- Email: [email protected]
P4-295: Small vessel disease–induced microvascular protein leakage provides a possible pathogenetic link to Alzheimer's disease
T758 P4-295
Poster Presentations P4: SMALL VESSEL DISEASE–INDUCED MICROVASCULAR PROTEIN LEAKAGE PROVIDES A POSSIBLE PATHOGENETIC LINK TO ALZHEIMER’S DISEASE
Dietmar R. Thal1, Irfan Y. Tamboli2, Jochen Walter2, Gerd Birkenmeier3, Claus U. Pietrzik4, Sabrina Utter2, 1University of Ulm, Ulm, Germany; 2University of Bonn, Bonn, Germany; 3University of Leipzig, Leipzig, Germany; 4University of Mainz, Mainz, Germany. Contact e-mail: [email protected] Background: Apolipoprotein E (apoE) plays a role in the pathogenesis of Alzheimer’s disease (AD). It is involved in the receptor-mediated cellular clearance of the amyloid -protein as well as in the perivascular drainage of the extracellular fluid. Microvascular changes are also associated with AD and have been discussed as a possible reason for altered perivascular drainage. Methods: To further clarify the role of apoE in the perivascular and vascular pathology of AD we studied its occurrence and distribution in the perivascular space, the perivascular neuropil and in the vessel wall of 10 AD and 20 control cases with and without microvascular changes due to small vessel disease (SVD) in the basal ganglia. Results: ApoE was found in a diffuse lake-like distribution in the neuropil as well as in the perivascular space around arteries of the basal ganglia in control and AD cases. The ␣2-macroglobulin receptor/ low-density lipoprotein receptor-related protein (LRP) was likewise expressed in perivascular astrocytes in AD as well as in control cases without major differences. In contrast, A occurred within apoE-positive perivascular astrocytes in AD cases but not in controls. In blood vessels, apoE was detected in the vessel wall of the basal ganglia arteries in association with SVD. ApoE was found here in the extracellular space, in smooth muscle cells and in perivascular macrophages. The severity of SVD was associated with the occurrence of apoE in the vessel wall as well as with the accumulation of perivascular A-containing astrocytes. In addition to apoE, IgG was also found in vascular lesions. Moreover, in AD and SVD cases IgG was frequently found in the perivascular space whereas controls exhibited only small or negligible amounts of perivascular space-IgG. Conclusions: These results point to a critical involvement of apoE in perivascular clearance of A presumably triggered by SVD-induced plasma protein leakage into the perivascular space in the human brain. ApoE is also involved in the pathogenesis of SVD. A pathogenetic link between SVD and AD by SVD-induced plasma protein leakage is discussed. P4-296
QUANTITATIVE DYNAMIC CONTRAST ENHANCED MRI IN MILD COGNITIVE IMPAIRMENT: EVIDENCE OF ALTERED REGIONAL BLOOD VOLUME
Valerie C. Anderson1, Jeffrey M. Njus1, William J. Woodward2, Joseph F. Quinn1, Jeffrey A. Kaye1, William D. Rooney1, 1Oregon Health & Science University, Portland, OR, USA; 2Siker Medical Imaging and Intervention, Portland, OR, USA. Contact e-mail: [email protected] Background: Changes in the microvascular environment may be an early feature of Alzheimer’s disease. Dynamic contrast enhanced (DCE) MRI provides a quantitative measure of fractional blood water (pb) based on changes in 1H2O relaxation after injection of contrast reagent (CR). The goal of this study is to determine regional cerebral pb in subjects with mild cognitive impairment (MCI) and cognitively normal controls (CN) using DCE-MRI. Methods: 10 subjects with amnestic MCI (69⫾ 4 yrs, CDR 0.5) and 7 controls (70 ⫾ 5 yrs) were enrolled. Images were acquired at 3T using a multislice MPRAGE sequence with inversion times of 100, 600, 1200, and 4800 ms. A gadoteridol (0.11 mmol/kg) CR was delivered intravenously at 2 mL/s. Preand post-CR parametric R1 maps were obtained by fitting the signal intensity of each voxel to a monoexponential inversion recovery equation after coregistration of image sets. Regions of interest (ROI) were selected in the white matter (WM; forceps minor, centrum semiovale, posterior parietal and temporal WM) and gray matter (GM; thalamus, caudate, putamen, and posterior cingulate), bilaterally. Mean blood R1 values were measured from ROIs
placed in the sagittal sinus. pb was determined from an equation for two-site (transendothelial) exchange assuming a spatially independent transendothelial 1H2O extravasation rate constant and no crossing of CR into the brain parenchyma.1 Results: Mean ROI R1 values were increased in all subjects post-CR. Non-linearity of blood vs. tissue R1 plots was pronounced in both MCI and HC subjects at low [CR] in GM, but not WM. The mean (⫾ SD) pb of GM was 4.48 ⫾ 0.15% in MCI and 3.62 ⫾ 0.45% in CN subjects (P⬍ 0.05). In WM, pb was decreased in MCI compared to CN subjects but the difference was not statistically significant. Conclusions: Compared to CN subjects, regional blood volume is increased in the GM in MCI, possibly due to angiogenic or vasodilatory changes. If pb is perturbed in the WM in MCI subjects, the effect is not large compared to cognitively normal controls. 1 Njus, Vigeland, Li, Springer, Taylor, Telang , Coyle, Rooney. Proc Intl Soc Mag Reson Med 15 (2007): 2193. P4-297
ORTHOSTATIC BLOOD PRESSURE AND CEREBRAL BLOOD FLOW AND OXYGENATION IN PATIENTS WITH ALZHEIMER’S DISEASE
Arenda H. E. A. Van Beek, Jurgen A. H. R. Claassen, Willy N. J. M. Colier, Rene W. M. M. Jansen, Marcel G. M. Olde Rikkert, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands. Contact e-mail: [email protected] Background: An increased prevalence of orthostatic hypotension in Alzheimer’s Disease (AD) has been suggested. Together with accumulating evidence for cerebrovascular dysfunction in AD, this implies that AD patients are exposed to repeated episodes of cerebral hypoperfusion. Aim of this ongoing study is to assess systemic and cerebral hemodynamic changes, including cortical oxygenation, during reductions in blood pressure (BP) induced by a sit-to-stand procedure in AD. Methods: 8 healthy elderly subjects, 74 (SD 2) y, and 6 patients with early AD, 73 (5) y, underwent measurements of cerebral blood flow velocity (CBFV) using transcranial Doppler, along with continuous measurements of BP (Finapres), heart rate and end-tidal CO2. Frontal cerebral oxygenation was measured by near infrared spectroscopy (NIRS), detecting changes in cortical tissue concentration of oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (hHb), and total hemoglobin (tHb). All subjects performed three repetitions of a single sit-stand maneuver (120s sitting followed by 60s standing). Results: While seated, BP was similar in AD and elderly, whereas CBFV was reduced in AD (AD 35.3 (4.6), elderly 40.4 (8.4) cm/s, p ⫽ 0.009). The orthostatic fall in BP was much smaller in AD (AD from 94 to 83 mmHg) than elderly (from 90 to 73 mmHg, p ⫽ 0.098). AD patients reached a lower CBFV during standing (lowest value AD 32.7 (6.4) vs. 37.4 (8.0) cm/s in elderly, p ⫽ 0.015), however, the absolute reductions in CBFV (AD 2.7 cm/s, elderly 2.9 cm/s) and in O2Hb (AD 0.98, elderly 1.11 mol) and tHb (AD 0.73, elderly 0.93) were similar. Conclusions: In terms of BP control, orthostatic tolerance was preserved and possibly augmented rather than impaired in AD, as the orthostatic fall in BP was much lower in AD. We speculate that central BP control is altered in AD. Furthermore, during an orthostatic challenge, nutritional blood flow to the brain was preserved in AD as in healthy elderly subjects. However, from the viewpoint of cerebral autoregulation, the observed combination of a similar reduction in flow and tissue oxygenation together with a smaller decrease in BP in AD suggests cerebrovascular dysregulation. P4-298
SSAO INDUCTION IN ENDOTHELIAL CELLS BY BETA-AMYLOID COULD CONTRIBUTE TO VASCULAR CELL DAMAGE IN CEREBRAL AMYLOID ANGIOPATHY
Mercedes Unzeta1, Montse Sole´1, Mar Hernandez-Guillamo´n2, Merce` Boada3, 1Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain; 2Institut de Recerca de la Vall d⬘Hebron, Barcelona, Spain; 3Fundacio´ ACE-Institut Catala´ de Neurocie`ncies aplicades, Barcelona, Spain. Contact e-mail: [email protected]
Poster Presentations P4: SMALL VESSEL DISEASE–INDUCED MICROVASCULAR PROTEIN LEAKAGE PROVIDES A POSSIBLE PATHOGENETIC LINK TO ALZHEIMER’S DISEASE
Dietmar R. Thal1, Irfan Y. Tamboli2, Jochen Walter2, Gerd Birkenmeier3, Claus U. Pietrzik4, Sabrina Utter2, 1University of Ulm, Ulm, Germany; 2University of Bonn, Bonn, Germany; 3University of Leipzig, Leipzig, Germany; 4University of Mainz, Mainz, Germany. Contact e-mail: [email protected] Background: Apolipoprotein E (apoE) plays a role in the pathogenesis of Alzheimer’s disease (AD). It is involved in the receptor-mediated cellular clearance of the amyloid -protein as well as in the perivascular drainage of the extracellular fluid. Microvascular changes are also associated with AD and have been discussed as a possible reason for altered perivascular drainage. Methods: To further clarify the role of apoE in the perivascular and vascular pathology of AD we studied its occurrence and distribution in the perivascular space, the perivascular neuropil and in the vessel wall of 10 AD and 20 control cases with and without microvascular changes due to small vessel disease (SVD) in the basal ganglia. Results: ApoE was found in a diffuse lake-like distribution in the neuropil as well as in the perivascular space around arteries of the basal ganglia in control and AD cases. The ␣2-macroglobulin receptor/ low-density lipoprotein receptor-related protein (LRP) was likewise expressed in perivascular astrocytes in AD as well as in control cases without major differences. In contrast, A occurred within apoE-positive perivascular astrocytes in AD cases but not in controls. In blood vessels, apoE was detected in the vessel wall of the basal ganglia arteries in association with SVD. ApoE was found here in the extracellular space, in smooth muscle cells and in perivascular macrophages. The severity of SVD was associated with the occurrence of apoE in the vessel wall as well as with the accumulation of perivascular A-containing astrocytes. In addition to apoE, IgG was also found in vascular lesions. Moreover, in AD and SVD cases IgG was frequently found in the perivascular space whereas controls exhibited only small or negligible amounts of perivascular space-IgG. Conclusions: These results point to a critical involvement of apoE in perivascular clearance of A presumably triggered by SVD-induced plasma protein leakage into the perivascular space in the human brain. ApoE is also involved in the pathogenesis of SVD. A pathogenetic link between SVD and AD by SVD-induced plasma protein leakage is discussed. P4-296
QUANTITATIVE DYNAMIC CONTRAST ENHANCED MRI IN MILD COGNITIVE IMPAIRMENT: EVIDENCE OF ALTERED REGIONAL BLOOD VOLUME
Valerie C. Anderson1, Jeffrey M. Njus1, William J. Woodward2, Joseph F. Quinn1, Jeffrey A. Kaye1, William D. Rooney1, 1Oregon Health & Science University, Portland, OR, USA; 2Siker Medical Imaging and Intervention, Portland, OR, USA. Contact e-mail: [email protected] Background: Changes in the microvascular environment may be an early feature of Alzheimer’s disease. Dynamic contrast enhanced (DCE) MRI provides a quantitative measure of fractional blood water (pb) based on changes in 1H2O relaxation after injection of contrast reagent (CR). The goal of this study is to determine regional cerebral pb in subjects with mild cognitive impairment (MCI) and cognitively normal controls (CN) using DCE-MRI. Methods: 10 subjects with amnestic MCI (69⫾ 4 yrs, CDR 0.5) and 7 controls (70 ⫾ 5 yrs) were enrolled. Images were acquired at 3T using a multislice MPRAGE sequence with inversion times of 100, 600, 1200, and 4800 ms. A gadoteridol (0.11 mmol/kg) CR was delivered intravenously at 2 mL/s. Preand post-CR parametric R1 maps were obtained by fitting the signal intensity of each voxel to a monoexponential inversion recovery equation after coregistration of image sets. Regions of interest (ROI) were selected in the white matter (WM; forceps minor, centrum semiovale, posterior parietal and temporal WM) and gray matter (GM; thalamus, caudate, putamen, and posterior cingulate), bilaterally. Mean blood R1 values were measured from ROIs
placed in the sagittal sinus. pb was determined from an equation for two-site (transendothelial) exchange assuming a spatially independent transendothelial 1H2O extravasation rate constant and no crossing of CR into the brain parenchyma.1 Results: Mean ROI R1 values were increased in all subjects post-CR. Non-linearity of blood vs. tissue R1 plots was pronounced in both MCI and HC subjects at low [CR] in GM, but not WM. The mean (⫾ SD) pb of GM was 4.48 ⫾ 0.15% in MCI and 3.62 ⫾ 0.45% in CN subjects (P⬍ 0.05). In WM, pb was decreased in MCI compared to CN subjects but the difference was not statistically significant. Conclusions: Compared to CN subjects, regional blood volume is increased in the GM in MCI, possibly due to angiogenic or vasodilatory changes. If pb is perturbed in the WM in MCI subjects, the effect is not large compared to cognitively normal controls. 1 Njus, Vigeland, Li, Springer, Taylor, Telang , Coyle, Rooney. Proc Intl Soc Mag Reson Med 15 (2007): 2193. P4-297
ORTHOSTATIC BLOOD PRESSURE AND CEREBRAL BLOOD FLOW AND OXYGENATION IN PATIENTS WITH ALZHEIMER’S DISEASE
Arenda H. E. A. Van Beek, Jurgen A. H. R. Claassen, Willy N. J. M. Colier, Rene W. M. M. Jansen, Marcel G. M. Olde Rikkert, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands. Contact e-mail: [email protected] Background: An increased prevalence of orthostatic hypotension in Alzheimer’s Disease (AD) has been suggested. Together with accumulating evidence for cerebrovascular dysfunction in AD, this implies that AD patients are exposed to repeated episodes of cerebral hypoperfusion. Aim of this ongoing study is to assess systemic and cerebral hemodynamic changes, including cortical oxygenation, during reductions in blood pressure (BP) induced by a sit-to-stand procedure in AD. Methods: 8 healthy elderly subjects, 74 (SD 2) y, and 6 patients with early AD, 73 (5) y, underwent measurements of cerebral blood flow velocity (CBFV) using transcranial Doppler, along with continuous measurements of BP (Finapres), heart rate and end-tidal CO2. Frontal cerebral oxygenation was measured by near infrared spectroscopy (NIRS), detecting changes in cortical tissue concentration of oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (hHb), and total hemoglobin (tHb). All subjects performed three repetitions of a single sit-stand maneuver (120s sitting followed by 60s standing). Results: While seated, BP was similar in AD and elderly, whereas CBFV was reduced in AD (AD 35.3 (4.6), elderly 40.4 (8.4) cm/s, p ⫽ 0.009). The orthostatic fall in BP was much smaller in AD (AD from 94 to 83 mmHg) than elderly (from 90 to 73 mmHg, p ⫽ 0.098). AD patients reached a lower CBFV during standing (lowest value AD 32.7 (6.4) vs. 37.4 (8.0) cm/s in elderly, p ⫽ 0.015), however, the absolute reductions in CBFV (AD 2.7 cm/s, elderly 2.9 cm/s) and in O2Hb (AD 0.98, elderly 1.11 mol) and tHb (AD 0.73, elderly 0.93) were similar. Conclusions: In terms of BP control, orthostatic tolerance was preserved and possibly augmented rather than impaired in AD, as the orthostatic fall in BP was much lower in AD. We speculate that central BP control is altered in AD. Furthermore, during an orthostatic challenge, nutritional blood flow to the brain was preserved in AD as in healthy elderly subjects. However, from the viewpoint of cerebral autoregulation, the observed combination of a similar reduction in flow and tissue oxygenation together with a smaller decrease in BP in AD suggests cerebrovascular dysregulation. P4-298
SSAO INDUCTION IN ENDOTHELIAL CELLS BY BETA-AMYLOID COULD CONTRIBUTE TO VASCULAR CELL DAMAGE IN CEREBRAL AMYLOID ANGIOPATHY
Mercedes Unzeta1, Montse Sole´1, Mar Hernandez-Guillamo´n2, Merce` Boada3, 1Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain; 2Institut de Recerca de la Vall d⬘Hebron, Barcelona, Spain; 3Fundacio´ ACE-Institut Catala´ de Neurocie`ncies aplicades, Barcelona, Spain. Contact e-mail: [email protected]