Neuroimaging study on function-structure relationship of olfactory deficit in AD

Project Summary

We are studying olfactory deficits in early Alzheimer’s disease (AD) using a full set of MR sequences collecting information on function (fMRI), quantitative volume (vMRI), and maps of additional physical and physiological parameters (pMRI) related to brain integrity, including brain perfusion and directional diffusion. Olfactory deficits are prevalent in AD patients and can be detected in the early stages of AD. This well established finding provides a unique opportunity for us to examine the direct relationship between pathological changes in the site of early degeneration and the associated functional deficit. Studying such a relationship has been difficult and confounded with neurocognitive variables. Our long-term objective is to understand the olfactory deficits occurring in early AD and to develop reliable diagnostic tools for the early detection, monitoring and understanding of the functional-pathological processes of AD. The study is designed in response to NIH PA- 04-158, Ancillary Studies to the AD Neuroimaging Initiative (ADNI). This design will add a significant amount of data to the ADNI overall cohort. Ancillary to ADNI, we will determine how the local atrophy in the primary olfactory cortex, entorhinal and hippocampus relates to the olfactory fMRI activation in the same structures and how these sets of measurement relate to the AD psychophysical and clinical expressions. This project is driven by two hypotheses: 1) the olfactory deficits in early AD can be identified by olfactory fMRI; 2) olfactory fMRI activation in the primary olfactory cortex (POC) and entorhinal/hippocampal regions correlates with the degree of atrophy in these regions in MCI and AD.

SPECIFIC AIMS: We will study the olfactory deficits in early Alzheimer’s disease (AD) with fMRI, vMRI, and pMRI. The long-term objective of this research is to understand the olfactory deficits occurring in the early stages of the disease and to develop reliable diagnostic tools for early detection, monitoring and understanding of the functional-pathological processes of AD.

To achieve our objective, we will establish: 1) Reliable fMRI methods producing consistent olfactory activation maps; 2) The relationship between olfactory fMRI activation maps and comprehensive behavioral measures (olfactory thresholds, intensity and identification) in normal and early AD subjects; and 3) The relationship of fMRI activation maps with markers of early AD neuropathology through vMRI and pMRI measurements of key structures.

Acquiring an olfactory fMRI activation map is challenging because of the severe magnetic susceptibility artifacts in the olfactory areas in the base of the brain. With our previous experience in the development of novel MRI techniques to remove these artifacts from MR images, we are well positioned to pursue this project.

We propose the following hypotheses: 1) The olfactory deficits in early AD can be identified by olfactory fMRI; 2) Olfactory fMRI activation in the primary olfactory cortex (POC) and entorhinal/hippocampal regions correlates with the degree of atrophy in these regions in mild cognitive impairment (MCI) and AD subjects. To test our hypotheses, we will pursue the following specific aims:

Specific Aim 1: Develop, validate and standardize olfactory fMRI methods, and the corresponding data analysis methods on the POC, entorhinal cortex and hippocampus
We are currently able to detect olfactory fMRI activations in the POC, entorhinal cortex, hippocampus, and orbitofrontal cortex. We will 1) Develop and optimize reliable fMRI acquisition methods by incorporating our method with the parallel acquisition (PA) technique to further reduce the magnetic susceptibility artifacts in brain olfactory areas. 2) Determine the reproducibility of data acquisition methods and olfactory stimulation paradigm. 3) Characterize the changes and variability of fMRI data due to normal aging.

Specific Aim 2: Characterize olfactory fMRI signal and its relationships with odor threshold and intensity in young and old normal controls (NC), and changes in fMRI activation and perception of odor intensity in mild cognitive impairment (MCI) and early AD
We will 1) Evaluate NC, MCI and AD subjects with odor threshold and intensity tests. 2) Characterize olfactory fMRI signal with respect to odor threshold and intensity in NC, MCI and AD. 3) Test hypothesis 1 and conduct sensitivity analysis of olfactory fMRI with odor threshold and intensity for discriminating NC, MCI and AD.

Specific Aim 3: Identify and quantify the relationship between atrophy, berfusion, brain, integrity, and olfactory dysfunction at the sites of early degeneration
We will 1) Perform concurrent measurements of olfactory fMRI and brain atrophy in the POC, entorhinal cortex and hippocampus in MCI, AD and age-matched NC subjects. 2) Determine the correlations of atrophy with olfactory fMRI results in the POC, entorhinal cortex and hippocampus among the three groups. 3) Test hypothesis 2 and conduct sensitivity analysis on discriminating MCI, AD and age-matched NC subjects with fMRI, vMRI, and pMRI measurements.

Significance

AD is the most common cause of dementia, accounting for the majority of patients over the age of 65 years with abnormal mental decline (1, 2). The cost of caring for patients with this disorder exceeds 11 billion dollars annually (3), and the human toll on families is incalculable. A broad range of research in many areas has been put forward to study this disease. Functional MRI (fMRI) has emerged as a powerful modality for studying brain function and the altered neuropathological correlates of various diseases. We propose a concurrent fMRI, quantitative volumetric MRI measurement (vMRI) and behavioral study on the olfactory deficits occurring in MCI and early AD patients, drawing upon our novel imaging techniques published in the peer-reviewed literature and summarized in the Preliminary Studies section. The motivation and rationale for this project are based on the following welldocumented findings:

1. Olfactory deficits are prevalent in AD patients (3-20).
2. Olfactory deficits can be detected in the early stages of AD.
3. 3. Brain histopathology in patients with AD demonstrates greater degeneration in central olfactory regions compared to visual, auditory, motor and other sensory systems.
4. Initial AD pathology occurs in the entorhinal cortex and progresses to the hippocampus. Both these regions are involved in olfaction as well as memory and other cognitive functions.
5. The initial AD pathology can be detected with quantitative volumetric MRI measurement.

We propose to gather the functional, morphological, physiological, and physical data using MRI needed to establish and quantify the relationship between atrophy, degeneration, and dysfunction related to olfaction in early AD.

Innovation

The importance of this project lies in rigorously testing an olfactory hypothesis in AD with concurrent measurements of behavior, in vivo morphometry (vMRI), functional brain activity (fMRI), and physical/physiological properties including perfusion and diffusion (pMRI). A clear understanding of olfactory deficits and their relation to the most prominent pathophysiology in AD has the potential to shed light on the cause of the associated functional disturbances of this disease. We have made significant advances to successfully perform fMRI of olfaction, detecting activiation even in areas near nasal sinuses, where typically significant signal loss due to B0 inhomogeneity is seen in fMRI (21-24). To our knowledge there is no other study focused on studying these aspects with regards to olfaction in AD. The project is innovative on many levels: 1) We will establish a connection between the degree of atrophy in specific key brain locations in early AD and the associated impairments. 2) Our olfactory fMRI paradigm offers a straightforward and reproducible probe that stimulates the very sites of early degeneration. 3) We will establish the functional pathology for olfactory deficits as a potential pre-clinical marker. 4) Our project addresses a critical national need for AD research. 5) Our contribution to the ADNI project and database will be unique.

Approach

In this investigation, we will study olfactory deficits in early AD with fMRI, vMRI, pMRI, and neurobehavioral examinations in three subject samples: MCI, early AD and aged-matched normal controls. The subjects will be recruited with the same screening and neurocognitive evaluation criteria of ADNI. This design will allow the neurocognitive, biological (blood and urine) and brain morphological data acquired by this project to be incorporated seamlessly into the ADNI overall cohort. Ancillary to ADNI, we will determine how the local atrophy in the POC, entorhinal cortex and hippocampus relates to the olfactory fMRI activation in the same structures, and how these sets of measurement relate to the AD psychophysical and clinical expressions.

To achieve our aims, significant data is acquired in each subject. The sequences we currently use are described in the following table. Because the total amount of imaging time required for all studies is a little over 61 minutes, the data is currently acquired in two separate sessions. All sets are currently acquired with a reduction factor of 2.