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Berislav V. Zlokovic
Alzforum Webinar Feb 17 2015
Leaky Blood-Brain Barrier a Harbinger of Alzheimer's?
Courtesy of Zlokovic lab
Neuronal computation and normal functioning of
the CNS requires tight control of the chemical
com...
Brain endothelial cells and pericytes form the
BBB, which limits entry of neurotoxic plasma-
derived proteins, circulating...
Blood-brain barrier breakdown in disease
Studies in Tg models have shown that a chronic BBB breakdown leads to
accumulatio...
Pericyte-deficient mice: a small vessel disease model -PDGFRb-PDGF-BB
v
*
*
v
v
v
1 6 6
F7
6
10 µm 10 µm 10 µm10 µm
TUNELT...
Blood-brain barrier breakdown in Alzheimer’s disease
 Post-mortem studies have shown BBB damage in AD
• Accumulation in t...
Ryu and McLarnon, J. Cell. Mol. Med., 2009
Fiala…..Vinters, J., Eur. J. Clin. Invest., 2002
Cortes-Cantelli et al., J Alzh...
Pericyte degeneration and BBB breakdown in post-mortem AD brain tissue
Sengillo, Winkler….Zlokovic (Brain Pathology 2013)
Hulltman et al., JCBFM, 2013
Postmortem brain tissue studies in Alzheimer’s disease
– accelerated BBB breakdown in APOE4 c...
At what stage BBB breakdown occurs in the living human brain and
whether it contributes to cognitive impairment?
 Early n...
Dynamic contrast enhanced MRI
64 subjects of various ages with no cognitive impairment (NCI), mild
cognitive impairment (M...
Dynamic MRI
Common Carotid Artery (CCA)
Individual Arterial Input Function (AIF)
Extensive simulation results (Barnes et a...
Blood-Brain Barrier Breakdown in the Aging Human Hippocampus in
NCI
• improved spatial resolution
• improved SNR ratio
• n...
Blood-Brain Barrier Breakdown in the Hippocampus
worsens in MCI
Age-matched NCI and MCI participants were evaluated using ...
Hippocampus volume and lateral ventricular volume
SMP8 was used to segment T2-weighted images
BBB breakdown before atrophy...
sPDGFRβ, a marker of cell injury to BBB-associated pericytes
NCI, older
MCI
Increased Qalb and CSF levels of sPDGFRb , a p...
sPDGFRb is elevated in CSF in pericyte-deficient mice and Tg2576 mice that bo
progressive pericyte degeneration by brain t...
CSF biomarkers in MCI compared to age-matched NCI
• Increased Qalb CSF/plasma quotient and sPDGFRb
• No changes in endothe...
Small vessels disease
- a target for mutifactorial pathogenesis of Alzheimer's’ disease and dementia
Modified from
Videoab...
Blood-brain barrier breakdown in the aging hippocampus
Highlights
High resolution MRI analysis of regional BBB permeabili...
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Alzforum Berislav Zlokovic

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Leaky Blood-Brain Barrier a Harbinger of Alzheimer s Disease - presentation made at Alzforum's live webinar of February 17, 2015. See details at: http://www.alzforum.org/webinars/leaky-blood-brain-barrier-harbinger-alzheimers

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Alzforum Berislav Zlokovic

  1. 1. Berislav V. Zlokovic Alzforum Webinar Feb 17 2015 Leaky Blood-Brain Barrier a Harbinger of Alzheimer's?
  2. 2. Courtesy of Zlokovic lab Neuronal computation and normal functioning of the CNS requires tight control of the chemical composition of the neuronal ‘milieu’ that is maintained by the BLOOD-BRAIN BARRIER. Zlokovic, Nat Rev Nsci, 2011
  3. 3. Brain endothelial cells and pericytes form the BBB, which limits entry of neurotoxic plasma- derived proteins, circulating metals, red blood cells and leukocytes into the brain.
  4. 4. Blood-brain barrier breakdown in disease Studies in Tg models have shown that a chronic BBB breakdown leads to accumulation of blood-derived neurotoxic proteins in the CNS (e.g., fibrin, thrombin, hemoglobin, free iron, plasmin) causing progressive neurodegeneration with loss of neurons mediated by direct neuronal toxicity, oxidant stress and/or detachment of neurons from the extracellular matrix.
  5. 5. Pericyte-deficient mice: a small vessel disease model -PDGFRb-PDGF-BB v * * v v v 1 6 6 F7 6 10 µm 10 µm 10 µm10 µm TUNELTUNEL Lectin Pdgfrb+/+ Pdgfrb+/- PDGFRb Age (months): 1 mo Pdgfrb+/- 8 mo Pdgfrb+/- 50 mm 16 mo Pdgfrb+/-Pdgfrb+/+ 50 mm 50 mm 50 mm 2000kDaDextran FibrinCD31 Pdgfrb+/+ 8 mo Pdgfrb +/- 16 mo Pdgfrb+/- 1 mo Pdgfrb+/- 20 mm 20 mm 20 mm 20 mm Capillary degeneration 1 mo BBB breakdown 1 mo Pdgfrb+/+ 8 mo Pdgfrb+/-1 mo Pdgfrb+/- 16 mo Pdgfrb+/- 50 mm 50 mm 50 mm 50 mm 2-4 mo Pdgfrβ+/+ 2-4 mo PdgfrβF7/F7 Perfusion deficit 1 mo Normal neuronal phenotype 1 mo Loss of white matter fibers at 2-4 mo Loss of hippocampal neurons at 6-8 mo Bell et al., Neuron, 2010 Armulik et al., Nature 2010 Daneman et al., Nature 2010
  6. 6. Blood-brain barrier breakdown in Alzheimer’s disease  Post-mortem studies have shown BBB damage in AD • Accumulation in the hippocampus and cortex of blood-derived proteins (e.g., immunoglobulins, albumin, fibrinogen, and thrombin) • Degeneration of pericytes  Brain imaging studies • Microbleeds and accumulation of iron in AD • Particularly in the hippocampus CSF studies (increased Qalb - CSF/plasma albumin ratio) • Associated with vascular risk factors, white matter lesions, vascular dementia and vascular disorders (e.g., hypertension, diabetes, ischemic heart disease) • In all dementias – AD and vascular • In individuals at genetic risk for AD (i.e., APOE4) • Mild cognitive impairment (MCI)
  7. 7. Ryu and McLarnon, J. Cell. Mol. Med., 2009 Fiala…..Vinters, J., Eur. J. Clin. Invest., 2002 Cortes-Cantelli et al., J Alzheimer’s Dis., 2012 BBB breakdown in Alzheimer's’ disease: postmortem brain tissue studies
  8. 8. Pericyte degeneration and BBB breakdown in post-mortem AD brain tissue Sengillo, Winkler….Zlokovic (Brain Pathology 2013)
  9. 9. Hulltman et al., JCBFM, 2013 Postmortem brain tissue studies in Alzheimer’s disease – accelerated BBB breakdown in APOE4 carriers Halliday, Rege et al., JCBFM, 2015 in press
  10. 10. At what stage BBB breakdown occurs in the living human brain and whether it contributes to cognitive impairment?  Early neuroimaging attempts to measure the BBB permeability Ktrans constant in MCI and AD patients failed to detect significant changes in BBB integrity.  These studies might have been hampered by their relatively long time resolution and the semi-quantitative nature of their analyses.  More recent studies acquired at higher field strengths and using more sophisticated kinetic modeling have determined that the Ktrans of healthy BBB is low but not zero, and detected differences in the white matter in patients with multiple sclerosis.  Montagne et al., Neuron 2015 developed an advanced method using • individual arterial input function (AIF) • improved spatial resolution • improved SNR (signal-to-noise) ratio • new software ‘ROCKETSHIP’ • simultaneous measurements of BBB integrity in different gray and white matter re
  11. 11. Dynamic contrast enhanced MRI 64 subjects of various ages with no cognitive impairment (NCI), mild cognitive impairment (MCI) and multiple sclerosis (MS) without history of cognitive complaints were injected with gadolinium-based contrast agent (MultiHance 0.05 mmol/kg). Patlak unidirectional linear analysis Ktrans Tissue (CNS), Ct Blood,Cp 𝐶𝑡 𝑡 = 𝐾𝑡𝑟𝑎𝑛𝑠 0 𝑡 𝐶 𝑝 𝑢 𝑑𝑢 + 𝑣 𝑝 𝐶 𝑝 𝑡 Modified DCE-MRI protocol + post-processing imaging (homemade software) Montagne et al., Neuron 2015
  12. 12. Dynamic MRI Common Carotid Artery (CCA) Individual Arterial Input Function (AIF) Extensive simulation results (Barnes et al., Magnetic Resonance Med., in revision) suggests that the present Patlak model using AIF individual curves can accurately determine Ktrans in the presence of various blood volumes, blood flows, and noise.
  13. 13. Blood-Brain Barrier Breakdown in the Aging Human Hippocampus in NCI • improved spatial resolution • improved SNR ratio • new software ‘ROCKETSHIP’ Aging effect - Cognitively normal participants - a- CA1; b- CA3; c- Dentate Gyrus  BBB breakdown during normal aging begins in the hippocampus. Montagne et al., Neuron 2015
  14. 14. Blood-Brain Barrier Breakdown in the Hippocampus worsens in MCI Age-matched NCI and MCI participants were evaluated using the Uniform Data Set (UDS) and additional neuropsychological tests: California Verbal Learning Test, block design, letter-number sequencing, letter fluency, and token test  Accelerated BBB breakdown in the hippocampus may contribute to cognitive impairment. Montagne et al., Neuron 2015
  15. 15. Hippocampus volume and lateral ventricular volume SMP8 was used to segment T2-weighted images BBB breakdown before atrophy Montagne et al., Neuron 2015
  16. 16. sPDGFRβ, a marker of cell injury to BBB-associated pericytes NCI, older MCI Increased Qalb and CSF levels of sPDGFRb , a pericyte injury marker, in MCI vs. NCI subjects correlate with an increase in Ktrans BBB permeability values Montagne et al., Neuron 2015
  17. 17. sPDGFRb is elevated in CSF in pericyte-deficient mice and Tg2576 mice that bo progressive pericyte degeneration by brain tissue biomarkers analysis Pericyte- deficient mice Mouse model of AD Montagne et al., Neuron 2015
  18. 18. CSF biomarkers in MCI compared to age-matched NCI • Increased Qalb CSF/plasma quotient and sPDGFRb • No changes in endothelial biomarkers, inflammatory response, Ab or tau Neurovascular Unit CSF biomarkers of cell- and system-specific injury Montagne et al., Neuron 2015
  19. 19. Small vessels disease - a target for mutifactorial pathogenesis of Alzheimer's’ disease and dementia Modified from Videoabstract: Montagne……Zlokovic, Neuron, 2015
  20. 20. Blood-brain barrier breakdown in the aging hippocampus Highlights High resolution MRI analysis of regional BBB permeability in the living human brain. BBB breakdown during normal aging begins in the hippocampus, a region critical for learning and memory. BBB breakdown in the hippocampus worsens with mild cognitive impairment and correlates with injury to BBB-associated cell pericyte. Montagne et al., Neuron 2015

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