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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.
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”.
PMCID: PMC3063444  PMID: 21255741
3.  Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions 
Van Deerlin, Vivianna M. | Sleiman, Patrick M. A. | Martinez-Lage, Maria | Chen-Plotkin, Alice | Wang, Li-San | Graff-Radford, Neill R | Dickson, Dennis W. | Rademakers, Rosa | Boeve, Bradley F. | Grossman, Murray | Arnold, Steven E. | Mann, David M.A. | Pickering-Brown, Stuart M. | Seelaar, Harro | Heutink, Peter | van Swieten, John C. | Murrell, Jill R. | Ghetti, Bernardino | Spina, Salvatore | Grafman, Jordan | Hodges, John | Spillantini, Maria Grazia | Gilman, Sid' | Lieberman, Andrew P. | Kaye, Jeffrey A. | Woltjer, Randall L. | Bigio, Eileen H | Mesulam, Marsel | al-Sarraj, Safa | Troakes, Claire | Rosenberg, Roger N. | White, Charles L. | Ferrer, Isidro | Lladó, Albert | Neumann, Manuela | Kretzschmar, Hans A. | Hulette, Christine Marie | Welsh-Bohmer, Kathleen A. | Miller, Bruce L | Alzualde, Ainhoa | de Munain, Adolfo Lopez | McKee, Ann C. | Gearing, Marla | Levey, Allan I. | Lah, James J. | Hardy, John | Rohrer, Jonathan D. | Lashley, Tammaryn | Mackenzie, Ian R.A. | Feldman, Howard H. | Hamilton, Ronald L. | Dekosky, Steven T. | van der Zee, Julie | Kumar-Singh, Samir | Van Broeckhoven, Christine | Mayeux, Richard | Vonsattel, Jean Paul G. | Troncoso, Juan C. | Kril, Jillian J | Kwok, John B.J. | Halliday, Glenda M. | Bird, Thomas D. | Ince, Paul G. | Shaw, Pamela J. | Cairns, Nigel J. | Morris, John C. | McLean, Catriona Ann | DeCarli, Charles | Ellis, William G. | Freeman, Stefanie H. | Frosch, Matthew P. | Growdon, John H. | Perl, Daniel P. | Sano, Mary | Bennett, David A. | Schneider, Julie A. | Beach, Thomas G. | Reiman, Eric M. | Woodruff, Bryan K. | Cummings, Jeffrey | Vinters, Harry V. | Miller, Carol A. | Chui, Helena C. | Alafuzoff, Irina | Hartikainen, Päivi | Seilhean, Danielle | Galasko, Douglas | Masliah, Eliezer | Cotman, Carl W. | Tuñón, M. Teresa | Martínez, M. Cristina Caballero | Munoz, David G. | Carroll, Steven L. | Marson, Daniel | Riederer, Peter F. | Bogdanovic, Nenad | Schellenberg, Gerard D. | Hakonarson, Hakon | Trojanowski, John Q. | Lee, Virginia M.-Y.
Nature genetics  2010;42(3):234-239.
Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP)1. FTLD-TDP is frequently familial resulting from progranulin (GRN) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains TMEM106B in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (P=1.08×10−11; odds ratio (OR) minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P=2×10−4). TMEM106B variants may confer risk by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in patients with GRN mutations. Our data implicate TMEM106B as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.
PMCID: PMC2828525  PMID: 20154673
4.  Clinical Features of Alzheimer Disease With and Without Lewy Bodies 
JAMA neurology  2015;72(7):789-796.
Lewy bodies are a frequent coexisting pathology in late-onset Alzheimer disease (AD). Previous studies have examined the contribution of Lewy bodies to the clinical phenotype of late-onset AD with variable findings.
To determine whether the presence of Lewy body pathology influences the clinical phenotype and progression of symptoms in longitudinally assessed participants with AD.
Retrospective clinical and pathological cohort study of 531 deceased participants who met the neuropathologic criteria for intermediate or high likelihood of AD according to the National Institute on Aging–Ronald Reagan Institute guidelines for the neuropathologic diagnosis of AD. All participants had a clinical assessment within 2 years of death. The data were obtained from 34 AD centers maintained by the National Alzheimer Coordinating Center and spanned from September 12, 2005, to April 30, 2013.
Standardized neuropathologic assessment and then brain autopsy after death.
Clinical and neuropsychiatric test scores.
The mean (SD) age at death was statistically significantly younger for participants who had AD with Lewy bodies (77.9 [9.5] years) than for participants who had AD without Lewy bodies (80.2 [11.1] years) (P = .01). The mean (SD) age at onset of dementia symptoms was also younger for participants who had AD with Lewy bodies (70.0 [9.9] years) than for participants who had AD without Lewy bodies (72.2 [12.3] years) (P = .03). More men than women had AD with Lewy bodies (P = .01). The frequency of having at least 1 APOE ε4 allele was higher for participants who had AD with Lewy bodies than for participants who had AD without Lewy bodies (P = .03). After adjusting for age, sex, education, frequency of plaques (neuritic and diffuse), and tangle stage, we found that participants who had AD with Lewy bodies had a statistically significantly higher mean (SD) Neuropsychiatric Inventory Questionnaire score (6.59 [1.44] [95% CI, 3.75–9.42] vs 5.49 [1.39] [95% CI, 2.76–8.23]; P = .04) and a statistically significantly higher mean (SD) Unified Parkinson Disease Rating Scale motor score (0.81 [0.18] [95% CI, 0.45–1.17] vs 0.54 [0.18] [95% CI, 0.19–0.88]; P < .001) than did participants who had AD without Lewy bodies.
Participants with both AD and Lewy body pathology have a clinical phenotype that may be distinguished from AD alone. The frequency of Lewy bodies in AD and the association of Lewy bodies with the APOE ε4 allele suggest potential common mechanisms for AD and Lewy body pathologies.
PMCID: PMC4501861  PMID: 25985321
5.  The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia 
NeuroImage : Clinical  2015;8:246-252.
Background and purpose
Elevated levels of amyloid deposition as well as white matter damage are thought to be risk factors for Alzheimer Disease (AD). Here we examined whether qualitative ratings of white matter damage predicted cognitive impairment beyond measures of amyloid.
Materials and methods
The study examined 397 cognitively normal, 51 very mildly demented, and 11 mildly demented individuals aged 42–90 (mean 68.5). Participants obtained a T2-weighted scan as well as a positron emission tomography scan using 11[C] Pittsburgh Compound B. Periventricular white matter hyperintensities (PVWMHs) and deep white matter hyperintensities (DWMHs) were measured on each T2 scan using the Fazekas rating scale. The effects of amyloid deposition and white matter damage were assessed using logistic regressions.
Levels of amyloid deposition (ps < 0.01), as well as ratings of PVWMH (p < 0.01) and DWMH (p < 0.05) discriminated between cognitively normal and demented individuals.
The amount of amyloid deposition and white matter damage independently predicts cognitive impairment. This suggests a diagnostic utility of qualitative white matter scales in addition to measuring amyloid levels.
•White matter damage was quantified using the Fazekas rating scale.•Measures of amyloid were measured using positron emission tomography.•There was a greater severity of damage in demented individuals.•White matter damage significantly predicted dementia after controlling for amyloid.•There is a clinical utility to using the Fazekas scale in addition to amyloid levels.
PMCID: PMC4474174  PMID: 26106548
Alzheimer's; White matter; Amyloid; Biomarkers; Vascular; Myelin
6.  Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN) 
It has been hypothesized that the relatively rare autosomal dominant Alzheimer disease (ADAD) may be a useful model of the more frequent, sporadic, late-onset AD (LOAD). Individuals with ADAD have a predictable age at onset and the biomarker profile of ADAD participants in the preclinical stage may be used to predict disease progression and clinical onset. However, the extent to which the pathogenesis and neuropathology of ADAD overlaps with that of LOAD is equivocal. To address this uncertainty, two multicenter longitudinal observational studies, the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN), leveraged the expertise and resources of the existing Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, Missouri, USA, to establish a Neuropathology Core (NPC). The ADNI/DIAN-NPC is systematically examining the brains of all participants who come to autopsy at the 59 ADNI sites in the USA and Canada and the 14 DIAN sites in the USA (8), Australia (3), UK (1), and Germany (2). By 2014, 41 ADNI and 24 DIAN autopsies (involving 9 participants and 15 family members) had been performed. The autopsy rate in the ADNI cohort in the most recent year was 93% (total since NPC inception: 70%). In summary, the ADNI/DIAN NPC has implemented a standard protocol for all sites to solicit permission for brain autopsy and to send brain tissue to the NPC for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI and DIAN of the implementation of the NPC is very clear. The NPC provides final ‘gold standard’ neuropathological diagnoses and data against which the antecedent observations and measurements of ADNI and DIAN can be compared.
PMCID: PMC4521391  PMID: 25964057
Autosomal dominant; Alzheimer disease; Late-onset Alzheimer disease; neuropathologic diagnostic criteria; neuropathologic heat map; PET-PiB amyloid imaging
7.  Clinical and Psychological Characteristics of Initial Cohort of the Dominantly Inherited Alzheimer Network (DIAN) 
Neuropsychology  2013;28(1):10.1037/neu0000030.
To describe clinical, cognitive, and personality characteristics at baseline assessment of 249 participants 19 to 60 years of age in a multinational longitudinal study (DIAN) of autosomal dominant Alzheimer disease (ADAD).
Participants (74% cognitively normal) were from ADAD families with mutations in one of three genes (APP, PSEN1, or PSEN2). Mixed model analyses including family as a random variable and controlling for years from expected time of symptomatic onset of ADAD based on parental age at onset compared three groups (cognitively normal mutation noncarriers, cognitively normal mutation carriers, very mildly impaired mutation carriers).
Global cognitive deficits similar to those observed in late-life sporadic Alzheimer disease (AD) existed in very mild ADAD compared with cognitively normal carriers and noncarriers on all but two measures (Digit Span Backward, Letter Fluency for FAS) of episodic memory, semantic memory, working memory, attention, and speeded visuospatial abilities. Demented individuals were less extraverted, open, and conscientious than cognitively normal participants on the International Personality Item Pool. Differences in the relation between three measures (Logical Memory, Digit Symbol, attention switching) and time to expected age at symptomatic onset indicate that cognitive deficits on some measures can be detected in mutation carriers prior to symptomatic AD and hence should be useful markers in subsequent longitudinal follow-up.
Overall cognitive and personality deficits in very mild ADAD are similar to those seen in sporadic AD. Cognitive deficits also occur in asymptomatic mutation carriers who are closer to the expected time of dementia onset.
PMCID: PMC3877741  PMID: 24219606
Alzheimer disease; early onset; preclinical; cognition; personality
8.  Neuropsychological changes in asymptomatic persons with Alzheimer disease neuropathology 
Neurology  2014;83(5):434-440.
To determine whether asymptomatic persons with Alzheimer disease (AD) neuropathologic change differ in the trajectory of their cognitive performance compared to asymptomatic persons without AD neuropathologic change.
Longitudinal performance on standard neuropsychological tests was examined in participants who died within 2 years of their last cognitive assessment and who were never diagnosed with mild cognitive impairment or dementia (Clinical Dementia Rating global score of 0 at all assessments). Using cognitive and neuropathologic data collected between 2005 and 2013 from the 34 National Institute on Aging–sponsored Alzheimer's Disease Centers, cognitive trajectories were compared for persons with and without evidence of AD neuropathologic change. We evaluated rates of decline in 4 domains (episodic memory, language, attention/working memory, executive function). The significance of the differences (β) in rates of decline was tested using linear regression, adjusting for age, education, sex, and other neuropathologic lesions.
Participants who had low to high levels of AD neuropathologic change (n = 131) showed a greater rate of decline on the attention/working memory domain score (β = −0.11; 95% confidence interval = −0.19, −0.02; p = 0.02) when compared to 80 participants who died without evidence of AD neuropathologic change.
Clinically normal individuals who come to autopsy with AD neuropathologic change exhibit subtle evidence of declining cognitive trajectories for attention/working memory.
PMCID: PMC4132573  PMID: 24951474
9.  A survey of attitudes toward clinical trials and genetic disclosure in autosomal dominant Alzheimer’s disease 
Because of its genetic underpinnings and consistent age of onset within families, autosomal dominant Alzheimer’s disease (ADAD) provides a unique opportunity to conduct clinical trials of investigational agents as preventative or symptom-delaying treatments. The design of such trials may be complicated by low rates of genetic testing and disclosure among persons at risk of inheriting disease-causing mutations.
To better understand the attitudes toward genetic testing and clinical trials of persons at risk for ADAD, we surveyed participants in the Dominantly Inherited Alzheimer’s Network (DIAN), a multisite longitudinal study of clinical and biomarker outcomes in ADAD that does not require learning genetic status to participate.
Eighty participants completed a brief anonymous survey by mail or on-line; 40 % reported knowing if they carried a gene mutation, 15 % did not know but expressed a desire to learn their genetic status, and 45 % did not know and did not desire to know their genetic status. Among participants who knew or wished to know their genetic status, 86 % were interested in participating in a clinical trial. Seventy-two percent of participants who did not wish to learn their genetic status reported that they would change their mind, if learning that they carried a mutation gave them the opportunity to participate in a clinical trial. Nearly all participants responded that they would be interested if an open-label extension were offered.
These results suggest that the availability of clinical trials to prevent ADAD can affect persons’ desire to undergo genetic testing and that consideration can be given to performing studies in which such testing is required.
PMCID: PMC4511231  PMID: 26203303
10.  Vaginal type-II mucosa is an inductive site for primary CD8+ T-cell mucosal immunity 
Nature communications  2015;6:6100.
The structured lymphoid tissues are considered the only inductive sites where primary T cell immune responses occur. The naïve T cells in structured lymphoid tissues, once being primed by antigen -bearing dendritic cells, differentiate into memory T cells and traffic back to the mucosal sites through the bloodstream. Contrary to this belief, here we show that the vaginal type-II mucosa itself, despite lack of structured lymphoid tissues, can act as an inductive site during primary CD8+ T cell immune responses. We provide evidence that the vaginal mucosa supports both the local immune priming of naïve CD8+ T cells and the local expansion of antigen-specific CD8+ T cells, thereby demonstrating a different paradigm for primary mucosal T cell immune induction.
PMCID: PMC4348041  PMID: 25600442
11.  Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies 
Anti-Cancer Drugs  2015;26(7):785-792.
Supplemental Digital Content is available in the text.
Taxane–gemcitabine combinations have demonstrated antitumor activity. This phase I study (NCT01001221) aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus gemcitabine and to assess the preliminary efficacy of this combination. The patients included had metastatic or unresectable solid tumors and had exhausted standard treatment. Cohorts of three to six patients received cabazitaxel (15–20 mg/m2) before (part 1a) or after (part 1b) gemcitabine (700–1000 mg/m2) on Day 1 and gemcitabine alone on Day 8. Prophylactic growth factors were not allowed in cycle 1. In part 1a (n=12), five patients received 20 mg/m2 cabazitaxel plus 1000 mg/m2 gemcitabine (20/1000), five received 15/900, two received 15/700. In part 1b, all six patients received the lowest dose (700/15). At all doses, two or more patients experienced a DLT, regardless of administration sequence, including febrile neutropenia (n=4), grade 4 neutropenia (n=2), grade 4 thrombocytopenia (n=2), and grade 3 aspartate transaminase increase (n=1). The MTD was not established as all cohorts exceeded the MTD by definition. All patients experienced an adverse event; the most frequent all-grade nonhematologic events were fatigue (66.7%), decreased appetite (50.0%), and diarrhea (44.4%). The most frequent grade 3–4 hematologic abnormalities were neutropenia (83.3%), leukopenia (77.8%), and lymphopenia (72.2%). Toxicity was sequence-independent but appeared worse with gemcitabine followed by cabazitaxel. Durable partial responses were observed in three patients (prostate cancer, appendiceal cancer, and melanoma). The unacceptable DLTs with cabazitaxel plus gemcitabine, at doses reduced more than 25% from single-agent doses, preclude further investigation.
PMCID: PMC4484664  PMID: 26020806
advanced solid tumors; cabazitaxel; dose escalation; gemcitabine; phase I
12.  Missense variant in TREML2 protects against Alzheimer’s Disease 
Neurobiology of aging  2013;35(6):1510.e19-1510.e26.
TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer’s disease (AD). In addition, common SNPs in this genomic region are associated with cerebrospinal fluid (CSF) biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, CSF biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated GWAS signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.
PMCID: PMC3961557  PMID: 24439484
13.  Ptau-Aβ42 ratio as a continuous trait for biomarker discovery for early stage Alzheimer’s disease in multiplex immunoassay panels of Cerebrospinal fluid 
Biological psychiatry  2014;75(9):723-731.
Identification of the physiological changes that occur during the early stages of Alzheimer’s disease (AD) may provide critical insights for the diagnosis, prognosis and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome.
We applied a novel approach to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay and detected common associations in the Knight- Alzheimer’s Disease Research Center (ADRC;N=311) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI;N=293) cohorts. CSF ptau181-Aβ42 ratio was used as a continuous trait, rather than case control status in these analyses.
We demonstrate the ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches and that the levels of CSF Fatty Acid Binding Protein (H-FABP) and 12 other correlated analytes increase as the disease progresses. These results were validated using the traditional case control status model. Stratification of our dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in non-demented individuals with AD pathology (low ptau181, low Aβ42) compared to pathology-negative elderly control subjects (low ptau181, high Aβ42). FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor
Our results clearly indicate that the approach presented here can be employed to correctly identify novel biomarkers for AD, and that CSF H-FABP levels start to increase at very early stages of the disease.
PMCID: PMC4007142  PMID: 24548642
Alzheimer’s disease; Biomarkers; cerebrospinal fluid (CSF); Ptau-Aβ42 ratio; Heart Fatty Acid binding protein; Brain Proteome - Rules Based Medicine Discovery Multi-Analyte Profile 1.0
14.  Longitudinal Associations between Physical and Cognitive Performance among Community-Dwelling Older Adults 
PLoS ONE  2015;10(4):e0122878.
To assess the directionality of the association between physical and cognitive decline in later life, we compared patterns of decline in performance across groups defined by baseline presence of cognitive and/or physical impairment [none (n = 217); physical only (n = 169); cognitive only (n = 158), or both (n = 220)] in a large sample of participants in a cognitive aging study at the Knight Alzheimer’s Disease Research Center at Washington University in St. Louis who were followed for up to 8 years (3,079 observations). Rates of decline reached 20% for physical performance and varied across cognitive tests (global, memory, speed, executive function, and visuospatial skills). We found that physical decline was better predicted by baseline cognitive impairment (slope = -1.22, p<0.001), with baseline physical impairment not contributing to further decline in physical performance (slope = -0.25, p = 0.294). In turn, baseline physical impairment was only marginally associated with rate of cognitive decline across various cognitive domains. The cognitive-functional association is likely to operate in the direction of cognitive impairment to physical decline although physical impairment may also play a role in cognitive decline/dementia. Interventions to prevent further functional decline and development of disability and complete dependence may benefit if targeted to individuals with cognitive impairment who are at increased risk.
PMCID: PMC4395358  PMID: 25875165
15.  Quantitative Amyloid Imaging Using Image-Derived Arterial Input Function 
PLoS ONE  2015;10(4):e0122920.
Amyloid PET imaging is an indispensable tool widely used in the investigation, diagnosis and monitoring of Alzheimer’s disease (AD). Currently, a reference region based approach is used as the mainstream quantification technique for amyloid imaging. This approach assumes the reference region is amyloid free and has the same tracer influx and washout kinetics as the regions of interest. However, this assumption may not always be valid. The goal of this work is to evaluate an amyloid imaging quantification technique that uses arterial region of interest as the reference to avoid potential bias caused by specific binding in the reference region. 21 participants, age 58 and up, underwent Pittsburgh compound B (PiB) PET imaging and MR imaging including a time-of-flight (TOF) MR angiography (MRA) scan and a structural scan. FreeSurfer based regional analysis was performed to quantify PiB PET data. Arterial input function was estimated based on coregistered TOF MRA using a modeling based technique. Regional distribution volume (VT) was calculated using Logan graphical analysis with estimated arterial input function. Kinetic modeling was also performed using the estimated arterial input function as a way to evaluate PiB binding (DVRkinetic) without a reference region. As a comparison, Logan graphical analysis was also performed with cerebellar cortex as reference to obtain DVRREF. Excellent agreement was observed between the two distribution volume ratio measurements (r>0.89, ICC>0.80). The estimated cerebellum VT was in line with literature reported values and the variability of cerebellum VT in the control group was comparable to reported variability using arterial sampling data. This study suggests that image-based arterial input function is a viable approach to quantify amyloid imaging data, without the need of arterial sampling or a reference region. This technique can be a valuable tool for amyloid imaging, particularly in population where reference normalization may not be accurate.
PMCID: PMC4388540  PMID: 25849581
16.  Diagnostic Value of Subjective Memory Complaints Assessed with a Single Item in Dominantly Inherited Alzheimer's Disease: Results of the DIAN Study 
BioMed Research International  2015;2015:828120.
Objective. We examined the diagnostic value of subjective memory complaints (SMCs) assessed with a single item in a large cross-sectional cohort consisting of families with autosomal dominant Alzheimer's disease (ADAD) participating in the Dominantly Inherited Alzheimer Network (DIAN). Methods. The baseline sample of 183 mutation carriers (MCs) and 117 noncarriers (NCs) was divided according to Clinical Dementia Rating (CDR) scale into preclinical (CDR 0; MCs: n = 107; NCs: n = 109), early symptomatic (CDR 0.5; MCs: n = 48; NCs: n = 8), and dementia stage (CDR ≥ 1; MCs: n = 28; NCs: n = 0). These groups were subdivided by the presence or absence of SMCs. Results. At CDR 0, SMCs were present in 12.1% of MCs and 9.2% of NCs (P = 0.6). At CDR 0.5, SMCs were present in 66.7% of MCs and 62.5% of NCs (P = 1.0). At CDR ≥ 1, SMCs were present in 96.4% of MCs. SMCs in MCs were significantly associated with CDR, logical memory scores, Geriatric Depression Scale, education, and estimated years to onset. Conclusions. The present study shows that SMCs assessed by a single-item scale have no diagnostic value to identify preclinical ADAD in asymptomatic individuals. These results demonstrate the need of further improvement of SMC measures that should be examined in large clinical trials.
PMCID: PMC4398930  PMID: 25922840
17.  Functional connectivity and graph theory in preclinical Alzheimer’s disease 
Neurobiology of aging  2013;35(4):10.1016/j.neurobiolaging.2013.10.081.
Alzheimer’s disease (AD) has a long preclinical phase in which amyloid and tau cerebral pathology accumulate without producing cognitive symptoms. Resting state functional connectivity MRI (rs-fcMRI) has demonstrated that brain networks degrade during symptomatic AD. It is unclear to what extent these degradations exist prior to symptomatic onset. In this study, we investigated graph theory metrics of functional integration (path length), functional segregation (clustering coefficient), and functional distinctness (modularity) as a function of disease severity. Further, we assessed whether these graph metrics were affected in cognitively normal participants with cerebrospinal fluid evidence of preclinical AD. Clustering coefficient and modularity, but not path length, were reduced in AD. Cognitively normal participants who harbored AD biomarker pathology also showed reduced values in these graph measures, demonstrating brain changes similar to, but smaller than, symptomatic AD. Only modularity was significantly affected by age. We also demonstrate that AD has a particular effect on hub-like regions in the brain. We conclude that AD causes large-scale disconnection that is present before onset of symptoms.
PMCID: PMC3880636  PMID: 24216223
Alzheimer’s disease; biomarker; functional connectivity; graph theory; resting-state
18.  The effect of APOE ε4 allele on cholinesterase inhibitors in patients with Alzheimer’s disease: Evaluation of the feasibility of resting state functional connectivity magnetic resonance imaging 
This work is to determine whether apolipoprotein E (APOE) genotype modulates the effect of cholinesterase inhibitor (ChEI) treatment on resting state functional connectivity magnetic resonance imaging (rs-fcMRI) in patients with Alzheimer’s disease (AD). We retrospectively studied very mild and mild AD participants who were treated (N=25) or untreated (N=19) with ChEIs with respect to rs-fcMRI measure of 5 resting state networks (RSNs): default mode, dorsal attention (DAN), control (CON), salience (SAL), and sensory-motor. For each network, a composite score was computed as the mean of Pearson’s correlations between pairwise time courses extracted from areas comprising this network. The composite scores were analyzed as a function of ChEI treatment and APOE ε4 allele. Across all participants, significant interactions between ChEI treatment and APOE ε4 allele were observed for all 5 RSNs. Within APOE ε4 carriers, significantly greater composite scores were observed in the DAN, CON and SAL for treated compared to untreated participants. Within APOE ε4 non-carriers, treated and untreated participants did not have significantly different composite scores for all RSNs. These data suggest that APOE genotype affects the response to ChEI using rs-fcMRI. Rs-fcMRI may be useful for assessing the therapeutic effect of medications in AD clinical trials.
PMCID: PMC4024181  PMID: 24830360
Alzheimer’s disease (AD); functional magnetic resonance imaging (fMRI); Cholinesterase inhibitor; Apolipoprotein E (APOE); resting state functional connectivity
19.  Reliability of Monitoring the Clinical Dementia Rating in Multicenter Clinical Trials 
The Clinical Dementia Rating (CDR) is quickly becoming a criterion standard in multicenter clinical trials in Alzheimer disease. An abbreviated version, with formal monitoring for consistency across sites and raters, is currently used in the Alzheimer’s Disease Cooperative Study (ADCS).
To demonstrate the degree of agreement on CDR scoring of clinical monitors working independently from ADCS-CDR worksheets.
Three members of the ADCS who are experienced and highly trained with respect to the CDR independently reviewed the ADCS-CDR worksheets of 15 subjects, assigning box and global CDR scores according to the prescribed algorithm.
The ratings were assigned during a single, 3-hour session in a closed room.
Two clinical monitors and one project director/clinical monitor supervisor.
Main Outcome Measures
Percent agreement, Kendall’s tau-b, and Cohen’s kappa were used to assess the degree of agreement of the raters with the previously established gold standard assessment on global and box scores for the 15 subjects.
Raters, blinded to patient groupings, were in agreement with the Gold Standard global CDR assessment on 87% of ratings. Kappa values indicated good (κ = 0.66, orientation and judgment & problem solving boxes) to excellent (κ = 0.83, global CDR) agreement.
The ADCS-CDR worksheets were reliably and consistently scored by clinical monitors, who may be considered proxy gold standards for CDR assessment.
PMCID: PMC4367865  PMID: 15592134
20.  Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer disease 
Science translational medicine  2014;6(226):226ra30.
Clinicopathologic evidence suggests the pathology of Alzheimer disease (AD) begins many years prior to cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic (“pre-clinical”) stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study comparing cerebrospinal fluid (CSF), plasma and in vivo amyloid imaging, cross-sectional data obtained at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network (DIAN) demonstrate reduced concentrations of CSF amyloid-β1-42 (Aβ1–42) associated with the presence of β-amyloid plaques, and elevated concentrations of CSF tau, ptau181 and VILIP-1, markers of neurofibrillary tangles and/or neuronal injury/death, in asymptomatic mutation carriers 10-20 years prior to their estimated age at symptom onset (EAO), and prior to detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within-individuals decrease after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.
PMCID: PMC4038930  PMID: 24598588
21.  Amyloid burden in cognitively normal elderly is associated with preferential hippocampal subfield volume loss 
The earliest sites of brain atrophy in Alzheimer’s disease are in the medial temporal lobe, following widespread cerebral cortical amyloid deposition. We assessed 74 cognitively normal participants with clinical measurements, Aβ-PET imaging, MRI, and a newly developed technique for MRI-based hippocampal subfield segmentation to determine the differential association of amyloid deposition and hippocampal subfield volume. Compared to amyloid-negative participants, amyloid-positive participants had significantly smaller hippocampal tail, presubiculum, subiculum, and total hippocampal gray matter volumes. We conclude that, prior to the development of cognitive impairment, atrophy in particular hippocampal subfields (HS) occurs preferentially with Aβ accumulation.
PMCID: PMC4351157  PMID: 25428255
Amyloid accumulation; hippocampal subfield volumes; cognitively normal elderly; subiculum; presubiculum
22.  Objective Assessment of Image Quality VI: Imaging in Radiation Therapy 
Physics in medicine and biology  2013;58(22):8197-8213.
Earlier work on Objective Assessment of Image Quality (OAIQ) focused largely on estimation or classification tasks in which the desired outcome of imaging is accurate diagnosis. This paper develops a general framework for assessing imaging quality on the basis of therapeutic outcomes rather than diagnostic performance. By analogy to Receiver Operating Characteristic (ROC) curves and their variants as used in diagnostic OAIQ, the method proposed here utilizes the Therapy Operating Characteristic or TOC curves, which are plots of the probability of tumor control vs. the probability of normal-tissue complications as the overall dose level of a radiotherapy treatment is varied. The proposed figure of merit is the area under the TOC curve, denoted AUTOC. This paper reviews an earlier exposition of the theory of TOC and AUTOC, which was specific to the assessment of image-segmentation algorithms, and extends it to other applications of imaging in external-beam radiation treatment as well as in treatment with internal radioactive sources. For each application, a methodology for computing the TOC is presented. A key difference between ROC and TOC is that the latter can be defined for a single patient rather than a population of patients.
PMCID: PMC4326059  PMID: 24200954
23.  Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci 
JAMA neurology  2014;71(11):1394-1404.
As APOE locus variants contribute to both risk of late-onset Alzheimer disease and differences in age-at-onset, it is important to know if other established late-onset Alzheimer disease risk loci also affect age-at-onset in cases.
To investigate the effects of known Alzheimer disease risk loci in modifying age-at-onset, and to estimate their cumulative effect on age-at-onset variation, using data from genome-wide association studies in the Alzheimer’s Disease Genetics Consortium (ADGC).
Design, Setting and Participants
The ADGC comprises 14 case-control, prospective, and family-based datasets with data on 9,162 Caucasian participants with Alzheimer’s occurring after age 60 who also had complete age-at-onset information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single nucleotide polymorphisms (SNPs) most significantly associated with risk at ten confirmed LOAD loci were examined in linear modeling of AAO, and individual dataset results were combined using a random effects, inverse variance-weighted meta-analysis approach to determine if they contribute to variation in age-at-onset. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Main Outcomes and Measures
Age at disease onset abstracted from medical records among participants with late-onset Alzheimer disease diagnosed per standard criteria.
Analysis confirmed association of APOE with age-at-onset (rs6857, P=3.30×10−96), with associations in CR1 (rs6701713, P=7.17×10−4), BIN1 (rs7561528, P=4.78×10−4), and PICALM (rs561655, P=2.23×10−3) reaching statistical significance (P<0.005). Risk alleles individually reduced age-at-onset by 3-6 months. Burden analyses demonstrated that APOE contributes to 3.9% of variation in age-at-onset (R2=0.220) over baseline (R2=0.189) whereas the other nine loci together contribute to 1.1% of variation (R2=0.198).
Conclusions and Relevance
We confirmed association of APOE variants with age-at-onset among late-onset Alzheimer disease cases and observed novel associations with age-at-onset in CR1, BIN1, and PICALM. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on age-at-onset are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on age-at-onset may be significant, additional genetic contributions to age-at-onset are individually likely to be small.
PMCID: PMC4314944  PMID: 25199842
Alzheimer Disease; Alzheimer Disease Genetics; Alzheimer’s Disease - Pathophysiology; Genetics of Alzheimer Disease; Aging
24.  Relationships between late-life hypertension, blood pressure, and Alzheimer's disease 
Relationships between late-life hypertension and AD remain less clear. Both cross-sectional and longitudinal methods were used to examine whether systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), mean arterial pressure (MAP), and self-reported hypertension (S-HTN) in late life were associated with having and developing AD. In the cross-sectional examination were 1,768 individuals with AD and 818 nondemented individual, and AD was not significantly associated with S-HTN or any of blood pressure measures (S-HTN: p=0.236; SBP: p=0.095; DBP: p=0.429; PP: p=0.145; MAP: p=0.162). In the longitudinal examination, 594 nondemented individuals, 171 with and 423 without self-reported hypertension at entry, were included. DBP was significantly related to the development of AD (p=0.030), but not S-HTN (p=0.251), SBP (p=0.294) PP (p=0.919), and MAP (p=0.060). The association underscores the necessity of further investigation to outline the detailed mechanisms and biological relevance, if any, of late-life DBP to later AD.
PMCID: PMC3312309  PMID: 21921085
hypertension; systolic blood pressure; diastolic blood pressure; pulse pressure; mean arterial pressure; Alzheimer's disease
25.  Lung cancer vaccines: current status and future prospects 
Designing a cancer treatment that very specifically targets and kills tumor cells with little to no side effects is the “holy grail” of oncology. Cancer vaccines have this potential. Vaccines utilize the immune system to specifically target and eliminate tumor cells. Historically, vaccination approaches against lung cancer have been disappointing. However, over the past decade, a greater understanding of the immune system and of the antigens expressed by tumors, coupled with advances in immunoadjuvants and improved delivery systems, has led to advances in the use of immunotherapy including vaccines to target lung cancer. Proof of principle phase I/II clinical trials targeting the MAGE-A3 and MUC1 tumor antigens, as well as cell-based vaccines such as belagenpumatucel-L have suggested improved survival, leading to larger scale phase III clinical trials. This review will discuss cancer vaccines in relation to lung cancer and present clinical data supporting their use.
PMCID: PMC4367609  PMID: 25806280
Lung cancer; cancer vaccines; immunotherapy; clinical trials

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