Patients with early-onset Alzheimer's disease (EOAD) are reported to be different from those with late-onset Alzheimer's disease (LOAD) in terms of neuropsychological and neuroimaging findings. In this study, we aimed to compare the longitudinal volume changes of 6 subcortical structures (the amygdala, hippocampus, thalamus, putamen, globus pallidus, and caudate nucleus) between patients with EOAD and LOAD for 3 years. We prospectively recruited 36 patients with probable Alzheimer's disease (14 EOAD, 22 LOAD) and 14 normal control subjects. We analyzed the volume of subcortical structures using an automatic surface-based method. At baseline, there were no differences in the volumes of subcortical structures between patients with EOAD and LOAD. However, over 3 years of longitudinal follow-up, patients with EOAD showed more rapid volumetric decline in the caudate, putamen, and thalamus than patients with LOAD, which is consistent with neuropsychological results. Our findings suggested that the cognitive reserve theory might be applicable to explain different decline rates of the volumes of the basal ganglia and thalamus according to onset age.
Alzheimer's disease (AD) is the most common cause of degenerative dementia. In typical cases, AD changes initially affect memory, then language and visuospatial, and frontal functions as AD progresses. However, there might be some differences in the clinical manifestations between patients with early-onset AD (EOAD) and late-onset AD (LOAD) (Koedam et al., 2010; Mendez et al., 2012; van der Flier et al., 2011). Patients with EOAD tend to display more diverse cognitive impairments and neurological deficits than those with LOAD, such as language, visuospatial, and executive dysfunctions (Chui et al., 1985; Fujimori et al., 1998; Mendez et al., 2012; Ossenkoppele et al., 2012; Seltzer and Sherwin, 1983; Smits et al., 2012), and extrapyramidal signs (Chui et al., 1985), whereas patients with LOAD present cognitive impairment of the amnesia-predominant type (Binetti et al., 1993; Mendez et al., 2012; Ossenkoppele et al., 2012; Smits et al., 2012).
In line with these clinical differences, cross-sectional neuroimaging studies have also shown greater cortical atrophy, particularly in the lateral parietal and precuneus in patients with EOAD than in those with LOAD, whereas more medial temporal lesions have been documented in patients with LOAD than in those with EOAD (Frisoni et al., 2005, 2007; Ishii et al., 2005). Although recent studies of subcortical structural volume differences have been reported in AD patients (de Jong et al., 2008; Pievani et al., 2012; Roh et al., 2011), of these, only 1 study compared EOAD with LOAD in terms of volume and shape of subcortical structures (Pievani et al., 2012). The authors suggested that the presence of significant differences in shape changes in the caudate nucleus between patients with EOAD and young controls. These findings were consistent with previous studies showing that patients with EOAD had more extrapyramidal signs and frontal dysfunction than patients with LOAD (Chui et al., 1985; Frisoni et al., 2007; Kim et al., 2005). Volumes of the basal ganglia and thalamus are the main structures of the frontal-subcortical circuits, which are responsible for frontal dysfunction. To our knowledge, however, there has not been any longitudinal study comparing volume changes in subcortical structures between patients with EOAD and LOAD.
Longitudinal studies on EOAD versus LOAD were available for cognitive decline, total brain volumes, and cortical thinning (Chan et al., 2003; Cho et al., 2012a; Jacobs et al., 1994; Koss et al., 1996; Seltzer and Sherwin, 1983) and showed that patients with EOAD progress more rapidly in terms of cognition and brain atrophy. Previous studies suggested that more rapid progression in EOAD than in LOAD might be in accord with the cognitive reserve theory. More specifically, younger patients have more cognitive reserve than older patients such that younger patients are better at coping with brain damage by effectively recruiting pre-existing cognitive networks or by enlisting compensatory strategies (Katzman et al., 1988; Stern, 2002). Therefore, more widespread atrophy in the brain should have occurred for patients with EOAD to have the same level of cognitive impairment as in LOAD. However, when AD starts to progress, it progresses more rapidly in patients with EOAD than LOAD, because AD pathology in EOAD is already more severe so that there is generally less brain substrate left to function properly. This cognitive reserve theory can also be applied to the decline rate of subcortical structures according to onset age. Specifically, it is possible that patients with EOAD might show more rapid decline in the volume of subcortical structures than patients with LOAD. In contrast, regarding the volume of the hippocampus, because patients with LOAD display more severe memory impairment and hippocampal atrophy than patients with EOAD (Binetti et al., 1993; Frisoni et al., 2007), hippocampal volume reduction over time might be more rapid in patients with LOAD than in those with EOAD.
In this study, we aimed to test our hypotheses based on the Alzheimer Disease and Positron Emission Tomography (ADAPET) cohort, which is a 5-year longitudinal study. At the 3-year follow-up, we hypothesized that patients with EOAD will have progressed more rapidly than patients with LOAD in terms of volume changes in the basal ganglia and thalamus, along with more rapid decline of frontal function. Likewise, patients with LOAD might undergo more rapid volume reduction of the amygdala and hippocampus along with more rapid decline of memory function than those with EOAD.
