Article Figures & Data
Figures
- Figure 1.
Serial in vivo imaging reveals progression of CAA on individual segments of leptomeningeal vessels and clearance after treatment with anti-Aβ antibody. Using multiphoton microscopy of individual segments, CAA-laden leptomeningeal vessels were visualized through cranial windows on day 0 (A1, B1), day 7 (A2, B2), and day 14 (A3, B3) after a single subdural antibody application of 16B5 (A1–A3) or 10D5 (B1–B3) antibodies. Z-stack images were taken as described previously, with Aβ deposits identified by fluorescence from systemically administered Methoxy-XO4 (gray pseudocolor). A1–A3, In 16B5-treated animals, an increase on CAA burden is observed through the three imaging sessions. B1–B3, In contrast, serial imaging of a 10D5-treated mouse revealed a modest reduction on CAA burden on day 7, with subsequent increase in vessel Aβ deposition by day 14 (B3); two areas of CAA showing these changes are indicated by arrows. C1, Amyloid deposits in a representative vessel from an animal treated with 10D5 are color-coded for changes in Aβ deposition at each time point and overlaid into a single image. C2, Deposits of CAA that were cleared between days 0 and 7. C3, Deposits of CAA that were unaltered during the same time interval. C4, Deposits of CAA that appeared during this interval (progression).
- Figure 2.
Single exposure to anti-Aβ antibody treatment decreases the progression of CAA. Measurements of CAA burden as percentage of available vessel area are plotted as a function of age in days, with treatment initiated at the time of the first data point for each animal. The variation in absolute CAA burden as a function of animal age and vessel segment involvement at that age account for the variation in position along the axes; the mixed-effects linear regression model compensates for this biological variation (Robbins et al., 2006). A, Animals treated with a single dose of 16B5 (n = 16 vessel segments from 3 mice) show progression of CAA burden over time, independent of the absolute level of disease at the time of the first observation. B, Mice treated with a single dose of 10D5 (n = 19 vessel segments from 4 mice) show overall clearance of Aβ at the second time point (day 7) but progression of disease during the interval from days 7 to 14.
- Figure 3.
Representative images of ThioS-positive plaque clearance after single topical application of anti-Aβ antibody. Images of a half-hemisphere of a brain of a mouse treated with 10D5 (left) and a mouse treated with 16B5 (right) are shown. The area of the cranial window is indicated by the yellow circle. Thio-S-positive plaques are shown in red.
- Figure 4.
Pattern of CAA clearance after single exposure to anti-Aβ antibody. The average change in the length of gaps (areas free of CAA) between deposits of Aβ measured at days 7 and 14 after single exposure to either 10D5 (black bars) or a 16B5 (white bars) is shown. A positive result indicates an increase in gap size, which corresponds to clearance of CAA. There was an increase in gap size only during the first week of treatment with anti-Aβ antibody (n = 29 gaps from 4 mice). The decrease in gap size during the subsequent week and during both weeks after treatment with control antibody 16B5 (n = 22 gaps from 3 mice) reflects the increase of CAA burden through propagation of deposits, as previously shown (Robbins et al., 2006). Error bars represent mean ± SD.
- Figure 5.
Chronic exposure to anti-Aβ antibody results in greater clearance of CAA. Measurements of CAA burden are plotted as in Figure 2. A, Animals treated with continuous infusion of 16B5 (n = 12 vessel segments from 4 mice) show progression of CAA burden over time, independent of the absolute level of disease at the time of the first observation. B, Mice treated with continuous infusion of 10D5 (n = 36 vessel segments from 8 mice) show overall clearance of Aβ at both the second time point (day 7) and third (day 14) imaging sessions. Experimental animals had either three or two imaging sessions.
- Figure 6.
Serial in vivo imaging reveals greater clearance of CAA on individual segments of leptomeningeal vessels after continuous treatment with anti-Aβ antibody. Serial imaging of individual segments of CAA-laden leptomeningeal vessels was performed at day 0 (A1, B1), day 7 (A2, B2), and day 14 (A3, B3) relative to initiation of continuous delivery of 16B5 (A1–A3) or 10D5 (B1–B3) antibodies by an osmotic pump. Z-stack images were taken as described previously, with Aβ deposits identified by fluorescence from systemically administered Methoxy-XO4 (red pseudocolor). Angiograms were performed to identify fiduciary markers (blue pseudocolor). A1–A3, In 16B5-treated animals, an increase on CAA burden is observed through the three imaging sessions. B1–B3, In contrast, serial imaging of a 10D5-treated mouse revealed a significant reduction on CAA burden on day 7, which persisted through day 14 (B3). Scale bar, 100 μm.
Tables
- Table 1.
Clearance of dense-core amyloid-β deposits after single topical application of anti-Aβ antibody
Treatment 16B5 10D5 p Plaque burden inside window 6.0 (3.2–11.2)a 3.2 (1.7–5.7)a <0.0001 Plaque burden outside window 6.5 (1.7–5.7)a 8.5 (5.0–14.3)a NS -
Plaque burden indicates the mean number of ThioS-positive plaques inside and outside the window calculated for each group under study.
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↵a95% confidence interval.
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16B5 10D5 p Single dose Slope (days 0–7) 0.5 ± 0.20 −0.49 ± 0.15 <0.0001 Slope (days 7–14) 0.34 ± 0.20 0.84 ± 0.10 0.028 Continued dose Slope (days 0–7) 0.35 ± 0.17 −0.6 ± 0.10 <0.0001 Slope (days 7–14) 0.6 ± 0.13 −0.23 ± 0.13 <0.0001 -
The rate of progression of CAA as measured by the slope of the line determined by a mixed-effects linear regression model of quantitative measures obtained from in vivo imaging sessions after single or continued subdural antibody application of 16B5 or 10D5 antibodies is shown. Values are expressed as mean ± SE. Negative slopes (shown in italics) reflect clearance of CAA burden, whereas positive slopes reflect progression of disease.
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