Abstract 6: The Effect of Vascular Amyloid on White Matter Disease is Mediated by Vascular Dysfunction in Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is associated with white matter hyperintensities (WMH) but the physiopathological mechanisms remain unclear. We hypothesized that the relationship between vascular amyloid load and WMH is mediated by vascular dysfunction. Methods: The study cohort included 38 non-demented probable CAA patients who underwent advanced multimodal structural and functional MRI (fMRI) and amyloid PET scans. White matter hyperintensity volume was quantified using FreeSurfer and expressed as a percent of total intracranial volume (pWMHv). Time-to-peak [TTP] of blood oxygen level-dependent [BOLD] response to visual stimulation using fMRI was used as an established measure of vascular dysfunction. Mean cortical Pittsburg Compound B uptake representing amyloid load was calculated. A bootstrapping procedure was used to test the mediation hypothesis adjusting for age, sex, and presence of intracerebral hemorrhage (ICH). Results: Of 38 patients with CAA (mean age 70±7.1, 86.8% male), 25 (65.8%) had ICH, while the remaining 13 patients (34.2%) presented with multiple strictly cortical microbleeds. Higher amyloid load correlated with prolonged TTP response (r=0.373, p=0.021) and higher pWMHv (r=0.337, p=0.039), and prolonged TTP response correlated with higher pWMHv (r=0.485, p=0.002). Amyloid load no longer predicted pWMHv (p=0.254) after controlling for TTP. In the bootstrapping model, TTP response had a significant indirect effect (ab=0.977, 95% CI: 0.15-2.42), showing that the association between amyloid load and pWMHv is mediated by TTP. Discussion: Our findings confirm the hypothesis that the effect of vascular amyloid load on the extent of white matter disease is mediated by vascular dysfunction in patients with CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.

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Abstract 47: White Matter Atrophy in Cerebral Amyloid Angiopathy

Stroke ◽

10.1161/str.47.suppl_1.47 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Panagiotis Fotiadis ◽

Aaron Schultz ◽

Trey Hedden ◽

Sergi Martinez-Ramirez ◽

Yael Reijmer ◽

...

Keyword(s):

White Matter ◽

Cerebral Amyloid Angiopathy ◽

Cortical Thickness ◽

Tissue Loss ◽

White Matter Hyperintensity ◽

Aging Brain ◽

Amyloid Angiopathy ◽

Intracranial Volume ◽

White Matter Volume ◽

Cerebral Amyloid

Background/Purpose: Cerebral Amyloid Angiopathy (CAA) leads to leukoaraiosis, lacunar infarcts and cortical tissue loss. We hypothesized that CAA is also associated with white matter atrophy (WMA). Methods: We have compared volumetric multimodal MRIs from 72 prospectively enrolled non-demented patients with probable CAA (per Boston criteria), to 3 other well-studied cohorts: 289 Healthy Controls (HC) from the Harvard Aging Brain (HAB) study, 231 HC and 198 patients with AD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Validated FreeSurfer algorithms were used to calculate White Matter Volume (WMV), white matter hyperintensity volume (WMHv), and cortical thickness. Microbleeds (MBs) were counted on SWI-MRI. Measures were obtained from the contralateral hemisphere if intracerebral hemorrhage present. All volumes were corrected for total intracranial volume (ICV), so reported as percent of ICV. Results: The CAA patients were significantly younger (mean age: 70.1) compared to both HC cohorts (ADNI-HC: 76.0, p<0.001, HAB-HC: 73.8, p < 0.001), and to patients with AD (75.5, p < 0.001). Despite being younger, patients with CAA presented significantly lower global WMV (28% ± 2.6) than both ADNI-HC (29.2% ± 2.2, p < 0.001), HAB-HC (29.0% ± 2.5, p = 0.001), and patients with AD (28.7% ± 2.2, p = 0.02) [Figure]. The association persisted after correcting for age, gender and WMHv. Within the CAA cohort, there was a negative correlation between WMV and lobar MB counts (rho = -0.26, p = 0.03), it remained significant after correcting for age, gender, WMHv (p=0.016). There were no significant associations however between WMV and neither WMHv, nor cortical thickness (both p>0.2). Conclusions: Patients with CAA show WMA when compared to older HC and AD. WMA independently correlates with MBs, a marker of CAA severity. Consistent spatial patterns of atrophy especially in posterior regions when compared to both HC and AD [Figure] might represent the “WMA signature of CAA”.

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White matter atrophy in cerebral amyloid angiopathy

Neurology ◽

10.1212/wnl.0000000000010017 ◽

2020 ◽

Vol 95 (5) ◽

pp. e554-e562 ◽

Cited By ~ 1

Author(s):

Panagiotis Fotiadis ◽

Yael D. Reijmer ◽

Susanne J. Van Veluw ◽

Sergi Martinez-Ramirez ◽

Fikret Isik Karahanoglu ◽

...

Keyword(s):

Executive Function ◽

White Matter ◽

Cerebral Amyloid Angiopathy ◽

Amyloid Angiopathy ◽

Intracranial Volume ◽

White Matter Volume ◽

Cognitive Changes ◽

Important Mediator ◽

Multivariable Analyses ◽

Cerebral Amyloid

ObjectiveWe postulated that cerebral amyloid angiopathy (CAA) is associated with white matter atrophy (WMA) and that WMA can be related to cognitive changes in CAA.MethodsWhite matter volume expressed as percent of intracranial volume (pWMV) of prospectively enrolled patients without dementia diagnosed with probable CAA was compared to age-matched healthy controls (HC) and patients with Alzheimer disease (AD). Cognitive scores were also sought to understand the potential effects of WMA on cognitive function.ResultsPatients with CAA (n = 72) had significantly lower pWMV (27.97% ± 2.63) when compared to age-matched HC (n = 72; mean difference [MD], 2.38%; p < 0.0001) and patients with AD (n = 72; MD, 1.57%; p < 0.0001). Differences were most pronounced in the posterior occipital regions in both comparisons. When comparisons were restricted to groups of patients with CAA but no intracerebral hemorrhage (n = 32) or hypertension (n = 32), and age-matched HC and AD, the significant differences were unaltered. Within the CAA cohort, higher age, lobar microbleed counts, and presence of hypertension were associated with lower pWMV (p = 0.0007, p = 0.031, and p = 0.003, respectively). All associations remained independent in multivariable analyses. Within the CAA cohort, higher pWMV independently correlated with better scores of executive function.ConclusionsPatients with CAA show WMA when compared to age-matched HC and patients with AD. WMA independently correlates with the number of lobar microbleeds, a marker of CAA severity. Consistent spatial patterns of WMA especially in posterior regions might be related to CAA. The association between WMA and measures of executive function suggests that WMA might represent an important mediator of CAA-related neurologic dysfunction.

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Cerebral Amyloid Angiopathy, Subcortical White Matter Disease and Dementia: Literature Review and Study in OPTIMA

Brain Pathology ◽

10.1111/bpa.12221 ◽

2014 ◽

Vol 25 (1) ◽

pp. 51-62 ◽

Cited By ~ 33

Author(s):

Margaret Esiri ◽

Steven Chance ◽

Catharine Joachim ◽

Donald Warden ◽

Aidan Smallwood ◽

...

Keyword(s):

White Matter ◽

Literature Review ◽

Cerebral Amyloid Angiopathy ◽

Subcortical White Matter ◽

Amyloid Angiopathy ◽

White Matter Disease ◽

Cerebral Amyloid

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Abstract 9: Peak Width of Skeletonized Mean Diffusivity and Cognition in Cerebral Amyloid Angiopathy

Stroke ◽

10.1161/str.52.suppl_1.9 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Mitchell J Horn ◽

Elif Gokcal ◽

J. A Becker ◽

Alvin S Das ◽

Kristin Schwab ◽

...

Keyword(s):

White Matter ◽

Regression Model ◽

Cerebral Amyloid Angiopathy ◽

Mean Diffusivity ◽

Multiple Regression Model ◽

Amyloid Angiopathy ◽

Peak Width ◽

Symbol Substitution ◽

Relevant Variables ◽

Cerebral Amyloid

Background: We hypothesized that Peak Width of Skeletonized Mean Diffusivity (PSMD), an automated marker of cerebral microangiopathy representing microstructural disruption of white matter (WM), would be increased in patients with cerebral amyloid angiopathy (CAA) compared to healthy controls (HCs) and increased PSMD would be associated with lower processing speed scores (PSSs) in patients with CAA. Methods: Seventy-two nondemented probable CAA patients and 23 HCs prospectively underwent high-resolution brain MRIs and cognitive tests. PSMD scores were quantified from a probabilistic skeleton of the WM tracts as previously validated (http://www.psmd-marker.com). In subjects with intracerebral hemorrhage (ICH, n=27), ICH regions were masked and removed from the PSMD pipeline. The analyses were repeated in the non-ICH hemisphere. Raw scores of Trail Making Test-B and Symbol Substitution Test were transformed into standardized z -scores and averaged to obtain PSSs. Results: The mean age (p=0.366) and sex (p=0.811) were similar between CAA patients and HCs. PSMD was higher in the CAA group [(3.95±0.9) х 10 –4 mm 2 /s] compared to HCs [(3.32±0.6) х 10 –4 mm 2 /s] (p=0.003). This association remained significant in a linear regression model corrected for age and sex (β=0.700, 95%CI 0.3-1, p=0.001). Within the CAA cohort, higher PSMD was associated with higher WM hyperintensity volume in a multiple regression model adjusted for all relevant variables (β=0.890, 95%CI 0.7-1, p<0.001). In a regression model corrected for age, sex, years of education and presence of ICH, a lower PSS was independently associated with increased PSMD (β=-0.405, 95%CI {-0.6}-{-0.2}, p<0.001). These results did not change when the non-ICH hemisphere was used for PSMD processing. Conclusion: PSMD is increased in CAA and is associated with worse PSSs supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA.

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Amyloid-PET in cerebral amyloid angiopathy

Neurology ◽

10.1212/wnl.0000000000004548 ◽

2017 ◽

Vol 89 (14) ◽

pp. 1437-1438 ◽

Cited By ~ 1

Author(s):

Nicolas Raposo ◽

Joshua A. Sonnen

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Amyloid Angiopathy ◽

Amyloid Pet ◽

Cerebral Amyloid

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Abstract 36: The Boston Criteria V2.0 for Cerebral Amyloid Angiopathy: Updated Criteria and Multicenter MRI-Neuropathology Validation

Stroke ◽

10.1161/str.52.suppl_1.36 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Andreas Charidimou ◽

Gregoire Boulouis ◽

Matthew Frosch ◽

Jean-Claude Baron ◽

Marco Pasi ◽

...

Keyword(s):

White Matter ◽

Intracerebral Hemorrhage ◽

Diagnostic Accuracy ◽

Cerebral Amyloid Angiopathy ◽

Brain Mri ◽

Amyloid Angiopathy ◽

Perivascular Spaces ◽

Validation Sample ◽

Temporal Validation ◽

Cerebral Amyloid

Introduction: The Boston criteria are used worldwide for in vivo diagnosis of cerebral amyloid angiopathy (CAA). Given substantial advances in CAA research, we aimed to update the Boston criteria and externally validate their diagnostic accuracy across the spectrum of CAA-related presentations and across international sites. Methods: As part of an International CAA Association multicenter study, we identified patients age 50 or older with potential CAA-related clinical presentations (spontaneous intracerebral hemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathologic assessment for the diagnosis of CAA. We derived Boston criteria v2.0 by selecting MRI features to optimize diagnostic specificity and sensitivity in a pre-specified derivation sample (Boston cases 1994 to 2012, n=159), then externally validated in pre-specified temporal (Boston cases 2012-2018, n=59) and geographical (non-Boston cases 2004-2018; n=123) validation samples and compared their diagnostic accuracy to the currently used modified Boston criteria. Results: Based on exploratory analyses in the derivation sample, we derived provisional criteria for probable CAA requiring presence of at least 2 strictly lobar hemorrhagic lesions (intracerebral hemorrhage, cerebral microbleed, or cortical superficial siderosis focus) or at least 1 strictly lobar hemorrhagic lesion and 1 white matter characteristic (severe degree of visible perivascular spaces in centrum semiovale or white matter hyperintensities multispot pattern). Sensitivity/specificity of the criteria were 74.8/84.6% in the derivation sample, 92.5/89.5% in the temporal validation sample, 80.2/81.5% in the geographic validation sample, and 74.5/95.0% in cases across all samples with autopsy as the diagnostic gold standard. The v2.0 criteria for probable CAA had superior accuracy to the currently modified Boston criteria (p<0.005) in the autopsied cases. Conclusion: The Boston criteria v.2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their high specificity. Validation of the criteria across independent patient settings firmly supports their adoption into clinical practice and research.

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