Blood-brain barrier impairment in Alzheimer disease: stability and functional significance.
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.
Bowman
G L
GL
Department of Neurology, Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, OR, USA. bowmang@ohsu.edu
Kaye
J A
JA
Moore
M
M
Waichunas
D
D
Carlson
N E
NE
Quinn
J F
JF
D000367:Age Factors; D000368:Aged; D000418:Albumins / Q000134:cerebrospinal fluid*; D000544:Alzheimer Disease / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000032:analysis / Q000097:blood / Q000134:cerebrospinal fluid; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology*; D015992:Body Mass Index; D001921:Brain / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D002561:Cerebrovascular Disorders / Q000150:complications / Q000175:diagnosis; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000150:complications; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D011237:Predictive Value of Tests; D012307:Risk Factors; D012737:Sex Factors
D000418:Albumins; D001057:Apolipoproteins E; D015415:Biomarkers