The relationship between cerebrovascular disease, cognition and amyloid-beta (Aβ) deposition as occurs in Alzheimer’s Disease (AD) and related disorders has been a topic of much debate and research. Cardiovascular risk factors such as hypertension and diabetes independently increase the risk of vascular cognitive impairment (VCI) and AD, and histopathologic analysis shows considerable overlap between the pathologic features of the two conditions. Despite this, studies in human subjects that attempt to establish a causal relationship between ischemia and Aβ deposition have been mostly negative. Sahathevan et al. sought to investigate the relationship between ischemia and Aβ deposition both in the acute setting and over time. In a single-center cohort of patients with acute ischemic stroke, they quantitatively assessed Aβ using amyloid PET imaging (11C-PiB-PET) around the time of their event and again several months later.
Forty-eight patients who presented with a first-ever acute ischemic stroke were scanned within 40 days of the event with 11C-PiB-PET and MRI for anatomic co-registration. Patients with previous intracerebral hemorrhage, head trauma, brain surgery, brain tumor and known neurodegenerative disorders were excluded. Baseline data included demographics, vascular risk factor profiles, stroke topography and the presence or absence of hemorrhagic transformation, white matter lesions and carotid stenosis. Standard uptake value ratios (SUVR) on amyloid PET imaging were generated for the infarct and peri-infarct regions and compared to a mirrored reference region in the contralesional hemisphere. Ipsilesional and contralesional hemisphere SUVR values were also generated. A cut-off of SUVR=1.40 was used to identify high versus low uptake based on prior studies by the authors. Assessment of hemorrhagic transformation on MRI (which was found to be correlated to increased SUVR in a previous study by the authors) was performed for inclusion as a confounding variable. The presence of white matter lesions based on Fazekas scores and presence of carotid disease were used as surrogate markers to investigate the potential effect of chronic ischemia as another confounding variable.
Of the initial 48 patients, 27 did not return for repeat scans due to medical or other reasons. Baseline demographics were not significantly different between those who did and did not have a second amyloid PET scan, except that a higher percentage of patients with hypertension declined to return. The median time to second scan was 222 days.
The SUVR of the infarct areas were >1.4 in 57.9% patients at baseline, compared to 51.1% in the reference region. The median difference (0.07) was not significant (p=0.452). The median difference in SUVR of the infarct zone at time of follow-up imaging was -0.08 (p=0.04), suggesting a significant decrease over time. Similarly, nonsignificantly higher values in the affected region coupled with a statistically significant decrease on follow-up imaging were found in the peri-infarct zone as well as the stroke-specific hemisphere. There was no effect of hemorrhagic transformation or carotid disease. The presence of periventricular WML did affect the decrease in hemisphere-specific SUVR on follow-up imaging (p=0.03), but this effect was not found in the infarct or peri-infarct regions. Deep WML did not affect any of the studied regions.
This study provides valuable insights into the complex pathology behind Aβ deposition in the brain despite the high attrition rate, low number of patients, and variation in time between scans. The authors’ hypothesis of reactive Aβ deposition based on their prior work with a smaller group of subjects was not supported, and the significant reduction in 11C-PiB-PET accumulation over time across all studied regions suggests the increased uptake around the time of the ischemic event is due to a transient increase in blood brain barrier permeability that occurs following an acute stroke. Further study with larger cohorts and standardized, serial PET imaging would likely provide more clarity in this regard.
The lack of association with carotid stenosis contrasts with a smaller previous study of demented patients with unilateral carotid stenosis that showed increased uptake in the hemisphere distal to the stenosis. That observation is of particular interest as it suggests that ischemia and cerebrovascular disease may play a modulating role in Aβ pathology that is more pronounced in demented patients who likely have other predisposing factors towards Aβ deposition. An extended longitudinal study using amyloid PET imaging to compare the evolution of Aβ uptake over time in patients with stroke who went on to develop AD versus those who did not could be helpful, as well as examining the role of APoE allele status in a similarly designed study.
