Assessment of Extent and Role of Tau in Subcortical Vascular Cognitive Impairment Using 18F-AV1451 Positron Emission Tomography Imaging

Abstract

Importance: Amyloid-β (Aβ), tau, and cerebral small vessel disease (CSVD), which occasionally coexist, are the most common causes of cognitive impairments in older people. However, whether tau is observed in patients with subcortical vascular cognitive impairment (SVCI), as well as its associations with Aβ and CSVD, are not yet established. More importantly, the role of tau underlying cognitive impairments in SVCI is unknown.

Objective: To investigate the extent and the role of tau in patients with SVCI using 18F-AV1451, which is a new ligand to detect neurofibrillary tangles in vivo.

Design, setting, and participants: This cross-sectional study recruited 64 patients with SVCI from June 2015 to December 2016 at Samsung Medical Center, Seoul, Korea. The patients had significant ischemia on brain magnetic resonance imaging, defined as periventricular white matter hyperintensity at least 10 mm and deep white matter hyperintensity at least 25 mm. We excluded 3 patients with SVCI owing to segmentation error during AV1451 positron emission tomography analysis.

Main outcomes and measures: We calculated CSVD scores based on the volumes of white matter hyperintensities, numbers of lacunes, and microbleeds using magnetic resonance imaging data. The presence of Aβ was assessed using fluorine 18-labeled (18F) florbetaben positron emission tomography. Tau was measured using 18F-AV1451 positron emission tomography. We determined the spreading order of tau by sorting the regional frequencies of cortical involvement. We evaluated the complex associations between Aβ, CSVD, AV1451 uptake, and cognition in patients with SVCI.

Results: Of the 61 patients with SVCI, 44 (72.1%) were women and the mean (SD) age was 78.7 (6.3) years. Patients with SVCI, especially patients with Aβ-negative SVCI, showed higher AV1451 uptake in the inferior temporal areas compared with normal control individuals. In patients with SVCI, Aβ positivity and CSVD score were each independently associated with increased AV1451 uptake in the medial temporal and inferior temporal regions, respectively. Involvement frequency of AV1451 uptake in the fusiform gyrus, inferior temporal, and precuneus regions were higher than that in the parahippocampal region. In patients with SVCI, higher AV1451 uptake in the inferior temporal and medial temporal regions correlated with worse language and general cognitive function. In patients with SVCI, Aβ positivity and CSVD score each correlated with worse general cognitive function, which was completely mediated by AV1451 uptake in the entorhinal cortex and inferior temporal gyrus, respectively.

Conclusions and relevance: Our findings suggest that in SVCI, both Aβ and CSVD were independently associated with increased tau accumulation. Furthermore, tau burden played a pivotal role because it was the final common pathway for the cognitive impairment in patients with SVCI.

Figure 1.. AV1451 Uptake in Patients With Subcortical Vascular Cognitive Impairment (SVCI)

A, Mean AV1451 uptakes in each group. B-D, Comparisons of AV1451 uptake between groups after controlling for age (B) and independent association of amyloid β (Aβ) (C) or cerebral small vessel disease (CSVD) score (D) with AV1451 uptake in SVCI after controlling for age. T2.4, T3.0, and T5.0 correspond to uncorrected P = .01, P = .002, and P < .001, respectively. ADCI indicates Alzheimer disease cognitive impairment; NC, normal control.

Figure 2.. In Vivo Cortical Spreading Order of AV1451 in Subcortical Vascular Cognitive Impairment (SVCI), Amyloid β (Aβ)–Negative Patients With SVCI, and Aβ-Positive Patients With SVCI

Color-coded 2-dimensional heat map shows the statistical significance for the comparison of the frequencies of regional involvement between the regions. Color bars represent logarithmic scale of P value (-log₁₀P). AM indicates amygdala; EN, entorhinal; FU, fusiform; iPA, inferior parietal; iTE, inferior temporal; mTE, middle temporal; PA, paracentral; PH, parahippocampal; PC, precuneus; pCI, posterior cingulate.

Figure 3.. Path Analyses of Amyloid-β (Aβ) or Cerebral Small Vessel Disease (CSVD) for Mini-Mental State Examination (MMSE)

Regional AV1451 uptake completely mediates the association between Aβ or CSVD and cognition after controlling for age and education. InfTemp indicates inferior temporal gyrus; SUVR, standardized uptake value ratio.