Conversion of Mild Cognitive Impairment to Alzheimer Disease Predicted by Hippocampal Atrophy Maps

Laboratory of Neuro Imaging, Department of Neurology, The David Geffen School of Medicine at UCLA, University of California-Los Angeles, Los Angeles, CA, USA.
JAMA Neurology (Impact Factor: 7.42). 06/2006; 63(5):693-9. DOI: 10.1001/archneur.63.5.693
Source: PubMed


While most patients with mild cognitive impairment (MCI) transition to Alzheimer disease (AD), others develop non-AD dementia, remain in the MCI state, or improve.
To test the following hypotheses: smaller hippocampal volumes predict conversion of MCI to AD, whereas larger hippocampal volumes predict cognitive stability and/or improvement; and patients with MCI who convert to AD have greater atrophy in the CA1 hippocampal subfield and subiculum.
Prospective longitudinal cohort study.
University of California-Los Angeles Alzheimer's Disease Research Center.
We followed up 20 MCI subjects clinically and neuropsychologically for 3 years.
Baseline regional hippocampal atrophy was analyzed with region-of-interest and 3-dimensional hippocampal mapping techniques.
During the 3-year study, 6 patients developed AD (MCI-c), 7 remained stable (MCI-nc), and 7 improved (MCI-i). Patients with MCI-c had 9% smaller left and 13% smaller right mean hippocampal volumes compared with MCI-nc patients. Radial atrophy maps showed greater atrophy of the CA1 subregion in MCI-c. Patients with MCI-c had significantly smaller hippocampi than MCI-i patients (left, 24%; right, 27%). Volumetric analyses showed a trend for greater hippocampal atrophy in MCI-nc relative to MCI-i patients (eg, 16% volume loss). After permutation tests corrected for multiple comparison, the atrophy maps showed a significant difference on the right. Subicular differences were seen between MCI-c and MCI-i patients, and MCI-nc and MCI-i patients. Multiple linear regression analysis confirmed the group effect to be highly significant and independent of age, hemisphere, and Mini-Mental State Examination scores at baseline.
Smaller hippocampi and specifically CA1 and subicular involvement are associated with increased risk for conversion from MCI to AD. Patients with MCI-i tend to have larger hippocampal volumes and relative preservation of both the subiculum and CA1.

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    • "Since our results were controlled for age, it is unlikely that the involvement of the subiculum reflects normal aging processes, but it might reflect other etiologies than AD in SCD even more than in MCI. Previous studies using other methodological approaches frequently reported atrophy within both CA1 and the subiculum in very mild AD (CDR = 0.5) [16], in MCI [20] and in SCD [22] compared to controls, as well as in MCI patients who later converted to AD compared to the non converter MCI [20]. Similarly, both CA1 and subiculum atrophy was found in cognitively normal individuals who declined to MCI within 3 years [21]. "
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    ABSTRACT: Background: Subjective cognitive decline (SCD) may be the first clinical sign of Alzheimer's disease (AD). SCD individuals with normal cognition may already have significant hippocampal atrophy, a well-known feature of AD. Objective: To test the hypothesis that SCD, compared to healthy individuals without SCD, have a pattern of hippocampal subfield atrophy similar to that measured in the AD pathology. Methods: 17 SCD, 21 AD, and 40 matched controls underwent a standard T1-weighted MRI and a dedicated high-resolution MRI proton-density hippocampal sequence. For each participant, three hippocampal regions-of-interest were manually delineated on the proton-density hippocampal sequence corresponding to the CA1, subiculum, and other (including CA2-3-4 and dentate gyrus) subfields. Total intracranial volume (TIV)-normalized subfield volumes were compared between-group. Voxelwise group comparisons assessed from the standard T1 MRI were also projected on 3D hippocampal surface views. Results: Both patient groups showed significant TIV-normalized volume decrease in hippocampus global volume and in CA1 and subiculum subfields as well as in the other subfield in AD compared to controls. Significant differences were observed between SCD and AD in hippocampus global TIV-normalized volume. Atrophy maps on hippocampal surface showed major involvement of the lateral part (CA1) in both SCD and AD, with larger overlap of other regions in AD. Conclusion: The findings indicate topographically similar hippocampal subfield changes in SCD individuals as those found in AD. This further highlights the relevance of SCD recruited from a memory clinic in assessing predementia AD stages.
    Journal of Alzheimer's disease: JAD 09/2015; 48(s1). DOI:10.3233/JAD-150087 · 4.15 Impact Factor
    • "Accordingly, atrophy of the CA subfields (grouped together in a single region) seem to account for associative memory deficits observed in MCI patients (Atienza et al., 2011), and correlates with patients' inability to benefit from semantic processing while encoding new information. Looking at cognitive correlates of hippocampal radial atrophy, associations have been found between impaired delayed recall and CA1 and subiculum volumes in MCI (Apostolova et al., 2006b). In an equivalent analysis run on 490 individuals (including controls, MCI and AD patients from the Alzheimer's disease neuroimaging initiative), authors did not identify specific correlates in healthy controls, while areas corresponding to CA1 and subiculum were associated with delayed recall performances in MCI, and to a lesser extent in AD patients (Apostolova et al., 2010a). "
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    ABSTRACT: Hippocampal atrophy, as evidenced using magnetic resonance imaging (MRI), is one of the most validated, easily accessible and widely used biomarkers of Alzheimer's disease (AD). However, its imperfect sensitivity and specificity have highlighted the need to improve the analysis of MRI data. Based on neuropathological data showing a differential vulnerability of hippocampal subfields to AD processes, neuroimaging researchers have tried to capture corresponding morphological changes within the hippocampus. The present review provides an overview of the methodological developments that allow the assessment of hippocampal subfield morphology in vivo, and summarizes the results of studies looking at the effects of AD and normal aging on these structures. Most studies highlighted a focal atrophy of the CA1 subfield in the early (predementia or even preclinical) stages of AD, before atrophy becomes more widespread at the dementia stage, consistent with the pathological literature. Preliminary studies have indicated that looking at this focal atrophy pattern rather than standard whole hippocampus volumetry improves diagnostic accuracy at the Mild Cognitive Impairment (MCI) stage. However, controversies remain regarding changes in hippocampal subfield structure in normal aging and regarding correlations between specific subfield volume and memory abilities, very likely because of the strong methodological variability between studies. Overall, hippocampal subfield analysis has proven to be a promising technique in the study of AD. However, harmonization of segmentation protocols and studies on larger samples are needed to enable accurate comparisons between studies and to confirm the clinical utility of these techniques. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 08/2015; DOI:10.1016/j.neuroscience.2015.08.033 · 3.36 Impact Factor
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    • "Not only altered PSA-NCAM levels have been reported in depression, schizophrenia and neurodegenerative disorders [60], [67]–[70], but also diminished NCAM levels were evidenced in some of these pathologies and in animal models of these diseases [45]–[49], [71], [72]. Hippocampal atrophy precedes synaptic and neuronal loss in a sequence of changes that could indicate different stages in the progression of the disease [37], [38], [73]. Therefore, it could be speculated that prevention or reversion of glutamate-induced atrophy could result in a successful early intervention. "
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    ABSTRACT: Dendritic and synapse remodeling are forms of structural plasticity that play a critical role in normal hippocampal function. Neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) participate in neurite outgrowth and synapse formation and plasticity. However, it remains unclear whether they contribute to dendritic retraction and synaptic disassembly. Cultured hippocampal neurons exposed to glutamate (5 µM) showed a reduced MAP-2 (+) area in the absence of neuronal death 24 h after the insult. Concomitantly, synapse loss, revealed by decreased synaptophysin and post-synaptic density-95 cluster number and area, together with changes in NCAM and PSA-NCAM levels were found. Dendritic atrophy and PSA-NCAM reduction proved NMDA-receptor dependent. Live-imaging experiments evidenced dendritic atrophy 4 h after the insult; this effect was preceded by smaller NCAM clusters (1 h) and decreased surface and total PSA-NCAM levels (3 h). Simultaneously, total NCAM cluster number and area remained unchanged. The subsequent synapse disassembly (6 h) was accompanied by reductions in total NCAM cluster number and area. A PSA mimetic peptide prevented both the dendritic atrophy and the subsequent synaptic changes (6 h) but had no effect on the earliest synaptic remodeling (3 h). Thus, NCAM-synaptic reorganization and PSA-NCAM level decrease precede glutamate-induced dendritic atrophy, whereas the NCAM level reduction is a delayed event related to synapse loss. Consequently, distinctive stages in PSA-NCAM/NCAM balance seem to accompany glutamate-induced dendritic atrophy and synapse loss.
    PLoS ONE 10/2014; 9(10):e108921. DOI:10.1371/journal.pone.0108921 · 3.23 Impact Factor
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