Clinical Studies

Magnetic resonance imaging (MRI) is frequently used to document in vivo neuropathology in humans, such as stroke, multiple sclerosis and Alzheimer's disease. However, this imaging technology has also been applied to human aging studies, in both cross-sectional and longitudinal designs. The utility of repeated imaging is that each individual serves as his or her own baseline, avoiding many of the pitfalls of cross-sectional studies (secular trends). In general, these studies have concentrated on the evaluation of dual-echo or 3-dimensional scans generated by MRI sequences (SPGR, MPRAGE), which yield high-resolution images that can be used to measure total brain volume or segmented into various tissue compartments (gray, white, cerebrospinal fluid) or specific anatomical regions.

The results of these clinical studies have, in general, revealed age-related declines in overall brain volume or gray and white matter, with a concomitant increase of the volume of cerebrospinal fluid (CSF). For example, a significant trend for an age-related loss of total brain volume (and increased CSF) was observed in elderly (66-90 years) men and women, which correlated with cognitive deficits (Coffey et al., 2001). Examination of a broader age range (1-80 yrs) confirmed that the volume of gray matter decreased in the oldest adults (Courchesne et al., 2000, Good et al., 2001), while another study of men and women (20-86 years) demonstrated decreases in overall volumes of both gray and white matter with age (Ge et al., 2002). However, in a study with good representation of men and women in their 60s and 70s, white matter loss was more evident (Guttman et al., 1998). Age-related volumetric loss was also observed in sub-regions of the brain, including the hippocampus, cortical and cerebellar gray and white matter (Jernigan et al., 2001). It is also important to note that these recent studies concentrate on healthy subjects, prescreened for general health and free of neuropathology, and as such represent normative aging.

Longitudinal studies of the effects of aging on brain structure have revealed results similar to reports using a cross-sectional design. An earlier report, looking at the effect of aging on the size of the hippocampus, used repeated annual scans across almost four years in the oldest-old (>84 years) and found a progressive diminution in volume (Kaye et al., 1997). Another study examined a broad range of subject (14-77 years) and reported a longitudinal decrease in white matter and hippocampal volume in older subjects at a second timepoint of 3.5 years (Liu et al., 2003). Resnick et al. (2000) reported a cross-sectional difference in brain volume utilizing subjects (59-85 years) from the Baltimore Longitudinal Study, in which after one year, the subjects experienced a further increase in CSF volume. A follow-up study four years after baseline also revealed a significant loss of both gray and white matter with an increase in the volume of CSF (Resnick et al., 2003).

MRI has also more recently been utilized to examine the underlying chemical nature of modifications in the white matter as a function of age (Bartzokis et al., 2004, Davatzikos et al., 2002). Similarly, documentation of age-related volumetric losses in brain sub-regions has provided a functional-anatomical basis for behavioral changes, including the cortex (Bartzokis et al., 2004; Covit et al., 2001)], and striatum (Raz et al., 2003). Clinical data have also shown age by sex differences in brain volume (Raz et al., 2004a), with hormone replacement having a significant protective effect on the maintenance of cortical volume (Raz et al., 2004b). Thus, clinical MR imaging studies of normative brain aging have revealed volumetric and neurochemical changes that are related to behavioral and physiological manifestations of senescence.

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