Michael W. Weiner, MD, SUNY Upstate Medical Center, Syracuse - US grants

The goal of this project is to determine the stoichiometric relationships between O2 consumption, ATP synthesis, and Na transport by the intact kidney in vivo. The Na/O2 ratio of the kidney is greater than the theoretical maximum of 18 (assuming ATP/O = 3, ATP/O2 = 6, Na/ATP = 3). It has been proposed that the high Na/O2 is due to passive reabsorption of Na in the proximal tubule. This hypothesis will be tested by measuring ATP synthesis using 31P NMR saturation transfer and simultaneously determining O2 consumption and Na reabsorption by clearance techniques. In order to test certain assumptions which are necessary for an unambiguous interpretation of the NMR results, we will: 1) Reduce or eliminate the contribution of extracellular Pi and red cell metabolites to the intracellular Pi peak. 2) Determine if a NMR-invisible Pi pool participates in ATP synthesis by comparing the rates of synthesis and hydrolysis. 3) Determine if NMR measures ATP synthesis or Pi-ATP exchange by measuring the sensitivity of the reaction to cyanide or rotenone; ATP synthesis is inhibited by these agents while ATP-Pi exchange is not. 4) Determine if the ATP/O can be measured with reasonable precision by error analysis experiments. It is expected that these experiments will demonstrate with reasonable certainty that the ATP/O in vivo is 2-3. It has been proposed that the high Na/O2 of the kidney is due to passive Na reabsorption (Na/ATP greater than 3) in the proximal tubule. To test this we will measure: 1) the effect of inhibiting the loop of Henle with furosemide and 2) the effect of inhibiting the proximal tubule with acetazolamide, mannitol, or vanadate. The results should indicate the tubular segment responsible for the high Na/O2. Finally, to determine if the stoichiometry between O2 consumption, ATP synthesis, and Na transport varies in a regulated fashion, we will measure ATP/O and Na/ATP during the following maneuvers: 1) changes of glomerular filtration rate. 2) Hypoxia. 3) Hypo - and hyperthyroidism. The significance of this project is that: 1) Important assumptions necessary to interpret saturation transfer measurements of ATP synthesis will be tested. 2) The stoichiometry of oxidative phosphorylation in vivo will be measured. 3) The site of the high Na/ATP in the kidney will be determined. 4) Factors which may alter coupling of oxidative phosphorylation and ATP utilization for Na transport may be identified.

The goal of this project is to determine the metabolic disturbances within tissue produced by disease and therapy. High- energy phosphates, pH, lactate, and other metabolites will be measured in surface tumors, heart, and kidneys of human patients, using 31P and 1H NHR. Both Bo and B1 localization techniques will be developed, simulated, tested on phantoms, normal subjects, and patients. Cancer studies will examine the possibility that metabolic changes are a sensitive and early index of the response to therapy. These studies will begin with large superficial squamous cell carcinomas of the head and neck. After completing a survey to characterize metabolic composition, heterogeneity, and variability, pilot experiments will determine the effects and time course of chemo- and radiation therapy. A prospective trial will correlate the spectral changes with the ultimate response to therapy, determined by MRI, CT, and ultimate outcome. Heart studies are designed to test the hypothesis that disorders of cardiac energy metabolism may be responsible for functional abnormalities in cardiac disease. 31P and 1H NMR studies of coronary ischemia in the pig will be continued using surgically implanted coils. Spectral localization techniques will be developed using the pig and human subjects. The effects of exercise and pacing will be determined and the metabolic alterations produced by myocardiopathy, hypertrophy, transplant rejection, and ischemia will be examined. Human kidney studies are aimed at investigating the metabolic changes produced by acute tubular necrosis. Once localization techniques are developed, and the normal kidney is examined, the changes associated with acute tubular necrosis will be characterized. Renal function will be correlated with NMR results to determine if spectral changes predict the outcome, or the response to therapy in a series of patients with ATN.

The goal of this project is to determine the metabolic disturbances within tissue produced by disease and therapy. High- energy phosphates, pH, lactate, and other metabolites will be measured in surface tumors, heart, and kidneys of human patients, using 31P and 1H NHR. Both Bo and B1 localization techniques will be developed, simulated, tested on phantoms, normal subjects, and patients. Cancer studies will examine the possibility that metabolic changes are a sensitive and early index of the response to therapy. These studies will begin with large superficial squamous cell carcinomas of the head and neck. After completing a survey to characterize metabolic composition, heterogeneity, and variability, pilot experiments will determine the effects and time course of chemo- and radiation therapy. A prospective trial will correlate the spectral changes with the ultimate response to therapy, determined by MRI, CT, and ultimate outcome. Heart studies are designed to test the hypothesis that disorders of cardiac energy metabolism may be responsible for functional abnormalities in cardiac disease. 31P and 1H NMR studies of coronary ischemia in the pig will be continued using surgically implanted coils. Spectral localization techniques will be developed using the pig and human subjects. The effects of exercise and pacing will be determined and the metabolic alterations produced by myocardiopathy, hypertrophy, transplant rejection, and ischemia will be examined. Human kidney studies are aimed at investigating the metabolic changes produced by acute tubular necrosis. Once localization techniques are developed, and the normal kidney is examined, the changes associated with acute tubular necrosis will be characterized. Renal function will be correlated with NMR results to determine if spectral changes predict the outcome, or the response to therapy in a series of patients with ATN.

This project addresses four major areas of inquiry in subcortical ischemic vascular dementia (SVID): the role of ongoing subcortical ischemia; the role of infarction and neuron loss; the role of disconnection of subcortical and cortical structures in the pathogenesis of SIVD; and the relative differences in subcortical and cortical changes between SIVD and Alzheimer's Disease (AD). We will use 31P magnetic resonance spectroscopic imaging (31p MRSI) to detect high energy phosphate metabolites as measures of ongoing ischemia. 1H MRSI to detect NAA as a measure of neuron density, and rCMRglc/NAA (in conjuction with Project 1 - Bruce Reed, Ph.D., P.I.) as a measure of the metabolic rate of viable neurons. Studies will be performed on the following groups: Group A: 50 demented subjects with subcortical lacunar infarcts (SIVD); Group B: 50 non-demented control subjects with lacunar infarcts; Group C: 50 non-demented control subjects without lacunar infarcts; Group D: 50 demented subjects without lacunar infarcts (AD). To determine the extent of ongoing ischemia in SIVD, we will test the hypothesis that: high energy phosphate ratios (Par/Pi, etc) are lower in subcortical white and grey matter in SIVD compared to controls and that these reductions are related to the extent of WMSH and lacunae. To determine the extent of neuron loss in SIVD, we will test the hypothesis that: NAA is lower in subcortical white and grey matter in SIVD compared to controls and that these reductions are related to the extent of SMSH and lacunae. To determine the extent of subcortical-cortical disconnection, we will test the hypothesis that: cortical function (neuropsychological measures and cortical rCMRglc/NAA) is reduced in proportion to subcortical energy phosphate ratios, NAA, WMSH, and lacunae in SIVD and in controls with and without lacunes. To determine severity of subcortical and cortical disease in SIVD versus AD, we will test the hypothesis that: subcortical energy phosphates and NAA and cortical rCMRglc/NAA are lower in SIVD than in AD. This project will provide a greater understanding of the pathogenesis of dementia in patients with cerebrovascular disease and AD, and will improve the antemortem diagnosis of both disorders.

DESCRIPTION (Adapted from Applicant's Abstract): The long term goal of this project is to detect, diagnose, and monitor progression of Alzheimer's disease (AD). This project has studied 176 AD subjects and developed multislice 1H MRSI (TE=30) which measures N-acetyl aspartate (MAA), myo-inositol, and other metabolites in surface cortex and hippocampus. This will be used with segmented/volumed MRI, genetic and neuropsychological tests. Subjects (from the UCSF and the Northern California Alzheimer s Center) will include: AD (N=220), Frontotemporal Dementia (n=50), non-demented subjects with a Clinical Dementia Rating of 0.5 (n-100), and age matched Controls (n=140). Subjects will be followed to autopsy. Hypotheses: 1) Regional metabolic changes: The greatest antemortem changes of MRS-detectable metabolites (especially NAA and myo-inositol) occur in the hippocampus and in temporoparietal cortex in AD. 2) Anatomical- neuropsychological correlations: Neuron loss and other metabolite change (detected by MRSI) in specific brain regions is associated with specific types of cognitive impairment. 3) Diagnosis of AD: 1H MRSI and MRI, together with clinical measures provide more sensitive and specific diagnosis of AD than do MRI and clinical measures alone. 4) Diagnosis of Frontotemporal dementia (FTD): FTD is associated with both decreased NAA in the frontal lobes and genetic mutation in 17q21-22, and can be reliably distinguished from AD. Finally, a pilot study will be performed to determine the extent that 1H MRSI and MRI together with genetic and clinical measures identify changes consistent with early AD in non demented subjects (n=100) with a Clinical Dementia Rating of 0.5, compared to genetic and clinical measures alone. It is expected that this project will lead to the development of improved antemortem diagnostic technique (which could be used by many MR scanners) for: assessment of, screening of subjects at risk for, and monitoring progression of dementia.

The HIV epidemic is a major public health problem in the United States and the world. Nervous disease is a frequent cause of morbidity and mortality for the more than 1 million people infected with HIV in the U.S. Recently, with the success of protease inhibitor therapy in the treatment of systemic HIV disease and the limited penetration of protease inhibitors into the nervous system, there is a developing awareness that CNS disease may become of even more importance in the clinical management of HIV disease and the HIV epidemic. Although heavy alcohol use, which has its own CNS and PNS toxicity, is common in populations at high risk for HIV infection, almost no research directly addresses the effect of heavy alcohol use on HIV disease severity and progression. The primary goal of this Program Project is to determine the effect of chronic heavy alcohol use on CNS and PNS morbidity in HIV disease. This effect may result from behavioral and biological effects of chronic alcohol use increasing the rapidity of the progression of the overall HIV disease process or decreasing the response to HIV treatment and from alcohol's own nervous system toxicity. These mechanisms and their effects will be evaluated in a longitudinal study of HIV+ and HIV-chronic heavy drinkers (HIV+ HDs & HIV-HDs) and light/non-drinkers (HIV + L/NDs & HIV-L/NDs). The Program Project goals are to: . Determine whether HIV+ HDs have decrease care seeking and HIV treatment adherence, an increased prevalence of unprotected sex, poorer nutrition, and/or decreased drug levels of HIV treatment medications. . Determine whether a) HIV + HDs have a greater rate of HIV systemic disease progression or reduced treatment response, and b) the degree to which the behavioral and drug metabolism effects of chronic heavy drinking underlie any increased rate of HIV systemic disease progression or reduced treatment response. . Determine whether HIV+ HDs have greater CNS and PNS morbidity and progression of such morbidity than HIV+ LDs. Determine whether these effects of chronic heavy alcohol use are additive or exceed additive effects. . Determine the impact of CNS and PNS morbidity on the quality of life of HIV+ individuals. . In HIV+ subjects, determine the association of CNS and PNS morbidity and its progression with systemic measures of viral load, immune suppression and nutritional status, and with CSF measures of CNS disease, and determine whether these associations differ between heavy chronic alcohol drinkers and light/non-drinkers. We will study four groups of subjects: 120 HIV+ HDs, 120 HIV+ L/NDs, 60 HIV-HDs, and 60 HIV-L/NDs.

Briefly, the findings of this project (total of 120 subjects, divided into 6 groups of 20 each) were: 1.) Reduced N-acetyl aspartate [NAA] in cortical gray matter (cGM) and hippocampus of demented patients (D) with lacunes (+L many of whom have subcortical ischemic vascular dementia (SIVD)) compared to elderly controls (CN), similar to changes in D without lacunes (many of whom have Alzheimer's). 2) Frontal cGM [NAA] was reduced to patients with thalamic lacunes, compared to those with non thalamic L. 3) cGM [NAA] was reduced in proportion to number of L and to % white matter lesions (WML). 4) MMSE and specific neuropsychological tests correlated with cGM [NAA]. Taken together, these finding strongly support the view that cGM [NAA] is reduced in D, and that this reduction is proportional in extent and location to subcortical infarction. We interpret the reduced cGM[NAA] to indicate either injury, reduced size, or reduced number, or cortical neurons, in response to subcortical infarction. This project will extend these findings by using short TE 1H MRSI to measure myo-inositol (a putative marker of Alzheimer's disease) and by using arterial spin labeled perfusion MRI to quantitate cortical and subcortical perfusion. The sample size will be about 60 subjects/group, followed autopsy for final pathological diagnosis of Alzheimer's and/or infarction. All subjects will have MRI with segmentation and hippocampal voluming, and multi-slice short TE 1H MRSI. Other related goals are to: 1.) Determine the relative extent that NAA, myoinositol, and perfusion are altered in SIVD and AD. 2.) To determine the relative extent to which subcortical infarction and cortical neuron damage contribute to dementia. 3.) To develop antemortem classification methods which reliably distinguish between SIVD and AD. 4.) To establish reliable products of cognitive decline in SIVD and AD. This project will help determine the effects of subcortical infarction on cognition, predict the effects of subcortical infarction our cognitive decline, and help distinguish between SIVD and AD. The significance is that this work will provide new understanding concerning the pathogenesis of SIVD and AD, improve the antemortem diagnosis of both disorders, and provide methods for evaluation the results of clinical treatment trials.

The overall goal of the Neuroimaging core is to provide quantitative analysis of brain structures, measured by MRIs acquired at two sites in Southern and Northern California, using identical protocol which permit combined use of data. The Core receives data from both sites, transfers the data to a common format, archives the MRIs, processes the data in various ways and archives processed images, transfers all data to a data base which is heavily used by all Cores and Projects. During the previous funding period, this Core developed a number of image segmentation (gray matter, white matter, CSF, white matter lesions, lacunes) voluming (hippocampus and entorhinal cortex, and localizing tools (lacune location), all of which have been incorporated into a semiautomated, user friendly, software package. During the current funding period the total processing performed was: segmentation= 581, edited (WML and lacunes identified) = 569, hippocampaI voluming = 335, ERC voluming = 236, longitudinal change= 50. The results have been used in two major publications from this PPG, both which emphasized the importance of decreased cortical and hippocampal gray matter as determinants of cognition, and de-emphasized the significance of white matter lesions and lacunes. Additionally, most other publications from this PPG used Imaging Core data. During the proposed funding period this Core will continue to perform image analysis of MRls collected in both Northern and Southern California and make this data available to PPG investigators. In addition, during the current funding period this core has implemented several new MRI analysis techniques : 1) Non-linear registration techrdques. These were used for: lobar marking, identifying shape changes due to AD, SIVD, and presence of lacunes in controls, measuring longitudinal atrophy and effects of white matter lesions and lacunes on this process, correlating shape changes with clinical and cognitive data. We propose continued development of these tools and applying them to more refined analysis of clinical data. 2) Completely automated probabilistic segmentation of 3D T 1 weighted MRIs. We propose to extend this approach to a more automated method for classifying WMLS detected on T-2 weighted MRI. 3) Semiautomated hippocampal voluming. This has been validated and applied to measurement of cross sectional and longitudinal clinical data. 4) Manual measurement of entorhinal cortex. This was validated and used for cross sectional and longitudinal studies. In summary, this Core provides an invaluable service function to process MRIs and also develops state of the art, automated image processing methods aimed at achieving the goals of this PPG.

The primary goal of this project is to establish an 1H MRSI measurement of N-acetylaspartate (NAA) as a surrogate marker for quantitative measurements of upper motor neuron (UMN) loss in amyotrophic lateral sclerosis (ALS), and to detect ALS in an early stage of the disease. This proposal uses a newly developed short TE multislice 1H MRSI method with high test retest reproducibility, which samples surface cerebral cortex with minimal lipid contamination and which provides atrophy corrected [NAA], [creatine(Cr)], (choline (Cho)], and [myo-inositol (mI)]. MRI segmentation quantifies the gray and white matter, and cerebrospinal fluid in each MRSI voxel. A pilot study showed significant decreases in NAA (-11.9%), Cre (-10.7%), and Cho (-19.5%) in motor cortex of ALS after 3 months of enrollment in our study. This technique will be used to study the following subject groups in a longitudinal fashion. Clinically definite or probable ALS (n=20) and clinically possible or suspected ALS (n=20) will have MRI/1H MRSI every 3 months. Age and sex matched controls will have one MRI/1H MRSI. Hypotheses: l) Regional metabolic changes: The greatest neuron loss (assessed from [NAA] loss) in ALS brain occur in the primary motor cortex and the corticospinal tract (CST), 2) NAA as a surrogate marker of UMN function: Neuron loss (assessed from [NAA] loss) in motor cortex and CST of ALS patients correlates with clinical measures of UMN dysfunction, 3) Prediction of course of ALS: The long term time course of motor cortex neuron loss (assessed from (NAA]) in an individual can be predicted from 2-3 measurements in 6-9 months, 4) Early detection of UMN impairment: UMN loss (assessed from (NAA] loss) occurs before clinical UMN dysfunction is apparent. In addition to these hypotheses, changes in metabolites other than NAA, especially mI, will be explored. The ability of arterial spin labeled perfusion MRI to detect changes in motor and other brain regions and a small pilot study to determine the effects of oral creatine supplementation will be explored. It is expected that this project will lead to the development of improved diagnostic techniques for assessment, screening of subjects at risk for, monitoring progression of, and quantifying treatment effects of ALS and other motor neuron disease.

DESCRIPTION (provided by applicant): This application requests a Varian 4 Tesla MRI/MRS(I) system to continue our 15-yr focus on investigation of neurodegenerative diseases (ND). Goals, to: 1) determine the pathophysiology of various ND including cross sectional and longitudinal changes of anatomic (i.e. spatial) patterns of brain structure, perfusion, and metabolites; 2) develop improved diagnostic methods which can be applied to clinical practice; 3) develop methods for staging and monitoring disease progression which can be used in treatment trials; and 4) detect ND at an early, preclinical stage so that preventative treatment can be effectively initiated. This is a continuation of collaborative work between MR physicists, who develop new MRI/MRS(I) techniques, and clinical investigators. We believe that we have done more MRI/MRS(I) of ND than any other group in the world (> 2500 subjects/ 8 yrs). Our physicists have developed many new MRS(I) techniques (pulse sequences, RF pulses, coils, data processing); this emphasizes their ability to develop 4T techniques aimed at ND. Our clinical collaborators have funded projects on normal aging, Alzheimer's disease, frontotemporal dementia, vascular dementia, Lewy Body disease, epilepsy, Parkinson's disease, amyotrophic lateral sclerosis, post traumatic stress disorder, schizophrenia, bipolar disorder, HN, alcoholism, and gulf war illness. Each project uses quantified MRI/MRS(I) data together with clinical/cognitive measures to test hypotheses statistically. Benefits of an increased field from 1.5-4T: Improved sensitivity for MRI in detecting anatomical change because of increased contrast as well as improved perfusion and diffusion MRI due to longer T1; Improved MRS(I) because of 3-fold increased S/N, allowing increased accuracy, smaller voxels, and increased spectral dispersion, facilitating measurement of glutamate (implicated in neurodegeneration), GABA, and other metabolites. ND has growing importance because of the aging population. Improved understanding of ND has led to development of new treatments and clinical trials. This project will focus advanced MRI/MRS(I) techniques at 4T on ND in order to increase knowledge concerning pathophysiology of ND, improve diagnosis and treatment monitoring, and finally to detect ND before debilitating symptoms develop, allowing preventative measures. These expected results emphasize the practical outcome and significance of this research.

DESCRIPTION (provided by applicant): The overall goal of this project is to determine the pattern of longitudinal structural, perfusion, and metabolic changes in the brain, which best predict future cognitive decline and dementia due to Alzheimer's disease (AD). Specifically we will determine the predictive "value added" of MRI/MRS to cognitive testing. We will perform longitudinal clinical evaluation, cognitive testing, and MRI/MRS studies on 130 completed non-demented subjects > 65 yr, presenting with memory complaints. The independent variables will be obtained from MRI/MRS at 0, 6, 12,and 24 mo. to measure brain structure, perfusion, and metabolism. Dependent variables will be decline of memory and executive function scores, assessed annually. Clinical dementia rating scale and conversion to dementia will be used as secondary dependent variables. The overall hypothesis is that MRI/MRSI predicts cognitive decline/dementia. Hypotheses: 1.) Initial entorhinal cortex (ERC) volume predicts cognitive decline/dementia and adds to the predictive value of baseline memory function. 2.) In addition to baseline memory function and ERC volume, rate of ERC atrophy improves prediction of cognitive decline. 3.) The best MRI predictors for memory decline are volume change over time of ERC and hippocampus, and these add to the predictive value of baseline memory function. The best predictors of executive function decline are volume changes in frontal gray matter and these add to the predictive value of baseline cognitive function. 4.) In addition to baseline memory function and changes of ERC volume, perfusion and metabolite (NAA, mI) changes over time in hippocampus temporal and parietal lobe further improve prediction of cognitive decline. In addition to the above hypotheses, we will explore what combination of cognitive, genetic (APOE) and MRI/MRS measures, and what between-scan interval, best predicts subsequent cognitive decline/dementia. This project is expected to improve methods for predicting cognitive decline/dementia due to AD; these techniques should identify those subjects at high risk for AD, who are candidates for primary prevention.

DESCRIPTION (provided by applicant): The goal of this project is to determine relationships among the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the entire spectrum of Alzheimer's disease (AD), as pathology evolves from normal aging to very mild symptoms, to mild cognitive impairment (MCI), to dementia. ADNl will inform the neuroscience of AD, identify diagnostic and prognostic markers, identify outcome measures that can be used in clinical trials, and help develop the most effective clinical trial scenarios. ADNI2 continues the currently funded AD Neuroimaging Initiative (ADNI1), a public/private collaboration between academia and industry to study biomarkers of AD as well as a recently funded Grand Opportunities grant that supplements ADNl goals and activities (GO). New aspects of ADNl include enrolling subjects with early MCI (EMCI), F18 amyloid imaging, and obtaining all clinical/cognitive, lumbar puncture CSF and plasma biomarker, and MRI/PET data on all subjects. The goals of this ADNl renewal will be accomplished by: 1) continuing annual clinical/cognitive/MRI follow up of the 476 normal controls and late MCI (LMCI) subjects previously enrolled in ADNI1;2) following the 200 EMCI subjects enrolled in the GO ADNl grant;3) additional enrollment of new healthy controls (n=150), EMCI (n=100 which adds to the 200 subjects enrolled in GO), LMCI (n=150), and AD (n=150) subjects;4) performance of F18 amyloid PET (using F18 AV-45 from AVID, Inc.) on all new subjects enrolled in ADNI2, together with FDG PET, and to obtain a 2nd F18 amyloid PET on all remaining ADNI1, GO, and ADNI2 subjects 2 years after the baseline scan;5) continue to obtain annual clinical/cognitive/blood draw/lumbar puncture for CSF, and MRI on all subjects. All collected data will be processed and analyzed by ADNl investigators including the Biostatistical Core, and made available to all qualified scientists in the world who request a password, without embargo. Hypotheses developed from current ADNl data will be replicated and new hypotheses tested, especially concerning EMCI and F18 amyloid imaging. ADNl spawned large multisite projects in other countries. No other large multisite study in the world addresses these complex issues with the sample size and statistical power of this application. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) causes cognitive impairment and dementia in millions of Americans and costs more than $100 billion/year in the USA. This ADNl project will provide new information which will greatly facilitate design of clinical treatment trials and will help develop new diagnostic techniques which identify AD at an early stage, ultimately leading to effective treatment and prevention of AD. REVIEW OF THE OVERALL PROGRAM

brain morphology; mental disorder diagnosis; cognition disorders; magnetic resonance imaging; biomedical resource; nuclear magnetic resonance spectroscopy; bioimaging /biomedical imaging; clinical research;

The overall long term goal of this Imaging Core is to identify structural, perfusion, and metabolic changes in the brain that predict future cognitive decline and conversion to dementia. The overall approach will be to initially study healthy elders ands age/gender matched patients with well-characterized dementia associated with Alzheimer's disease and Frontotemporal dementia using a newly acquired 4 Tesla BrukedSiemens MRI/MRS scanner, which will be optimized for investigation of neurodegenerative disease. These initial studies will provide imaging characteristics of established dementia. We will also study a group of subjects with MCI-Peterson criteria. In subsequent years we will study increasing numbers of subjects with MCI subtypes and MCI-Peterson who likely represent early stages of AD and FTD and who are expected to ultimately convert to dementia. All subjects will be recruited and evaluated by the Clinical Core.

This project will: determine the effects of chronic subcortical cerebrovascular disease on cortical integrity, quantify the effects of subcortical and cortical changes on cognition, and develop improved diagnostic markers which classify subcortical ischemic vascular dementia (SIVD) from Alzheimer's disease (AD). This project will use structural magnetic resonance imaging (MR/), arterial spin labeling perfusion MRI (pMRI), diffusion tensor imaging (DTI), and 1H magnetic resonance spectroscopic imaging (MRSI) on subjects with and without SIVD and AD, and follow them to autopsy. Our new finding is that SIVD subjects have reduced NAA in frontal cGM and higher NAA in hippocampus compared to AD. We will extend these results using new MRI techniques. The major hypotheses are: 1.) Both cross sectionally and longitudinally, frontal lobe cGM, volume, NAA, and perfusion will be decreased and ml increased, to a greater extent in SIVD compared with AD and will correlate with an increase of WML and subcortical lacunes, and a decrease of FA. In contrast, parietal and temporal cGM, NAA, and perfusion and hippocampal volume and NAA will be decreased, and mI increased, to a greater extent in AD compared with SIVD and will not be as closely correlated with WML, lacunes, and FA as are frontal lobe measures. 2.) Executive function will correlate with frontal lobe measures of gray matter integrity (cGM volume, NAA, mI and perfusion) and white matter integrity (WMLs, lacunes, and FA). Correlations in SIVD will be more significant than in AD. Frontal lobe measures of gray matter integrity and white matter integrity will predict, and correlate with, executive function decline in SIVD more than in AD. Memory function wfl| correlate with hippocampal measures (volume, NAA), language function will correlate with left parietal-temporal (cGM volume, NAA, perfusion, FA), visuospatial function will correlate with fight parietal-temproral (cGM volume, NAA, perfusion, FA). Measures of white matter integrity (WMLs, lacunes, FA) will correlate with memory, language function, and visuospatial function to a greater extent in SIVD than in AD. Measures ofhippocampal and temporo-parietaI cortical integrity will predict and correlate with memory, language, and visiospatiaI function to a greater extent in AD than in SIVD. 3.) Addition of NAA, mI, perfusion, and FA data will significant improve classification of AD from SIVD over structural MRI measures alone. Classifications will be performed using clinical diagnoses, and pathologically confirmed diagnoses from the Pathology Core.

[unreadable] DESCRIPTION (provided by applicant): This application is for a supplement to the program project, Alzheimer's Disease Neuroimaging Initiative (ADNI). Although the research participants in this study will be extensively investigated, no mechanism exists for the systematic pathological validation of the clinical diagnoses made during life. Neuropathology is the gold standard for defining age-related brain changes and the diagnosis of dementias. Therefore, neuropathology is essential in order to validate the clinical assessments of ADNI participants during life. A centralized core is required to ensure uniformity and reliability of neuropathological assessment of tissues from multiple sites (Alzheimer's Disease Research Centers (ADRCs and ADCs, n=29; and non-ADRC/ADC sites, n=30) which use diverse processing, staining, and immunohistochemical procedures. In addition, participants who come to autopsy during the study period and beyond will be an invaluable resource for clinicopathological studies and will facilitate the aims of the biomarker studies of ADNI. To achieve these goals, the ADNI-Neuropathology Core (ADNI-NPC) will: 1. Assist sites in obtaining provisional consent for autopsy from ADNI participating centers; 2. Provide central, uniform neuropathologic diagnoses to validate clinical assessment and facilitate clinicopathological correlations, including determining the relationship between the molecular neuropathology, structural, and functional changes, including Pittsburgh Compound-B (PIB), in early Alzheimer's disease; 3. Maintain a state-of-the-art brain tissue resource to advance collaborative research, and to facilitate ADNI's biomarker studies headed by John Trojanowski, Center for Neurodegenerative Disease Research, University of Pennsylvania, PA; 4. Interact with ADNI components, including the ADNI Coordinating Center, in order to support ADNI's research objectives. This supplement will focus on undertaking a neuropathological assessment of all cases recruited to ADNI who come to autopsy in the grant period of this project. Clinical, neuropsychological, and neuroimaging data obtained from ADNI will be available for correlation with the earliest changes in Alzheimer's disease (AD), mild cognitive impairment (MCI), normal aging, and other dementing diseases identified after neuropathological assessment. These studies will help us to assess the probability and rate that AD will progress within the brain. The harvesting of frozen brain tissue from the cases will facilitate the biomarkers study. Biochemical methods will be used to investigate changes in protein solubility which may offer early and novel targets for therapeutic intervention. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with more than 4.5 million Americans currently suffering from the disease. Clinical management of AD is complicated by lack of effective methods for early and accurate diagnosis of the disease. Thus, there is a significant unmet need for Alzheimer's disease diagnostic tools. The hypothesis of this project is that single photon emission computed tomography (SPECT) imaging with 123 I-IMPY provides a biomarker for detection of amyloid plaques useful for both 1) Early and definitive diagnosis of AD in the community setting and for 2) Evaluating new therapies targeted and reducing plaque burden in large multi-site clinical trials. To test this hypothesis, a novel 123 I -labeled radiopharmaceutical, 123 I-IMPY, was developed to specifically and sensitively bind A[unreadable] (the chief constituent of amyloid plaques). Working with our collaborators, we have recently demonstrated the safety and biodistribution of this radiopharmaceutical in an initial Phase I clinical trial. In other ongoing clinical trials we are beginning to demonstrate the efficacy of this diagnostic imaging agent, however additional validation work as described in this grant is still required. Thus Phase I of this project will now assess the feasibility and reliability of using this radiopharmaceutical as a biomarker for measuring plaque burden in AD patients. If 123 I-IMPY has suitable clinical properties as a biomarker for measuring amyloid plaques then Phase II will test the characteristics of the biomarker in longitudinal studies of AD and mild cognitive impairment (MCI) patients. Successful accomplishment of these studies will yield an innovative radiopharmaceutical product for the evaluation and diagnosis of AD. A widely available SPECT imaging test for AD will yield significant scientific, commercial and societal benefits. RELEVANCE Successful accomplishment of this Phase I project will result in the validation of 123 I-IMPY as an imaging biomarker for amyloid plaques in AD. Development of such a product will represent a significant technological and scientific innovation that will allow for widespread clinical benefits by facilitating early and accurate diagnosis of AD, using a technique (SPECT imaging) appropriate for the primary care / community medical setting. In addition, it will allow for scientific and technological benefits by improving our understanding of AD and catalyzing the development and evaluation of novel therapies for this devastating disease. [unreadable] [unreadable] [unreadable]

The overall goals of this project are 1) to determine the extent to which arteriosclerosis (measured by C-IMT, R-AV ratio) is associated with changes of brain perfusion, and the volume and integrity of gray matter (GM) and white matter (WM) and 2) the extent to which this association relates to the changes in brain and cognition caused by Alzheimer's disease pathology. This project will use state of the art MRI at high field to measure changes occurring in the brains of 470 subjects with two or more scans in 260 subjects. Data will include structural MRI to measure gray matter and white matter lesions (WMLs), hippocampal subfields, arterial spin labeled perfusion (ASL) MRI to quantify cerebral blood flow, and diffusion tensor imaging (DTI) to quantify measures of integrity of white matter tracts. Image analysis will use: registration and spatial normalization, segmentation, tractography, voxel based analyses and region of interest selection, to test statistically the following hypotheses cross sectionally and longitudinally (prediction of change in the outcome variable): 1.) Arteriosclerosis correlates with reduced brain perfusion, WMLs and lacunar infarcts, GM atrophy, and reduced fractional anisotropy of WM tracts, especially the superior longitudinal fasciculus and the occipital frontal tracts. 2.) White matter lesions (WMLs, especially periventricular WMLs in the frontal lobe) and lacunar infarcts correlate with reduced perfusion of frontal lobe and reduced FA of white matter tracts, especially the superior longitudinal fasciculus and occipital frontal tract. 3.) Atrophy of hippocampal subfields (a marker of AD pathology) correlates with reduced perfusion of the posterior cingulate GM and reduced FA of the cingulum tract WM. 4.) Regions of: frontal lobe perfusion, FA of frontal lobe white matter, and volume frontal lobe GM correlate with executive function while hippocampal volumes, posterior cingulate perfusion, and FA of cingulum tract correlate with memory function. Finally, we will explore the relationship of PIB uptake (amyloid load), and FDG uptake, to the structural, perfusion, and DTI changes detected by MRI.

Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Ammon Horn; Apoplexy; Archives; Arteriosclerosis; Atlases; Autopsy; Body Tissues; Brain; Brain region; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Clinical; Collection; Computer Programs; Computer software; Cornu Ammonis; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Development; Diffusion; Diffusion MRI; Diffusion Magnetic Resonance Imaging; Diffusion Weighted MRI; Encephalon; Encephalons; Ensure; Functional Imaging; Goals; Hand; Hippocampus; Hippocampus (Brain); Image; Infarction; Investigators; Lacunar Infarctions; Lesion; Lobe; Los Angeles; MR Imaging; MR Tomography; MRI; MRI Scans; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Manuals; Measurement; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Methods; Methods and Techniques; Methods, Other; NIH; NMR Imaging; NMR Tomography; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Nuclear Magnetic Resonance Imaging; Outcome Measure; Perfusion; Physiologic Imaging; Primary Senile Degenerative Dementia; Procedures; Process; Programs (PT); Programs [Publication Type]; Qualifying; Quality Control; RDST; Reading; Research Personnel; Researchers; San Francisco; Scanning; Scans, MRI; Segmentation, imaging; Site; Software; Spin Labels; Stroke; Structure; Techniques; Testing; Thick; Thickness; Time; Tissues; United States National Institutes of Health; Validation; Vascular Accident, Brain; Weight; Work; Zeugmatography; base; brain attack; cerebral vascular accident; clinical data repository; clinical data warehouse; cognitive change; cohesion; computer program/software; computerized data processing; data processing; data repository; dementia of the Alzheimer type; diffusion tensor imaging; expectation; experience; hippocampal; image processing; imaging; imaging Segmentation; improved; infarct; member; necropsy; neurodegenerative illness; neuroimaging; postmortem; primary degenerative dementia; programs; radiologist; relational database; repository; senile dementia of the Alzheimer type; signal processing; stroke; substantia alba; white matter

DESCRIPTION (provided by applicant): Our overall goal is to develop, optimize, and validate innovative and improved MRI techniques for the diagnosis, early detection, treatment monitoring, and investigation of neurodegenerative diseases (ND), which will be made available to the scientific community. These techniques will provide increased signal and contrast to noise and resolution per unit scan time, reduced susceptibility and motion artifacts, in order to improve disease detection. The techniques include improved MRI/MRS acquisition, image reconstruction methods, and processing/analysis methods for high magnetic field MRI/MRS. The results will be distributed to the scientific community. This proposal represents a continuation of collaborative work between MRI physicists, computer scientists and clinical investigators aimed at a single theme: neurodegenerative diseases. The specific aims of this Biotechnology Research Resource are to develop, optimize and validate: 1) MR acquisition methods for structural, perfusion, and diffusion spectrum MRI, and spectroscopic imaging. The focus of the work will be on developing new sequences to capture alterations of brain structure, physiology (blood flow), and metabolism with improved sensitivity and resolution and increased reliability and precision. 2) Image reconstruction methods for increasing speed, efficiency, and quantitative accuracy of MRI. The focus of the work will be on exploiting the properties of Bayesian prior information for either deterministic or statistical image modeling to improve image quality, signal-to-noise and resolution. 3) MR image processing techniques for extraction of accurate and reproducible anatomical information. The focus of the work will be on developing novel tissue segmentation techniques and new spatial normalization strategies. 4) We will utilize these improvements in collaborative/service projects concerning NDs 5) We will provide training for investigators and staff within and outside the Research Resource. 6) We will disseminate the knowledge, tools, and data generated by this resource The significance of this project is several fold: First, the prevalence of NDs is rapidly growing due to aging of the population and methods for early detection are urgently needed. Second, due to advances in basic knowledge, treatments for NDs are under development and sensitive methods to determine treatment response are required. This Research Resource will develop improved techniques for clinical diagnosis, early detection, and monitoring of progression and treatment effects of common NDs, and these technical advances will also be applicable to many other clinical problems.

DESCRIPTION (provided by applicant): Our goal is to determine the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the early (pre-dementia) stages of Alzheimer's disease (AD). The project builds on the NIA-funded AD Neuroimaging Initiative (ADNI1) and serves as a bridge to the planned renewal of ADNI (ADNI2). Our model posits: AD begins with A2 deposition in cortex, leading to synaptic dysfunction, neurodegeneration, and cognitive/ functional decline. The earliest detectable changes are decreased CSF A2 and increased PET amyloid tracer retention. Subsequently, neurodegeneration is detected by increased CSF tau species, synaptic dysfunction by FDG-PET retention and neuron loss indicated by hippocampal atrophy (measured with MRI). These changes ultimately lead to memory loss then general cognitive decline and dementia. This sequence is influenced by factors including age, APOE genotype, cerebrovascular disease, and other pathologies. We propose three overarching themes with specific operational hypotheses using data from ADNI1 and GO. 1) Reductions of CSF A2 and increased amyloid PET intensity are present in some asymptomatic individuals, indicating the early stage of AD neurobiology. 2) Subsequently, CSF tau increases accompanied by reduced brain glucose metabolism (assessed by FDG-PET) and an increased rate of medial temporal lobe atrophy, and 3) after the aforementioned events, memory impairment appears, eventually progressing to dementia. Our specific aims are: 1: Define and enroll subjects with early amnestic MCI (EMCI) to fill the gap between controls and "late MCI (LMCI)" subjects currently enrolled in ADNI. EMCI subjects will meet clinical criteria for amnestic MCI, performing between 0.0 and 1.5 SD below the mean of elderly controls on delayed paragraph recall performance. Long term follow-up of the subjects will be accomplished by the renewal of ADNI (ADNI2). 2: Perform F18 amyloid imaging on the normal and LMCI subjects from ADNI1 and the newly enrolled EMCI subjects from GO. This will establish a national network for F18 amyloid imaging, and test hypotheses concerning the prevalence and severity of brain amyloid in this group relating amyloid deposition to current and previous changes in clinical state, MRI, FDG PET and CSF and plasma biomarkers from ADNI1. 3: Continue longitudinal studies of LMCI and cognitively normals of ADNI1 for an additional year. 4: Analyze all existing and new clinical biochemical neuroimaging and biomarker data from ADNI1 and GO. ADNI1 was funded and only provided to analyze the first year's data, but subjects have now been followed for 3-4 years with more follow-up in GO. Thus a large longitudinal data set will be analyzed. Taken together, the overall impact of this GO grant will be: 1) increased knowledge concerning the sequence of events leading to AD dementia;2) development of improved clinical and biomarker methods for early detection of AD;3) improved imaging/biomarkers for monitoring progression of AD, facilitating drug discovery. PUBLIC HEALTH RELEVANCE: The goal of this project is to determine the relationships among the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the early (pre-dementia) stages of Alzheimer's disease (AD). The project builds on the NIA- currently funded AD Neuroimaging Initiative (ADNI1, a collaboration between academia and industry to study biomarkers of AD) and serves as a bridge to the renewal of ADNI (termed ADNI2). The overall impact of this project will be: 1) increased knowledge concerning the sequence of events leading to AD dementia;2) development of improved clinical and biomarker methods for early detection of AD;and 3) improved imaging and chemical biomarker methods for monitoring progression of AD, facilitating clinical trials of treatments to slow disease progression, and ultimately contributing to the prevention of AD dementia.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Administrative Core is responsible for the overall administrative and financial aspects of the Biotechnology Research Resource. In addition, personnel who are responsible for the database and some scientific programming support are also included under the Admininstrative Core. The major objectives for the first year were: 1) The execution of the subcontracts for the different cores. 2) Find replacements for scientists that were no longer involved in the roject. 3) Coordinate the meetings of all core leaders and researchers.

DESCRIPTION (provided by applicant): Our goal is to determine the "value added" of regional and longitudinal brain structural, perfusion, and diffusion tensor MRI, to predict future cognitive decline/Alzheimer's disease (AD). During the previous grant period we recruited and followed longitudinally 145 subjects scanned at 1.5T with mild cognitive complaints and impairments. We found that even after accounting for baseline memory function, memory decline was significantly predicted by entorhinal cortex volume, fractional anisotropy of the parahippocampal cingulum white matter, and perfusion of the posterior cingulate gyrus. These important new findings confirmed our original a priori hypothesis, and also demonstrated the value of DTI which was added on after the grant was funded. We also developed new methods and performed pilot MRI studies at 4 T and found that mild cognitive impairment is associated with atrophy of specific hippocampal subfields. Diffusion tensor imaging of cingulum white matter and perfusion of posterior cingulate also provide sensitive measures to detect early AD. We propose to follow subjects already enrolled at 1.5 T and also study 240 new nondemented elders at increased risk for cognitive decline with longitudinal 4T MRI including: high-resolution measurements of hippocampal subfields, diffusion spectral imaging (DSI) and perfusion MRI. Predictors will be obtained from MR at baseline and 12 months. Outcomes will be cognitive decline (change from baseline of memory function) assessed annually for the duration of the study. Our primary hypothesis is that after baseline cognition is accounted for, we can predict decline of memory function using a combination of: volume loss in CA 1-2 transition zone (a hippocampal subfield found to show significant changes in MCI), reduced fractional anisotropy of the cingulum white matter tract, and posterior cingulate perfusion. We will test whether the combined multiple correlations between the selected set of variables and the outcome are significant. We will also perform a series of structured explorations to test our biological model by 1) examining correlations and other predictors not included in the primary hypotheses and outcomes, 2) determining correlations between: hippocampal subfields, FA of parahippocampal cingulum, posterior cingulate perfusion, other MRI measures and memory, 3) exploring the prediction of imaging for decline of non-memory cognition, 4) exploring the added predictive value of longitudinal imaging. The proposed project is unique because we will use: quantification of hippocampal subfields, diffusion spectrum imaging and 3D perfusion MRI (accounting for transit time) to determine the pathophysiology of the prodromal stages of AD. Additional significance of this project is that optimum methods to predict cognitive decline/dementia will lead to improved detection of early AD, and sensitive outcome measures for treatment and prevention trials, helping ultimately to treat and prevent AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a devastating illness with no effective treatment, affecting more than four million Americans, with a rapidly growing incidence due to aging of the population. Once a treatment is identified, it will be important to identify subjects who are not demented but who are at high risk for developing future Alzheimer's disease, so that the dementia can be prevented. This application uses MRI scanning to "predict cognitive decline" in nondemented elders and will lead to methods which identify subjects at risk, who can then be put on preventive treatment once it's available.

DESCRIPTION (provided by applicant): The goal of this project is to determine relationships among the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the entire spectrum of Alzheimer's disease (AD), as pathology evolves from normal aging to very mild symptoms, to mild cognitive impairment (MCI), to dementia. ADNl will inform the neuroscience of AD, identify diagnostic and prognostic markers, identify outcome measures that can be used in clinical trials, and help develop the most effective clinical trial scenarios. ADNI2 continues the currently funded AD Neuroimaging Initiative (ADNI1), a public/private collaboration between academia and industry to study biomarkers of AD as well as a recently funded Grand Opportunities grant that supplements ADNl goals and activities (GO). New aspects of ADNl include enrolling subjects with early MCI (EMCI), F18 amyloid imaging, and obtaining all clinical/cognitive, lumbar puncture CSF and plasma biomarker, and MRI/PET data on all subjects. The goals of this ADNl renewal will be accomplished by: 1) continuing annual clinical/cognitive/MRI follow up of the 476 normal controls and late MCI (LMCI) subjects previously enrolled in ADNI1; 2) following the 200 EMCI subjects enrolled in the GO ADNl grant; 3) additional enrollment of new healthy controls (n=150), EMCI (n=100 which adds to the 200 subjects enrolled in GO), LMCI (n=150), and AD (n=150) subjects; 4) performance of F18 amyloid PET (using F18 AV-45 from AVID, Inc.) on all new subjects enrolled in ADNI2, together with FDG PET, and to obtain a 2nd F18 amyloid PET on all remaining ADNI1, GO, and ADNI2 subjects 2 years after the baseline scan; 5) continue to obtain annual clinical/cognitive/blood draw/lumbar puncture for CSF, and MRI on all subjects. All collected data will be processed and analyzed by ADNl investigators including the Biostatistical Core, and made available to all qualified scientists in the world who request a password, without embargo. Hypotheses developed from current ADNl data will be replicated and new hypotheses tested, especially concerning EMCI and F18 amyloid imaging. ADNl spawned large multisite projects in other countries. No other large multisite study in the world addresses these complex issues with the sample size and statistical power of this application.

ABSTRACT The goal of this project is to develop, implement, optimize, and validate online methods to predict and monitor cognitive and functional decline in elders with normal cognition (CN), subjective memory complaints (SMC), and mild cognitive impairment (MCI). We will develop online versions of the Clinical Dementia Rating Scale (CDR) and the Financial Capacity Instrument-Short Form (FCI-SF). We will also use the existing Brain Health Registry (BHR) and the Cogstate Brief Battery. Using all information together we will develop composite scores that predict ?-amyloid (A?) positivity and cognitive and functional decline. A major obstacle to providing care and developing new therapeutics is the difficulty identifying those at risk for Alzheimer?s disease (AD) or undergoing cognitive and functional decline. Therefore, the development and validation of scalable, accessible screening tools is a critical unmet need. We will use established cohorts at UCSF, Mayo Clinic, Washington University, and University of Alabama Birmingham, comprised of participants who are already followed longitudinally through uniform data set (UDS) collection and are well-characterized in terms of clinical, cognitive, functional, and A? status. All online instruments will be implemented within the BHR, an online registry with over 52,000 participants and a well-established infrastructure for collecting self- and study-partner- reported data and remote cognitive testing. First, during a one-year Pilot Phase, we will develop, implement, and optimize electronic versions of the CDR and FCI-SF (e-CDR and the e-FCI), first using item response theory and then iteratively optimizing electronic instruments based on usability, user feedback, internal consistency, reliability, convergent/divergent validity, and input from experts. These pilot studies will be performed on 310 CN, SMC, and MCI participants and study partners across 3 sites with existing, longitudinal clinical data. Second, during a 4-year validation phase, we will validate e-instruments by comparing data obtained at home online with data obtained in research clinics in 520 participants and study partners across 4 sites. In addition to the newly-developed eCDR and eFCI, BHR data will include the Cogstate Brief Battery and additional self-report questionnaires. Third, we will determine whether online instruments both measure and predict cognitive and functional decline by following the participants longitudinally for 4 years. Fourth, we will determine the ability of online instruments to predict A? PET positivity. An essential component of these analyses will be the development and validation of new cognitive and functional composite scores, composed of multiple online measures. The results of this project are likely to lead to improved methods for AD screening that can be used in clinical trials. Ultimately these highly scalable online methods may be used in clinical practice and multiple healthcare settings to identify people at risk for and with cognitive and functional decline and AD, leading to prevention of AD and improved healthcare for neurodegenerative disorders.

Overall Summary The prevalence of dementia increases with advancing age. However, some cognitive decline is expected to occur as part of normal aging beginning in early adulthood. Differentiating normal from pathological cognitive change across the adult lifespan along with associated risk factors is essential for both preventing and treating abnormal cognitive decline. Unfortunately, current ability to do this is hampered by a lack of sensitive assessment tools that can be easily and widely deployed in diverse research designs and populations. We will address this limitation by developing, validating, norming, and disseminating a MobileToolbox of cognitive assessments appropriate for remote smartphone administration in adults aged 20 to 85. We will accomplish this objective via the following aims: 1. Create the MobileToolbox Library of iOS and Android smart-phone based assessments. These will draw from our existing work within NIH Toolbox, International Cognitive Ability Resource (ICAR), ResearchKit, ResearchStack, and the FaceName Test. The MobileToolbox will also enable delivery of additional measures of variables (e.g., mood) known to be important co-variates of cognition including measures from the Patient Reported Outcomes Measurement Information System (PROMIS) and other measurement collections. The library will be open source and available for integration of additional externally developed tests. 2. Develop and maintain the MobileToolbox Research Platform, a software platform to support clinical researchers and software developers in the dynamic, customizable integration of Mobile Toolbox Library into research studies. This will be developed as an extension of the platform built by Sage Bionetworks to support the 2015 launch of Apple?s ResearchKit. The Platform will support researchers to contribute or select assessments, to manage study and assessment protocols, and to receive, store, aggregate, analyze and share (as appropriate) data collected using iOS and/or Android smartphone devices. 3. Conduct psychometric activities to validate, norm and assess the reliability of the MobileToolbox in both general population and various research samples to create general population reference norms. The cognitive assessments will be validated against gold standard measures in healthy adults ages 20-85. The measures will then be normed and 3-month, 12-month and 24-month change scores calculated in an age- stratified (20-85), iOS vs Android, national sample matching the 2020 US Census (N=6,800) for gender, race, ethnicity, SES and level of education. Additional validation and longitudinal evaluation will be conducted in healthy and clinical samples, including persons at risk for MCI or AD, cognitively impaired and those with Parkinson?s disease.

Project Summary Our research project will be a collaborative effort supported by all of the MobileToolbox Cores. The project will function as the vehicle within which we develop and psychometrically evaluate our cognitive assessment tools. We will do this by accomplishing the following specific aims. Aim 1: We will develop a repository of public-domain cognitive ability measures that enhance the assessment of cognitive change across the lifespan by enabling self-administered testing via iOS and Android smartphones. The MobileToolbox measures will be designed around the technical specifications of a flexible and open software platform that enables external researchers to customize use of the mobile app to fit the needs of their studies. Researchers will be able to choose from a diverse selection of cognitive measures, including several cognitive tasks highly sensitive to change, along with measures of contextual variables of relevance to cognitive functioning (e.g., mood, personality, health status). Aim 2: Evaluate the psychometric properties of MobileToolbox instruments through implemention of a series of data collection protocols aimed at calibration, norming, and face-to-face validation against existing gold standards. We will calibrate Item Response Theory based measures by administering them to a large (N=4,800) general population calibration sample. All newly developed MobileToolbox measures will be validated against existing gold standards in a sample of healthy adults ages 20-85. The validation protocol will include face-to-face administration of the NIH Toolbox Cognition Battery, core sub-tests of the Wechsler Adult Intelligence Scale (WAIS-IV), and additional tests as needed. During this cross-sectional validation session, respondents (N=260) will complete the self-administered MobileToolbox via smartphone in an un-proctored setting. Additional validation will be undertaken in existing clinical (e.g., cognitively impaired, Parkinson?s disease) and general population (e.g. Healthy Aging Study, N=100,000) samples. Finally, we will identify normative values for the MobileToolbox measures using a large, nationally-representative sample (N=6,800). Sub-samples of respondents will be used to identify normative cognitive change by completing 3-, 12- and 24- month follow-up assessments.

ABSTRACT The overall goal of this proposal is to optimize and automate our existing online platform for recruitment, screening, and longitudinal monitoring of elders to accelerate interdisciplinary clinical aging research. This will be accomplished using the Brain Health Registry (BHR), an online registry and cohort with over 62,000 participants enrolled. The BHR collects longitudinal cognitive, health, and lifestyle data using self- and study partner-report surveys and neuropsychological tests. The BHR platform has been used by many collaborators. We will expand platform capabilities, optimize for efficient deployment in research settings, and automate manual steps for scalability. We will facilitate the work of multiple clinical researchers by providing them user friendly access to the BHR website, software and data. Specific Aims: 1. Study Partner First: Currently an innovative online BHR tool collects study partner (SP) information, but an enrolled BHR participant must nominate a SP to join. We will develop and deploy SP-First to allow SPs to be recruited de novo and for the SP to be the first or only point of contact with BHR. This will facilitate recruitment and engagement of older adults into BHR and eventually into other Alzheimer?s disease (AD) studies and clinical trials. 2. Referrals: To optimize and automate our current system which has referred over 27,000 BHR participants to clinical AD and aging studies, including clinical trials and observational studies. This will greatly increase use of this program, with the overall goal of facilitating recruitment and screening for AD and aging clinical studies. 3. Co-enrollments: To optimize and fully automate our current system for enrolling existing clinical cohorts in BHR with data linkage. We will automate the co-enrollment process for investigators to enable efficient, scalable, and adaptation of the tool for multiple aging studies. Co-enrollment can facilitate validation of online methods, and is likely to improve longitudinal engagement and retention of participants in in-clinic studies. 4. Software as a Service (SaaS): BHR licenses the BHR platform as a software service to collaborators who will create their own registries or referral programs under their own IRB, removing the need to create new registry platforms. We will automate the SaaS process to facilitate highly scalable use by many investigators. 5. Data Sharing: To automate the process of data linkage, creating datasets, enabling highly scalable data access, and data distribution. De-identified data from the general BHR study data will be made available to the research community. A novel interface will allow investigators to query the database, create customized datasets, upload and download data. In addition, we will expand and automate the capability to collect biofluids for biomarker and genetic testing, and to integrate biofluids data into the BHR database. Our innovative, highly-scalable platform will be of great value to investigators by providing them with user-friendly internet tools for recruitment, assessment and longitudinal monitoring of their cohorts.