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1.  CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders 
Translational Psychiatry  2013;3(8):e293-.
β-amyloid (Aβ) plaque accumulation is a hallmark of Alzheimer's disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aβ1–42 (Aβ42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Aβ metabolism predict the development of Aβ plaques, assessed by longitudinal CSF Aβ42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2–4 years). There was an overall reduction in Aβ42 from a mean concentration of 211–195 pg ml−1 after 4 years. Linear mixed-effects models using longitudinal Aβ42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Aβ metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aβ42. The most significant proteins were angiotensin-converting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiver-operating characteristic analysis identified 11 proteins with significant effects on longitudinal Aβ42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aβ42 reduction only in subjects with normal baseline Aβ42, and not in subjects with reduced baseline Aβ42. We conclude that baseline CSF proteins related to Aβ metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders. The finding that some proteins only predict Aβ42 reduction in subjects with normal baseline Aβ42 suggest that they predict future development of the brain Aβ pathology at the earliest stages of AD, prior to widespread development of Aβ plaques.
doi:10.1038/tp.2013.69
PMCID: PMC3756294  PMID: 23962923
Alzheimer's disease; beta-amyloid; biomarker; cerebrospinal fluid; longitudinal; microglia
2.  Genome-wide association study of CSF biomarkers Aβ1-42, t-tau, and p-tau181p in the ADNI cohort 
Neurology  2010;76(1):69-79.
Objectives:
CSF levels of Aβ1-42, t-tau, and p-tau181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aβ1-42, t-tau, p-tau181p, p-tau181p/Aβ1-42, and t-tau/Aβ1-42).
Methods:
A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p < 0.01 (uncorrected p < 3.10 × 10−8) and secondarily examined SNPs with uncorrected p values less than 10−5 to identify potential candidates.
Results:
Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates.
Conclusions:
In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.
doi:10.1212/WNL.0b013e318204a397
PMCID: PMC3030225  PMID: 21123754
3.  Plasma biomarkers of depressive symptoms in older adults 
Translational Psychiatry  2012;2(1):e65-.
The pathophysiology of negative affect states in older adults is complex, and a host of central nervous system and peripheral systemic mechanisms may play primary or contributing roles. We conducted an unbiased analysis of 146 plasma analytes in a multiplex biochemical biomarker study in relation to number of depressive symptoms endorsed by 566 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) at their baseline and 1-year assessments. Analytes that were most highly associated with depressive symptoms included hepatocyte growth factor, insulin polypeptides, pregnancy-associated plasma protein-A and vascular endothelial growth factor. Separate regression models assessed contributions of past history of psychiatric illness, antidepressant or other psychotropic medicine, apolipoprotein E genotype, body mass index, serum glucose and cerebrospinal fluid (CSF) τ and amyloid levels, and none of these values significantly attenuated the main effects of the candidate analyte levels for depressive symptoms score. Ensemble machine learning with Random Forests found good accuracy (∼80%) in classifying groups with and without depressive symptoms. These data begin to identify biochemical biomarkers of depressive symptoms in older adults that may be useful in investigations of pathophysiological mechanisms of depression in aging and neurodegenerative dementias and as targets of novel treatment approaches.
doi:10.1038/tp.2011.63
PMCID: PMC3309547  PMID: 22832727
Alzheimer's disease neuroimaging initiative; biochemical biomarker; geriatric depression; mild cognitive impairment
4.  Novel CSF biomarkers for frontotemporal lobar degenerations(e–Pub ahead of print) 
Neurology  2010;75(23):2079-2086.
Objective:
To identify antemortem CSF diagnostic biomarkers that can potentially distinguish between the 2 main causes of frontotemporal lobar degeneration (FTLD), i.e., FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau).
Methods:
CSF samples were collected antemortem from 23 patients with FTLD with known pathology to form a autopsy cohort as part of a comparative biomarker study that additionally included 33 living cognitively normal subjects and 66 patients with autopsy-confirmed Alzheimer disease (AD). CSF samples were also collected from 80 living patients clinically diagnosed with frontotemporal dementia (FTD). Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in neuropeptides, cytokines, and growth factors, along with levels of CSF biomarkers for AD.
Results:
CSF levels of multiple analytes differed between FTLD-TDP and FTLD-tau, including Fas, neuropeptides (agouti-related peptide and adrenocorticotropic hormone), and chemokines (IL-23, IL-17). Classification by random forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%) in the autopsy cohort. When the classification algorithm was applied to a living FTD cohort, semantic dementia was the phenotype with the highest predicted proportion of FTLD-TDP. When living patients with behavioral variant FTD were examined in detail, those predicted to have FTLD-TDP demonstrated neuropsychological differences vs those predicted to have FTLD-tau in a pattern consistent with previously reported trends in autopsy-confirmed cases.
Conclusions:
Clinical cases with FTLD-TDP and FTLD-tau pathology can be potentially identified antemortem by assaying levels of specific analytes that are well-known and readily measurable in CSF.
GLOSSARY
= Alzheimer disease;
= Aguti-related protein;
= angiopoietin-2;
= adrenocorticotropic hormone;
= amyotrophic lateral sclerosis;
= apolipoprotein B;
= behavioral variant FTD;
= corticobasal syndrome;
= frontotemporal dementia;
= frontotemporal lobar degeneration;
= frontotemporal lobar degeneration with tau pathology;
= frontotemporal lobar degeneration with TDP-43 pathology;
= interleukin;
= macrophage-derived chemokine;
= progressive nonfluent aphasia;
= primary progressive aphasia;
= progressive supranuclear palsy;
= S100 calcium binding protein b;
= semantic dementia;
= tumor necrosis factor-related apoptosis-inducing ligand receptor 3.
doi:10.1212/WNL.0b013e318200d78d
PMCID: PMC2995537  PMID: 21048198
5.  Effective Vaccination Policies 
Information sciences  2010;180(19):3728-3744.
We present a framework for modeling the spread of pathogens throughout a population and generating policies that minimize the impact of those pathogens on the population. This framework is used to study the spread of human viruses between cities via airplane travel. It combines agent-based simulation, mathematical analysis, and an Evolutionary Algorithm (EA) optimizer. The goal of this study is to develop tools that determine the optimal distribution of a vaccine supply in the model. Using plausible benchmark vaccine allocation policies of uniform and proportional distribution, we compared their effectiveness to policies found by the EA. We then designed and tested a new, more effective policy which increased the importance of vaccinating smaller cities that are flown to more often. This “importance factor” was validated using U.S. influenza data from the last four years.
doi:10.1016/j.ins.2010.06.005
PMCID: PMC2967767  PMID: 21057602
epidemiology; evolutionary algorithm; influenza; migration; vaccination
6.  CSF amyloid β 1-42 predicts cognitive decline in Parkinson disease(e–Pub ahead of print) 
Neurology  2010;75(12):1055-1061.
Objective:
Cognitive decline associated with Parkinson disease (PD) is common and highly disabling. Biomarkers that help identify patients at risk for cognitive decline would be useful additions to the clinical management of the disease.
Methods:
A total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation. CSF was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2). CSF was tested for amyloid β 1-42 (Aβ1-42), p-tau181p, and total tau levels using the Luminex xMAP platform. Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time.
Results:
Lower baseline CSF Aβ1-42 was associated with more rapid cognitive decline. Subjects with CSF Aβ1-42 levels ≤192 pg/mL declined an average of 5.85 (95% confidence interval 2.11–9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cutoff, after adjustment for age, disease duration, and baseline cognitive status. CSF total tau and p-tau181p levels were not significantly associated with cognitive decline.
Conclusions:
Reduced CSF Aβ1-42 was an independent predictor of cognitive decline in patients with PD. This observation is consistent with previous research showing that Alzheimer disease pathology contributes to cognitive impairment in PD. This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD.
GLOSSARY
= Alzheimer disease;
= Alzheimer's Disease Neuroimaging Initiative;
= confidence interval;
= dementia with Lewy bodies;
= Dementia Rating Scale (version 2);
= Hoehn & Yahr;
= Parkinson disease;
= Parkinson disease dementia.
doi:10.1212/WNL.0b013e3181f39a78
PMCID: PMC2942062  PMID: 20720189
7.  Comparing predictors of conversion and decline in mild cognitive impairment(Podcast)(e–Pub ahead of print) 
Neurology  2010;75(3):230-238.
Objective:
A variety of measurements have been individually linked to decline in mild cognitive impairment (MCI), but the identification of optimal markers for predicting disease progression remains unresolved. The goal of this study was to evaluate the prognostic ability of genetic, CSF, neuroimaging, and cognitive measurements obtained in the same participants.
Methods:
APOE ε4 allele frequency, CSF proteins (Aβ1-42, total tau, hyperphosphorylated tau [p-tau181p]), glucose metabolism (FDG-PET), hippocampal volume, and episodic memory performance were evaluated at baseline in patients with amnestic MCI (n = 85), using data from a large multisite study (Alzheimer's Disease Neuroimaging Initiative). Patients were classified as normal or abnormal on each predictor variable based on externally derived cutoffs, and then variables were evaluated as predictors of subsequent conversion to Alzheimer disease (AD) and cognitive decline (Alzheimer's Disease Assessment Scale–Cognitive Subscale) during a variable follow-up period (1.9 ± 0.4 years).
Results:
Patients with MCI converted to AD at an annual rate of 17.2%. Subjects with MCI who had abnormal results on both FDG-PET and episodic memory were 11.7 times more likely to convert to AD than subjects who had normal results on both measures (p ≤ 0.02). In addition, the CSF ratio p-tau181p/Aβ1-42 (β = 1.10 ± 0.53; p = 0.04) and, marginally, FDG-PET predicted cognitive decline.
Conclusions:
Baseline FDG-PET and episodic memory predict conversion to AD, whereas p-tau181p/Aβ1-42 and, marginally, FDG-PET predict longitudinal cognitive decline. Complementary information provided by these biomarkers may aid in future selection of patients for clinical trials or identification of patients likely to benefit from a therapeutic intervention.
GLOSSARY
= Alzheimer disease;
= Alzheimer's Disease Assessment Scale–Cognitive Subscale;
= Alzheimer's Disease Neuroimaging Initiative;
= Auditory Verbal Learning Test;
= Clinical Dementia Rating;
= confidence interval;
= [18F]fluorodeoxyglucose;
= mild cognitive impairment;
= Montreal Neurological Institute;
= hyperphosphorylated tau;
= receiver operating characteristic;
= total tau.
doi:10.1212/WNL.0b013e3181e8e8b8
PMCID: PMC2906178  PMID: 20592257
8.  Serial MRI and CSF biomarkers in normal aging, MCI, and AD 
Neurology  2010;75(2):143-151.
Objective:
To compare the annual change in MRI and CSF biomarkers in cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer disease (AD). Comparisons were based on intergroup discrimination, correlation with concurrent cognitive/functional changes, relationships to APOE genotype, and sample sizes for clinical trials.
Methods:
We used data from the Alzheimer's Disease Neuroimaging Initiative study consisting of CN, aMCI, and AD cohorts with both baseline and 12-month follow-up CSF and MRI. The annual change in CSF (total-tau [t-tau], Aβ1-42) and MRI (change in ventricular volume) was obtained in 312 subjects (92 CN, 149 aMCI, 71 AD).
Results:
There was no significant average annual change in either CSF biomarker in any clinical group except t-tau in CN; moreover, the annual change did not differ by clinical group in pairwise comparisons. In contrast, annual increase in ventricular volume increased in the following order, AD > aMCI > CN, and differences were significant between all clinical groups in pairwise comparisons. Ventricular volume increase correlated with concurrent worsening on cognitive/functional indices in aMCI and AD whereas evidence of a similar correlation with change in CSF measures was unclear. The annual changes in MRI differed by APOE ε4 status overall and among aMCI while annual changes in CSF biomarkers did not. Estimated sample sizes for clinical trials are notably less for MRI than the CSF or clinical measures.
Conclusions:
Unlike the CSF biomarkers evaluated, changes in serial structural MRI are correlated with concurrent change on general cognitive and functional indices in impaired subjects, track with clinical disease stage, and are influenced by APOE genotype.
GLOSSARY
= Alzheimer disease;
= Alzheimer's Disease Assessment Scale–cognitive subscale;
= Alzheimer's Disease Neuroimaging Initiative;
= amnestic mild cognitive impairment;
= area under the receiver operator characteristic curve;
= boundary shift integral;
= Clinical Dementia Rating–sum of boxes;
= cognitively normal;
= Mini-Mental State Examination;
= neurofibrillary tangle;
= neuropil thread;
= Pittsburgh compound B;
= total-tau.
doi:10.1212/WNL.0b013e3181e7ca82
PMCID: PMC2905929  PMID: 20625167
9.  Clinical core of the Alzheimer's Disease Neuroimaging Initiative: progress and plans 
The Clinical Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has provided clinical, operational and data management support to ADNI since its inception. This paper reviews the activities and accomplishments of the core in support of ADNI aims. These include the enrollment and follow-up of over 800 subjects in the three original cohorts: healthy controls, amnestic MCI (now referred to as late MCI, or LMCI) and mild Alzheimer's disease (AD) in the first phase of ADNI (ADNI 1), with baseline longitudinal clinical and cognitive assessments. These data, when combined with genetic, neuroimaging and cerebrospinal fluid measures, have provided important insights into the neurobiology of the AD spectrum. Further, these data have facilitated the development of novel clinical trial designs. ADNI has recently been extended with funding from an NIH Grand Opportunities (GO) award, and the new ADNI GO phase has been launched; this includes the enrollment of a new cohort, called early MCI (EMCI), with milder episodic memory impairment than the LMCI group. An application for a further 5 years of ADNI funding (ADNI 2) was recently submitted. This funding would support ongoing follow-up of the original ADNI 1 and ADNI GO cohorts, as well as additional recruitment into all categories. The resulting data would provide valuable data on the earliest stages of AD, and support the development of interventions in these critically important populations.
doi:10.1016/j.jalz.2010.03.006
PMCID: PMC2867843  PMID: 20451872
Alzheimer's disease; ADNI; clinical trials
10.  Alzheimer's Disease Neuroimaging Initiative (ADNI) 
Neurology  2010;74(3):201-209.
Background:
Neuroimaging measures and chemical biomarkers may be important indices of clinical progression in normal aging and mild cognitive impairment (MCI) and need to be evaluated longitudinally.
Objective:
To characterize cross-sectionally and longitudinally clinical measures in normal controls, subjects with MCI, and subjects with mild Alzheimer disease (AD) to enable the assessment of the utility of neuroimaging and chemical biomarker measures.
Methods:
A total of 819 subjects (229 cognitively normal, 398 with MCI, and 192 with AD) were enrolled at baseline and followed for 12 months using standard cognitive and functional measures typical of clinical trials.
Results:
The subjects with MCI were more memory impaired than the cognitively normal subjects but not as impaired as the subjects with AD. Nonmemory cognitive measures were only minimally impaired in the subjects with MCI. The subjects with MCI progressed to dementia in 12 months at a rate of 16.5% per year. Approximately 50% of the subjects with MCI were on antidementia therapies. There was minimal movement on the Alzheimer's Disease Assessment Scale–Cognitive Subscale for the normal control subjects, slight movement for the subjects with MCI of 1.1, and a modest change for the subjects with AD of 4.3. Baseline CSF measures of Aβ-42 separated the 3 groups as expected and successfully predicted the 12-month change in cognitive measures.
Conclusion:
The Alzheimer's Disease Neuroimaging Initiative has successfully recruited cohorts of cognitively normal subjects, subjects with mild cognitive impairment (MCI), and subjects with Alzheimer disease with anticipated baseline characteristics. The 12-month progression rate of MCI was as predicted, and the CSF measures heralded progression of clinical measures over 12 months.
GLOSSARY
= Alzheimer disease;
= Alzheimer's Disease Assessment Scale–Cognitive subscale;
= Alzheimer's Disease Neuroimaging Initiative;
= confidence interval;
= mild cognitive impairment;
= Mini-Mental State Examination.
doi:10.1212/WNL.0b013e3181cb3e25
PMCID: PMC2809036  PMID: 20042704
11.  Relationships between biomarkers in aging and dementia 
Neurology  2009;73(15):1193-1199.
Background:
PET imaging using [18F]fluorodeoxyglucose (FDG) and [11C]Pittsburgh compound B (PIB) have been proposed as biomarkers of Alzheimer disease (AD), as have CSF measures of the 42 amino acid β-amyloid protein (Aβ1-42) and total and phosphorylated tau (t-tau and p-tau). Relationships between biomarkers and with disease severity are incompletely understood.
Methods:
Ten subjects with AD, 11 control subjects, and 34 subjects with mild cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative underwent clinical evaluation; CSF measurement of Aβ1-42, t-tau, and p-tau; and PIB-PET and FDG-PET scanning. Data were analyzed using continuous regression and dichotomous outcomes with subjects classified as “positive” or “negative” for AD based on cutoffs established in patients with AD and controls from other cohorts.
Results:
Dichotomous categorization showed substantial agreement between PIB-PET and CSF Aβ1-42 measures (91% agreement, κ = 0.74), modest agreement between PIB-PET and p-tau (76% agreement, κ = 0.50), and minimal agreement for other comparisons (κ <0.3). Mini-Mental State Examination score was significantly correlated with FDG-PET but not with PIB-PET or CSF Aβ1-42. Regression models adjusted for diagnosis showed that PIB-PET was significantly correlated with Aβ1-42, t-tau, and p-tau181p, whereas FDG-PET was correlated only with Aβ1-42.
Conclusions:
PET and CSF biomarkers of Aβ agree with one another but are not related to cognitive impairment. [18F]fluorodeoxyglucose-PET is modestly related to other biomarkers but is better related to cognition. Different biomarkers for Alzheimer disease provide different information from one another that is likely to be complementary.
GLOSSARY
β1-42 = 42 amino acid β-amyloid protein;
= Alzheimer disease;
= Alzheimer’s Disease Neuroimaging Initiative;
= Clinical Dementia Rating;
= confidence interval;
= [18F]fluorodeoxyglucose;
= mild cognitive impairment;
= Mini-Mental State Examination;
= magnetic resonance;
= [11C]Pittsburgh compound B;
= phosphorylated tau;
= receiver operating characteristic;
= region of interest;
= standardized uptake value ratio;
= total tau;
= Wechsler Memory Scale–Revised.
doi:10.1212/WNL.0b013e3181bc010c
PMCID: PMC2764726  PMID: 19822868
12.  Inhibition of protein kinase CK2 suppresses angiogenesis and hematopoietic stem cell recruitment to retinal neovascularization sites 
Molecular and cellular biochemistry  2008;316(1-2):177-186.
Ubiquitous protein kinase CK2 participates in a variety of key cellular functions. We have explored CK2 involvement in angiogenesis. As shown previously, CK2 inhibition reduced endothelial cell proliferation, survival and migration, tube formation, and secondary sprouting on Matrigel. Intraperitoneally administered CK2 inhibitors significantly reduced preretinal neovascularization in a mouse model of proliferative retinopathy. In this model, CK2 inhibitors had an additive effect with somatostatin analog, octreotide, resulting in marked dose reduction for the drug to achieve the same effect. CK2 inhibitors may thus emerge as potent future drugs aimed at inhibiting pathological angiogenesis. Immunostaining of the retina revealed predominant CK2 expression in astrocytes. In human diabetic retinas, mRNA levels of all CK2 subunits decreased, consistent with increased apoptosis. Importantly, a specific CK2 inhibitor prevented recruitment of bone marrow-derived hematopoietic stem cells to areas of retinal neovascularization. This may provide a novel mechanism of action of CK2 inhibitors on newly forming vessels.
doi:10.1007/s11010-008-9831-4
PMCID: PMC2913688  PMID: 18612802
CK2; Retina; Endothelial; Astrocyte; Diabetes; Neovascularization; Hematopoietic stem cell; TBB; TBCA; Emodin; DRB
13.  MRI and CSF biomarkers in normal, MCI, and AD subjects 
Neurology  2009;73(4):287-293.
Objective:
To assess the correlations of both MRI and CSF biomarkers with clinical diagnosis and with cognitive performance in cognitively normal (CN) subjects and patients with amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD).
Methods:
This is a cross-sectional study with data from the Alzheimer's Disease Neuroimaging Initiative, which consists of CN subjects, subjects with aMCI, and subjects with AD with both CSF and MRI. Baseline CSF (t-tau, Aβ1-42, and p-tau181P) and MRI scans were obtained in 399 subjects (109 CN, 192 aMCI, 98 AD). Structural Abnormality Index (STAND) scores, which reflect the degree of AD-like anatomic features on MRI, were computed for each subject.
Results:
We found no significant correlation between CSF biomarkers and cognitive scores in any of the 3 clinical groups individually. Conversely, STAND scores correlated with both Clinical Dementia Rating–sum of boxes and Mini-Mental State Examination in aMCI and AD (p ≤ 0.01). While STAND and all CSF biomarkers were predictors of clinical group membership (CN, aMCI, or AD) univariately (p < 0.001), STAND was more predictive than CSF both univariately and in combined models.
Conclusions:
CSF and MRI biomarkers independently contribute to intergroup diagnostic discrimination and the combination of CSF and MRI provides better prediction than either source of data alone. However, MRI provides greater power to effect cross-sectional groupwise discrimination and better correlation with general cognition and functional status cross-sectionally. We therefore conclude that although MRI and CSF provide complementary information, MRI reflects clinically defined disease stage better than the CSF biomarkers tested.
GLOSSARY
= Alzheimer disease;
= Alzheimer's Disease Neuroimaging Initiative;
= amnestic mild cognitive impairment;
= area under the receiver operating characteristic curve;
= Clinical Dementia Rating–sum of boxes score;
= confidence interval;
= cognitively normal;
= evidence-based medicine;
= entorhinal cortex;
= Mini-Mental State Examination;
= neurofibrillary tangle;
= proportional odds logistic regression;
= Structural Abnormality Index.
doi:10.1212/WNL.0b013e3181af79e5
PMCID: PMC2715210  PMID: 19636048
14.  MRI and CSF biomarkers in normal, MCI, and AD subjects 
Neurology  2009;73(4):294-301.
Objective:
To investigate the relationship between baseline MRI and CSF biomarkers and subsequent change in continuous measures of cognitive and functional abilities in cognitively normal (CN) subjects and patients with amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD) and to examine the ability of these biomarkers to predict time to conversion from aMCI to AD.
Methods:
Data from the Alzheimer's Disease Neuroimaging Initiative, which consists of CN, aMCI, and AD cohorts with both CSF and MRI, were used. Baseline CSF (t-tau, Aβ1–42, and p-tau181P) and MRI scans were obtained in 399 subjects (109 CN, 192 aMCI, 98 AD). Structural Abnormality Index (STAND) scores, which reflect the degree of AD-like features in MRI, were computed for each subject.
Results:
Change on continuous measures of cognitive and functional performance was modeled as average Clinical Dementia Rating–sum of boxes and Mini-Mental State Examination scores over a 2-year period. STAND was a better predictor of subsequent cognitive/functional change than CSF biomarkers. Single-predictor Cox proportional hazard models for time to conversion from aMCI to AD showed that STAND and log (t-tau/Aβ1–42) were both predictive of future conversion. The age-adjusted hazard ratio for an interquartile change (95% confidence interval) of STAND was 2.6 (1.7, 4.2) and log (t-tau/Aβ1–42) was 2.0 (1.1, 3.4). Both MRI and CSF provided information about future cognitive change even after adjusting for baseline cognitive performance.
Conclusions:
MRI and CSF provide complimentary predictive information about time to conversion from amnestic mild cognitive impairment to Alzheimer disease and combination of the 2 provides better prediction than either source alone. However, we found that MRI was a slightly better predictor of future clinical/functional decline than the CSF biomarkers tested.
GLOSSARY
= Alzheimer disease;
= Alzheimer's Disease Neuroimaging Initiative;
= amnestic mild cognitive impairment;
= Clinical Dementia Rating–sum of boxes score;
= confidence interval;
= cognitively normal;
= hazard ratio;
= Mini-Mental State Examination;
= neurofibrillary tangle;
= Structural Abnormality Index.
doi:10.1212/WNL.0b013e3181af79fb
PMCID: PMC2715214  PMID: 19636049
15.  Diagnostic and clinical perspectives of fusion imaging in cardiology: is the total greater than the sum of its parts? 
Heart  2005;93(1):16-22.
Positron emission tomography, cardiovascular magnetic resonance and multislice computed tomography have contributed to changing our pathophysiological understanding of many conditions. Clinically, they have provided new tools for the identification of preclinical disease and a better understanding of how disease progresses. The application of these imaging modalities to preclinical disease and the use of these techniques in patients with overt cardiovascular disease are reviewed.
doi:10.1136/hrt.2005.075283
PMCID: PMC1861351  PMID: 16387827
16.  Effects of probiotics on atopic dermatitis 
PMCID: PMC2065998  PMID: 16551799
probiotics; atopic dermatitis
17.  MRI of hippocampal volume loss in early Alzheimer's disease in relation to ApoE genotype and biomarkers 
Brain  2009;132(4):1067-1077.
Hippocampal volume change over time, measured with MRI, has huge potential as a marker for Alzheimer's disease. The objectives of this study were: (i) to test if constant and accelerated hippocampal loss can be detected in Alzheimer's disease, mild cognitive impairment and normal ageing over short periods, e.g. 6–12 months, with MRI in the large multicentre setting of the Alzheimer's Disease Neuroimaging Initiative (ADNI); (ii) to determine the extent to which the polymorphism of the apolipoprotein E (ApoE) gene modulates hippocampal change; and (iii) to determine if rates of hippocampal loss correlate with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, such as the β-amyloid (Aβ1–42) and tau proteins (tau). The MRI multicentre study included 112 cognitive normal elderly individuals, 226 mild cognitive impairment and 96 Alzheimer's disease patients who all had at least three successive MRI scans, involving 47 different imaging centres. The mild cognitive impairment and Alzheimer's disease groups showed hippocampal volume loss over 6 months and accelerated loss over 1 year. Moreover, increased rates of hippocampal loss were associated with presence of the ApoE allele ɛ4 gene in Alzheimer's disease and lower CSF Aβ1–42 in mild cognitive impairment, irrespective of ApoE genotype, whereas relations with tau were only trends. The power to measure hippocampal change was improved by exploiting correlations statistically between successive MRI observations. The demonstration of considerable hippocampal loss in mild cognitive impairment and Alzheimer's disease patients over only 6 months and accelerated loss over 12 months illustrates the power of MRI to track morphological brain changes over time in a large multisite setting. Furthermore, the relations between faster hippocampal loss in the presence of ApoE allele ɛ4 and decreased CSF Aβ1–42 supports the concept that increased hippocampal loss is an indicator of Alzheimer's disease pathology and a potential marker for the efficacy of therapeutic interventions in Alzheimer's disease.
doi:10.1093/brain/awp007
PMCID: PMC2668943  PMID: 19251758
MRI; mild cognitive impairment; ageing; human brain mapping; hippocampus
18.  Myocardial perfusion scintigraphy: the evidence 
This review summarises the evidence for the role of myocardial perfusion scintigraphy (MPS) in patients with known or suspected coronary artery disease. It is the product of a consensus conference organised by the British Cardiac Society, the British Nuclear Cardiology Society and the British Nuclear Medicine Society and is endorsed by the Royal College of Physicians of London and the Royal College of Radiologists. It was used to inform the UK National Institute of Clinical Excellence in their appraisal of MPS in patients with chest pain and myocardial infarction. MPS is a well-established, non-invasive imaging technique with a large body of evidence to support its effectiveness in the diagnosis and management of angina and myocardial infarction. It is more accurate than the exercise ECG in detecting myocardial ischaemia and it is the single most powerful technique for predicting future coronary events. The high diagnostic accuracy of MPS allows reliable risk stratification and guides the selection of patients for further interventions, such as revascularisation. This in turn allows more appropriate utilisation of resources, with the potential for both improved clinical outcomes and greater cost-effectiveness. Evidence from modelling and observational studies supports the enhanced cost-effectiveness associated with MPS use. In patients presenting with stable or acute chest pain, strategies of investigation involving MPS are more cost-effective than those not using the technique. MPS also has particular advantages over alternative techniques in the management of a number of patient subgroups, including women, the elderly and those with diabetes, and its use will have a favourable impact on cost-effectiveness in these groups. MPS is already an integral part of many clinical guidelines for the investigation and management of angina and myocardial infarction. However, the technique is underutilised in the UK, as judged by the inappropriately long waiting times and by comparison with the numbers of revascularisations and coronary angiograms performed. Furthermore, MPS activity levels in this country fall far short of those in comparable European countries, with about half as many scans being undertaken per year. Currently, the number of MPS studies performed annually in the UK is 1,200/million population/year. We estimate the real need to be 4,000/million/year. The current average waiting time is 20 weeks and we recommend that clinically appropriate upper limits of waiting time are 6 weeks for routine studies and 1 week for urgent studies.
doi:10.1007/s00259-003-1344-5
PMCID: PMC2562441  PMID: 15129710
19.  Cardiac imaging in coronary artery disease: differing modalities 
Heart  2005;91(8):1110-1117.
doi:10.1136/hrt.2005.061408
PMCID: PMC1769025  PMID: 16020614
coronary artery disease; atherosclerosis; imaging; diagnosis
20.  Myocardial perfusion scintigraphy and cost effectiveness of diagnosis and management of coronary heart disease 
Heart  2004;90(Suppl 5):v34-v36.
doi:10.1136/hrt.2003.019133
PMCID: PMC1876325  PMID: 15254007
21.  Hepatitis C virus among childbearing women in Scotland: prevalence, deprivation, and diagnosis 
Gut  2004;53(4):593-598.
Objectives: (A) To examine the prevalence and demographic characteristics of hepatitis C virus (HCV) infection among childbearing women in Scotland; and (B) to determine the extent of maternal HCV infection diagnosed prior to birth.
Methods: (A) Residual dried blood spot samples from routine neonatal screening, collected throughout Scotland during March-October 2000, were unlinked from identifiers and tested anonymously for HCV antibodies; and (B) electronic record linkage of Scotland’s databases of births and diagnosed HCV infections was performed.
Results: (A) Of 30 259 samples, 121 were enzyme linked immunosorbent assay repeat reactive and 88 of these were confirmed as anti-HCV positive in the recombinant immunoblot assay, representing a seroprevalence of 0.29–0.40%. HCV seroprevalence was high among 25–29 year olds (0.4–0.57%), in high deprivation areas (0.92–1.07%), and in Greater Glasgow (0.83–0.96%) and Grampian (0.38–0.62%). Adjusted relative risk for HCV infection was highest among residents in high deprivation areas of Glasgow (7.2 (95% confidence interval 2.0–25.5)). (B) Of 121 HCV infections found among women at delivery, 24% and 46% were estimated to have been diagnosed prior to pregnancy and birth, respectively.
Conclusions: HCV prevalence among Scottish childbearing women is consistent with that expected from injecting drug use. Based on reported rates of mother to child transmission, 8–11 paediatric infections are expected per annum. Diagnosis in only 24% of infected women prior to pregnancy indicates the extent to which HCV goes unrecognised in the injecting community. The current HCV screening approach—to test only those with a history of injecting drug use (or other risk factors for infection)—identifies approximately a quarter of previously undetected infections among pregnant women.
doi:10.1136/gut.2003.027383
PMCID: PMC1774001  PMID: 15016757
hepatitis C; pregnancy; deprivation; antenatal screening
22.  Pneumococcal nasopharyngeal carriage in children following heptavalent pneumococcal conjugate vaccination in infancy 
Archives of Disease in Childhood  2003;88(3):211-214.
Aims: To ascertain whether the reduction in nasopharyngeal carriage of vaccine serotypes induced by pneumococcal conjugate vaccine (PnCV) administered to infants persists beyond the age of 2 years.
Methods: Non-randomised, unblinded controlled study of 2–5 year old children who had received three doses of heptavalent PnCV (7VPnCV) in infancy and 23-valent pneumococcal polysaccharide vaccine at 13 months, and unimmunised controls. Nasopharyngeal swabs were taken in summer (150 vaccinated subjects, 126 controls) and winter (143 vaccinated subjects, 188 controls). The swabs were cultured and serotyped for Streptococcus pneumoniae.
Results: Carriage rates (vaccinated subjects: 24.7% and 43.4%; controls: 27.0% and 41.0%, in summer and winter respectively) and carriage of vaccine serotypes (subjects: 10.0% and 30.0%; controls: 13.5% and 31.5%, in summer and winter respectively) were similar in the two groups.
Conclusions: Effects of vaccination in infancy on rates of nasal carriage of pneumococcus and serotype replacement in children living in a largely unvaccinated population are no longer evident by 2–5 years of age.
doi:10.1136/adc.88.3.211
PMCID: PMC1719498  PMID: 12598380
23.  Safety of a new conjugate meningococcal C vaccine in infants 
Archives of Disease in Childhood  2001;85(5):391-397.
BACKGROUND—Group C conjugate meningococcal vaccines (Men C) were introduced into the UK primary immunisation schedule in November 1999.There has been extensive professional and public interest in their efficacy and safety.
AIM—To determine the occurrence of at least one uncommon adverse event in infants related to the administration of the Chiron Men C vaccine.
METHODS—A total of 2796 infants aged approximately 2 months were recruited into the study from areas in and around Sheffield and from Scotland. They were vaccinated with the Chiron Men C vaccine at 2, 3, and 4 months along with routine immunisations. Data on adverse events occurring one month after each dose were collected actively and prospectively and reviewed for possible relation to the vaccine.
RESULTS—There were no deaths. There were no serious adverse events considered definitely or probably caused by the vaccine. Four infants developed serious adverse events (hypotonia, screaming syndrome, maculopapular rash, and agitation, respectively) that were considered possibly related to the vaccine. All recovered completely. Adverse events were seen in 1804 children but were considered possibly related to the vaccine in only 49 (1.8%). On subsequent immunisation there were no recurrences of adverse events considered to be possibly related to the vaccine.


doi:10.1136/adc.85.5.391
PMCID: PMC1718967  PMID: 11668101
24.  Identification of genes differentially expressed in T cells following stimulation with the chemokines CXCL12 and CXCL10 
BMC Immunology  2004;5:17.
Background
Chemokines are involved in many biological activities ranging from leukocyte differentiation to neuronal morphogenesis. Despite numerous reports describing chemokine function, little is known about the molecular changes induced by cytokines.
Methods
We have isolated and identified by differential display analysis 182 differentially expressed cDNAs from CXCR3-transfected Jurkat T cells following treatment with CXCL12 or CXCL10. These chemokine-modulated genes were further verified using quantitative RT-PCR and Western blot analysis.
Results
One hundred and forty-six of the cDNAs were successfully cloned, sequenced, and identified by BLAST. Following removal of redundant and non-informative clones, seventeen mRNAs were found to be differentially expressed post treatment with either chemokine ligand with several representing known genes with established functions. Twenty-one genes were upregulated in these transfected Jurkat cells following both CXCL12 and CXCL10, four genes displayed a discordant response and seven genes were downregulated upon treatment with either chemokine. Identified genes include geminin (GEM), thioredoxin (TXN), DEAD/H box polypeptide 1 (DDX1), growth hormone inducible transmembrane protein (GHITM), and transcription elongation regulator 1 (TCERG1). Subsequent analysis of several of these genes using semi-quantitative PCR and western blot analysis confirmed their differential expression post ligand treatment.
Conclusions
Together, these results provide insight into chemokine-induced gene activation and identify potentially novel functions for known genes in chemokine biology.
doi:10.1186/1471-2172-5-17
PMCID: PMC514893  PMID: 15296517
25.  Electronic communication in ethics committees: experience and challenges 
Journal of Medical Ethics  2001;27(Suppl 1):i30-i32.
Experience with electronic communication in ethics committees at two hospitals is reviewed and discussed. A listserver of ethics committee members transmitted a synopsis of the ethics consultation shortly after the consultation was initiated. Committee comments were sometimes incorporated into the recommendations. This input proved to be most useful in unusual cases where additional, diverse inputs were informative. Efforts to ensure confidentiality are vital to this approach. They include not naming the patient in the e-mail, requiring a password for access to the listserver, and possibly encryption. How this electronic communication process alters group interactions in ethics committees is a fruitful area for future investigation.
Key Words: Clinical ethics committees • electronic communication • confidentiality
doi:10.1136/jme.27.suppl_1.i30
PMCID: PMC1765532  PMID: 11314609

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