"Ventricular enlargement and its clinical correlates in the imaging cohort from the ADCS MCI donepezil/vitamin E study"Apostolova, Liana G; Babakchanian, Sona; Hwang, Kristy S; Green, Amity E; Zlatev, Dimitar; Chou, Yi-Yu; DeCarli, Charlie; Jack, Clifford R Jr; Petersen, Ronald C; AISEN, PAUL S; Cummings, Jeffrey L; Toga, Arthur W; Thompson, Paul M
GRANTS:AG16570/AG/NIA NIH HHS/United States;EB01651/EB/NIBIB NIH HHS/United States;LM05639/LM/NLM NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P41 RR013642/RR/NCRR NIH HHS/United States;R01 MH071940/MH/NIMH NIH HHS/United States;RR019771/RR/NCRR NIH HHS/United States;U54 RR021813/RR/NCRR NIH HHS/United States
We analyzed the baseline and 3-year T1-weighted magnetic resonance imaging data of 110 amnestic mild cognitive impairment (MCI) participants with minimal hippocampal atrophy at baseline from the Alzheimer's Disease Cooperative Study group MCI Donepezil/Vitamin E trial. Forty-six subjects converted to Alzheimer disease (AD) (MCIc), whereas 64 remained stable (MCInc). We used the radial distance technique to examine the differences in lateral ventricle shape and size between MCIc and MCInc and the associations between ventricular enlargement and cognitive decline. MCIc group had significantly larger frontal and right body/occipital horns relative to MCInc at baseline and significantly larger bilateral frontal, body/occipital, and left temporal horns at follow-up. Global cognitive decline measured with AD Assessment scale cognitive subscale and Mini-Mental State Examination and decline in activities of daily living (ADL) were associated with posterior lateral ventricle enlargement. Decline in AD Assessment scale cognitive subscale and ADL were associated with left temporal and decline in Mini-Mental State Examination with right temporal horn enlargement. After correction for baseline hippocampal volume, decline in ADL showed a significant association with right frontal horn enlargement. Executive decline was associated with right frontal and left temporal horn enlargement..
"Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease"Benzinger, Tammie L S; Blazey, Tyler; Jack, Clifford R Jr; Koeppe, Robert A; Su, Yi; Xiong, Chengjie; Raichle, Marcus E; Snyder, Abraham Z; Ances, Beau M; Bateman, Randall J; Cairns, Nigel J; Fagan, Anne M; Goate, Alison; Marcus, Daniel S; AISEN, PAUL S; Christensen, Jon J; Ercole, Lindsay; Hornbeck, Russ C; Farrar, Angela M; Aldea, Patricia; Jasielec, Mateusz S; Owen, Christopher J; Xie, Xianyun; Mayeux, Richard; Brickman, Adam; McDade, Eric; Klunk, William; Mathis, Chester A; Ringman, John; Thompson, Paul M; Ghetti, Bernardino; Saykin, Andrew J; Sperling, Reisa A; Johnson, Keith A; Salloway, Stephen; Correia, Stephen; Schofield, Peter R; Masters, Colin L; Rowe, Christopher; Villemagne, Victor L; Martins, Ralph; Ourselin, Sebastien; Rossor, Martin N; Fox, Nick C; Cash, David M; Weiner, Michael W; Holtzman, David M; Buckles, Virginia D; Moulder, Krista; Morris, John C
GRANTS:1S10RR022984-01A1/RR/NCRR NIH HHS/United States;U19AG032438/AG/NIA NIH HHS/United States;UL1 TR000448/TR/NCATS NIH HHS/United States;UL1 TR000448/TR/NCATS NIH HHS/United States
Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease..
"A phase 3 trial of semagacestat for treatment of Alzheimer's disease"Doody, Rachelle S; Raman, Rema; Farlow, Martin; Iwatsubo, Takeshi; Vellas, Bruno; Joffe, Steven; Kieburtz, Karl; He, Feng; Sun, Xiaoying; Thomas, Ronald G; AISEN, PAUL S; Siemers, Eric; Sethuraman, Gopalan; Mohs, Richard
GRANTS:U01 AG010483/AG/NIA NIH HHS/United States;U19 AG010483/AG/NIA NIH HHS/United States
BACKGROUND: Alzheimer's disease is characterized by the presence of cortical amyloid-beta (Abeta) protein plaques, which result from the sequential action of beta-secretase and gamma-secretase on amyloid precursor protein. Semagacestat is a small-molecule gamma-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease. METHODS: We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used. RESULTS: The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated. CONCLUSIONS: As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT00594568.).
"Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020"Hampel, Harald; Lista, Simone; Teipel, Stefan J; Garaci, Francesco; Nistico, Robert; Blennow, Kaj; Zetterberg, Henrik; Bertram, Lars; Duyckaerts, Charles; Bakardjian, Hovagim; Drzezga, Alexander; Colliot, Olivier; Epelbaum, Stephane; Broich, Karl; Lehericy, Stephane; Brice, Alexis; Khachaturian, Zaven S; AISEN, PAUL S; Dubois, Bruno
Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD..
"Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers"Jack, Clifford R Jr; Knopman, David S; Jagust, William J; Petersen, Ronald C; Weiner, Michael W; AISEN, PAUL S; Shaw, Leslie M; Vemuri, Prashanthi; Wiste, Heather J; Weigand, Stephen D; Lesnick, Timothy G; Pankratz, Vernon S; Donohue, Michael C; Trojanowski, John Q
GRANTS:AG11378/AG/NIA NIH HHS/United States;R01 AG011378/AG/NIA NIH HHS/United States
In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid beta (Abeta) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Abeta pathophysiology can accelerate antecedent limbic and brainstem tauopathy..
"Focal hemosiderin deposits and beta-amyloid load in the ADNI cohort"Kantarci, Kejal; Gunter, Jeffrey L; Tosakulwong, Nirubol; Weigand, Stephen D; Senjem, Matthew S; Petersen, Ronald C; AISEN, PAUL S; Jagust, William J; Weiner, Michael W; Jack, Clifford R Jr
GRANTS:K01 AG030514/AG/NIA NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P50 AG016574/AG/NIA NIH HHS/United States;R01 AG011378/AG/NIA NIH HHS/United States;R01 AG040042/AG/NIA NIH HHS/United States;R01 AG11378/AG/NIA NIH HHS/United States;R01 AG40042/AG/NIA NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;Canadian Institutes of Health Research/Canada
BACKGROUND: Prevalence and risk factors for focal hemosiderin deposits are important considerations when planning amyloid-modifying trials for treatment and prevention of Alzheimer's disease (AD). METHODS: Subjects were cognitively normal (n = 171), early-mild cognitive impairment (MCI) (n = 240), late-MCI (n = 111), and AD (n = 40) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Microhemorrhages and superficial siderosis were assessed at baseline and on all available MRIs at 3, 6, and 12 months. beta-amyloid load was assessed with (18)F-florbetapir positron emission tomography. RESULTS: Prevalence of superficial siderosis was 1% and prevalence of microhemorrhages was 25% increasing with age (P < .001) and beta-amyloid load (P < .001). Topographic densities of microhemorrhages were highest in the occipital lobes and lowest in the deep/infratentorial regions. A greater number of microhemorrhages at baseline was associated with a greater annualized rate of additional microhemorrhages by last follow-up (rank correlation = 0.49; P < .001). CONCLUSIONS: Focal hemosiderin deposits are relatively common in the ADNI cohort and are associated with beta-amyloid load..
"Influence of genetic variation on plasma protein levels in older adults using a multi-analyte panel"Kim, Sungeun; Swaminathan, Shanker; Inlow, Mark; Risacher, Shannon L; Nho, Kwangsik; Shen, Li; Foroud, Tatiana M; Petersen, Ronald C; AISEN, PAUL S; Soares, Holly; Toledo, Jon B; Shaw, Leslie M; Trojanowski, John Q; Weiner, Michael W; McDonald, Brenna C; Farlow, Martin R; Ghetti, Bernardino; Saykin, Andrew J
GRANTS:IIS-1117335/PHS HHS/United States;K01 AG030514/AG/NIA NIH HHS/United States;K99 LM011384/LM/NLM NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P30 AG010133/AG/NIA NIH HHS/United States;P30AG010133/AG/NIA NIH HHS/United States;P30AG10133-18S1/AG/NIA NIH HHS/United States;R01 AG019771/AG/NIA NIH HHS/United States;R01 AG19771/AG/NIA NIH HHS/United States;R01 LM011360/LM/NLM NIH HHS/United States;R01AG19771/AG/NIA NIH HHS/United States;TL1 RR025759/RR/NCRR NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;U01AG032984/AG/NIA NIH HHS/United States;U24AG021886/AG/NIA NIH HHS/United States;Canadian Institutes of Health Research/Canada
Proteins, widely studied as potential biomarkers, play important roles in numerous physiological functions and diseases. Genetic variation may modulate corresponding protein levels and point to the role of these variants in disease pathophysiology. Effects of individual single nucleotide polymorphisms (SNPs) within a gene were analyzed for corresponding plasma protein levels using genome-wide association study (GWAS) genotype data and proteomic panel data with 132 quality-controlled analytes from 521 Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Linear regression analysis detected 112 significant (Bonferroni threshold p=2.44x10(-5)) associations between 27 analytes and 112 SNPs. 107 out of these 112 associations were tested in the Indiana Memory and Aging Study (IMAS) cohort for replication and 50 associations were replicated at uncorrected p<0.05 in the same direction of effect as those in the ADNI. We identified multiple novel associations including the association of rs7517126 with plasma complement factor H-related protein 1 (CFHR1) level at p<1.46x10(-60), accounting for 40 percent of total variation of the protein level. We serendipitously found the association of rs6677604 with the same protein at p<9.29x10(-112). Although these two SNPs were not in the strong linkage disequilibrium, 61 percent of total variation of CFHR1 was accounted for by rs6677604 without additional variation by rs7517126 when both SNPs were tested together. 78 other SNP-protein associations in the ADNI sample exceeded genome-wide significance (5x10(-8)). Our results confirmed previously identified gene-protein associations for interleukin-6 receptor, chemokine CC-4, angiotensin-converting enzyme, and angiotensinogen, although the direction of effect was reversed in some cases. This study is among the first analyses of gene-protein product relationships integrating multiplex-panel proteomics and targeted genes extracted from a GWAS array. With intensive searches taking place for proteomic biomarkers for many diseases, the role of genetic variation takes on new importance and should be considered in interpretation of proteomic results..
"The effect of subsyndromal symptoms of depression and white matter lesions on disability for individuals with mild cognitive impairment"Mackin, R Scott; Insel, Philip; Tosun, Duygu; Mueller, Susanne G; Schuff, Norbert; Truran-Sacrey, Diana; Raptentsetsang, Sky T; Lee, Jun-Young; Jack, Clifford R Jr; AISEN, PAUL S; Petersen, Ronald C; Weiner, Michael W
GRANTS:K01 AG030514/AG/NIA NIH HHS/United States;KO8 MH081065/MH/NIMH NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P41 RR023953/RR/NCRR NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States
OBJECTIVE: To assess the effect of subsyndromal symptoms of depression (SSD) on ratings of disability for individuals with mild cognitive impairment (MCI). METHODS: Data from 405 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were analyzed. Participants were evaluated at baseline and at 6-month intervals over 2 years. Severity of depressive symptoms was rated utilizing the Geriatric Depression Scale. Disability was assessed utilizing the Functional Assessment Questionnaire (FAQ). Other clinical variables included white matter lesion (WML) and intracranial brain (ICV) volumes derived from magnetic resonance imaging, ratings of overall cognitive function (Alzheimer's Disease Assessment Scale, ADAS), and apolipoprotein E (ApoE) status. Demographic variables included age, education, and gender. RESULTS: SSD individuals had a lower volume of WML and higher frequency of ApoE varepsilon4 alleles than nondepressed participants but the two groups did not differ with respect to other clinical or demographic variables. At baseline, SSD individuals were 1.77 times more likely to have poorer FAQ scores than individuals with no symptoms of depression after controlling for the effect of cognitive functioning, ICV, WML, and ApoE status. The presence of SSD at baseline was not associated with a poorer course of disability outcomes, cognitive functioning, or conversion to dementia over 24 months. CONCLUSIONS: SSD demonstrated a significant impact on disability for MCI individuals, who are also at high risk for functional limitations related to neurodegenerative disease. Therefore, the treatment of SSD may represent a significant avenue to reduce the burden of disability in this vulnerable patient population..
"Neuropsychiatric Symptoms and Regional Neocortical Atrophy in Mild Cognitive Impairment and Alzheimer's Disease"Rafii, Michael S; Taylor, Curtis S; Kim, Hyun T; Desikan, Rahul S; Fleisher, Adam S; Katibian, David; Brewer, James B; Dale, Anders M; AISEN, PAUL S
Background:To assess the relationship between regional neocortical atrophy and psychotic symptoms in adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD).Methods: Rates of change in regional neocortical atrophy as measured by longitudinal magnetic resonance imaging scans and the occurrence of psychotic symptoms and/or the long-term use of antipsychotic medications in 389 outpatients with MCI or AD in Alzheimer's Disease Neuroimaging Initiative.Results: Atrophy rate of 3 specific neocortical regions, lateral frontal, lateral parietal, and anterior cingulate gyrus, was significantly associated with the onset of psychosis including delusions, agitation, wandering, and hallucinations and/or the need for chronic antipsychotic medications. Atrophy rate of the lateral frontal lobe correlated most significantly with onset of psychotic symptoms or need for chronic antipsychotic medications.Conclusions: Psychosis was associated with volume loss in specific regions of the lateral frontal and parietal lobes as well as anterior cingulate gyrus..
"The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI)"Risacher, Shannon L; Kim, Sungeun; Shen, Li; Nho, Kwangsik; Foroud, Tatiana; Green, Robert C; Petersen, Ronald C; Jack, Clifford R Jr; AISEN, PAUL S; Koeppe, Robert A; Jagust, William J; Shaw, Leslie M; Trojanowski, John Q; Weiner, Michael W; Saykin, Andrew J
GRANTS:P30 AG010133/AG/NIA NIH HHS/United States;R01 LM011360/LM/NLM NIH HHS/United States
Objective: Our goal was to evaluate the association of APOE with amyloid deposition, cerebrospinal fluid levels (CSF) of Abeta, tau, and p-tau, brain atrophy, cognition and cognitive complaints in E-MCI patients and cognitively healthy older adults (HC) in the ADNI-2 cohort. Methods: Two-hundred and nine E-MCI and 123 HC participants from the ADNI-2 cohort were included. We evaluated the impact of diagnostic status (E-MCI vs. HC) and APOE epsilon4 status (epsilon4 positive vs. epsilon4 negative) on cortical amyloid deposition (AV-45/Florbetapir SUVR PET scans), brain atrophy (structural MRI scans processed using voxel-based morphometry and Freesurfer version 5.1), CSF levels of Abeta, tau, and p-tau, and cognitive performance and complaints. Results: E-MCI participants showed significantly impaired cognition, higher levels of cognitive complaints, greater levels of tau and p-tau, and subcortical and cortical atrophy relative to HC participants (p < 0.05). Cortical amyloid deposition and CSF levels of Abeta were significantly associated with APOE epsilon4 status but not E-MCI diagnosis, with epsilon4 positive participants showing more amyloid deposition and lower levels of CSF Abeta than epsilon4 negative participants. Other effects of APOE epsilon4 status on cognition and CSF tau levels were also observed. Conclusions: APOE epsilon4 status is associated with amyloid accumulation and lower CSF Abeta, as well as increased CSF tau levels in early prodromal stages of AD (E-MCI) and HC. Alternatively, neurodegeneration, cognitive impairment, and increased complaints are primarily associated with a diagnosis of E-MCI. These findings underscore the importance of considering APOE genotype when evaluating biomarkers in early stages of disease..
"Age and apolipoprotein E genotype influence rate of cognitive decline in nondemented elderly"Salmon, David P; Ferris, Steven H; Thomas, Ronald G; Sano, Mary; Cummings, Jeffery L; Sperling, Reisa A; Petersen, Ronald C; AISEN, PAUL S
GRANTS:AG10483/AG/NIA NIH HHS/United States
Objective: This study examined the impact of age and apolipoprotein E (APOE) genotype on the rate of cognitive decline in nondemented elderly participants in a simulated Alzheimer's disease (AD) primary prevention treatment trial carried out by the Alzheimer's Disease Cooperative Study. Method: Cognitive tests were administered at baseline and at four subsequent annual evaluations to 417 nondemented participants (172 men, 245 women) between the ages of 74 and 93 (M = 79.13 +/- 3.34). APOE genotyping was available for 286 of the participants. Results: Four-year decline was evident on measures of orientation, memory, executive function, and language. Faster decline was evident in APOE epsilon4+ (a genetic risk factor for AD; n = 73) than in epsilon4- participants (n = 213), even after controlling for education, gender, ethnicity, and baseline functional and cognitive abilities. This discrepancy increased with age, indicating an Age x Genotype interaction. Conclusion: These results are consistent with population-based studies, and extend the findings to a carefully screened sample that meets inclusion and exclusion criteria for an AD primary prevention trial. The interaction between age and APOE genotype on rate of decline suggests that preclinical disease may be overrepresented in older epsilon4+ individuals. Thus, APOE genotype and age should be considered in the design of AD primary prevention treatment trials. (PsycINFO Database Record (c) 2013 APA, all rights reserved)..
"Developing dementia prevention trials: baseline report of the home-based assessment study"Sano, Mary; Egelko, Susan; Donohue, Michael; Ferris, Steven; Kaye, Jeffrey; Hayes, Tamara L; Mundt, James C; Sun, Chung-Kai; Paparello, Silvia; AISEN, PAUL S
GRANTS:P30 AG024978/AG/NIA NIH HHS/United States
This report describes the baseline experience of the multicenter, Home-Based Assessment study, designed to develop methods for dementia prevention trials using novel technologies for test administration and data collection. Nondemented individuals of 75 years of age or more were recruited and evaluated in-person using established clinical trial outcomes of cognition and function, and randomized to one of 3 assessment methodologies: (1) mail-in questionnaire/live telephone interviews [mail-in/phone (MIP)]; (2) automated telephone with interactive voice recognition; and (3) internet-based computer Kiosk. Brief versions of cognitive and noncognitive outcomes were adapted to each methodology and administered at baseline and repeatedly over a 4-year period. "Efficiency" measures assessed the time from screening to baseline, and staff time required for each methodology. A total of 713 individuals signed consent and were screened; 640 met eligibility and were randomized to one of 3 assessment arms; and 581 completed baseline. Dropout, time from screening to baseline, and total staff time were highest among those assigned to internet-based computer Kiosk. However, efficiency measures were driven by nonrecurring start-up activities suggesting that differences may be mitigated over a long trial. Performance among Home-Based Assessment instruments collected through different technologies will be compared with established outcomes over this 4-year study..
"Association of plasma and cortical amyloid beta is modulated by APOE epsilon4 status"Swaminathan, Shanker; Risacher, Shannon L; Yoder, Karmen K; West, John D; Shen, Li; Kim, Sungeun; Inlow, Mark; Foroud, Tatiana; Jagust, William J; Koeppe, Robert A; Mathis, Chester A; Shaw, Leslie M; Trojanowski, John Q; Soares, Holly; AISEN, PAUL S; Petersen, Ronald C; Weiner, Michael W; Saykin, Andrew J
GRANTS:P30 AG010133/AG/NIA NIH HHS/United States;R01 AG019771/AG/NIA NIH HHS/United States;RC2 AG036535/AG/NIA NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States
BACKGROUND: Apolipoprotein E (APOE) epsilon4 allele's role as a modulator of the relationship between soluble plasma amyloid beta (Abeta) and fibrillar brain Abeta measured by Pittsburgh compound B positron emission tomography ([11C]PiB PET) has not been assessed. METHODS: Ninety-six Alzheimer's Disease Neuroimaging Initiative participants with [11C]PiB scans and plasma Abeta1-40 and Abeta1-42 measurements at the time of PET scanning were included. Regional and voxelwise analyses of [11C]PiB data were used to determine the influence of APOE epsilon4 allele on association of plasma Abeta1-40, Abeta1-42, and Abeta1-40/Abeta1-42 with [11C]PiB uptake. RESULTS: In APOE epsilon4- but not epsilon4+ participants, positive relationships between plasma Abeta1-40/Abeta1-42 and [11C]PiB uptake were observed. Modeling the interaction of APOE and plasma Abeta1-40/Abeta1-42 improved the explained variance in [11C]PiB binding compared with using APOE and plasma Abeta1-40/Abeta1-42 as separate terms. CONCLUSIONS: The results suggest that plasma Abeta is a potential Alzheimer's disease biomarker and highlight the importance of genetic variation in interpretation of plasma Abeta levels..
"The Alzheimer's Disease Neuroimaging Initiative: a review of papers published since its inception"Weiner, Michael W; Veitch, Dallas P; AISEN, PAUL S; Beckett, Laurel A; Cairns, Nigel J; Green, Robert C; Harvey, Danielle; Jack, Clifford R; Jagust, William; Liu, Enchi; Morris, John C; Petersen, Ronald C; Saykin, Andrew J; Schmidt, Mark E; Shaw, Leslie; Shen, Li; Siuciak, Judith A; Soares, Holly; Toga, Arthur W; Trojanowski, John Q
GRANTS:P30 AG010133/AG/NIA NIH HHS/United States;R01 AG019771/AG/NIA NIH HHS/United States
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by beta-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, beta-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants..
"Health-Related Resource Use and Costs in Elderly Adults with and without Mild Cognitive Impairment"Zhu, Carolyn W; Sano, Mary; Ferris, Steven H; Whitehouse, Peter J; Patterson, Marian B; AISEN, PAUL S
GRANTS:R01-AG030048/AG/NIA NIH HHS/United States;R01-AG16381/AG/NIA NIH HHS/United States;U01-AG024904/AG/NIA NIH HHS/United States;U01AG10483/AG/NIA NIH HHS/United States
OBJECTIVES: To assess differences in resource use and cost between older adults with and without mild cognitive impairment (MCI) over time. DESIGN: Multicenter, longitudinal study. SETTING: Sixty-eight Alzheimer's Disease Cooperative Study (ADCS) sites in the United States. PARTICIPANTS: Two hundred fifty-nine individuals diagnosed with MCI and 107 cognitively normal elderly adults followed annually for 3 years. MEASUREMENTS: The Resource Use Instrument (RUI) was used to capture medical and nonmedical care use. Generalized linear latent and mixed models were used to estimate differences in resource use and costs in older adults with and without MCI after controlling for clinical and demographic characteristics. RESULTS: At baseline, average annual direct medical cost per person was substantially higher for participants with MCI ($6,499) than for those without ($2,969) P < .001). Informal care use was also substantially higher (33% vs 8.4%, P < .001). Results from multivariate analyses of longitudinal data show that, after controlling for participant and informant characteristics, direct medical costs were 44% higher for participants with MCI than for those without. Participants with MCI were almost five times as likely to use informal care as those without. Number of medical conditions and older age were associated with higher medical cost. Worse functional and cognitive status, older age, being married, and being female were associated with higher likelihood of informal care use. Having an adult child informant was associated with higher likelihood of using informal care. CONCLUSION: The RUI captured differences in resource use and costs between individuals with and without MCI. Clinicians who care for individuals with MCI should address informal care needs early in the disease course..
"Symptomatic and nonamyloid/tau based pharmacologic treatment for Alzheimer disease" [Historical Article]AISEN, PAUL S; Cummings, Jeffrey; Schneider, Lon S
GRANTS:NIA R01-AG030048/AG/NIA NIH HHS/United States;NIA U01-AG024904/AG/NIA NIH HHS/United States;R01-AG16381/AG/NIA NIH HHS/United States;U01-AG10483/AG/NIA NIH HHS/United States
In this work we consider marketed drugs for Alzheimer disease (AD) including acetylcholinesterase inhibitors (AChE-Is) and antiglutamatergic treatment involving the N-methyl-d-aspartate (NMDA) receptor. We discuss medications and substances available for use as cognitive enhancers that are not approved for AD or cognitive impairment, and other neurotransmitter-related therapies in development or currently being researched. We also review putative therapies that aim to slow disease progression by mechanisms not directly related to amyloid or tau..
"Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans"Bakken, Trygve E; Roddey, J Cooper; Djurovic, Srdjan; Akshoomoff, Natacha; Amaral, David G; Bloss, Cinnamon S; Casey, B J; Chang, Linda; Ernst, Thomas M; Gruen, Jeffrey R; Jernigan, Terry L; Kaufmann, Walter E; Kenet, Tal; Kennedy, David N; Kuperman, Joshua M; Murray, Sarah S; Sowell, Elizabeth R; Rimol, Lars M; Mattingsdal, Morten; Melle, Ingrid; Agartz, Ingrid; Andreassen, Ole A; Schork, Nicholas J; Dale, Anders M; Weiner, Michael; AISEN, PAUL; Petersen, Ronald; Jack, Clifford R Jr; Jagust, William; Trojanowki, John Q; Toga, Arthur W; Beckett, Laurel; Green, Robert C; Saykin, Andrew J; Morris, John; Liu, Enchi; Montine, Tom; Gamst, Anthony; Thomas, Ronald G; Donohue, Michael; Walter, Sarah; Gessert, Devon; Sather, Tamie; Harvey, Danielle; Kornak, John; Dale, Anders; Bernstein, Matthew; Felmlee, Joel; Fox, Nick; Thompson, Paul; Schuff, Norbert; Alexander, Gene; DeCarli, Charles; Bandy, Dan; Koeppe, Robert A; Foster, Norm; Reiman, Eric M; Chen, Kewei; Mathis, Chet; Cairns, Nigel J; Taylor-Reinwald, Lisa; Trojanowki, J Q; Shaw, Les; Lee, Virginia M Y; Korecka, Magdalena; Crawford, Karen; Neu, Scott; Foroud, Tatiana M; Potkin, Steven; Shen, Li; Kachaturian, Zaven; Frank, Richard; Snyder, Peter J; Molchan, Susan; Kaye, Jeffrey; Quinn, Joseph; Lind, Betty; Dolen, Sara; Schneider, Lon S; Pawluczyk, Sonia; Spann, Bryan M; Brewer, James; Vanderswag, Helen; Heidebrink, Judith L; Lord, Joanne L; Johnson, Kris; Doody, Rachelle S; Villanueva-Meyer, Javier; Chowdhury, Munir; Stern, Yaakov; Honig, Lawrence S; Bell, Karen L; Morris, John C; Ances, Beau; Carroll, Maria; Leon, Sue; Mintun, Mark A; Schneider, Stacy; Marson, Daniel; Griffith, Randall; Clark, David; Grossman, Hillel; Mitsis, Effie; Romirowsky, Aliza; deToledo-Morrell, Leyla; Shah, Raj C; Duara, Ranjan; Varon, Daniel; Roberts, Peggy; Albert, Marilyn; Onyike, Chiadi; Kielb, Stephanie; Rusinek, Henry; de Leon, Mony J; Glodzik, Lidia; De Santi, Susan; Doraiswamy, P Murali; Petrella, Jeffrey R; Coleman, R Edward; Arnold, Steven E; Karlawish, Jason H; Wolk, David; Smith, Charles D; Jicha, Greg; Hardy, Peter; Lopez, Oscar L; Oakley, MaryAnn; Simpson, Donna M; Porsteinsson, Anton P; Goldstein, Bonnie S; Martin, Kim; Makino, Kelly M; Ismail, M Saleem; Brand, Connie; Mulnard, Ruth A; Thai, Gaby; Mc-Adams-Ortiz, Catherine; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Diaz-Arrastia, Ramon; King, Richard; Weiner, Myron; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I; Lah, James J; Cellar, Janet S; Burns, Jeffrey M; Anderson, Heather S; Swerdlow, Russell H; Apostolova, Liana; Lu, Po H; Bartzokis, George; Silverman, Daniel H S; Graff-Radford, Neill R; Parfitt, Francine; Johnson, Heather; Farlow, Martin R; Hake, Ann Marie; Matthews, Brandy R; Herring, Scott; van Dyck, Christopher H; Carson, Richard E; MacAvoy, Martha G; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Ging-Yuek; Hsiung, Robin; Feldman, Howard; Mudge, Benita; Assaly, Michele; Kertesz, Andrew; Rogers, John; Trost, Dick; Bernick, Charles; Munic, Donna; Kerwin, Diana; Mesulam, Marek-Marsel; Lipowski, Kristina; Wu, Chuang-Kuo; Johnson, Nancy; Sadowsky, Carl; Martinez, Walter; Villena, Teresa; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A; Johnson, Keith A; Marshall, Gad; Frey, Meghan; Yesavage, Jerome; Taylor, Joy L; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan; Belden, Christine; Jacobson, Sandra; Kowall, Neil; Killiany, Ronald; Budson, Andrew E; Norbash, Alexander; Johnson, Patricia Lynn; Obisesan, Thomas O; Wolday, Saba; Bwayo, Salome K; Lerner, Alan; Hudson, Leon; Ogrocki, Paula; Fletcher, Evan; Carmichael, Owen; Olichney, John; Kittur, Smita; Borrie, Michael; Lee, T-Y; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M; Potkin, Steven G; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Fleisher, Adam; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W; Kataki, Maria; Zimmerman, Earl A; Celmins, Dzintra; Brown, Alice D; Pearlson, Godfrey D; Blank, Karen; Anderson, Karen; Santulli, Robert B; Schwartz, Eben S; Sink, Kaycee M; Williamson, Jeff D; Garg, Pradeep; Watkins, Franklin; Ott, Brian R; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J; Miller, Bruce L; Mintzer, Jacobo; Longmire, Crystal Flynn; Spicer, Kenneth; Finger, Elizabether; Rachinsky, Irina; Drost, Dick; Jernigan, Terry; McCabe, Connor; Grant, Ellen; Ernst, Thomas; Kuperman, Josh; Chung, Yoon; Murray, Sarah; Bloss, Cinnamon; Darst, Burcu; Pritchett, Lexi; Saito, Ashley; Amaral, David; DiNino, Mishaela; Eyngorina, Bella; Sowell, Elizabeth; Houston, Suzanne; Soderberg, Lindsay; Kaufmann, Walter; van Zijl, Peter; Rizzo-Busack, Hilda; Javid, Mohsin; Mehta, Natasha; Ruberry, Erika; Powers, Alisa; Rosen, Bruce; Gebhard, Nitzah; Manigan, Holly; Frazier, Jean; Kennedy, David; Yakutis, Lauren; Hill, Michael; Gruen, Jeffrey; Bosson-Heenan, Joan; Carlson, Heatherly
GRANTS:5UL1RR025774/RR/NCRR NIH HHS/United States;N01MH22005/MH/NIMH NIH HHS/United States;P50MH081755/MH/NIMH NIH HHS/United States;P50NS22343/NS/NINDS NIH HHS/United States;R01AG030474/AG/NIA NIH HHS/United States;R01AG031224/AG/NIA NIH HHS/United States;R01AG035020/AG/NIA NIH HHS/United States;R01AG22381/AG/NIA NIH HHS/United States;R01DA030976/DA/NIDA NIH HHS/United States;R01HL089655/HL/NHLBI NIH HHS/United States;R01MH078151-01A1/MH/NIMH NIH HHS/United States;R01MH080134/MH/NIMH NIH HHS/United States;RC2DA029475/DA/NIDA NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;U01DA024417/DA/NIDA NIH HHS/United States;U19AG023122-01/AG/NIA NIH HHS/United States;U54CA143906/CA/NCI NIH HHS/United States;U54NS056883/NS/NINDS NIH HHS/United States;UL1 RR033173/RR/NCRR NIH HHS/United States
Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 x 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 x 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception..
"Clinical and biomarker changes in dominantly inherited Alzheimer's disease"Bateman, Randall J; Xiong, Chengjie; Benzinger, Tammie L S; Fagan, Anne M; Goate, Alison; Fox, Nick C; Marcus, Daniel S; Cairns, Nigel J; Xie, Xianyun; Blazey, Tyler M; Holtzman, David M; Santacruz, Anna; Buckles, Virginia; Oliver, Angela; Moulder, Krista; AISEN, PAUL S; Ghetti, Bernardino; Klunk, William E; McDade, Eric; Martins, Ralph N; Masters, Colin L; Mayeux, Richard; Ringman, John M; Rossor, Martin N; Schofield, Peter R; Sperling, Reisa A; Salloway, Stephen; Morris, John C
GRANTS:P30 AG010133/AG/NIA NIH HHS/United States;U19 AG032438/AG/NIA NIH HHS/United States;UL1 TR000124/TR/NCATS NIH HHS/United States;UL1 TR000448/TR/NCATS NIH HHS/United States
BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Abeta)(42) in the CSF appeared to decline 25 years before expected symptom onset. Abeta deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)..