Age- and sex-related effects on the neuroanatomy of healthy elderly
Introduction
The increase of life expectancy during the last century has led to a growing number of dementia cases in the aging population. Prevalence studies suggested that, in 2000, the number of persons with Alzheimer's disease in the United States was 4.5 million and predicted to rise to 13.2 million by 2050 (Hebert et al., 2003). This dementia incidence upsurge has reinforced the importance of characterizing the mechanisms of the human brain aging during the seventh and eighth decades of life. Indeed, a better understanding of the normal neuroanatomical aging could be of high interest for dissociating processes specifically associated with pathologic brain changes from those associated to normal changes.
During the past two decades, several studies have investigated the effect of aging on the human brain. More often than not, these studies investigated cerebral changes over life span (from 20 up to 80 years). Their findings have led to a large consensus regarding the global morphological changes due to aging. First, postmortem studies have described, starting at the fourth decade, a decrease of the brain weight and an increase of the cerebrospinal fluid volume (CSF) (Dekaban, 1978). Then, studies using Magnetic Resonance Imaging (MRI) have confirmed and refined these findings by showing that the gray matter (GM) volume starts to decrease earlier in the life (at the end of the first decade), whereas the white matter (WM) volume starts to decrease at the fourth decade (Courchesne et al., 2000, Pfefferbaum et al., 1994).
There seems to exist, however, a large variability in the way the different brain areas are reacting to aging. These selective age-related neuroanatomical changes could be explained by several aging theories. One of them is based on brain ontogeny and phylogeny and states that the age-related changes of the various cerebral regions follow a time pattern that is the reverse sequence of their maturation during development (Braak et al., 1999, Raz et al., 1997). According to this model, late maturating unimodal or high-order heteromodal associative cortices are the first and the most age-sensitive, while early maturating primary areas are subject to later and smaller age-related changes. In agreement with this model, several studies have specifically focused on associative cortices and have shown a preferential atrophy of the regions belonging to the prefrontal cortex (Coffey et al., 1992, Jernigan et al., 2001, Salat et al., 2001). Other studies have reported focal atrophy localized into the temporal lobe (Bigler et al., 2002) including the hippocampus (Raz et al., 2004b, Tisserand et al., 2000). However, other aging hypotheses based on the dysfunction of the principal neurotransmitter systems could also explain the affliction of these cerebral regions in healthy elderly subjects. Indeed, the age-related decline of dopaminergic (Volkow et al., 2000) and cholinergic (Podruchny et al., 2003) systems, which project on the frontal and limbic structures, respectively, could be associated to this cerebral pattern of atrophy.
Meanwhile, using whole brain exploratory approaches, several other studies were aimed at identifying other potential targets of normal aging. These studies have found an age-related atrophy of associative cortices but, more surprisingly, an implication of several primary cortices normally considered as spared by aging (Good et al., 2001, Sowell et al., 2003, Van Laere and Dierckx, 2001). For example, Salat et al. (2004) found that regional cortical thinning with age (which has been found highly correlated with regional GM density, Narr et al., in press) is widespread over large parts of the cortex including motor, auditory, and visual primary areas, as well as association cortices such as the inferior lateral prefrontal cortex. Interestingly, a few recent studies have specifically focused on the seventh and subsequent decades, a period of life where maturation processes no longer interfere with aging, and have reported a similar pattern of regional age-related atrophy (Resnick et al., 2003, Tisserand et al., 2004).
Beside age, sex is another major player of the inter-individual brain morphology variability and several studies have been interested in the potential impact of sex on age-related brain changes. As a rule, these studies concluded that men exhibited larger age-related brain atrophy and CSF increase than women over the entire life span (Coffey et al., 1998, Gur et al., 1999, Yue et al., 1997), this effect being enhanced in the frontal and temporal lobes (Gur et al., 2002, Murphy et al., 1996, Raz et al., 1997, Raz et al., 2004a). Conversely, reports of regional age-related atrophy higher in women than in men are rare, although larger reduction of gray matter in women have been reported in the visual cortex (Raz et al., 1993), the parietal lobes and the hippocampus (Murphy et al., 1996).
Actually, as the majority of these studies were based on large age range cohorts, little is actually known about the effect of sex on age-related changes in brain structure of healthy elderly subjects. In the present study, we have investigated this issue by taking advantage of a large epidemiology study dealing with vascular aging for which a large cohort of subjects in their seventh or eighth decades were recruited and examined with MRI.
Section snippets
Subjects
The sample of subjects who participated to the present protocol is a sub-sample of the EVA (Epidemiology of Vascular Aging) cohort (n = 1389), a longitudinal study on vascular aging and cognitive decline in healthy elderly subjects, the characteristics of which have been described elsewhere (Dufouil et al., 2001). Subjects, born between 1922 and 1932, were recruited from electoral rolls in Nantes (West of France) from June 1991 to June 1993. All participants gave their written informed consent
A brain atlas for healthy elderly
Fig. 2 shows selected slices through the average T1 volume, and the GM, WM, and CSF probability maps computed over the sample of 662 subjects. Such maps constitute a probabilistic brain atlas in healthy elderly human subjects aged between 63 and 75 years. GM and WM atrophy, and CSF enlargement, are the most prominent features of these maps when compared with their counterparts in young healthy adults. As such maps could be of value for others working with anatomical/functional brain images of
Enhanced CSF compartment using multi-spectral segmentation in the elderly
Including T2 images in the tissue segmentation procedure resulted in a better characterization of the outer border of the CSF compartment and a more realistic CSF probability values in the ventricles and major sulci. This was expected since T2 images exhibit a good contrast between the subarachnoidal CSF and the dura mater adhering to the inner skull surface. However, the larger slice thickness of the original T2 images (5 mm) as compared to the original T1 images (1.4 mm) induced an important
Conclusion
Modifications of brain anatomy in the seventh and eighth decades appear to be characterized by (1) a shrinkage due to approximate equal loss of gray and white matter, (2) an inhomogeneous cortical pattern of atrophy rates, larger rates being observed in primary cortices as well as in associative and limbic areas. These modifications seem to be sex independent.
Acknowledgments
This study has been conducted within the framework of the ICBM project (http://www.loni.ucla.edu/ICBM/). The authors are grateful to N. Tzourio-Mazoyer for her thoughtful comments on the manuscript. H. Lemaître and B. Grassiot are supported by grants from the Commissariat à l'Energie Atomique and the Basse-Normandie Regional Council.
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