HHS Public Access Author manuscript Author Manuscript
Lancet Neurol. Author manuscript; available in PMC 2017 July 01. Published in final edited form as: Lancet Neurol. 2016 July ; 15(8): 811–819. doi:10.1016/S1474-4422(16)30030-8.
Cortical Atrophy in Hereditary and Sporadic Forms of Cerebral Amyloid Angiopathy: an observational case-control study
Author Manuscript
Panagiotis Fotiadis, BS#1, Sanneke van Rooden, PhD#2, Jeroen van der Grond, PhD2, Aaron Schultz, PhD3,4, Sergi Martinez-Ramirez, MD1, Eitan Auriel, MD, MSc1, Yael Reijmer, PhD1, Anna M. van Opstal, PhD2, Alison Ayres, BA1, Kristin M. Schwab, BA1, The Alzheimer's Disease Neuroimaging Initiative¶, Trey Hedden, PhD3,4, Jonathan Rosand, MD, MSc1,4, Anand Viswanathan, MD, PhD1,4, Marieke Wermer, MD, PhD5, Gisela Terwindt, MD, PhD5, Reisa A. Sperling, MD, MMSc3,4, Jonathan R. Polimeni, PhD3,4, Keith A. Johnson, MD3,4, Mark A. van Buchem, MD, PhD2, Steven M. Greenberg, MD, PhD1,4, and M. Edip Gurol, MD, MSc1,4,* 1Hemorrhagic
Stroke Research Group, Massachusetts General Hospital, Boston, MA, USA of Radiology, Leiden University Medical Center, Leiden, The Netherlands 3Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA 4Harvard Medical School, Massachusetts General Hospital, Boston, MA 5Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands 2Department
#
These authors contributed equally to this work.
Author Manuscript
This manuscript version is made available under the CC BY-NC-ND 4.0 license. *
Corresponding author: Dr. M. Edip Gurol, MD, MSc, Hemorrhagic Stroke Research Group, Massachusetts General Hospital, 175 Cambridge Street #300, Boston, MA 02114, Phone: +1-617-726-5362, [email protected] or [email protected]. ¶Part of the data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu, last accessed on December 14, 2015). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ ADNI_Acknowledgement_List.pdf, last accessed on December 14, 2015 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Author Manuscript
Authors' Contributions: Literature search: Panagiotis Fotiadis, Eitan Auriel, Yael Reijmer, M. Edip Gurol Figures: Panagiotis Fotiadis, M. Edip Gurol Study design: Panagiotis Fotiadis, Keith A. Johnson, Mark A. van Buchem, Steven M. Greenberg, M. Edip Gurol Data collection: Panagiotis Fotiadis, Sanneke van Rooden, Jeroen van der Grond, Aaron Schultz, Anna M. van Opstal, Alison Ayres, Kristin M. Schwab, the Alzheimer's Disease Neuroimaging Initiative, Trey Hedden, Anand Viswanathan, Jonathan Rosand, Marieke Wermer, Gisela Terwindt, Reisa A. Sperling, Jonathan R. Polimeni, Keith A. Johnson, Mark A. van Buchem, Steven M. Greenberg, M. Edip Gurol Imaging Data analysis: Panagiotis Fotiadis, Sanneke van Rooden, Sergi Martinez-Ramirez, Eitan Auriel, MD, Yael Reijmer, Jonathan R. Polimeni, M. Edip Gurol Statistical Analysis: Panagiotis Fotiadis, Steven M. Greenberg, M. Edip Gurol Data interpretation: Sanneke van Rooden, Jonathan Rosand, Reisa A. Sperling, Jonathan R. Polimeni, Keith A. Johnson, Mark A. van Buchem, Steven M. Greenberg, M. Edip Gurol Manuscript Writing: Steven M. Greenberg, M. Edip Gurol Critical Review of the Manuscript: Panagiotis Fotiadis, Sanneke van Rooden, Jeroen van der Grond, Aaron Schultz, Sergi MartinezRamirez, Eitan Auriel, MD, Yael Reijmer, Anna M. van Opstal, Alison Ayres, Kristin M. Schwab, the Alzheimer's Disease Neuroimaging Initiative, Trey Hedden, Jonathan Rosand, Anand Viswanathan, Marieke Wermer, Gisela Terwindt, Reisa A. Sperling, Jonathan R. Polimeni, Keith A. Johnson, Mark A. van Buchem Conflicts of Interest No other conflicts of interest by any other author related to this study.
Fotiadis et al.
Page 2
Abstract Author Manuscript
Background—We postulated that Cerebral Amyloid Angiopathy (CAA), characterized by cortical vascular amyloid deposits, is associated with cortical tissue loss independent of parenchymal Alzheimer pathology. Patients with hereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA-D), a monogenetic model of essentially pure CAA with minimal or no concomitant Alzheimer pathology, constitute a unique disease model to test this hypothesis.
Author Manuscript
Methods—In this observational case-control study, the primary outcome measure, the cortical thickness of prospectively enrolled patients diagnosed with HCHWA-D using genetic testing and non-demented patients with probable CAA according to Boston criteria was compared to relevant age-matched contrast groups including healthy controls (HC) and Alzheimer's Disease (AD), the latter diagnosed with National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. The data were collected at Massachusetts General Hospital in Boston MA, at Leiden University in Netherlands, and sites contributing to Alzheimer's Disease Neuroimaging Initiative (ADNI). The correlations between cortical thickness and structural lesions as well as Blood-Oxygen-Level-Dependent Time-to-Peak (BOLD-TTP, a physiologic measure of vascular dysfunction) were sought to understand the potential mechanistic link.
Author Manuscript
Results—Data were collected from March 15, 2006 to December 1, 2014. Patients with HCHWA-D (n=26) had thinner cortices (2.31mm± 0.18) compared to their HC (n=28) group (mean difference [MD]= −0.112, 95% confidence interval [CI] −0.190, −0.034, p=0.006). Nondemented sporadic CAA patients (n=63) had globally thinner cortices (2.17±0.11) compared to the two HC (n=63 and n=126) cohorts (MD=−0.14, 95% CI −0.17, −0.10 and MD=−0.10, 95% CI −0.13, −0.06, pGln `Dutch' mutation on the production and stability of amyloid beta-protein. The Biochemical journal. 1999; 340(Pt 3):703–709. [PubMed: 10359654] 18. Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology. 2001; 56:537–539. [PubMed: 11222803] 19. Dagley A, LaPoint M, Huijbers W, et al. Harvard Aging Brain Study: Dataset and accessibility. NeuroImage. 2015 20. Jack CR Jr, Bernstein MA, Fox NC, et al. The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods. J Magn Reson Imaging. 2008; 27:685–691. [PubMed: 18302232] 21. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. NeuroImage. 1999; 9:179–194. [PubMed: 9931268] 22. Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. NeuroImage. 1999; 9:195–207. [PubMed: 9931269] 23. Segonne F, Dale AM, Busa E, et al. A hybrid approach to the skull stripping problem in MRI. NeuroImage. 2004; 22:1060–1075. [PubMed: 15219578] 24. Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A. 2000; 97:11050–11055. [PubMed: 10984517] 25. Salat DH, Buckner RL, Snyder AZ, et al. Thinning of the cerebral cortex in aging. Cerebral cortex. 2004; 14:721–730. [PubMed: 15054051] 26. Destrieux C, Fischl B, Dale A, Halgren E. Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature. NeuroImage. 2010; 53:1–15. [PubMed: 20547229] 27. Fischl B, Salat DH, Busa E, et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002; 33:341–355. [PubMed: 11832223] 28. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. The Lancet Neurology. 2009; 8:165–174. [PubMed: 19161908]
Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 12
Author Manuscript Author Manuscript
29. Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. Journal of personality and social psychology. 1986; 51:1173–1182. [PubMed: 3806354] 30. Sobel, ME. Asymptotic intervals for indirect effects in structural equations models. In: Leinhart, S., editor. Sociological methodology. Jossey-Bass; San Francisco: 1982. p. 290-312. 31. Bornebroek M, Haan J, Van Duinen SG, et al. Dutch hereditary cerebral amyloid angiopathy: structural lesions and apolipoprotein E genotype. Ann Neurol. 1997; 41:695–698. [PubMed: 9153536] 32. Jouvent E, Mangin JF, Duchesnay E, et al. Longitudinal changes of cortical morphology in CADASIL. Neurobiol Aging. 2012; 33:1002, e1029–1036. 33. Greenberg SM, Grabowski T, Gurol ME, et al. Detection of isolated cerebrovascular beta-amyloid with Pittsburgh compound B. Ann Neurol. 2008; 64:587–591. [PubMed: 19067370] 34. Johnson KA, Gregas M, Becker JA, et al. Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol. 2007; 62:229–234. [PubMed: 17683091] 35. Gurol ME, Dierksen G, Betensky R, et al. Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy. Neurology. 2012; 79:320–326. [PubMed: 22786597] 36. Dickerson BC, Bakkour A, Salat DH, et al. The cortical signature of Alzheimer's disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals. Cerebral cortex. 2009; 19:497– 510. [PubMed: 18632739] 37. Gregg NM, Kim AE, Gurol ME, et al. Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals. JAMA neurology. 2015; 72:1021–1028. [PubMed: 26167811] 38. Samuraki M, Matsunari I, Yoshita M, et al. Cerebral Amyloid Angiopathy-Related Microbleeds Correlate with Glucose Metabolism and Brain Volume in Alzheimer's Disease. Journal of Alzheimer's disease : JAD. 2015; 48:517–528. [PubMed: 26402015] 39. Maat-Schieman M, Roos R, van Duinen S. Hereditary cerebral hemorrhage with amyloidosisDutch type. Neuropathology. 2005; 25:288–297. [PubMed: 16382777]
Author Manuscript Author Manuscript Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 13
Author Manuscript
PANEL: Research in context Evidence before this study
Author Manuscript
We searched PubMed for articles on cerebral amyloid angiopathy (CAA) and cortical atrophy published between Jan 1, 1990, and Nov 1, 2015, with different combinations of the terms “cerebral amyloid angiopathy”, “cortical atrophy”, “cortical thickness”, ”cortical damage”. We have not found any article that addressed the association between CAA and cortical atrophy. We have then repeated PubMed searches within the same time interval using combinations of the term “cerebral amyloid angiopathy” and each one of the following terms: “leukoaraiosis”, “white matter”, “structural networks”, and “subcortical injury”. We have found multiple articles that established associations between CAA and subcortical tissue damage but the association of CAA and cortical atrophy was unknown. A major obstacle in clarifying this latter association has been the relatively common coexistence of CAA and parenchymal Alzheimer's Disease (AD) pathology, the latter being a well-established cause of cortical atrophy. Added value of this study This prospective study shows that patients with hereditary cerebral hemorrhage with amyloidosis–Dutch type, a monogenetic model of essentially pure CAA with minimal or no concomitant parenchymal AD pathology, have decreased cortical thickness when compared to age-matched controls. These findings were confirmed when comparing a well-defined cohort of common sporadic CAA patients to age-matched elderly controls. Mediation analyses also showed that vascular dysfunction explained at least part of the effect of CAA on cortical atrophy.
Author Manuscript
Implications of all the available evidence
Author Manuscript
Autopsy and imaging based studies show that vascular amyloid pathology and lobar microbleeds, the hallmarks of CAA, are common findings in otherwise healthy older adults as well as patients with mild cognitive symptoms. Multiple lines of evidence suggest that CAA is an important contributor to subcortical tissue injury through vascular dysfunction and ischemia. Cerebral amyloid angiopathy is also a well-established contributor to cognitive impairment in elderly, independent of intracerebral hemorrhages that constitute the other important consequences of the vascular amyloid. Our study for the first time suggests that CAA might also cause global cortical atrophy, an effect that might at least in part be mediated by vascular dysfunction. These new findings are important in better understanding the mechanisms of cerebral damage in CAA as they can potentially mediate disabling clinical effects and even confound therapeutic efforts. For example, some of the immunotherapies studied for Alzheimer's Disease resulted in superficial cerebral microbleeds typical of CAA and accelerated atrophy was observed in multiple antibody trials. Based on all available evidence, CAA will need to be taken into consideration in future efforts to develop therapies for AD and cognitive impairment.
Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 14
Author Manuscript Author Manuscript
Figure 1.
Topographic surface maps showing differences in cortical thickness between patients with hereditary cerebral hemorrhage with amyloidosis–Dutch type and their age-matched controls
Author Manuscript Author Manuscript Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 15
Author Manuscript Author Manuscript
Figure 2.
Topographic surface maps showing differences in cortical thickness between patients with sporadic cerebral amyloid angiopathy and their age-matched controls
Author Manuscript Author Manuscript Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 16
Table 1
Author Manuscript
Comparisons between hereditary CAA and healthy controls Hereditary CAA Patients (n = 26)
Healthy Controls (n = 28)
Demographics Age (mean ± SD)
45.8 ± 14
47.5 ± 12
# Female patients (%)
16 (61.5%)
17 (60.7%)
Cortical Thickness in mm, (mean ± SD)
2.31 ± 0.18
2.42 ± 0.1 p=0.006
HV % of ICV (mean ± SD)
0.54 ± 0.13
0.58 ± 0.07 p=0.113
Outcomes
The p values result from comparison to the same measure in the Hereditary CAA cohort CAA: cerebral amyloid angiopathy
Author Manuscript
HV % of ICV: Hippocampal volume percent of intracranial volume
Author Manuscript Author Manuscript Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 17
Table 2
Author Manuscript
Comparisons between sporadic CAA and contrast groups Sporadic CAA Patients (n = 63)
ADNI Healthy Controls (n = 63)
HAB Healthy Controls (n = 126)
ADNI AD Patients (n = 63)
Demographics Age (mean ± SD)
72.2 ± 5
72.3 ± 5
72.4 ± 5
72.2 ± 5
# Female patients (%)
14 (22.2%)
27 (42.9%)
54 (42.9%)
20 (31.7%)
Cortical Thickness in mm (mean ± SD)
2.17 ± 0.11
2.31 ± 0.07 p
Lancet Neurol. Author manuscript; available in PMC 2017 July 01. Published in final edited form as: Lancet Neurol. 2016 July ; 15(8): 811–819. doi:10.1016/S1474-4422(16)30030-8.
Cortical Atrophy in Hereditary and Sporadic Forms of Cerebral Amyloid Angiopathy: an observational case-control study
Author Manuscript
Panagiotis Fotiadis, BS#1, Sanneke van Rooden, PhD#2, Jeroen van der Grond, PhD2, Aaron Schultz, PhD3,4, Sergi Martinez-Ramirez, MD1, Eitan Auriel, MD, MSc1, Yael Reijmer, PhD1, Anna M. van Opstal, PhD2, Alison Ayres, BA1, Kristin M. Schwab, BA1, The Alzheimer's Disease Neuroimaging Initiative¶, Trey Hedden, PhD3,4, Jonathan Rosand, MD, MSc1,4, Anand Viswanathan, MD, PhD1,4, Marieke Wermer, MD, PhD5, Gisela Terwindt, MD, PhD5, Reisa A. Sperling, MD, MMSc3,4, Jonathan R. Polimeni, PhD3,4, Keith A. Johnson, MD3,4, Mark A. van Buchem, MD, PhD2, Steven M. Greenberg, MD, PhD1,4, and M. Edip Gurol, MD, MSc1,4,* 1Hemorrhagic
Stroke Research Group, Massachusetts General Hospital, Boston, MA, USA of Radiology, Leiden University Medical Center, Leiden, The Netherlands 3Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA 4Harvard Medical School, Massachusetts General Hospital, Boston, MA 5Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands 2Department
#
These authors contributed equally to this work.
Author Manuscript
This manuscript version is made available under the CC BY-NC-ND 4.0 license. *
Corresponding author: Dr. M. Edip Gurol, MD, MSc, Hemorrhagic Stroke Research Group, Massachusetts General Hospital, 175 Cambridge Street #300, Boston, MA 02114, Phone: +1-617-726-5362, [email protected] or [email protected]. ¶Part of the data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu, last accessed on December 14, 2015). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ ADNI_Acknowledgement_List.pdf, last accessed on December 14, 2015 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Author Manuscript
Authors' Contributions: Literature search: Panagiotis Fotiadis, Eitan Auriel, Yael Reijmer, M. Edip Gurol Figures: Panagiotis Fotiadis, M. Edip Gurol Study design: Panagiotis Fotiadis, Keith A. Johnson, Mark A. van Buchem, Steven M. Greenberg, M. Edip Gurol Data collection: Panagiotis Fotiadis, Sanneke van Rooden, Jeroen van der Grond, Aaron Schultz, Anna M. van Opstal, Alison Ayres, Kristin M. Schwab, the Alzheimer's Disease Neuroimaging Initiative, Trey Hedden, Anand Viswanathan, Jonathan Rosand, Marieke Wermer, Gisela Terwindt, Reisa A. Sperling, Jonathan R. Polimeni, Keith A. Johnson, Mark A. van Buchem, Steven M. Greenberg, M. Edip Gurol Imaging Data analysis: Panagiotis Fotiadis, Sanneke van Rooden, Sergi Martinez-Ramirez, Eitan Auriel, MD, Yael Reijmer, Jonathan R. Polimeni, M. Edip Gurol Statistical Analysis: Panagiotis Fotiadis, Steven M. Greenberg, M. Edip Gurol Data interpretation: Sanneke van Rooden, Jonathan Rosand, Reisa A. Sperling, Jonathan R. Polimeni, Keith A. Johnson, Mark A. van Buchem, Steven M. Greenberg, M. Edip Gurol Manuscript Writing: Steven M. Greenberg, M. Edip Gurol Critical Review of the Manuscript: Panagiotis Fotiadis, Sanneke van Rooden, Jeroen van der Grond, Aaron Schultz, Sergi MartinezRamirez, Eitan Auriel, MD, Yael Reijmer, Anna M. van Opstal, Alison Ayres, Kristin M. Schwab, the Alzheimer's Disease Neuroimaging Initiative, Trey Hedden, Jonathan Rosand, Anand Viswanathan, Marieke Wermer, Gisela Terwindt, Reisa A. Sperling, Jonathan R. Polimeni, Keith A. Johnson, Mark A. van Buchem Conflicts of Interest No other conflicts of interest by any other author related to this study.
Fotiadis et al.
Page 2
Abstract Author Manuscript
Background—We postulated that Cerebral Amyloid Angiopathy (CAA), characterized by cortical vascular amyloid deposits, is associated with cortical tissue loss independent of parenchymal Alzheimer pathology. Patients with hereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA-D), a monogenetic model of essentially pure CAA with minimal or no concomitant Alzheimer pathology, constitute a unique disease model to test this hypothesis.
Author Manuscript
Methods—In this observational case-control study, the primary outcome measure, the cortical thickness of prospectively enrolled patients diagnosed with HCHWA-D using genetic testing and non-demented patients with probable CAA according to Boston criteria was compared to relevant age-matched contrast groups including healthy controls (HC) and Alzheimer's Disease (AD), the latter diagnosed with National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. The data were collected at Massachusetts General Hospital in Boston MA, at Leiden University in Netherlands, and sites contributing to Alzheimer's Disease Neuroimaging Initiative (ADNI). The correlations between cortical thickness and structural lesions as well as Blood-Oxygen-Level-Dependent Time-to-Peak (BOLD-TTP, a physiologic measure of vascular dysfunction) were sought to understand the potential mechanistic link.
Author Manuscript
Results—Data were collected from March 15, 2006 to December 1, 2014. Patients with HCHWA-D (n=26) had thinner cortices (2.31mm± 0.18) compared to their HC (n=28) group (mean difference [MD]= −0.112, 95% confidence interval [CI] −0.190, −0.034, p=0.006). Nondemented sporadic CAA patients (n=63) had globally thinner cortices (2.17±0.11) compared to the two HC (n=63 and n=126) cohorts (MD=−0.14, 95% CI −0.17, −0.10 and MD=−0.10, 95% CI −0.13, −0.06, pGln `Dutch' mutation on the production and stability of amyloid beta-protein. The Biochemical journal. 1999; 340(Pt 3):703–709. [PubMed: 10359654] 18. Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology. 2001; 56:537–539. [PubMed: 11222803] 19. Dagley A, LaPoint M, Huijbers W, et al. Harvard Aging Brain Study: Dataset and accessibility. NeuroImage. 2015 20. Jack CR Jr, Bernstein MA, Fox NC, et al. The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods. J Magn Reson Imaging. 2008; 27:685–691. [PubMed: 18302232] 21. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. NeuroImage. 1999; 9:179–194. [PubMed: 9931268] 22. Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. NeuroImage. 1999; 9:195–207. [PubMed: 9931269] 23. Segonne F, Dale AM, Busa E, et al. A hybrid approach to the skull stripping problem in MRI. NeuroImage. 2004; 22:1060–1075. [PubMed: 15219578] 24. Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A. 2000; 97:11050–11055. [PubMed: 10984517] 25. Salat DH, Buckner RL, Snyder AZ, et al. Thinning of the cerebral cortex in aging. Cerebral cortex. 2004; 14:721–730. [PubMed: 15054051] 26. Destrieux C, Fischl B, Dale A, Halgren E. Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature. NeuroImage. 2010; 53:1–15. [PubMed: 20547229] 27. Fischl B, Salat DH, Busa E, et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002; 33:341–355. [PubMed: 11832223] 28. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. The Lancet Neurology. 2009; 8:165–174. [PubMed: 19161908]
Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 12
Author Manuscript Author Manuscript
29. Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. Journal of personality and social psychology. 1986; 51:1173–1182. [PubMed: 3806354] 30. Sobel, ME. Asymptotic intervals for indirect effects in structural equations models. In: Leinhart, S., editor. Sociological methodology. Jossey-Bass; San Francisco: 1982. p. 290-312. 31. Bornebroek M, Haan J, Van Duinen SG, et al. Dutch hereditary cerebral amyloid angiopathy: structural lesions and apolipoprotein E genotype. Ann Neurol. 1997; 41:695–698. [PubMed: 9153536] 32. Jouvent E, Mangin JF, Duchesnay E, et al. Longitudinal changes of cortical morphology in CADASIL. Neurobiol Aging. 2012; 33:1002, e1029–1036. 33. Greenberg SM, Grabowski T, Gurol ME, et al. Detection of isolated cerebrovascular beta-amyloid with Pittsburgh compound B. Ann Neurol. 2008; 64:587–591. [PubMed: 19067370] 34. Johnson KA, Gregas M, Becker JA, et al. Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol. 2007; 62:229–234. [PubMed: 17683091] 35. Gurol ME, Dierksen G, Betensky R, et al. Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy. Neurology. 2012; 79:320–326. [PubMed: 22786597] 36. Dickerson BC, Bakkour A, Salat DH, et al. The cortical signature of Alzheimer's disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals. Cerebral cortex. 2009; 19:497– 510. [PubMed: 18632739] 37. Gregg NM, Kim AE, Gurol ME, et al. Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals. JAMA neurology. 2015; 72:1021–1028. [PubMed: 26167811] 38. Samuraki M, Matsunari I, Yoshita M, et al. Cerebral Amyloid Angiopathy-Related Microbleeds Correlate with Glucose Metabolism and Brain Volume in Alzheimer's Disease. Journal of Alzheimer's disease : JAD. 2015; 48:517–528. [PubMed: 26402015] 39. Maat-Schieman M, Roos R, van Duinen S. Hereditary cerebral hemorrhage with amyloidosisDutch type. Neuropathology. 2005; 25:288–297. [PubMed: 16382777]
Author Manuscript Author Manuscript Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 13
Author Manuscript
PANEL: Research in context Evidence before this study
Author Manuscript
We searched PubMed for articles on cerebral amyloid angiopathy (CAA) and cortical atrophy published between Jan 1, 1990, and Nov 1, 2015, with different combinations of the terms “cerebral amyloid angiopathy”, “cortical atrophy”, “cortical thickness”, ”cortical damage”. We have not found any article that addressed the association between CAA and cortical atrophy. We have then repeated PubMed searches within the same time interval using combinations of the term “cerebral amyloid angiopathy” and each one of the following terms: “leukoaraiosis”, “white matter”, “structural networks”, and “subcortical injury”. We have found multiple articles that established associations between CAA and subcortical tissue damage but the association of CAA and cortical atrophy was unknown. A major obstacle in clarifying this latter association has been the relatively common coexistence of CAA and parenchymal Alzheimer's Disease (AD) pathology, the latter being a well-established cause of cortical atrophy. Added value of this study This prospective study shows that patients with hereditary cerebral hemorrhage with amyloidosis–Dutch type, a monogenetic model of essentially pure CAA with minimal or no concomitant parenchymal AD pathology, have decreased cortical thickness when compared to age-matched controls. These findings were confirmed when comparing a well-defined cohort of common sporadic CAA patients to age-matched elderly controls. Mediation analyses also showed that vascular dysfunction explained at least part of the effect of CAA on cortical atrophy.
Author Manuscript
Implications of all the available evidence
Author Manuscript
Autopsy and imaging based studies show that vascular amyloid pathology and lobar microbleeds, the hallmarks of CAA, are common findings in otherwise healthy older adults as well as patients with mild cognitive symptoms. Multiple lines of evidence suggest that CAA is an important contributor to subcortical tissue injury through vascular dysfunction and ischemia. Cerebral amyloid angiopathy is also a well-established contributor to cognitive impairment in elderly, independent of intracerebral hemorrhages that constitute the other important consequences of the vascular amyloid. Our study for the first time suggests that CAA might also cause global cortical atrophy, an effect that might at least in part be mediated by vascular dysfunction. These new findings are important in better understanding the mechanisms of cerebral damage in CAA as they can potentially mediate disabling clinical effects and even confound therapeutic efforts. For example, some of the immunotherapies studied for Alzheimer's Disease resulted in superficial cerebral microbleeds typical of CAA and accelerated atrophy was observed in multiple antibody trials. Based on all available evidence, CAA will need to be taken into consideration in future efforts to develop therapies for AD and cognitive impairment.
Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 14
Author Manuscript Author Manuscript
Figure 1.
Topographic surface maps showing differences in cortical thickness between patients with hereditary cerebral hemorrhage with amyloidosis–Dutch type and their age-matched controls
Author Manuscript Author Manuscript Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 15
Author Manuscript Author Manuscript
Figure 2.
Topographic surface maps showing differences in cortical thickness between patients with sporadic cerebral amyloid angiopathy and their age-matched controls
Author Manuscript Author Manuscript Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 16
Table 1
Author Manuscript
Comparisons between hereditary CAA and healthy controls Hereditary CAA Patients (n = 26)
Healthy Controls (n = 28)
Demographics Age (mean ± SD)
45.8 ± 14
47.5 ± 12
# Female patients (%)
16 (61.5%)
17 (60.7%)
Cortical Thickness in mm, (mean ± SD)
2.31 ± 0.18
2.42 ± 0.1 p=0.006
HV % of ICV (mean ± SD)
0.54 ± 0.13
0.58 ± 0.07 p=0.113
Outcomes
The p values result from comparison to the same measure in the Hereditary CAA cohort CAA: cerebral amyloid angiopathy
Author Manuscript
HV % of ICV: Hippocampal volume percent of intracranial volume
Author Manuscript Author Manuscript Lancet Neurol. Author manuscript; available in PMC 2017 July 01.
Fotiadis et al.
Page 17
Table 2
Author Manuscript
Comparisons between sporadic CAA and contrast groups Sporadic CAA Patients (n = 63)
ADNI Healthy Controls (n = 63)
HAB Healthy Controls (n = 126)
ADNI AD Patients (n = 63)
Demographics Age (mean ± SD)
72.2 ± 5
72.3 ± 5
72.4 ± 5
72.2 ± 5
# Female patients (%)
14 (22.2%)
27 (42.9%)
54 (42.9%)
20 (31.7%)
Cortical Thickness in mm (mean ± SD)
2.17 ± 0.11
2.31 ± 0.07 p
