Blood-brain barrier impairment in Alzheimer disease: stability and functional significance

Abstract

Objective: To determine the stability and functional significance of blood-brain barrier (BBB) integrity in patients with mild to moderate Alzheimer disease (AD).

Methods: Thirty-six patients (mean age 71 +/- 7 years) with mild to moderate AD (Mini-Mental State Examination [MMSE] 19 +/- 5) participated in a biomarker study involving clinical assessments, brain imaging, and CSF and plasma collection over 1 year. BBB integrity was assessed with the CSF-albumin index (CSF-AI).

Results: BBB disruption was present in an important subgroup of patients (n = 8/36, 22%) at all time points measured. CSF-AI was highly reproducible over 1 year with an intraclass correlation of 0.96. Age, sex, and APOE status did not correlate with CSF-AI. Vascular factors (blood pressure, Hachinski ischemia score, MR-derived white matter hyperintensity, body mass index) were not strongly associated with CSF-AI levels (p = 0.066). CSF/plasma IgG ratio correlated with CSF-AI in a manner indicating that peripheral IgG has greater access to the CNS in patients with an impaired BBB. Further evidence for the physiologic significance of the CSF-AI was noted in the form of correlations with rates of disease progression, including annual change on MMSE (r(2) = 0.11, p = 0.023), annual Clinical Dementia Rating sum-of-boxes change (r(2) = 0.29, p = 0.001), and annual ventricular volume change (r(2) = 0.17, p = 0.007).

Conclusions: Blood-brain barrier (BBB) impairment is a stable characteristic over 1 year and present in an important subgroup of patients with Alzheimer disease. Age, gender, APOE status, vascular risk factors, and baseline Mini-Mental State Examination score did not explain the variability in BBB integrity. A role for BBB impairment as a modifier of disease progression is suggested by correlations between CSF-albumin index and measures of disease progression over 1 year.

Figure 1. CSF-albumin index in Alzheimer disease

(A) Stability of CSF-albumin index (CSF-AI): within-patient CSF-AI on repeated measures over 1 year (baseline, 3 and 12 months). A level line indicates an identical value at each time point. (B) Functional significance of blood-brain barrier integrity in Alzheimer disease: relationship between baseline measures of CSF-AI and IgG levels (r² = 0.94, p < 0.0001).

Figure 2. Functional significance of blood-brain barrier (BBB) integrity in Alzheimer disease (AD): Relationship between baseline CSF-albumin index (CSF-AI) and measures of disease progression

Scatter plot and regression line describing relationships between baseline CSF-AI and (A) annual rate Clinical Dementia Rating (CDR) sumof-boxes (SOB) change in points/year (r² = 0.29, p = 0.001), (B) annual rate of Mini-Mental State Examination (MMSE) change in points/year (r² = 0.112, p = 0.023), and (C) annual ventricular volume change in cm³ (r² = 0.17, p = 0.007). (D) Clustered bar graph comparing subjects with BBB intact (CSF-AI < 9.0) against subjects with BBB impairment (CSF-AI ≥ 9.0) in terms of log-transformed annual mean value change in CDR-SOB (*p = 0.017, mean difference of 2.57), MMSE (p = 0.196, mean difference of 2.07 points), and ventricular volume (*p < 0.0001, mean difference 5.58 cm³).