• Develop improved methods which will lead to uniform standards for acquiring longitudinal, multi-site MRI and PET data on patients with AD, MCI, and elderly controls.
• Acquire a generally accessible data repositry which describes longitudinal changes in brain structure and metabolism.
• In parallel, acquire clinical cognitive and biomarker data for validation of imaging surrogates.
• Develop methods which will provide maximum power to determine treatment effects in trials involving these patients.
• Test a series of hypotheses based on the clinical and biomarker data as outlined in the statistical analysis section of the protocol.

We will enroll a total of 800 subjects with 400 subjects with MCI, 200 with early AD and 200 normal controls. Subjects with MCI and controls will be followed for 3 years, those with AD for 2 years. At 6-month intervals, all subjects will be seen in person or contacted by telephone.

Subjects will undergo clinical and neuropsychological evaluations each time scanning is performed. All subjects will undergo repeated 1.5% MRI scanning (MCI-N=6 scans/subjects, Controls-N=5 scans/subject, AD-N=4 scans/subject), 25% will undergo repeated 3% MRI scanning, and 50% will undergo repeated PET scanning with the same frequency of scanning used for the 1.5% MRI imaging.

Blood and urine biomarkers will be collected at each interval when imaging data is collected from all participants. Immortalized cell lines will be established from all subjects at baseline. All subjects will be approached for LP so that a minimum of 20% and as many as 50% of the cohort will undergo a lumbar puncture at baseline and at year 1 for analysis and storage of CSF.

The purpose of this research study is to better understand the biological basis for the changes in memory and thinking that can occur with aging and subcortical infarction

The data will be analyzed with respect to 3 specific aims:

• To test the hypothesis that hypometabolism of the frontal lobes is a marker for cerebrovascular pathology.
• To test the hypothesis that temporoparietal hypometabolism in the presence of lacunes is a marker for Alzheimer’s disease. 
• To test the hypothesis that strategically located lacunes are an important cause of cognitive impairment.

Thus, this study will involve studying patients using PET, MRI, and neuropsychological testing.  Only the PET protocol and neuropsychological testing is covered here.

This project evaluates the effect of stroke and Alzheimer's Disease on cognitive function. It is a multi-center collaborative project involving investigators at UC Davis, UC San Francisco, UCLA, and the University of Southern California. The goals of the project are to investigate the contribution of cerebrovascular lesions to behavioral alterations and dementia using a variety of techniques including neuropsychology, magnetic resonance imaging, magnetic resonance spectroscopy, and PET. UC Davis is one of three subject recruitment sites.

• Project 1 – PET Markers of Cerebrovascular Disease and Alzheimer’s Disease (Investigator-Reed)

This project uses PET with FDG to study a sample of patients with varying degrees of cerebrovascular disease. The goal of this project is to define PET markers associated with CVD as opposed to AD, and to define mechanisms whereby CVD produces cognitive change. Quantitative MRI and PET data are being linked to address study hypotheses.

• Project 5 - Vascular and Degenerative Contributions to Dementia (Investigator-Mungas)

The purpose of this project is to develop neuropsychological instruments to assess cognitive function in both English and Spanish speaking older individuals. Item response theory methods and community sampling are being used to develop and validate psychometrically matched English- and Spanish-language versions of neuropsychological tests which can be used to assess cognitive impairment and longitudinal change in cognitive function, in African Americans, Hispanics, and Caucasians.

We hope to learn more about making a determination as to whether or not a person has capacity to give informed consent to participate in a research study.  We are interested in learning about who makes these judgments, how much time they take, how they are related to patients’ degree of cognitive impairment and to patient diagnosis, and how practices may vary between different clinicians and sites. 

We will measure brain amyloid levels and glucose utilization by using a brain scanning technique called positron emission tomography (PET) that enables us to image brain function.  Brain amyloid deposition will be measured using PET with a radioactive substance [C-11]- 6-OH-BTA-1, nicknamed  “PIB” (for Pittsburgh compound B since it was invented at the University of Pittsburgh).   PIB is an experimental tracer. 

Brain glucose metabolism will be measured with a separate injection of a different radioactive substance [F-18]deoxyglucose or FDG. The PIB will be injected in a vein in your arm, and the PET scanner will be used to take pictures, following which the FDG will be injected into a vein in your arm and the PET scanner will take a separate set of pictures. The PET scans will be done at the Lawrence Berkeley National Laboratory.  The entire study can be done in one visit, although if you prefer, two separate visits, one for each scan, can be arranged.
Currently Enrolling in Martinez and Sacramento

The purpose of this study is to determine the neuropsychological and neurophysiological impacts of a computer-based training program designed to improve the cognitive performance of patients with mild cognitive impairment (MCI).  We will conduct a small randomized, double-blind, controlled trial of this intervention with three specific aims: 1) to assess the magnitude of improvements in memory, language function, and cognitive function following training, 2) to investigate the neurophysiological mechanisms underlying such neuropsychological improvements, and 3) to demonstrate the feasibility of using this kind of computer based training therapy in older populations. The study includes a training component, a neuropsychological assessment component, and three brain imaging components.  The training and neuropsychological assessment components are designed to replicate and extend preliminary studies that have suggested that substantial improvements in clinically relevant measures of cognitive performance can be driven in patients with MCI through the use of a standardized training paradigm (a modified version of an acoustic perceptual/language listening training program).  The training component will be composed of a four to seven weeklong regimen of daily computer-based training sessions that subjects will pursue at home.  The neuropsychological assessment component will be composed of pre-training and post-training assessments relevant to MCI measuring memory, attention, language, and executive function abilities. 

The three brain imaging components will be composed of standardized pre-training and post-training measures of brain function that will investigate the mechanisms underlying the neuropsychological changes that occur as a result of training using positron emission tomography (PET), magnetoencephalography (MEG) and electroencephalography (EEG), and functional magnetic resonance imaging (fMRI) studies. Some subjects who decline the PET study will be recruited to participate in the computer training and neuropsychological training sessions.

The purpose of this research is to collect clinical information about people with alzheimer's disease and their moods using questionnaires. The research is looking at how an AD patient's mood affects his/her thinking and ability to perform everyday activities. This information will be entered into a database for future uses in determining if people who have Alzheimer's disease are depressed.

Research Plan Overall Objective: 

Our work will cover the spectrum from human neurobiology and clinical efficacy studies, to health services research.  Prominent investigators in the field of dementia in Palo Alto will lead the dementia program.  Building upon a working research structure already existing in four of the six VISN facilities, these investigators will complete a VISN-wide structure for the evaluation of predictors of response and the effectiveness in “real world” situations of treatments of both cognitive and behavioral symptoms in dementia.  Similarly, the PTSD research program will be led by seasoned investigators in San Francisco who will extend a research structure, already working effectively in several facilities, to other VISN facilities.

Educational Plan Overall Objective: 

Our education plan is designed to disseminate current state-of-the-art knowledge as well as new information yielded from MIRECC research investigations specific to the care of two groups of veterans: (1) those with PTSD and (2) those with behavioral, cognitive, or functional problems associated with dementia.

Aim 1:To examine the impact of ethnicity (i.e. Mexican American Versus White non-Hispanic) and gender on spousal caregiver explanatory models (i.e. problem definition, attributions, and perceived seriousness), help-seeking behaviors, and treatment preferences for dementia neuropsychiatric symptoms.

Aim 2: To systematically compare spousal caregiver perspectives (i.e. accounts of help-seeking, explanatory models, and treatment preferences related to dementia neuropsychiatric symptoms) with those of the primary care clinician who is caring for the dementia-affected elderly.

Evidence suggests that significant memory impairment, short of dementia and often denoted as mild cognitive impairment (MCI) in the elderly may be a transition phase between the normal again process and AD. Individual trajectories of cognitive decline can be quite variable, however, and not all older individuals with cognitive impairment have memory loss as the predominant symptom suggesting considerable clinical and etiological heterogeneity.

In addition, since CVD is common to an aging population and potentially treatable, understanding the role CVD plays in the expression of MCI and progression to dementia could also result in clinical therapeutic trials aimed at the prevention of cerebrovascular-related cognitive impairment. The prevalence and impact of CVD on the natural history, patterns of cognitive performance or longitudinal cognitive changes in MCI are currently unknown.

To address this gap in current understanding, this project will examine the clinical and neurobiological substrate of MCI in a large group of MCI patients selected to have both memory and non-memory cognitive impairments as well as a broad spectrum of CVD severity.

The overall aim of this study is to see if there is a relationship among high levels of the stress hormone cortisol, the type of Apolipoprotein E (APOE) gene a person carries, and decline in memory and other brain functions. Cortisol plays a role in the body's response to physical and mental stress. We believe that if this hormone is overactive, it may worsen the changes in memory and other brain functions that result from normal aging and Alzheimer’s disease.
Enrollment Closed

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The Measurement and Prediction of Everyday Function in Dementia
Investigator-Farias

Currently Enrolling in Martinez and Sacramento

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UCD ADC CSF Tissue Bank
Investigator-DeCarli

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ERPs as Markers of Early AD Across Ethnic Groups in MCI
Investigator-John Olichney, MD

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Reducing the Amount of Aggregates of Amyloid-b Protein (Ab) in the Brain
Investigator-Lee-Way Jin, M.D., Ph.D.

This study will test a few compounds for their effects in reducing the amount of aggregates of amyloid-b protein (Ab) in the brain. Ab is the major protein component of the amyloid plaques in the brains of patients with Alzheimer's disease (AD).

Ab also exists in small aggregates that are present in early stages of the disease, either inside or outside the neurons in the brain. Many lines of studies strongly support the toxic effects of various Ab aggregates, which may cause dementia in AD. Methods to reduce the levels of Ab, prevent Ab aggregation or eliminate existing Ab aggregates have been proposed for AD therapies. In this proposal, we focus on discovering small molecule, "drug-like" compounds targeting those small Ab aggregates (oligomers) inside the neurons, which have been shown to be an early lesion and causally related to some cognitive deficits and neurodegeneration in AD animal models.

This group of compounds comes from well characterized amyloid ligands, originally developed for use as specific tracers for positron emission tomography (PET) or single photon emission computed tomography (SPECT) imaging of brain amyloid. The wish is that these compounds will locate and interact with the small Ab aggregates in the brain and somehow eliminate them. We have some evidence in the test tubes and cultured cells that this might work in living beings. Since animal experiments are a necessary step toward finding effective compounds, we will subject a new and robust AD transgenic model called 5XFAD mice to various regimens of treatments with the candidate compounds.

We will examine whether the compounds are able to reduce the levels of neuronal Ab deposits, and by doing so, ameliorate the synaptic and neuronal loss which are features similar to AD. The proposed experiments would help us to understand the causal relationship of various lesions in the brain of AD patients, and therefore might reveal the fundamental cause of AD. They would also help us to validate or reject our candidate compounds that may have a potential in reducing an early neurotoxic event in AD.

FTLD Diagnostic Study
Investigator-Joel Kramer, Psy.D. & Charles DeCarli, MD

FTLD is one of the most common presenile neurodegenerative diseases, representing around 15% of early-onset dementia cases (Ikeda). However, diagnostic accuracy is well below what has been achieved for AD, and misdiagnosis is common even at centers specializing in dementia.  Current diagnostic criteria have been criticized for being cumbersome and difficult to use, not designed for use by non-specialists, low inter-rater reliability, and an unacceptably high rate of misdiagnoses. 

To address these concerns, international groups of experts have convened to develop new, empirically-based criteria that reflect the recent major advances in our understanding of this group of diseases.  The purpose of this three-year consortium application is to test the inter-rater reliability and validity of these new criteria and develop training modules that will efficiently translate this knowledge to the state ARCCs and to community health care providers. 

The following specific aims will be addressed:

Specific Aim 1:   Assess the inter-rater reliability of the new FTLD diagnostic criteria

Specific Aim 2:   Assess the validity of the new FTLD diagnostic criteria by collecting pathologically-confirmed cases of FTLD and AD and retrospectively applying the diagnostic criteria 

Specific Aim 3:  Assess the validity of the new FTLD diagnostic criteria by prospectively following new cases of FTLD diagnosed with the new criteria.  Subjects will be studies with PIB and, in some instances, pathological confirmation of diagnosis will be possible. 

Specific Aim 4:   To develop educational materials for translate these improved diagnostic criteria to other ARCCs and to community health care providers.

Dr. DeCarli is currently involved in structural brain imaging in five NIH-funded projects and one project under submission. The funded research projects all have the common theme of evaluating changes in brain structure that reflect degenerative or vascular processes in large, longitudinally followed cohorts. These studies include:

1. MRI studies of offspring of the original Framingham cohort in an effort to define risk factors for dementia and relate these to cognition
2. MRI studies of the NHLBI twin cohort in order to examine heritability of brain morphology in a cross sectional and longitudinal fashion
3. The use of MRI as an outcome measure indicative of cerebrovascular disease in the Framingham cohort and the offspring of this cohort
4. The use of MRI as a measure of brain changes associated with AD and cerebrovascular disease in a biracial cohort in order to define the relative contribution of cerebrovascular disease to dementia
5. The use of MRI to evaluate brain structure in normal aging and incipient AD in the Framingham cohort
6. In a pending study, Dr. DeCarli will use MRI as a phenotypic measure in a quantitative trait design as part of the MIRAGE study.
   Not Enrolling
   

The aim of the current proposal is to test the hypothesis that the recollection deficits seen in normal aging are related to changes in white matter as indexed by WMHs. By measuring recollection and familiarity-based recognition in a group of aged subjects with a range of WMH loads, we will determine if recollection is related to white matter abnormalities.

The long term goal of this line of research is to understand the cognitive functions and brain mechanisms that are critical for encoding and retrieval of long term memory. If we can demonstrate a link between WMH and recollection, them future studies will be designed to further characterize the specific cognitive functions that contribute to normal recollection and familiarity-based recognition responses in aging.
Currently Enrolling in Martinez and Sacramento

Lipoproteins play a crucial role in brain cholesterol homeostasis, most likely through their ability to accept cellular cholesterol, the first step in reverse cholesterol transport. We are testing the hypothesis that microglia-derived oxidative stress alters lipoprotein regulated cholesterol homeostasis in the brain and contributes to Alzheimer's pathology. Our specific aims are:

1. to detect and characterize microglia-derived oxidation products in cerebrospinal fluid (CSF) lipoproteins in Alzheimer's patients using mass spectrometry and immunological methods.
2. to investigate the effect of oxidized CSF lipoproteins on cholesterol efflux. we will compare the efficacy of CSF from Alzheimer's Patients and controls for accepting cholesterol form cells.

This study will provide important insights into the role of lipoprotein oxidation on cholesterol homeostasis in the brain and its effects on amyloid plaque formation. These studies will have implications for the biological significance of oxidative reactions in Alzheimer's disease and other inflammatory diseases.
Enrollment Closed