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1.  CSF VILIP-1 predicts rates of cognitive decline in early Alzheimer disease 
Neurology  2012;78(10):709-719.
Measures of neuronal damage/dysfunction are likely good surrogates for disease progression in Alzheimer disease (AD). CSF markers of neuronal injury may offer utility in predicting disease progression and guiding prognostic and outcome assessments in therapeutic trials. Visinin-like protein-1 (VILIP-1) has demonstrated potential utility as a marker of neuronal injury. We here investigate the utility of VILIP-1 and VILIP-1/Aβ42 in predicting rates of cognitive decline in early AD.
Individuals with a clinical diagnosis of very mild or mild AD (n = 60) and baseline CSF measures of VILIP-1, tau, p-tau181, and Aβ42 were followed longitudinally for an average of 2.6 years. Annual assessments included the Clinical Dementia Rating (CDR), CDR–sum of boxes (CDR-SB), and global composite scores. Mixed linear models assessed the ability of CSF biomarker measures to predict rates of cognitive decline over time.
Baseline CSF VILIP-1 and VILIP-1/Aβ42 levels predicted rates of future decline in CDR-SB and global composite scores over the follow-up period. Individuals with CSF VILIP-1 ≥560 pg/mL (corresponding to the upper tercile) progressed much more rapidly in CDR-SB (1.61 boxes/year; p = 0.0077) and global scores (−0.53 points/year; p = 0.0002) than individuals with lower values (0.85 boxes/year and −0.15 points/year, respectively) over the follow-up period. CSF tau, p-tau181, tau/Aβ42, and p-tau181/Aβ42 also predicted more rapid cognitive decline in CDR-SB and global scores over time.
These findings suggest that CSF VILIP-1 and VILIP-1/Aβ42 predict rates of global cognitive decline similarly to tau and tau/Aβ42, and may be useful CSF surrogates for neurodegeneration in early AD.
PMCID: PMC3306162  PMID: 22357717
2.  Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial 
Revue neurologique  2013;169(10):10.1016/j.neurol.2013.07.017.
The Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer’s disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer’s disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.
PMCID: PMC3880800  PMID: 24016464
Alzheimer’s disease; Amyloid-beta (Aβ); Autosomal dominant; Amyloid deposition; Clinical trial
3.  Cognitively unimpaired HIV-positive subjects do not have increased 11C-PiB 
Neurology  2010;75(2):111-115.
Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV+) individuals. Similar abnormalities in brain amyloid-β42 (Αβ42) metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent 11C-Pittsburgh compound B (11C-PiB), a biomarker for Αβ42 deposition, in cognitively unimpaired HIV+ (n = 10) participants and matched community controls without dementia (n = 20).
In this case-control study, all participants had an 11C-PiB scan within 2 years of concomitant CSF studies and neuropsychometric testing. Statistical differences between HIV+ and community controls for demographic and clinical values were assessed by χ2 tests. Participants were further divided into either low (<500 pg/mL) or normal (≥500 pg/mL) CSF Αβ42 groups with Student t tests performed to determine if regional differences in fibrillar amyloid plaque deposition varied with CSF Αβ42.
Regardless of CSF Αβ42 level, none of the HIV+ participants had fibrillar amyloid plaques as assessed by increased 11C-PiB mean cortical binding potential (MCBP) or binding potential within 4 cortical regions. In contrast, some community controls with low CSF Αβ42 (<500 pg/mL) had high 11C-PiB MCBP with elevated binding potentials (>0.18 arbitrary units) within cortical regions.
Cognitively unimpaired HIV+ participants, even with low CSF Αβ42 (<500 pg/mL), do not have 11C-PiB parameters suggesting brain fibrillar amyloid deposition. The dissimilarity between unimpaired HIV+ and preclinical AD may reflect differences in Aβ42 production and/or formation of diffuse plaques. Future longitudinal studies of HIV+ participants with low CSF Aβ42 and normal 11C-PiB are required.
= amyloid-β42;
= Alzheimer disease;
= antiretroviral therapy;
= Clinical Dementia Rating;
= CNS Highly Activated Retroviral Therapy Effects Research;
= global deficit score;
= HIV-associated neurocognitive disorder;
= lumbar puncture;
= mean cortical binding potential;
= Pittsburgh compound B;
= region of interest;
= Washington University in St. Louis.
PMCID: PMC2905926  PMID: 20534887
4.  Improving CSF biomarker accuracy in predicting prevalent and incident Alzheimer disease 
Neurology  2011;76(6):501-510.
To investigate factors, including cognitive and brain reserve, which may independently predict prevalent and incident dementia of the Alzheimer type (DAT) and to determine whether inclusion of identified factors increases the predictive accuracy of the CSF biomarkers Aβ42, tau, ptau181, tau/Aβ42, and ptau181/Aβ42.
Logistic regression identified variables that predicted prevalent DAT when considered together with each CSF biomarker in a cross-sectional sample of 201 participants with normal cognition and 46 with DAT. The area under the receiver operating characteristic curve (AUC) from the resulting model was compared with the AUC generated using the biomarker alone. In a second sample with normal cognition at baseline and longitudinal data available (n = 213), Cox proportional hazards models identified variables that predicted incident DAT together with each biomarker, and the models' concordance probability estimate (CPE), which was compared to the CPE generated using the biomarker alone.
APOE genotype including an ε4 allele, male gender, and smaller normalized whole brain volumes (nWBV) were cross-sectionally associated with DAT when considered together with every biomarker. In the longitudinal sample (mean follow-up = 3.2 years), 14 participants (6.6%) developed DAT. Older age predicted a faster time to DAT in every model, and greater education predicted a slower time in 4 of 5 models. Inclusion of ancillary variables resulted in better cross-sectional prediction of DAT for all biomarkers (p < 0.0021), and better longitudinal prediction for 4 of 5 biomarkers (p < 0.0022).
The predictive accuracy of CSF biomarkers is improved by including age, education, and nWBV in analyses.
PMCID: PMC3053181  PMID: 21228296
5.  Alzheimer disease identification using amyloid imaging and reserve variables 
Neurology  2010;75(1):42-48.
Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help to accurately identify dementia of the Alzheimer type (DAT) when considered together with amyloid imaging.
Participants with normal cognition (n = 180) and with DAT (n = 25), aged 50 years or older, took part in clinical, neurologic, and psychometric assessments. PET with the Pittsburgh compound B (PiB) tracer was used to measure brain amyloid, yielding a mean cortical binding potential (MCBP) reflecting PiB uptake. Logistic regression was used to generate receiver operating characteristic curves, and the areas under those curves (AUC), to compare the predictive accuracy of using MCBP alone vs MCBP together with other variables selected using a stepwise selection procedure to identify participants with DAT vs normal cognition.
The AUC resulting from MCBP alone was 0.84 (95% confidence interval [CI] = 0.73–0.94; cross-validated AUC = 0.80, 95% CI = 0.68–0.92). The AUC for the predictive equation generated by a stepwise model including education, normalized whole brain volume, physical health rating, gender, and use of medications that may interfere with cognition was 0.94 (95% CI = 0.90–0.98; cross-validated AUC = 0.91, 95% CI = 0.85–0.96), an improvement (p = 0.025) over that yielded using MCBP alone.
Results suggest that factors reported to influence associations between AD pathology and dementia can improve the predictive accuracy of amyloid imaging for the identification of symptomatic AD.
β = amyloid-β;
= Alzheimer disease;
= area under receiver operating characteristic curve;
= binding potential;
= Clinical Dementia Rating;
= confidence interval;
= dementia of the Alzheimer type;
= distribution volume;
= mean cortical binding potential;
= normalized whole brain volume;
= odds ratio;
= Pittsburgh compound B;
= receiver operating characteristic curve;
= region of interest.
PMCID: PMC2906402  PMID: 20603484
6.  Resting bold fMRI differentiates dementia with Lewy bodies vs Alzheimer disease 
Neurology  2011;76(21):1797-1803.
Clinicopathologic phenotypes of dementia with Lewy bodies (DLB) and Alzheimer disease (AD) often overlap, making discrimination difficult. We performed resting state blood oxygen level–dependent (BOLD) functional connectivity MRI (fcMRI) to determine whether there were differences between AD and DLB.
Participants (n = 88) enrolled in a longitudinal study of memory and aging underwent 3-T fcMRI. Clinical diagnoses of probable DLB (n = 15) were made according to published criteria. Cognitively normal control participants (n = 38) were selected for the absence of cerebral amyloid burden as imaged with Pittsburgh compound B (PiB). Probable AD cases (n = 35) met published criteria and had appreciable amyloid deposits with PiB imaging. Functional images were collected using a gradient spin-echo sequence sensitive to BOLD contrast (T2* weighting). Correlation maps selected a seed region in the combined bilateral precuneus.
Participants with DLB had a functional connectivity pattern for the precuneus seed region that was distinct from AD; both the DLB and AD groups had functional connectivity patterns that differed from the cognitively normal group. In the DLB group, we found increased connectivity between the precuneus and regions in the dorsal attention network and the putamen. In contrast, we found decreased connectivity between the precuneus and other task-negative default regions and visual cortices. There was also a reversal of connectivity in the right hippocampus.
Changes in functional connectivity in DLB indicate patterns of activation that are distinct from those seen in AD and may improve discrimination of DLB from AD and cognitively normal individuals. Since patterns of connectivity differ between AD and DLB groups, measurements of BOLD functional connectivity can shed further light on neuroanatomic connections that distinguish DLB from AD.
PMCID: PMC3100121  PMID: 21525427
7.  Mucoepidermoid Carcinoma of the Lung: A Case Report and Literature Review 
Introduction. Mucoepidermoid carcinoma (MEC) of the lung is a rare form of lung cancer that is classified into low grade and high grade based on histological features. Surgical resection is the primary treatment for low-grade MEC with excellent outcomes, while high-grade MEC is a more aggressive form of malignancy. Clinical Case. We report a case of a 46-year-old woman who presented with dyspnea on exertion. Imaging studies revealed a mass involving the right upper lobe bronchus. Bronchoscopy, surgical resection, and pathological examination revealed a low-grade MEC with tumor-free margins. No adjuvant treatment was given. Discussion. Primary pulmonary MEC is a rare type of lung cancer with only few reported cases. This patient illustrates a typical presentation for low-grade MEC wherein surgical resection is considered curative. In contrast, high-grade MEC is a more aggressive malignancy with a poorer outcome. The role of targeted therapy directed against EGFR or a novel CRTC1-MAML2 fusion protein expressed in some high-grade tumors is yet to be determined.
PMCID: PMC3834989  PMID: 24303221
8.  Cancer linked to Alzheimer disease but not vascular dementia 
Neurology  2010;74(2):106-112.
To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD).
Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study–Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer.
The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20–0.84) and pure AD (HR = 0.31, 95% CI = 0.12–0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52–0.997) and pure AD (HR = 0.57; 95% CI = 0.36–0.90) among white subjects after adjustment for demographics, number of APOE ε4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD.
In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.
= modified Mini-Mental State Examination;
= Alzheimer disease;
= Alzheimer Disease Diagnostic and Treatment Centers;
= coronary heart disease;
= Cardiovascular Health Study;
= confidence interval;
= hazard ratio;
= International Classification of Diseases–Ninth Revision;
= mild cognitive impairment;
= National Institute of Neurological and Communicative Diseases and Stroke–Alzheimer's Disease and Related Disorders Association;
= Parkinson disease;
= vascular dementia.
PMCID: PMC2809029  PMID: 20032288
9.  Cognitive profiles in dementia 
Neurology  2008;71(22):1783-1789.
To re-examine proposed models of cognitive test performance that concluded separate factor structures were required for people with Alzheimer disease (AD) and older adults without dementia.
Five models of cognitive test performance were compared using multistep confirmatory factor analysis in 115 individuals with autopsy-confirmed AD and 191 research participants without clinical dementia from longitudinal studies at the Washington University AD Research Center. The models were then cross-validated using independent samples of 323 people with clinically diagnosed dementia of the Alzheimer type and 212 cognitively healthy older adults.
After controlling for Alzheimer-specific changes in episodic memory, performance on the battery of tests used here was best represented in people both with and without dementia by a single model of one general factor and three specific factors (verbal memory, visuospatial ability, and working memory). Performance by people with dementia was lower on the general factor than it was by those without dementia. Larger variances associated with the specific factors in the group with dementia indicated greater individual differences in the pattern of cognitive deficits in the stage of AD.
A hybrid model of general and specific cognitive domains simplifies cognitive research by allowing direct comparison of normal aging and Alzheimer disease performance. The presence of a general factor maximizes detection of the dementia, whereas the specific factors reveal the heterogeneity of dementia’s associated cognitive deficits.
= Alzheimer disease;
= Block Design;
= Boston Naming Test;
= Benton Visual Retention Test;
= Clinical Dementia Rating;
= confirmatory factor analysis;
= comparative fit index;
= dementia of the Alzheimer type;
= Digit Span Backward;
= Digit Span Forward;
= Digit Symbol;
= information;
= Lewy bodies;
= Logical Memory;
= Mental Control;
= National Institute on Aging;
= Paired Associate Learning;
= root mean square error of approximation;
= tests of invariance;
= Trailmaking A;
= Word Fluency.
PMCID: PMC2676971  PMID: 19029518
10.  CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease  
Neurology  2009;73(23):1982-1987.
HIV-associated neurologic disorders (HAND) continue to develop in many patients with HIV. CSF amyloid measurements in HAND have been reported to be similar to those in dementia of the Alzheimer type (DAT). Confirmatory evaluation of this finding in carefully evaluated subjects is needed.
CSF specimens were obtained from subjects clinically categorized with normal cognition from the general population, HIV+ subjects with normal cognition, HIV+ subjects with impaired cognition, or presumed HIV− subjects with mild DAT. CSF measurements of β-amyloid(1-42) (Aβ42), β-amyloid(1–40) (Aβ40), total tau (t-tau), and phosphorylated tau (p-tau181) were performed.
CSF Aβ42 measured in 49 HAND subjects had a median level of 501 pg/mL, which was lower than that of 50 controls of similar age who had median of 686 pg/mL (p < 0.0001) or 21 HIV+ subjects without cognitive impairment who had median of 716 pg/mL (p < 0.003). HAND subjects had similar CSF Aβ42 to 68 subjects with mild DAT. There was no difference of CSF Aβ40 between the groups. Tau and p-tau181 was elevated in DAT, but slightly lower than control in both HIV+ groups.
β-Amyloid(1-42) (Aβ42) measurements in CSF of cognitively impaired patients with HIV are similar to those in patients with mild dementia of the Alzheimer type (DAT). Normal or slightly depressed CSF tau and p-tau181 measurements distinguish these patients with HIV-associated neurologic disorders (HAND) from patients with DAT. Further evaluation of amyloid metabolism in patients with HIV cognitive disorder is needed to understand the implications of depressed CSF Aβ42 in the setting of HAND.
= β-amyloid;
= Alzheimer disease;
= amyloid precursor protein;
= Clinical Dementia Rating;
= CNS Highly Activated Retroviral Therapy Effects Research;
= dementia of the Alzheimer type;
= HIV-associated dementia;
= HIV-associated neurologic disorders;
= lipoprotein receptor related protein;
= mild cognitive disorder;
= National NeuroAIDS Tissue Consortium;
= phosphorylated tau;
= total tau.
PMCID: PMC2790234  PMID: 19907013
11.  TDP-43 proteinopathy in familial motor neuron disease with TARDBP A315T mutation: a case report 
PMCID: PMC2978282  PMID: 20819167
TARDBP; TDP-43; FUS; motor neuron disease; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; Alzheimer’s disease; mutation
12.  Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer's type 
Archives of neurology  2009;66(5):638-645.
Cerebrospinal fluid (CSF) levels of Aβ peptide 1-42 (Aβ42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer's disease (AD). We hypothesized that these biomarkers might predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT).
Retrospective analysis of CSF biomarkers and clinical data.
An academic Alzheimer's Disease Research Center.
Research volunteers in a longitudinal study of aging and cognition. Participants (n=49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All participants had at least one follow-up assessment (mean years of follow-up = 3.5 ± 1.8 years).
Main outcome measures
Baseline CSF levels of Aβ42, Aβ40, tau and tau phosphorylated at threonine 181 (ptau181), rate of dementia progression as measured by CDR-sum of boxes (CDR-SB) and by psychometric performance,
The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Aβ42, with higher tau or ptau181, or high tau/Aβ42 ratio. For example, the annual change in CDR-SB was 1.1 for the lowest two tertiles of Aβ42 values and 0.3 for the highest tertile of Aβ42 values.
In individuals with very mild DAT, lower CSF Aβ42, high tau or ptau181, or a high tau/Aβ42 ratio quantitatively predict more rapid progression of cognitive deficits and dementia. CSF biomarkers may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.
PMCID: PMC2759394  PMID: 19433664
amyloid beta; Aβ; tau; biomarker; dementia progression
An informant-based screening tool for dementia may be useful in population-based studies of minority populations.
Investigate the feasibility of screening for very mild dementia in a community sample of African Americans using an informant-based screening tool (AD8).
Cohort study
147 persons from the African American Health (AAH) project were screened for dementia; 61 of 93 who were invited had follow-up clinical assessments for dementia diagnosis.
The AD8, Mini-Mental State Examination (MMSE), Short Blessed Test (SBT), Brief Instrument for Dementia Detection (BIDD), and a neuropsychological battery were administered at visit 1. The Clinical Dementia Rating (CDR) was administered at visit 2 by clinicians blinded to visit 1 results; the presence of dementia was determined by a CDR greater than 0.
465 individuals from the AAH cohort were sent a letter describing the study and, among this group, 252 individuals were contacted by phone to request participation in this study. 6% (14 / 252) of participants contacted by phone were unable to identify an informant (required for the AD8). 150 individuals agreed by phone to participate of which 2% (n=3) did not have an informant available at the time of participation. The AD8 alone was effective at discriminating between CDR 0 and CDR 0.5 (area under the curve = .847; p <.001; 95% confidence interval 0.73-0.96).
A brief informant-based instrument, the AD8, has high sensitivity and specificity for distinguishing CDR 0 from CDR 0.5 in the community. Informant availability may not be a barrier to using the AD8 in an African American community sample; however, further study in larger samples with a higher response rate, different community settings (e.g., community clinics), and among older age groups (e.g., age 75+) is warranted to confirm this.
PMCID: PMC2763355  PMID: 19484913
African Americans; Dementia; Screening
14.  Undescended Testicle 
British Medical Journal  1960;1(5183):1428-1429.
PMCID: PMC1967644

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