future is a constant concern. The weekly Jewish holiday Shabbat, the day of rest at the end of the week, is supposed to remind people to focus on what is truly important.
Organizations at the University of Wisconsin-Madison like the Jewish Experience of Madison help spread this message by providing free Shabbat dinners for students every week.
JEM is a non-profit organization dedicated to Jewish education. It opened seven years ago, according to Shira Avitan, one of the JEM team members. Avitan and her husband, Rabbi Elie Avitan, moved to Madison from Israel where he was studying to become a Rabbi. This is their second year at JEM.
On Dobra Tea's last day in business, owner Adam Ernst invited the community to come visit the State Street shop to drink tea and shatter teapots from around the world.
The gesture offered him an opportunity to share some of the philosophies surrounding tea culture and to gain a sense of closure as the tea shop closed its doors Feb. 9 after five years in downtown Madison.
"Tea in general encourages us to embrace the imperfection in life, the impermanence in life, and thus smashing teaware is a kind of symbol to communicate to people," Ernst said. "We need that sort of catalytic breaking, smashing and severing of all contacts in order to see and reunite them. Simply as a symbol of impermanence it seemed very effective."
As a teenager, Ernst, a Madison native, discovered a passion for tea far from Wisconsin during a visit to the East Coast.
After four months of restoration, a bar inside the Memorial Union will reopen Monday.
Der Stiftskeller, originally opened in 1962, has had its murals restored, pool tables moved in and the serving bar reborn out of a Terrace tree, those managing the the University of Wisconsin-Madison project said Wednesday at a sneak preview of the restaurant.
In addition to its interior upgrades, the Stiftskeller will add a second window serving the Terrace.
Murals first painted in 1978 were restored, recreated, or in the case of the "Battle of Beer and Wine" painting, relocated from the west wall to the south wall, the UW-Madison said.
The renovations are part of phase one of the university's Memorial Union Reinvestment project, which kicked off in the summer of 2012.
Der Stiftskeller shares the bar with neighbor pub Der Rathskeller.
Madison-area folks are invited to take part in a funky food event next Friday with the chance to be part of a cooking reality TV show.
Madison Area Technical College's Truax campus on Wright Street will host the "Frankenfood" event from noon to 4 p.m. in the gourmet dining room. Frankenfood is a new buzzword for a dish made up of many contrasting parts that would not normally be paired together but stitched together as one, makes sense and tastes good (or at least tastes good to you).
If Madison area residents are looking for a cabin fever cure, area parks offer various trails for a fun snow activity.
Madison Parks spokeswoman Laura Whitmore said snowshoeing is a great way to get outdoors in Wisconsin's winter months and experience the Madison area parks.
In addition to Edna Taylor Conservation Park, snowshoe trails are offered at Cherokee Marsh Mendota and North units, Elvehjem Park, Garner Park, Heritage Prairie, Heritage Sanctuary, Hoyt Park, Knollwood Conservation Park, Mineral Point Park, Prairie Ridge Conservation Park, Sandburg Woods, Walnut Grove Park and Warner Park.
More information is available online at cityofmadison.com/parks/snowshoeing.
Watch News 3's Mary Jo Ola tackle the winter activity at Edna Taylor Conservation Park:
Overture Center for the Arts -
The Frequency
WISC-TV/Channel3000.com, 7025 Raymond Road, Madison, WI 53719
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1 Package of Pure Hydro Gel Under Eye Pads - 10 Pair per Package
These are more affordable alternative to the Blink Gel pads, they contain 10 pairs per package. These pads are lint free and supply a gel like adhesive side for extra strong sticking power.
Posted by Eileen Elliott on 5th Jun 2015
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Posted by Lash Lyn on 4th Jun 2015
I was totally in love with these eye pads, at first. I don't know why gel sometimes expands out. Not as bad as other brands. But occasionally does! I've been meaning to ask why
Posted by Beth on 12th May 2015
I did as instructed but my clients eyelid got glued to the pad...hot mess not good
Posted by erika on 14th Apr 2015
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Posted by Unknown on 26th Mar 2015
Posted by Unknown on 17th Mar 2015
These gel under eye pads are great for Lash lifts, lash tinting and extension work on Asian eyes. Narrow nose bridge area really helps keep lower lashes down or lifted up for tinting.
Posted by Unknown on 3rd Mar 2015
I buy these because the are priced better than a lot of product that is comparable. The only thing that I'm not a fan of with these is they have small rips in some of them from the package and then tear even more when applying to client. Just have to be very delicate when using this product.
Posted by Lash Lyn on 1st Mar 2015
What I like most about these are 1) the size, not too big 2) there isn't too much gel that seeps into clients eyes.
Posted by Unknown on 27th Feb 2015
I love these gel pads. The are slightly stickier than the blink gel pads and cheaper.
Posted by Mishel N on 11th Feb 2015
For the price, they can't be beat. Only problem I have is that they have a tendency to lift on the inner corners.
Posted by Lindsey N on 3rd Feb 2015
Love how cost efficient these ones are! They work great especially on my oilier clients-they stay in place great and don't slide!
Posted by Unknown on 29th Jan 2015
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Posted by caroline on 1st Jan 2015
There pads lift and I have to cut them to fit diff eyes. I also tape them down so they won't lift. I was very disappointed with these pads that I would rather pay a bit more and have a product that works first time round.
Posted by Natalia VP on 27th Nov 2014
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Posted by Unknown on 11th Nov 2014
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Posted by Pamela E on 7th Nov 2014
When i first used them i was so exited! I thought this is such an affordable alternative to spending much more on gel pads. But as i started using them more they really frustrated me with doing my lash sets. They keep moving. They do not have a strong grip nor to they stay in place or fit the eye. I would try to cut it to the shape of the eye, i thought that would fix it but it didn't. They actually lift very often. I didn't like them at all.
Posted by Meagan on 15th Oct 2013
This patch is a more affordable alternative to some of the other under eye gel patches I've tried. It works well for the price, but the shape doesn't fit under the eye very well so you have to cut it to fit the shape better. It also leaves a white goop if the clients' eyes are moist. I would give it 4-5 stars if it weren't for the white residue!


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Last Updated: July 1, 2015
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MVP Blue Hen Tournament 2015
Blue Sharks Practices Announced:
Practices will take place Mondays and Wednesday's beginning 5/27 thru Wednesday 7/15 @ the following times:
4:30-5:30 (3 & 4th Grade (2023/2024) teams)
5:30-7:00 (7th Grade (2020) team)
7:00-8:30 (Both 8th Grade (2019) teams)
Location & Directions:
Stillwell Park Fields
Directly across the street from Syosset HS
Mission Statement
Team Goal:
These next few years are critical for the development of our boys. Our goal is to build a cohesive team coached by experienced Lacrosse coaches (not a parent) with dedicated players and parents who are all united in the mission to develop players' skills and love for the game. The objective is for the team to begin reaching its full potential by the summer before 9th grade. Since we will be striving for individual player development, we will not be concerned with wins and losses in the short term. The team roster will be kept small for each tournament we attend to ensure a lot of playing time for each boy. There will be equal playing time and the #1 priority will be for all of the boys to learn the game and grow as players. The focus will be on individual development, team development and building team chemistry in a positive, family oriented environment where we can build a cohesive unit for the boys as well as the parents. Parent coaching from the sideline will be strongly discouraged, while support and positivity with respect to all of the boys – your own and their teammates - will be strongly encouraged. There will also be a parent liaison to ensure that any questions or concerns are addressed. There will also be a parent liaison whose purpose is to ensure that any questions or concerns are addressed immediately.
Julian Watts – Played 6 seasons in the MLL for the Long Island Lizards / Hamilton Nationals. Julian is currently coaching Varsity Lacrosse at Huntington High School where he is also a Health teacher.
Tom Maloney – Played at Nassau Community College and CW Post where he was the captain of both teams. Tom was an Assistant Varsity Lacrosse coach at St. Anthony's High School in 2012 where he has also taught Physical Education for the past 2 years.
Coaches' Creed:
All LIT Blue shark coaches will adhere to the following guidelines when coaching:
There will be equal playing time, since skill development and team chemistry is paramount over wins. There will be no "negative" berating or demeaning of the boys; the coaches will instill discipline, hard work and have set expectations of the boys and the team. The coaches will not have a set "man up" or "man down" team so that each player will have a chance to learn and participate in those roles. The coaches will implement a team-based offense, not one based on individual play.
For a complete calendar listing, click here!


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Special Events
Tuesday, September 8
Berkeley Open House
Learn more about OLLI's courses, lectures, and social programming and hear directly from the faculty about the courses and workshops they will be teaching.
Doors open at 9:30 a.m., program begins at 10:00 a.m. No need to RSVP!
Complimentary coffee.
Thursday, September 10
Lafayette Info Session
Meet Lafayette faculty and OLLI members and learn about the courses and workshops offered in Lafayette and Berkeley in the coming term.
Tech law attorney (and OLLI instructor) Eric Sinrod will also give a talk entitled "The Internet - Privacy Lost?"
Spring 2015
Spring term courses meet for six weeks, unless otherwise noted. When available, course syllabi can be viewed via the link below the instructor bio. If a course is full, call 510-642-9934 or email firstname.lastname@example.com to be added to a waitlist.
Wednesday, April 8
Annual Member Meeting
Keynote address by Gibor Basri, Vice Chancellor for Equity and Inclusion at UC Berkeley: "Diversity and Inclusion in a Lifelong Learning Community


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