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1.  COGNITIVELY NORMAL INDIVIDUALS WITH AD PARENTS MAY BE AT RISK FOR DEVELOPING AGING-RELATED CORTICAL THINNING PATTERNS CHARACTERISTIC OF AD 
Neuroimage  2012;61(3):525-532.
Children of Alzheimer's Disease (AD) patients are at heightened risk of developing AD due to genetic influences, including the apolipoprotein E4 (ApoE4) allele. In this study, we assessed the earliest cortical changes associated with AD in 71 cognitively healthy, adult children of AD patients (AD offspring) as compared with 69 with no family history of AD (non-AD offspring). Cortical thickness measures were obtained using FreeSurfer from 1.5T magnetic resonance (MR) scans. ApoE genotyping was obtained. Primary analyses examined family history and ApoeE4 effects on cortical thickness. Secondary analyses examined age effects within groups. All comparisons were adjusted using False Discovery Rate at a significance threshold of p < 0.05. There were no statistically significant differences between family history and ApoE4 groups. Within AD offspring, increasing age was related to reduced cortical thickness (atrophy) over large areas of the precuneus, superior frontal and superior temporal gyri, starting at around age 60. Further, these patterns existed within female and maternal AD offspring, but were absent in male and paternal AD offspring. Within non-AD offspring, negative correlations existed over small regions of the superior temporal, insula and lingual cortices. These results suggest that as AD offspring age, cortical atrophy is more prominent, particularly if the parent with AD is mother or if the AD offspring is female.
doi:10.1016/j.neuroimage.2012.03.083
PMCID: PMC3358455  PMID: 22503937
Antecedent biomarker; Familial risk; Alzheimer’s Disease; Dementia; Adult Children Study; Cortical thickness; Maternal risk
2.  Operationalizing diagnostic criteria for Alzheimer’s disease and other age-related cognitive impairment—Part 1* 
Population studies strive to determine the prevalence of Alzheimer dementia but prevalence estimates vary widely. The challenges faced by several noted population studies for Alzheimer dementia in operationalizing current clinical diagnostic criteria for Alzheimer’s disease (AD) are reviewed. Differences in case ascertainment, methodological biases, cultural and educational influences on test performance, inclusion of special populations such as underrepresented minorities and the oldest old, and detection of the earliest symptomatic stages of underlying AD are considered. Classification of Alzheimer dementia may be improved by the incorporation of biomarkers for AD if the sensitivity, specificity, and predictive value of the biomarkers are established and if they are appropriate for epidemiological studies as may occur should a plasma biomarker be developed. Biomarkers for AD also could facilitate studies of the interactions of various forms of neurodegenerative disorders with cerebrovascular disease, resulting in “mixed dementia”.
doi:10.1016/j.jalz.2010.11.005
PMCID: PMC3063444  PMID: 21255741
3.  Cerebrospinal fluid amyloid β42, phosphorylated tau181, and resting state functional connectivity 
JAMA neurology  2013;70(10):1242-1248.
Importance
Resting state functional connectivity magnetic resonance imaging (rs-fcMRI) has great potential for characterizing pathophysiological changes during the preclinical phase of Alzheimer’s disease (AD).
Objective
To assess the relationship between default mode network (DMN) integrity and cerebrospinal fluid (CSF) biomarkers of AD pathology in cognitively normal older individuals
Design
Cross-sectional cohort study
Setting
Knight Alzheimer’s Disease Research Center at Washington University in St Louis, Missouri.
Participants
207 older adults with normal cognition (Clinical Dementia Rating of 0).
Main Outcome measures
rs-fcMRI measures of DMN integrity.
Results
Decreased CSF Aβ42 or increased CSF phosphorylated tau181 (ptau181) were independently associated with reduced DMN integrity, with the most prominent decreases in functional connectivity observed between the posterior cingulate and medial temporal regions. Observed reductions in functional connectivity were not attributable to age or structural atrophy in the posterior cingulate and medial temporal areas. Similar rs-fcMRI findings in relation to CSF biomarkers were obtained using region-of-interest analyses and voxel-wise correlation mapping.
Conclusions
Both Aβ and tau pathology affect DMN integrity prior to clinical onset of AD.
doi:10.1001/jamaneurol.2013.3253
PMCID: PMC3836828  PMID: 23959173
4.  Viral Dose, Radioiodine Uptake, and Delayed Efflux in Adenovirus Mediated NIS Radiovirotherapy Correlates with Treatment Efficacy 
Gene therapy  2012;20(5):567-574.
We have constructed a prostate tumor specific conditionally replicating adenovirus (CRAd), named Ad5PB_RSV-NIS that expresses the human sodium iodine symporter gene (hNIS). LNCaP tumors were established in nude mice and infected with this CRAd to study tumor viral spread, NIS expression, and efficacy. Using quantitative polymerase chain reaction (QPCR) we found a linear correlation between the viral dose and viral genome copy numbers recovered after tumor infection. Confocal microscopy showed a linear correlation between adenovirus density and NIS expression. Radioiodine uptake vs. virus dose-response curves revealed that the dose response curve was not linear and displayed a lower threshold of detection at 107 vp and an upper plateau of uptake at 1011 vp. The outcome of radiovirotherapy was highly dependent upon viral dose. At 1010 vp no significant differences were observed between virotherapy alone or radiovirotherapy. However, when radioiodine therapy was combined with virotherapy at a dose of 1011 vp, significant improvement in survival was observed, indicating a relationship between viral dose-response uptake and the efficacy of radiovirotherapy. The reasons behind the differences in radioiodine therapy efficacy can be ascribed to more efficient viral tumor spread and a decrease in the rate of radioisotope efflux. Our results have important implications regarding the desirables and undesirable characteristics of vectors for clinical translation of virus-mediated NIS transfer therapy
doi:10.1038/gt.2012.71
PMCID: PMC3525803  PMID: 22972493
prostate cancer; probasin; adenovirus; sodium iodide symporter; virotherapy; gene therapy
5.  Progression of Alzheimer disease as measured by Clinical Dementia Rating sum of boxes scores 
Background
This study examined rates of dementia progression as ascertained by the Clinical Dementia Rating sum of boxes (CDR-SB) for symptomatic Alzheimer disease (sAD) and assessed participant characteristics as predictors of CDR-SB progression.
Methods
Participants (n = 792) were enrolled in longitudinal studies at an Alzheimer’s Disease Research Center, received a diagnosis of sAD with a global CDR of 0.5 (n = 466) or 1 (n = 326), and had at least one follow-up assessment. Progression in CDR-SB over time as a function of baseline global CDR was examined.
Results
A longitudinal increase (p<.0001) in CDR-SB was observed. The annual rate of change in CDR-SB scores was 1.43 (SE=.05) in the CDR 0.5 sample and 1.91 (SE=.07) in the CDR 1 sample. For participants followed from the beginning of the CDR stage, time to progression to a higher global CDR was longer for individuals who were CDR 0.5 (3.75 years; 95% CI 3.18-4.33) than those who were CDR 1 at baseline (2.98 years; 95%CI 2.75-3.22). In the total CDR 0.5 sample, the significant predictors of progression to the next global CDR stage (p<.01) were age at first sAD diagnosis and apolipoprotein E4 genotype.
Conclusions
The study findings are relevant to sAD clinical trial design and accurate, reliable ascertainment of the effect of disease-modifying treatments.
doi:10.1016/j.jalz.2012.01.005
PMCID: PMC3660405  PMID: 22858530
Alzheimer disease; assessment of dementia; Clinical Dementia Rating; Clinical Dementia Rating sum of boxes; cohort studies
6.  Clinicopathologic Study of Alzheimer’s Disease: Alzheimer mimics 
A definite diagnosis of Alzheimer disease (AD) can only be made at autopsy. Even at expert research centers, diagnostic accuracy is relatively low. We conducted this study to examine the accuracy of clinical diagnosis of AD and present a list of clinical and neuropsychological findings that could render the clinical diagnosis difficult. Using the National Alzheimer’s Coordinating Center database, the records of 533 patients who had been diagnosed clinically with AD and later underwent autopsy, were reviewed retrospectively. Since the pathologic results of 119 subjects did not meet the criteria for definite AD, we labeled them as Alzheimer “mimics”. The neuropathological diagnoses of Alzheimer mimics consisted of dementia with Lewy body (n=35, 29%), insufficient AD (n=22, 18%), vascular disease (n=15, 13%), frontotemporal lobar degeneration (n=14, 12%) and hippocampal sclerosis (n=10, 8%). History of pacemaker insertion (10.92% vs. 4.11%, p=0.005), congestive heart failure (13.45% vs. 6.04% p=0.007), hypertension (56.30% vs. 47.83%, p=0.037) and resting tremor (14.29% vs. 10.87%, p=0.170) was more prevalent in Alzheimer mimics. Clinical Dementia Rating score and frequency of Neuropsychiatric Inventory Questionnaire items reflecting delusions, agitation, depression and motor disturbance were more severe in confirmed AD. In addition to Mini-Mental State Examination (16.97±8.29 vs. 12.74±15.26, p<0.001), Logical Memory, Animal Fluency, Boston Naming Test and Digit Span scores showed more severe impairment in confirmed AD. Continuing systematic comparisons of the current criteria for the clinical and pathological dementia diagnoses are essential to clinical practice and research, and may also lead to further improvement of the diagnostic procedure.
doi:10.3233/JAD-121594
PMCID: PMC3725959  PMID: 23481687
Alzheimer’s disease; diagnosis; pathology; dementia with Lewy bodies
7.  Combining Multiple Markers to Improve the Longitudinal Rate of Progression-Application to Clinical Trials on the Early Stage of Alzheimer’s Disease 
Statistics in biopharmaceutical research  2013;5(1):10.1080/19466315.2012.756662.
Clinical trials on early stage Alzheimer’s disease (AD) are reaching a bottleneck because none of the current disease markers changes appreciably early in the disease process and therefore a huge sample is required to adequately power such trials. We propose a method to combine multiple markers so that the longitudinal rate of progression can be improved. The criterion is to maximize the probability that the combined marker will be decreased over time (assuming a negative mean slope for each marker). We propose estimates to the weights of markers in the optimum combination and a confidence interval estimate to the combined rate of progression through the maximum likelihood estimates and a bootstrap procedure. We conduct simulations to assess the performance of our estimates and compare our approach with the first principal component from a principal component analysis. The proposed method is applied to a real world sample of individuals with preclinical AD to combine measures from two cognitive domains. The combined cognitive marker is finally used to design future clinical trials on preclinical AD, demonstrating a significant improvement in reducing the sample sizes needed to power such trials when compared with individual markers alone.
doi:10.1080/19466315.2012.756662
PMCID: PMC3868484  PMID: 24363827
Bootstrap estimate; Delta method; Multivariate random coefficients models; Power; Preclinical Alzheimer’s disease (AD); Randomized clinical trials (RCT); Sample size
8.  Bootstrapping GEE models for fMRI regional connectivity 
NeuroImage  2012;63(4):1890-1900.
An Alzheimer’s fMRI study has motivated us to evaluate inter-regional correlations during rest between groups. We apply generalized estimating equation (GEE) models to test for differences in regional correlations across groups. Both the GEE marginal model and GEE transition model are evaluated and compared to the standard pooling Fisher-z approach using simulation studies. Standard errors of all methods are estimated both theoretically (model-based) and empirically (bootstrap). Of all the methods, we find that the transition models have the best statistical properties. Overall, the model-based standard errors and bootstrap standard errors perform about the same. We also demonstrate the methods with a functional connectivity study in a healthy cognitively normal population of ApoE4+ participants and ApoE4− participants who are recruited from the Adult Children’s Study conducted at the Washington University Knight Alzheimer’s Disease Research Center.
doi:10.1016/j.neuroimage.2012.08.036
PMCID: PMC3491908  PMID: 22906513
resting-state fMRI; time-series; temporal dependence; brain regional correlations; functional connectivity
9.  Increased in vivo Amyloid-β42 production, exchange, and irreversible loss in Presenilin Mutations Carriers 
Science translational medicine  2013;5(189):10.1126/scitranslmed.3005615.
Alzheimer’s disease is hypothesized to be caused by an over-production or reduced clearance of amyloid-beta (Aβ) peptide. Autosomal Dominant Alzheimer’s Disease (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related non-carriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of Aβ isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer, Pittsburgh compound B (PiB). CNS Aβ42 to Aβ40 production rates were 24% higher in mutation carriers compared to non-carriers and this was independent of fibrillar amyloid deposits quantified by PET PiB imaging. The fractional turnover rate of soluble Aβ42 relative to Aβ40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aβ42 into plaques leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF). Reversible exchange of Aβ42 peptides with pre-existing unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that Aβ42 is overproduced in the CNS of humans with presenilin mutations that cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF.
doi:10.1126/scitranslmed.3005615
PMCID: PMC3838868  PMID: 23761040
10.  Revised Criteria for Mild Cognitive Impairment May Compromise the Diagnosis of Alzheimer Disease Dementia 
Archives of neurology  2012;69(6):700-708.
Objective
To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a Workgroup sponsored by the National Institute on Aging and the Alzheimer’s Association, on the diagnosis of very mild and mild Alzheimer disease (AD) dementia.
Design
Retrospective review of ratings of functional impairment across diagnostic categories. Participants: The functional ratings of individuals (N = 17,535) with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer’s Disease Centers and submitted to the National Alzheimer’s Coordinating Center were assessed in accordance with the definition of “functional independence” allowed by the revised criteria.
Methods
Pairwise demographic differences between the 3 diagnostic groups were tested using t-tests for continuous variables and chi-square for categorical variables.
Results
Almost all (99.8%) of individuals currently diagnosed with very mild AD dementia and the large majority (92.7%) of those diagnosed with mild AD dementia could be reclassified as MCI with the revised criteria, based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home. Large percentages of these AD dementia individuals also meet the revised “functional independence” criterion for MCI as measured by the Functional Assessment Questionnaire.
Conclusions
The categorical distinction between MCI and milder stages of Alzheimer dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that “MCI due to AD” represents the earliest symptomatic stage of AD.
doi:10.1001/archneurol.2011.3152
PMCID: PMC3423496  PMID: 22312163
Dementia Diagnosis; Alzheimer disease; MCI
11.  A Steep Radioiodine Dose Response Scalable to Humans in Sodium Iodide Symporter (NIS) Mediated Radiovirotherapy for Prostate Cancer 
Cancer gene therapy  2012;19(12):839-844.
The sodium iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. We have extended the use of NIS-mediated radioiodine therapy to prostate cancer. We have developed a prostate tumor specific conditionally replicating adenovirus (CRAd) that expresses hNIS (Ad5PB_RSV-NIS). For radiovirotherapy to be effective in humans, the radioiodine dose administered in the pre-clinical animal model should scale to the range of acceptable doses in humans. We performed 131I dose-response experiments aiming to determine the dose required in mice to achieve efficient radiovirotherapy. Efficacy was determined by measuring tumor growth and survival times. We observed that individual tumors display disparate growth rates which preclude averaging within a treatment modality indicating heterogeneity of growth rate. We further show that a statistic and stochastic approach must be used when comparing the effect of an anti-cancer therapy on a cohort of tumors. Radiovirotherapy improves therapeutic value over virotherapy alone by slowing the rate of tumor growth in a more substantial manner leading to an increase in survival time. We also show that the radioiodine doses needed to achieve this increase scaled well within the current doses used for treatment of thyroid cancer in humans.
doi:10.1038/cgt.2012.68
PMCID: PMC3499676  PMID: 23037808
prostate cancer; probasin; adenovirus; sodium iodide symporter; virotherapy; gene therapy; allometry
12.  Quantitative Analysis of PiB-PET with FreeSurfer ROIs 
PLoS ONE  2013;8(11):e73377.
In vivo quantification of β-amyloid deposition using positron emission tomography is emerging as an important procedure for the early diagnosis of the Alzheimer's disease and is likely to play an important role in upcoming clinical trials of disease modifying agents. However, many groups use manually defined regions, which are non-standard across imaging centers. Analyses often are limited to a handful of regions because of the labor-intensive nature of manual region drawing. In this study, we developed an automatic image quantification protocol based on FreeSurfer, an automated whole brain segmentation tool, for quantitative analysis of amyloid images. Standard manual tracing and FreeSurfer-based analyses were performed in 77 participants including 67 cognitively normal individuals and 10 individuals with early Alzheimer's disease. The manual and FreeSurfer approaches yielded nearly identical estimates of amyloid burden (intraclass correlation = 0.98) as assessed by the mean cortical binding potential. An MRI test-retest study demonstrated excellent reliability of FreeSurfer based regional amyloid burden measurements. The FreeSurfer-based analysis also revealed that the majority of cerebral cortical regions accumulate amyloid in parallel, with slope of accumulation being the primary difference between regions.
doi:10.1371/journal.pone.0073377
PMCID: PMC3819320  PMID: 24223109
13.  Amyloid-β Dynamics in Human Plasma 
Archives of neurology  2012;69(12):10.1001/archneurol.2012.18107.
Background
A marked decrease of Aβ42 in the cerebrospinal fluid (CSF) of patients with incipient Alzheimer's Disease (AD) has been well documented. However, contradictory results have been reported from studies on plasma Aβ levels as diagnostic markers for AD.
Objective
To investigate dynamic changes in human plasma Aβ levels, evaluate the effects of aging and amyloidosis on these dynamics, and determine their correlation with CSF Aβ levels.
Design, Settings, and Participants
This was a repeated plasma and CSF sampling study conducted at the Washington University School of Medicine in St. Louis. Older adults with amyloid deposition (Amyloid +), age-matched controls without amyloid deposition (Amyloid −), and younger normal controls (YNC) were enrolled for the study.
Main Outcome Measures
Hourly measurements of plasma Aβ were compared between groups by age and amyloidosis. Plasma Aβ and CSF Aβ levels were compared for correlation, linear increase, and circadian patterns.
Results
Circadian patterns were observed in plasma Aβ, with diminished amplitudes with aging. Linear increase of Aβ was only observed for CSF Aβ in YNC and Amyloid − groups, but not in the Amyloid + group. No linear increase was observed for plasma Aβ. No significant correlations were found between plasma and CSF Aβ levels.
Conclusions
Plasma Aβ, like CSF, demonstrates a circadian pattern which is reduced in amplitude with increasing age but is unaffected by amyloid deposition. However, we found no evidence that plasma and CSF Aβ levels were related on an hourly or individual basis.
doi:10.1001/archneurol.2012.18107
PMCID: PMC3808092  PMID: 23229043
14.  Dominantly Inherited Alzheimer Network: facilitating research and clinical trials 
The Dominantly Inherited Alzheimer Network (DIAN) is an international registry of individuals at risk for developing autosomal dominant Alzheimer’s disease (AD). Its primary aims are to investigate the temporal ordering of AD pathophysiological changes that occur in asymptomatic mutation carriers and to identify those markers that herald the transition from cognitive normality to symptomatic AD. DIAN participants undergo longitudinal evaluations, including clinical and cognitive assessments and measurements of molecular and imaging AD biomarkers. This review details the unique attributes of DIAN as a model AD biomarker study and how it provides the infrastructure for innovative research projects, including clinical trials. The recent design and launch of the first anti-amyloid-beta secondary prevention trial in AD, led by the related DIAN Trials Unit, also are discussed.
doi:10.1186/alzrt213
PMCID: PMC3978584  PMID: 24131566
15.  Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease 
Human Molecular Genetics  2012;21(20):4558-4571.
The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 × 10−4) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aβ42 levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aβ42 levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aβ42 levels was independent of the APOE ɛ4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ɛ4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10−13). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE ɛ4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value <10−6. Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10−9).
doi:10.1093/hmg/dds296
PMCID: PMC3459471  PMID: 22821396
16.  Metric distances between hippocampal shapes indicate different rates of change over time in nondemented and demented subjects 
Current Alzheimer research  2012;9(8):972-981.
In this article, we use longitudinal morphometry (shape and size) measures of hippocampus in subjects with mild dementia of Alzheimer type (DAT) and nondemented controls in logistic discrimination. The morphometric measures we use are volume and metric distance measures at baseline and follow-up (two years apart from baseline). Morphometric differences with respect to a template hippocampus were measured by the metric distance obtained from the large deformation diffeomorphic metric mapping (LDDMM) algorithm. LDDMM assigns metric distances on the space of anatomical images, thereby allowing for the direct comparison and quantization of morphometric changes. We also apply principal component analysis (PCA) on volume and metric distance measures to obtain principal components that capture some salient aspect of morphometry. We construct classifiers based on logistic regression to distinguish diseased and healthy hippocampi (hence potentially diagnose the mild form of DAT). We consider logistic classifiers based on volume and metric distance change over time (from baseline to follow-up), on the raw volumes and metric distances, and on principal components from various types of PCA analysis. We provide a detailed comparison of the performance of these classifiers and guidelines for their practical use. Moreover, combining the information conveyed by volume and metric distance measures by PCA can provide a better biomarker for detection of dementia compared to volume, metric distance, or both.
PMCID: PMC3235259  PMID: 21875412
computational anatomy; dementia of Alzheimer Type; hippocampus; large deformation diffeomorphic metric mapping (LDDMM); logistic discrimination; morphometry; principal component analysis
17.  CSF Proteins Predict Longitudinal Hippocampal Degeneration in Early Stage Dementia of the Alzheimer Type 
Objective
Biomarkers are needed to improve the sensitivity and accuracy of diagnosis as well as prognosis in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau protein levels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of the Alzheimer type.
Design
A single CSF sample and longitudinal MR scans were collected. The CSF samples were assayed for tau, p-tau181, Aβ1–42 and Aβ1–40 by ELISA. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference.
Setting:
Patients or Other Participants
13 participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0).
Intervention
None.
Main Outcome Measures
Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum and CA2-4+DG cellular subfields. Their correlations with initial CSF measures.
Results
Lower CSF Aβ1–42 levels and higher tau/Aβ1–42 and p-tau181/Aβ1–42 ratios were strongly correlated with decreases in hippocampal volume and measure of progressive inward deformations of the CA1 subfield in participants with early AD, but not cognitively normal participants.
Conclusions
Despite small sample size, we found that Aβ1–42 and tau-related CSF measures were related to hippocampal degeneration in individuals with clinically diagnosed early AD, and may reflect an association with a common underlying disease mechanism.
doi:10.1097/WAD.0b013e31823c0cf4
PMCID: PMC3309103  PMID: 22156755
Magnetic Resonance Imaging (MRI); Hippocampal subfields; β-Amyloid; Tau; P-Tau; biomarkers
18.  Toward a multifactorial model of Alzheimer disease 
Neurobiology of aging  2012;33(10):2262-2271.
Relations among antecedant biomarkers of AD were evaluated using causal modeling; although correlation cannot be equated to causation, causation does require correlation. Individuals aged 43 to 89 years (N = 220) enrolled as cognitively normal controls in longitudinal studies had clinical and psychometric assessment, structural magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarkers, and brain amyloid imaging via positron emission tomography with Pittsburgh Compound B (PIB) obtained within 1 year. CSF levels of Aβ42 and tau were minimally correlated, indicating they represent independent processes. Aβ42, tau, and their interaction explained 60% of the variance in PIB. Effects of APOE genotype and age on PIB were indirect, operating through CSF markers. Only spurious relations via their common relation with age were found between the biomarkers and regional brain volumes or cognition. Hence, at least two independent hypothesized processes, one reflected by CSF Aβ42 and one by CSF tau, contribute to the development of fibrillar amyloid plaques preclinically. The lack of correlation between these two processes and brain volume in the regions most often affected in AD suggests the operation of a third process related to brain atrophy.
doi:10.1016/j.neurobiolaging.2011.11.029
PMCID: PMC3334456  PMID: 22261556
preclinical Alzheimer disease; amyloid-β; tau; PIB; amyloid plaque; APOE; brain volumetry; memory; biomarkers; cerebrospinal fluid
19.  Developing an international network for Alzheimer research: The Dominantly Inherited Alzheimer Network 
Clinical investigation  2012;2(10):975-984.
The Dominantly Inherited Alzheimer Network (DIAN) is a collaborative effort of international Alzheimer disease (AD) centers that are conducting a multifaceted prospective biomarker study in individuals at-risk for autosomal dominant AD (ADAD). DIAN collects comprehensive information and tissue in accordance with standard protocols from asymptomatic and symptomatic ADAD mutation carriers and their non-carrier family members to determine the pathochronology of clinical, cognitive, neuroimaging, and fluid biomarkers of AD. This article describes the structure, implementation, and underlying principles of DIAN, as well as the demographic features of the initial DIAN cohort.
doi:10.4155/cli.12.93
PMCID: PMC3489185  PMID: 23139856
Alzheimer disease; autosomal dominant; biomarkers of Alzheimer disease; PSEN1; PSEN2; APP; amyloid-beta; preclinical Alzheimer disease
20.  Alzheimer’s disease family history impacts resting state functional connectivity 
Annals of neurology  2012;72(4):571-577.
Objective
Offspring whose parents have Alzheimer’s disease (AD) are at increased risk for developing dementia. Patients with AD typically exhibit disruptions in the default mode network (DMN). The aim of this study was to investigate the effect of a family history of late-onset AD on DMN integrity in cognitively normal individuals. In particular, we determined whether a family history effect is detectable in apolipoprotein E (APOE) ε4 allele non-carriers.
Method
We studied a cohort of 348 cognitively normal participants with or without family history of late-onset AD. DMN integrity was assessed by resting state functional connectivity magnetic resonance imaging.
Results
A family history of late-onset AD was associated with reduced resting state functional connectivity between particular nodes of the DMN, namely the posterior cingulate and medial temporal cortex. The observed functional connectivity reduction was not attributable to medial temporal structural atrophy. Importantly, we detected a family history effect on DMN functional connectivity in APOE ε4 allele non-carriers.
Interpretation
Unknown genetic factors, embodied in a family history of late-onset AD, may affect DMN integrity prior to cognitive impairment.
doi:10.1002/ana.23643
PMCID: PMC3490438  PMID: 23109152
21.  PET Amyloid-Beta Imaging in Preclinical Alzheimer’s Disease 
Biochimica et Biophysica Acta  2011;1822(3):370-379.
doi:10.1016/j.bbadis.2011.11.005
PMCID: PMC3264790  PMID: 22108203
22.  Characterization of Infectivity-Enhanced Conditionally Replicating Adenovectors for Prostate Cancer Radiovirotherapy 
Human Gene Therapy  2012;23(9):951-959.
Abstract
Prostate cancer (PCa) is the second most commonly diagnosed and sixth leading cause of cancer death in American men and one for which no curative therapy exists after metastasis. To meet this need for novel therapies, our laboratory has previously generated conditionally replicating adenovirus (CRAd) vectors expressing the sodium iodide symporter (hNIS). This virus transduced PCa cells and induced functional NIS expression, allowing for noninvasive tumor imaging and combination therapy with radioiodide, referred to as radiovirotherapy. We have now generated two new modified vectors to further improve efficacy. Ad5/3PB-ADP-hNIS and Ad5/3PB-hNIS include a hybrid Ad5/3 fiber knob to improve transduction efficiency, and express NIS from the endogenous major late promoter to restrict NIS expression to target cells. Additionally, Ad5/3PB-ADP-hNIS includes the adenovirus death protein (ADP), which hastens the release of viral particles after assembly. These two vectors specifically induce radioisotope uptake, cytopathic effect, and viral replication in androgen receptor–expressing PCa cell lines with Ad5/3PB-ADP-hNIS showing earlier 131I uptake and cytolysis at low multiplicity of infection. SPECT-CT imaging of xenograft tumors infected with Ad5/3PB-hNIS showed steady uptake, whereas infection with Ad5/3PB-ADP-hNIS led to increasing uptake, indicating viral spread. Radiovirotherapy of xenograft LNCaP tumors with Ad5/3PB-ADP-hNIS showed the most significant survival extension versus control tumors (p=0.001), but the benefit of radiovirotherapy was not statistically significant compared with virotherapy alone in this model. These results show the potential of Ad5/3PB-ADP-hNIS as a vector for treatment of prostate cancer.
Oneal and colleagues report on two novel conditionally replicating adenoviral vectors that combine 131I therapy with conventional virotherapy, a treatment termed radiovirotherapy. They show that these vectors can specifically induce radioisotope uptake, cytopathic effect, and viral replication in androgen receptor-expressing prostate cancer cell lines. In vivo efficacy studies show that treatment of tumor-bearing xenograft mice with these vectors results in a significant oncolytic effect.
doi:10.1089/hum.2012.047
PMCID: PMC3440023  PMID: 22694073
23.  Differential effects of aging and Alzheimer's disease on medial temporal lobe cortical thickness and surface area 
Neurobiology of aging  2007;30(3):432-440.
The volume of parcellated cortical regions is a composite measure related to both thickness and surface area. It is not clear whether volumetric decreases in medial temporal lobe (MTL) cortical regions in aging and Alzheimer's disease (AD) are due to thinning, loss of surface area, or both, nor is it clear whether aging and AD differ in their effects on these properties. Participants included 28 Younger Normals, 47 Older Normals, and 29 patients with mild AD. T1-weighted MRI data were analyzed using a novel semi-automated protocol (presented in a companion article) to delineate the boundaries of entorhinal (ERC), perirhinal (PRC), and posterior parahippocampal (PPHC) cortical regions and calculate their mean thickness, surface area, and volume. Compared to Younger Normals, Older Normals demonstrated moderately reduced ERC and PPHC volumes, which were due primarily to reduced surface area. In contrast, the expected AD-related reduction in ERC volume was produced by a large reduction in thickness with minimal additional effect (beyond that of aging) on surface area. PRC and PPHC also showed large AD-related reductions in thickness. Of all these MTL morphometric measures, ERC and PRC thinning were the best predictors of poorer episodic memory performance in AD. Although the volumes of MTL cortical regions may decrease with both aging and AD, thickness is relatively preserved in normal aging, while even in its mild clinical stage, AD is associated with a large degree of thinning of MTL cortex. These differential morphometric effects of aging and AD may reflect distinct biologic processes and ultimately may provide insights into the anatomic substrates of change in memory-related functions of MTL cortex.
doi:10.1016/j.neurobiolaging.2007.07.022
PMCID: PMC3703585  PMID: 17869384
Entorhinal cortex; Perirhinal cortex; Parahippocampal cortex; Magnetic resonance imaging; Alzheimer's disease; Aging
24.  Agreement about diagnosis among patients, companions, and professionals following a dementia evaluation 
A dementia diagnosis is challenging to deliver and to hear, yet agreement about a diagnosis is essential for effective dementia care. We examined consensus about the results of a dementia evaluation in 90 patients assessed at an Alzheimer’s Disease Research Center. Diagnostic impressions were obtained from five sources: 1) the physician’s chart diagnosis, 2) the patient who was evaluated, 3) a companion present at the evaluation, 4) a diagnostic summary written by a nurse present during the evaluation, and 5) raters who watched a video of the diagnostic disclosure conversation. Overall, diagnostic consensus was only moderate. Patients and companions exhibited just fair agreement with one another. Agreement was better between physicians and companions compared to physicians and patients, though imperfect between the physician and video raters and the written summary. Agreement among sources varied by dementia severity, with lowest agreement occurring in instances of very mild dementia. This study documents discrepancies that can arise in diagnostic communication, which could influence adjustment to a dementia diagnosis and decisions regarding future planning and care.
doi:10.1097/WAD.0b013e3182351c04
PMCID: PMC3277665  PMID: 22037598
Alzheimer’s disease; dementia; diagnostic disclosure; doctor-patient communication; patient education
25.  A Longitudinal Study of Drivers with Alzheimer Disease 
Neurology  2008;70(14):1171-1178.
Objective
The goal of this study was to define the natural progression of driving impairment in persons who initially have very mild to mild dementia.
Methods
We studied 128 older drivers, including 84 with early Alzheimer’s disease (AD) and 44 age-matched control subjects without cognitive impairment. Subjects underwent repeated assessments of their cognitive, neurological, visual and physical function over three years. Self-reports of driving accidents and traffic violations were supplemented by reports from family informants and state records. Within two weeks of the office evaluation, subjects were examined by a professional driving instructor on a standardized road test.
Results
At baseline, AD subjects had experienced more accidents and performed more poorly on the road test, compared to controls. Over time, both groups declined in driving performance on the road test, with AD subjects declining more than controls. Survival analysis indicated that while the majority of subjects with AD passed the examination at baseline, greater severity of dementia, increased age, and lower education were associated with higher rates of failure and marginal performance.
Conclusions
This study confirms previous reports of potentially hazardous driving in persons with early AD, but also indicates that some individuals with very mild dementia can continue to drive safely for extended periods of time. Regular followup assessments, however, are warranted in those individuals.
doi:10.1212/01.wnl.0000294469.27156.30
PMCID: PMC3664938  PMID: 18216302

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