Abstract
The increased understanding that neuropathology begins decades before symptom onset, has led to the conceptualization and widespread utilization of Mild Cognitive Impairment (MCI) as an important transitional state between healthy aging and dementia. Further subcategorization to MCI subtype has led to more distinct prognoses and it is widely considered that amnestic and non-amnestic MCI (aMCI, naMCI) likely have distinct pathophysiologies. Yet, accurately classification remains contentious. Here, we differentiate hippocampal subfield volume between subtypes, diagnosed according to stringent clinical consensus criteria, where aMCI is characterized based on deficits in delayed recall (rather than encoding). We then identify memory performance correlates to subfield volume and associations with long-term cognitive performance and outcome. 3D T1-weighted structural MRI was acquired in 142 participants recruited from the Healthy Brain Aging (HBA) Clinic and diagnosed with aMCI (n = 38), naMCI (n = 84) or subjective memory complaints (SMC; n = 20). T1-weighted datasets were processed with the cortical and hippocampal subfield processing streams in FreeSurfer (v6.0). Subfield volumes, and associations with baseline and longitudinal objective memory scores were then examined. Subfield volumes were found to differentiate clinical profiles: subiculum, CA1, CA4 and dentate gyrus volumes were significantly reduced in aMCI compared to both naMCI and SMC. CA1 subfield volume was shown to predict concurrent memory performance in aMCI, while dentate gyrus volume significantly predicted longitudinal verbal learning and memory decline in the entire cohort. Our findings demonstrate that using a more stringent diagnostic approach to characterizing aMCI is well justified, as delayed recall deficits are strongly linked to underlying volumetric subfield reductions in CA1, CA4 and the dentate gyrus, subfields known to be associated with mnemonic processes. Further research is now warranted to replicate these findings in other MCI samples.
Highlights
Mild Cognitive Impairment (MCI), the transitional state between normal aging and dementia, is an important diagnostic entity in both clinical and research settings
This study provides further insight into the distinct structural and hippocampal pathophysiologies that likely underpin memory decline in subjective memory complaints (SMC) and MCI subgroups
Our work extends these previous findings, indicating that focusing on the delayed recall characteristics of memory decline for defining MCI subtypes is not merely theoretical, but is supported by key neuroanatomical differences in subiculum and dentate gyrus subfields. These subfields are heavily implicated in mnemonic consolidation processes (O’Mara et al, 2000) and localized atrophy of these subfields are associated with risk of progression from MCI to Alzheimer’s Disease (AD) (Apostolova et al, 2006, 2010)
Summary
Mild Cognitive Impairment (MCI), the transitional state between normal aging and dementia, is an important diagnostic entity in both clinical and research settings. Further subcategorization into the clinical phenotypes of amnestic and non-amnestic MCI (aMCI and naMCI) (i.e., depending on whether impairment is evident in memory or non-memory cognitive domains, respectively) has shown that aMCI is associated with the most pronounced risk of conversion to AD; approximately 50% within 5 years (Gauthier et al, 2006; Petersen et al, 2009). To enable the most appropriate clinical feedback for patients ( where modifiable risk factors play a role), accurate characterization of the clinical subtyping of MCI and accompanying neurodegeneration is important (Hughes et al, 2011; Norton et al, 2014) Another pertinent cohort when investigating cognition in aging are those that present with subjective memory complaints (SMC) but who do not demonstrate objective impairment on testing. They are health seeking and as such make an appropriate control group when investigating disease progression in clinic-based settings
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