18 F-AV-1451 PET Imaging in Three Patients with Probable Cerebral Amyloid Angiopathy

INTRODUCTION

Cerebral amyloid angiopathy (CAA) is a condition in which amyloid-β protein accumulates in the walls of small cortical and leptomeningeal arterioles and arteries [1]. Although definite CAA must be confirmed pathologically, the Boston clinical radiological criteria allow the diagnosis of CAA non-invasively with high specificity and sensitivity in patients with intracerebral hemorrhage [2]. Strictly lobar cerebral microbleeds (CMBs) or cortical superficial siderosis (cSS) are also radiologic markers of CAA [3, 4]. Previous studies showed that cerebrovascular amyloid can be detected by amyloid imaging studies using ¹¹C-Pittsburgh Compound B (PiB)-PET [5, 6].

Recent advances in in vivo tau imaging have led to a new era in neurodegenerative disease research. ¹⁸F-AV-1451 binds to paired helical filament tau, and has provided valuable data on the distribution of tau in Alzheimer’s disease [7, 8]. However, the relationship between lobar CMB and cSS with tau in CAA patients has not been defined. Previous reports suggest that abnormally phosphorylated tau is more abundant around amyloid-β laden arteries than blood vessels without amyloid-β [9–11]. We tested the hypothesis that CAA patients would have greater tau deposition in regions of lobar CMB and cSS using brain MRI, ¹⁸F-AV-1451-PET, and PiB-PET.

METHODS

RESULTS

In all three patients, the regions with CMBs or cSS largely overlapped with regions that showed increased ¹⁸F-AV-1451 uptake. The first case had multiple CMBs in the left parietal and temporal areas, which largely overlapped with ¹⁸F-AV-1451 uptake (Fig. 1). Florbetaben PET was positive as the BAPL score was 2 by visual assessment. The second case showed asymmetric multiple CMBs in the left temporal area, corresponding to the area of high PiB uptake. Asymmetric high ¹⁸F-AV-1451 uptake was observed in the inferior temporal area, parallel to the area of CMB or cSS identified by T2* weighted images (Fig. 1). The third case showed asymmetric CMB or cSS in the right parietal, occipital, and temporal areas, also co-localizing with high PiB uptake. Although high ¹⁸F-AV-1451 uptake was observed in the bilateral parietal, occipital, and temporal areas, there was preferential uptake on the right side, where CMBs or cSS were identified. More detailed images of each patient are shown in Supplementary Figures 1–3.

Quantitative analyses showed that lobes with CMB or cSS had higher regional AV1451 uptake compared to lobes on the other hemisphere of CMB or cSS (Fig. 2A). However, in this small case series, the relationship between CMB or cSS and PiB SUVR (Fig. 2B) or between the hemispheric ratios between regional PiB SUVR and regional AV1451 SUVR were not significant (Fig. 2C).

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Fig.1

Amyloid PET, tau PET, and T2* MR images of probable CAA patients. PiB, Pittsburgh compound B; CAA, cerebral amyloid angiopathy; SUVR, standardized uptake value ratio.

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Fig.2

Relationships between CMB or cSS and AV1451 SUVR (A), CMB or cSS and PiB SUVR (B), and PiB SUVR and AV1451 SUVR (C). ^*SUVR ratio, SUVR of each lobe with CMB or cSS / SUVR of each lobe on the other hemisphere.

DISCUSSION

We report the imaging findings of three patients with multiple lobar CMBs or cSS, indicating probable CAA: One patient had left hemispheric dominant distribution of CMBs, while the other two patients had a posterior distribution of CMBs. We found that lobes with CMB or cSS had higher regional AV1451 uptake compared to lobes on the other hemisphere of CMB or cSS. Our preliminary study raised the possibility that lobar CMB and cSS, which are characteristic markers of vascular amyloid, may be associated with increased AV1451 uptake which represents paired helical filament tau.

Our suggestion that CAA is associated with tau can be explained by several aspects. First, this association is in line with previous pathology studies [9–11, 19]. Immunohistochemical studies have shown that tau immunopositive neurites cluster around cortical arteries that are affected by amyloid angiopathy [9, 10], suggesting that peri-vascular accumulation of hyperphosphorylated tau may result from elevated levels of soluble amyloid-β_1 - 40 around cortical arteries and arterioles [9]. Our hypothesis that lobar CMB or cSS (indicating CAA) are related to local accumulation or production of tau is supported by a CSF biomarker study showing that patients with clinically probable CAA had higher total-tau and phosphorylated-tau compared to controls [20]. However, a recent in vitro study found no autoradiographic binding of ¹⁸F-AV-1451 in CAA or cSS lesions containing hemosiderin deposits [21]. We suspect that this discrepancy might be related to differences in binding conditions (in vivo versus in vitro autoradiographic binding). Second, as previous reports have suggested that the integrity of the blood-brain barrier is disrupted in CAA patients [22], the high ¹⁸F-AV-1451 uptake around CMB or cSS might be due to the leakage of ligands through the disrupted blood-brain barrier. Third, it is possible that these patients may also have combined Alzheimer’s disease as the patients were all cognitively impaired and were amyloid PET positive [23]. One might argue that, as tau pathology in Alzheimer’s disease and CAA both predominates posteriorly, the topographical correlation between ¹⁸F-AV-1451 uptake and CMB or cSS may reflect a mere coincidence rather than direct relationship. However, our quantitative analysis showed that AV1451 uptake was asymmetrically increased on the side where there was more CMB or cSS, which is not a common distribution of AV1451 uptake in Alzheimer’s disease. Finally, tau may exist in relation to rapidly progressive neurodegeneration, eventually resulting in axonal degeneration, rather than being specifically related to CAA [24].

We found that the distribution of PiB uptake in Cases 2 and 3 largely overlapped with CMBs or cSS in posterior brain regions. However, in the quantitative analysis CMB or cSS did not show significant relationship with regional PiB SUVR. It is possible that underlying Alzheimer’s disease pathology such as neuritic plaques might have overshadowed the effects of CAA on amyloid PET. In addition, the low statistical power might be due to the small sample size. In contrast, there was no increase in ¹⁸F-florbetaben uptake in the left hemisphere in Case 1, where there were many CMBs. Therefore, we cannot exclude the possibility that, despite meeting criteria for probable CAA, CMB or cSS are due to other pathologies such as vasculitis, subclinical trauma, or frontotemporal lobar degeneration. Alternatively, low ¹⁸F-florbetaben uptake could be due to the use of different amyloid tracers. Further amyloid PET imaging studies in a larger sample size using different amyloid tracers are needed.

Our study has several limitations. First, we did not have pathological confirmation of CAA in the three patients. Second, the use of different amyloid tracers might have affected the relationships between tau or CMB with amyloid. Third, the overlapping regions between CMB or cSS and ¹⁸F-AV-1451 uptake were based on visual assessment or crude correlation within each lobe. Lastly, since our patients were all cognitively impaired and might as well have Alzheimer’s disease, our findings have limited generalizability and one should be cautious when interpreting our data. To address the direct relationship between tau and CMB or cSS, studies on cognitively normal individuals with probable CAA are necessary to minimize the possibility of having Alzheimer’s disease. Further studies with a larger sample size would allow quantitative analysis to confirm our findings. Nevertheless, our findings raised the possibility that lobar CMB or cSS, which are characteristic markers of vascular amyloid, may be associated with local production of paired helical filament tau.