Regional coherence changes in the early stages of Alzheimer’s disease: A combined structural and resting-state functional MRI study

Abstract

Recent functional imaging studies have indicated that the pathophysiology of Alzheimer’s disease (AD) can be associated with the changes in spontaneous low-frequency (< 0.08 Hz) blood oxygenation level-dependent fluctuations (LFBF) measured during a resting state. The purpose of this study was to examine regional LFBF coherence patterns in early AD and the impact of regional brain atrophy on the functional results. Both structural MRI and resting-state functional MRI scans were collected from 14 AD subjects and 14 age-matched normal controls. We found significant regional coherence decreases in the posterior cingulate cortex/precuneus (PCC/PCu) in the AD patients when compared with the normal controls. Moreover, the decrease in the PCC/PCu coherence was correlated with the disease progression measured by the Mini-Mental State Exam scores. The changes in LFBF in the PCC/PCu may be related to the resting hypometabolism in this region commonly detected in previous positron emission tomography studies of early AD. When the regional PCC/PCu atrophy was controlled, these results still remained significant but with a decrease in the statistical power, suggesting that the LFBF results are at least partly explained by the regional atrophy. In addition, we also found increased LFBF coherence in the bilateral cuneus, right lingual gyrus and left fusiform gyrus in the AD patients. These regions are consistent with previous findings of AD-related increased activation during cognitive tasks explained in terms of a compensatory-recruitment hypothesis. Finally, our study indicated that regional brain atrophy could be an important consideration in functional imaging studies of neurodegenerative diseases.

Introduction

Functional neuroimaging studies of Alzheimer’s disease (AD) typically focus on exploring activation (Buckner et al., 2000, Grady et al., 1993, Remy et al., 2005) or deactivation (Rombouts et al., 2005, Lustig et al., 2003) alterations in patients during a task state compared with a baseline state. Many neuroimaging studies also use the resting state to examine AD-related changes in brain activity. For instance, positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) studies have found that AD patients have abnormally low resting cerebral blood flow (CBF) or cerebral metabolic rate for glucose (CMRGlu) in the posterior cingulate, parietal, temporal, and prefrontal cortex (Bokde et al., 2001, Herholz et al., 2002, Ibáñez et al., 1998, Leon et al., 2001, Salmon et al., 2000).

Recently, functional MRI (fMRI) studies have indicated that the pathophysiology of AD can be associated with the changes in spontaneous low-frequency (< 0.08 Hz) blood oxygenation level-dependent (BOLD) fluctuations (LFBF) measured during a resting state. As early as 1995, Biswal et al. (1995) found that spontaneous LFBF measured by resting-state fMRI was highly synchronous within the somatomotor system and concluded that it was physiologically meaningful. Following that study, high LFBF synchrony in healthy adults was also reported within the primary motor (Lowe et al., 1998, Cordes et al., 2001, Jiang et al., 2004), auditory (Cordes et al., 2001), and visual cortices (Kiviniemi et al., 2004, Kiviniemi et al., 2005, Lowe et al., 1998), as well as the nonprimary regions such as hippocampus (Rombouts et al., 2003), language (Hampson et al., 2002) and limbic systems (Greicius et al., 2003, Fox et al., 2005). Several recent studies have suggested that the LFBF can also be employed to characterize the pathophysiological changes of brain disorders, such as multiple sclerosis (Lowe et al., 2002), depression (Anand et al., 2005), schizophrenia (Liu et al., 2006), attention deficit hyperactivity disorder (ADHD) (Zang et al., in press, Cao et al., 2006) and acute brainstem ischemia (Salvador et al., 2005). To our knowledge, only three prior studies have examined AD-related LFBF activity using resting-state fMRI (Li et al., 2002, Maxim et al., 2005, Wang et al., 2006). In the first report, Li et al. (2002) exclusively examined functional synchrony of LFBF in the hippocampus and found it decreased significantly in the AD patients. The second study from Maxim et al. (2005) found that AD patients had greater persistence of resting fMRI noise in the medial and lateral temporal lobes, dorsal cingulate/medial premotor cortex, and insula. A very recent study from our research group found that AD patients showed abnormal hippocampal connectivity during resting state (Wang et al., 2006). Aside from these pure resting-state fMRI studies, using a low-frequency component derived from a simple sensory-motor task, Greicius et al. (2004) found that AD patients exhibited decreased resting-state activity within a default-mode network including the posterior cingulate cortex and inferior parietal lobe. Despite the limited number of reports, such intriguing studies have provided an insight into the pathophysiology of AD by means of spontaneous LFBF measured during rest. Of these, however, only one examined AD-related regional LFBF activity across the entire cortex (Maxim et al., 2005).

The first purpose of this study was to clarify and expand on AD-related regional LFBF changes by examining regional coherence in a pure resting state. Regional coherence was assessed using our previously published regional homogeneity (ReHo) method (Zang et al., 2004). In this study, we postulated that the medial parietal cortex [posterior cingulate cortex (PCC) and precuneus (PCu)] have decreased regional LFBF activity in the early stages of AD because the region is the most common site for AD-related functional changes such as the resting hypometabolism and hypoperfusion (Leon et al., 2001, Salmon et al., 2000, Volkow et al., 2002) and abnormal functional deactivation during the performance of cognitive tasks (Rombouts et al., 2005, Lustig et al., 2003). In addition, we also expected to observe AD-related LFBF changes in the other regions.

However, a number of key issues still remain given that we observed altered LFBF activity in the PCC/PCu and the other regions. The major concern is the possible impact of regional brain atrophy on the functional results. Many studies have indicated that AD patients have more brain tissue atrophy than normal controls in the PCC/PCu, medial temporal cortex, caudate nucleus and medial thalami (Rombouts et al., 2000, Karas et al., 2003, Baron et al., 2001). The brain atrophy may lead to artificial reduction in measured functional signals. While comparing functional differences between AD patients and normal controls, this issue could potentially be crucial due to individual and group differences in the degree of regional atrophy. Several PET studies have suggested that temporoparietal hypometabolism became nonsignificant in the AD patients after accounting for brain atrophy (Chawluk et al., 1990, Tanna et al., 1991). In fMRI studies, a few groups have made an attempt to explore the relationship between regional brain atrophy and functional activation in AD patients during cognitive tasks (Johnson et al., 2000, Prvulovic et al., 2002, Remy et al., 2005). To date, however, no studies have specifically examined the effect of brain atrophy on spontaneous LFBF measurements. Hence, determining the impact of regional atrophy on the LFBF results is the other purpose of this study.

To address these questions, in this resting-state study, we first used the ReHo method (Zang et al., 2004) to explore the changes of AD-related regional LFBF activity in the whole brain. The behavioral correlates of the LFBF activity were further examined in the AD patient group. Finally, the atrophy of the regions showing significant between-group ReHo difference was measured for each subject and its impact on the LFBF results was statistically evaluated.