Morphometric changes in the episodic memory network and tau pathologic features correlate with memory performance in patients with mild cognitive impairment

Abstract

Background and purpose: Mild cognitive impairment (MCI) may affect several cognitive domains, including attention and reasoning, but is often first characterized by memory deficits. The purpose of this study was to ask these 2 questions: 1) Can levels of CSF tau proteins and amyloid beta 42 peptide explain thinning of the cerebral cortex in patients with MCI? 2) How are brain morphometry, CSF biomarkers, and apolipoprotein E (APOE) allelic variation related to episodic memory function in MCI?

Materials and methods: Hippocampal volume and cortical thickness were estimated by MR imaging and compared for patients with MCI (n = 18) and healthy controls (n = 18). In addition, regions of interest (ROIs) were selected in areas where the MCI group had atrophy and which overlapped with the episodic memory network (temporal, entorhinal, inferior parietal, precuneus/posterior cingulate, and frontal). Relationships among morphometry, CSF biomarkers, APOE, and memory were tested. The analyses were repeated with an independent sample of patients with MCI (n = 19).

Results: Patients with MCI and pathologic CSF values had hippocampal atrophy. However, both patients with pathologic and patients with nonpathologic CSF had a thinner cortex outside the hippocampal area. CSF pathology was related to hippocampal volume, whereas relationships with cortical thickness were found mainly in one of the samples. Morphometry correlated robustly with memory performance across MCI samples, whereas less stable results were found for tau protein.

Conclusion: The differences in hippocampal volume between the MCI and the healthy control groups were only found in patients with pathologic CSF biomarkers, whereas differences in cortical thickness were also found for patients without such pathologic features. Morphometry in areas in the episodic memory network was robustly correlated with memory performance. It is speculated that atrophy in these areas may be associated with the memory problems seen in MCI.

Fig 1.

Hippocampal volume in patients with MCI versus controls. Hippocampal volume is calculated as the total volume of the right and left hippocampus and regressed on ICV. The standardized residuals are shown on the y-axis (z-scores). The patients are grouped according to whether they have pathologic (MCI pat CSF) or nonpathologic (MCI no CSF) values of tau or Aβ42. The blue-dotted lines indicate the mean value for each group. Independent samples t tests (Bonferroni corrected for multiple comparisons) showed that the patients with pathologic CSF biomarkers had significantly smaller hippocampal volume than the controls, whereas the other contrasts did not reach significance.

Fig 2.

Effects of diagnosis on cortical thickness. Points where patients with MCI have a significantly thinner cortex than normal controls are color coded as blue-green, whereas points showing the opposite pattern are coded as red-yellow. The P maps are projected onto the inflated mean brain of the total sample. From left to right is shown the right and left lateral view, and left and right medial view, respectively.

Fig 3.

Scatterplots of cortical thickness in patients versus controls. ROIs were chosen on the basis of the results from the cortical thickness comparisons. The ROIs are defined by the red lines. Mean thickness for each participant within each ROI was calculated.

Fig 4.

Distribution of P values. This figure shows the number of voxels for any given P value from the cortical comparisons illustrated in Fig 2. The left side of each chart (blue-green colors) represents a thicker cortex in healthy controls; the right side (red-yellow colors) represents a thicker cortex in the patients. As can be seen, the distribution of P values is shifted to the left, with almost no voxels to the right of the midline (indicating thicker cortex for patients). This shows clearly that the patients have a thinner cortex than the healthy controls and that it is very unlikely that this is a result of false-positives from multiple statistical comparisons.

Fig 5.

Relationships between tau pathologic features and brain morphometry. Hippocampal volume and mean thickness in left hemisphere entorhinal ROI compared across groups of pathologic (pato) versus nonpathologic (norm) T-tau or P-tau values.

Fig 6.

Relationships between cortical thickness and episodic memory. Hippocampal volume/mean thickness in left hemisphere ROIs from Fig 3 and RAVLT learning and 30 minutes delayed recall score. The y-axes depict the number of words recalled, whereas the x-axes depict thickness or ICV-corrected volume.