Cingulate island sign temporally changes in dementia with Lewy bodies

Abstract

The cingulate island sign (CIS) that reflects sparing of the posterior cingulate cortex (PCC) relative to the precuneus plus cuneus on FDG-PET and brain perfusion SPECT, has been proposed as a feature of dementia with Lewy bodies (DLB). As the CIS is influenced by concomitant Alzheimer's disease (AD)-type neurofibrillary tangle (NFT) pathology, we postulated that the CIS gradually disappears as DLB progresses. To determine temporal changes in the CIS, 24 patients with mild DLB and 7 with prodromal DLB underwent ¹²³I-IMP-SPECT and MMSE twice at an interval of two years. The CIS was evaluated as a ratio that was derived by dividing IMP accumulation in the PCC with that in the precuneus plus cuneus. We found that the CIS changed over time and that the relationship between CIS ratios and MMSE scores was inverted U-shaped. Thus, the CIS was most obvious in the vicinity of an MMSE score of 22 and it gradually diminished as the MMSE score decreased. Moreover, a lower CIS ratio in mild DLB was associated with a worse prognosis for cognitive decline, presumably due to concomitant AD-type NFT pathology. Our findings would provide a foundation for the appropriate usage of CIS as a biomarker.

Figure 1

Temporal changes in CIS ratios in 3D brain perfusion images from 4 patients. Values below each brain image are CIS ratios. (a) Male patient with mild DLB aged 75 years with higher initial CIS ratio. The 2nd SPECT evaluation shows that CIS has become unclear, but CIS ratio remains over 1.00. MMSE scores at 1st and 2nd SPECT were 22 and 19, respectively. (b) Male patient with mild DLB aged 74 years with higher initial CIS ratio that became unclear two years later, although it remained over 1.00. MMSE scores at 1st and 2nd SPECT were 22 and 20, respectively. (c) Male patient with mild DLB aged 78 years with lower 1st CIS ratio. MMSE scores at 1st and 2nd SPECT were 23 and 18, respectively. (d) Female patient aged 76 years with prodromal DLB. At 1st SPECT, CIS was unclear but became obvious at 2nd SPECT. MMSE scores at 1st and 2nd SPECT were 25 and 21, respectively.

Figure 2

Changes in CIS ratio between 1st and 2nd SPECT assessment. The CIS ratios significantly decreased in patients with mild DLB during two years of follow-up (blue; paired t-test: t = 6.525, df = 23, p < 0.001), but significantly increased among seven patients with prodromal DLB (green; paired t-test: t = −3.625, df = 6, p = 0.011).

Figure 3

Changes in MMSE scores and MTL atrophy in mild DLB. (a) Changes in MMSE scores. During two years of follow-up, MMSE scores decreased more in group with lower, than higher initial CIS ratio. The repeated measures ANCOVA with age and years of education as potential confounding covariates confirmed a significant group effect [F (1, 20) = 5.601, p = 0.028]. (b) Changes in MTL atrophy. The repeated measures ANCOVA with age and years of education as potential confounding covariates revealed the group effect on change in MTL atrophy [F (1, 20) = 14.439, p = 0.001]. Thus, MTL atrophy in the group with lower CIS ratio progressed more than that with higher CIS ratio during two-year follow-up.

Figure 4

Decrease in rCBF during two years in mild DLB with higher and lower initial CIS ratios. Brain regions in which rCBF decreased during two years in mild DLB patients were analyzed with SPM12 (a) mild DLB patients with higher initial CIS ratios; (b) those with lower initial CIS ratios (p = 0.001, uncorrected). The rCBF decrease in PCC was more evident in mild DLB patients with lower initial CIS ratios than in those with higher CIS ratios. It was proved by ROI analysis with repeated measures ANCOVA with age and years of education as potential confounding covariates [F (1, 20) = 8.068, p = 0.01].

Figure 5

Inverted U-shaped relationship between MMSE scores and CIS ratios at 1st and 2nd SPECT evaluations. The regression curve estimated by Curve Fitting Toolbox on MATLAB showed an inverted U-shaped relationship between the CIS ratio and MMSE. The CIS ratio peaked at an MMSE score of 22.1 on the estimated curve (solid line) [f(x) = 1.006 + 0.1133cos(0.3293x) + 0.1748sin(0.3293x): R ² = 0.5333, DFE = 58, adjusted R ² = 0.5091]. The upper and lower broken lines represent 95% prediction bounds.

Figure 6

MMSE scores and rCBFratio in PpC and PCC. The estimated curve for PCC (green) is [f(x) = −0.7978 − 2.026 × 10⁷(1 − cos(−1.696 × 10⁻⁵x)) − 9205 sin(−1.696 × 10⁻⁵x): R ² = 0.5963, DFE = 58, adjusted R ² = 0.5754]. The curve for PpC (blue) is [f(x) = 1.4323 + 2.867 × 10⁶(1 − cos(3.897 × 10⁻⁵x)) − 1670sin(3.897 × 10⁻⁵x): R ² = 0.3920, DFE = 58, adjusted R ² = 0.3605]. Curves for PpC and PCC start to decrease early and later, respectively, during DLB progression. Note that PCC curve is convex upward and PpC curve is convex downward.