Elsevier

Neurobiology of Aging

Volume 32, Issue 2, February 2011, Pages 200-209
Neurobiology of Aging

Effects of demographic factors on cortical thickness in Alzheimer's disease

https://doi.org/10.1016/j.neurobiolaging.2009.02.004Get rights and content

Abstract

The aim of this study was to investigate the effect of demographic factors (age of onset, sex and years of education) on the distribution of cortical thickness in a large sample of patients with Alzheimer's disease (AD). The study participants consisted of 193 AD patients and 142 controls with no cognitive impairment (NCI) that were measured with cortical thickness across the entire brain. The effects of demographic factors on cortical thickness were analyzed by applying linear regression after controlling confounding factors. Older individuals in NCI group showed more cortical thinning in frontal, temporal association cortices and insula than younger participants. Early onset AD was associated with cortical thinning in the parietal lobe, whereas late onset AD was associated with cortical thinning in the medial temporal region. The NCI group demonstrated sex-related differences in cortical thickness, although those differences were not present in the AD group. While the education effect was absent in NCI individuals, high levels of education in the AD group correlated with cortical thinning in the frontal and temporoparietal association cortices. Our results show that AD with earlier onset and higher education had suffered more pronounced cortical atrophy in specific parts of the brain than their counterparts, which may be related to cognitive reserve theory.

Introduction

Alzheimer's disease (AD) is pathologically characterized by the formation of neurofibrillary tangles and neuritic plaques, resulting in neuronal loss. Macroscopically, transentorhinal (stage I) and entorhinal regions (stage II) are initially affected, followed by the limbic area (stages III and IV), the neocortical high-order sensory association and prefrontal areas (stage V), and finally the primary sensory fields (Braak and Braak, 1991). Microscopically, pathologic changes in AD predominantly occur in cortical gray matter resulting in cortical atrophy (Mirra et al., 1991), although some studies also demonstrated white matter changes even in early stage of AD (Scheltens et al., 1995). Cognitive declines in AD correlate with cortical atrophy (Lerch et al., 2005).

Demographic factors such as onset age, gender, and years of education are known to affect cognitive deficits in AD. Clinically, patients with an early onset of AD (EOAD) show a greater degree of cortical dysfunctions such as aphasia, apraxia, and agnosia than those with a late onset of AD (LOAD) (Chui et al., 1985, Seltzer and Sherwin, 1983), while LOAD patients show memory disturbances out of proportion with other cognitive deficits (Binetti et al., 1993). Some studies suggest that there is a gender effect on cognitive dysfunctions in AD (Fratiglioni et al., 1997, Gao et al., 1998), but an 8-year longitudinal study showed that patterns of cognitive decline are similar in both older men and older women (Barnes et al., 2003). Finally, education has a significant effect on performance across a broad range of cognitive domains in AD patients (Doraiswamy et al., 1995). Because these demographic factors affect cognitive impairments in AD, we assume that they have an effect on the distribution pattern and degree of cortical atrophy.

Some pathologic studies have shown that the amount of AD pathology does not always correlate with the clinical severity of the disease (Katzman et al., 1988), suggesting that people differ in their capacity to withstand the deleterious effects of the pathologic insult. Identifying factors associated with the ability to tolerate the accumulation of AD pathology has important implications for disease prevention. Some of those factors could be demographic factors such as onset age, sex, and years of education since advanced age, female gender, and less education have been associated with increased incidence of AD (Zhang et al., 1990). Moreover, functional imaging studies using single photon emission computed tomography (SPECT) or positron emission tomography (PET) have shown that AD patients with these conditions (advanced age, female gender, and less education) demonstrate less severe perfusion and metabolism deficits after controlling for the severity of dementia. PET studies demonstrated that patients with EOAD had more hypometabolism in the lateral parietal region and precuneus than those with LOAD (Kim et al., 2005a, Sakamoto et al., 2002, Salmon et al., 2000). Male patients with AD show more pronounced metabolic indices of pathology in regions of the frontal, temporal, insular cortex and the hippocampus of the right hemisphere (Perneczky et al., 2007). Functional studies show that AD patients with a higher level of education have a flow reduction in the parietotemporal cortex (Stern et al., 1992) or hypometabolism in the posterior temporo-occipital association cortex (Perneczky et al., 2006). However, the alteration of perfusion or metabolism in functional images can be affected by such factors as metabolic disturbances and drug therapy other than cortical atrophy per se. Furthermore, it is debatable whether decreased cortical activity in glucose PET reflects true cortical hypometabolism or rather a partial volumetric effect that is secondary to cortical atrophy (Ibanez et al., 1998).

Recent methods for studying cortical gray matter volume losses in AD include magnetic resonance imaging (MRI) via voxel-based morphometry (VBM) (Karas et al., 2003), cortical pattern matching (Thompson et al., 2001), and surface-based cortical thickness analysis (Lerch et al., 2005). However, only a few studies have investigated the relationship between demographic factors and cortical atrophy using these structural imaging methods (Frisoni et al., 2007, Ishii et al., 2005). Furthermore, these limited studies involved relatively small samples. In this study, we used surface based cortical thickness analysis as a surrogate for cortical atrophy. This method may be more valid than VBM in measuring cortical thickness because it enables more precise measurements not only in gyri but also in deep sulci based on the actual thickness of the cortex in millimeters, thus allowing the search for associations between the depth of the cortex and demographic variables across the entire surface of the brain.

The aim of this study was to investigate the effects of onset age, gender, and education on the distribution of cortical thinning using surface-based cortical analysis of MRI in a large sample of AD patients. This large sample allows regression analyses using the onset of age and the duration of education as continuous variables rather than categorizing the AD population arbitrarily according to a cut-off value. It also enabled us to control for other demographic factors, general cognitive status, and premorbid brain size (Jenkins et al., 2000).

Section snippets

Participants

The patient group consisted of 196 patients with AD who underwent a high resolution T1 weighted volume MRI scan at the Samsung Medical Center in Seoul Korea between April 2000 and February 2007. All patients fulfilled the criteria for probable Alzheimer's disease proposed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS–ADRDA) (McKhann et al., 1984).

All AD patients underwent a clinical

Regional differences in cortical thickness in NCI and AD patients

Fig. 1 shows the results of ANCOVA for each vertex from the patients of two groups. The differences in cortical thickness were significant in widespread regions except for the sensory and motor cortices and the occipital lobe. The most significant differences were noted in the medial temporal lobe, temporoparietal association cortex, posterior parietal medial regions, and prefrontal cortex, as indicated by the regions shaded purple in Fig. 1.

The effect of demographic factors on the average thickness across the entire cortex

NCI group showed that old age was an independent

Discussion

Group differences between the NCI and AD groups emerged in widespread regions except for in the sensorimotor motor cortices, particularly in the temporoparietal association cortices and the medial temporal lobe; these results are consistent with those of previous surface-based cortical analyses in AD (Lerch et al., 2005, Singh et al., 2006) and also those of pathology investigations (Braak and Braak, 1991).

Regarding the mean cortical volume, previous MRI studies using VBM showed that cortical

Disclosure

All authors had no actual or potential conflicts of interest, and this study was approved by the Institutional Review Board of the Samsung Medical Center.

Acknowledgments

This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A050079) and the Korea Science and Engineering Foundation (KOSEF) NRL program grant funded by the Korean government (MEST) (R0A-2007-000-20068-0).

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