Journal of Cerebral Blood Flow & Metabolism (2015), 1–10 © 2015 ISCBFM All rights reserved 0271-678X/15 $32.00 www.jcbfm.com

REVIEW ARTICLE

Ischemic brain injury in cerebral amyloid angiopathy Yael D Reijmer1, Susanne J van Veluw1,2 and Steven M Greenberg1 Cerebral amyloid angiopathy (CAA) is a common form of cerebral small vessel disease and an important risk factor for intracerebral hemorrhage and cognitive impairment. While the majority of research has focused on the hemorrhagic manifestation of CAA, its ischemic manifestations appear to have substantial clinical relevance as well. Findings from imaging and pathologic studies indicate that ischemic lesions are common in CAA, including white-matter hyperintensities, microinfarcts, and microstructural tissue abnormalities as detected with diffusion tensor imaging. Furthermore, imaging markers of ischemic disease show a robust association with cognition, independent of age, hemorrhagic lesions, and traditional vascular risk factors. Widespread ischemic tissue injury may affect cognition by disrupting white-matter connectivity, thereby hampering communication between brain regions. Challenges are to identify imaging markers that are able to capture widespread microvascular lesion burden in vivo and to further unravel the etiology of ischemic tissue injury by linking structural magnetic resonance imaging (MRI) abnormalities to their underlying pathophysiology and histopathology. A better understanding of the underlying mechanisms of ischemic brain injury in CAA will be a key step toward new interventions to improve long-term cognitive outcomes for patients with CAA. Journal of Cerebral Blood Flow & Metabolism advance online publication, 6 May 2015; doi:10.1038/jcbfm.2015.88 Keywords: amyloid angiopathy; brain imaging; dementia; focal ischemia; vascular cognitive impairment

INTRODUCTION Cerebral amyloid angiopathy (CAA) is a common small vessel disease (SVD) and refers to the accumulation of β-amyloid (Aβ) in the walls of cortical blood vessels. It is traditionally known as a primary cause of intracerebral hemorrhage (ICH).1 In recent years, CAA has also been identified as an important risk factor for vascular cognitive impairment and dementia.2 Autopsy series have shown that the prevalence of CAA is about twice as high in cases with dementia compared with those without.3,4 The relatively high prevalence of CAA among cases with dementia has led many to postulate that CAA affects cognition through its deleterious effect on the cerebral microvasculature. However, the exact mechanisms by which CAA affects cognition are not firmly established. Besides hemorrhagic brain injury, CAA is associated with widespread ischemic tissue injury, including white-matter hyperintensities (WMHs) and microinfarcts.5–9 Some of these ischemic lesions are not visible on conventional magnetic resonance imaging (MRI), and their prevalence in CAA has therefore long been underestimated.10 To unravel the potential role of ischemic brain injury in CAA, researchers have aimed to identify new imaging markers that are able to capture these subtle vascular lesions in vivo. Studies using high-resolution brain MRI techniques and diffusion imaging methods show promising results. The identification of these new imaging markers and their validation by clinical–pathological studies is critical to understand disease mechanisms and progression, and to evaluate the efficacy of candidate treatment approaches. This review focuses on findings from neuroimaging and autopsy studies on ischemic cerebral SVD in CAA and discusses the role of ischemic SVD in CAA-related cognitive impairment. Improved

understanding of the ischemic effects of advanced CAA would have substantial implications for prevention and treatment of vascular cognitive impairment in future clinical trials.

PATHOLOGIC MANIFESTATION OF CEREBRAL AMYLOID ANGIOPATHY Sporadic CAA is a frequent pathologic finding in the elderly human brain. Results from autopsy studies suggest that any form of CAA occurs in about 25% of adults 470 years and in 50% to 80% of cases with dementia.3,11–13 Moderate-to-severe CAA occurs in about 15% of older adults and 30% of cases with dementia.4,12,13 There are also several hereditary forms of CAA, but those are rare (see for review, e.g., Zhang-Nunes et al14). Cerebral amyloid angiopathy is characterized by the accumulation of Aβ in the vessel wall of small cortical and leptomeningeal arteries and arterioles, and to a lesser extent in the wall of cortical capillaries.15,16 The process of Aβ accumulation in CAA is not fully understood. An earlier theory suggested that Aβ in CAA directly originates from smooth muscle cells in the vessel wall.17,18 More recent models have suggested that Aβ in CAA is predominantly generated by neurons19–21 and subsequently deposited in the vessel wall because of impairment in Aβ clearance. Impaired Aβ clearance may be caused by alterations in perivascular drainage pathways22–24 and deficits in endothelial-mediated active transport of Aβ into the blood.25 Factors such as age-related arterial stiffening may contribute to the failure of perivascular drainage of Aβ.23 Pathologic examination of blood vessels in both sporadic and familial CAA shows degeneration of smooth muscle cells, vessel wall thickening, luminal narrowing, concentric splitting of the

1 Department of Neurology, Hemorrhagic Stroke Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA and 2Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. Correspondence: Dr YD Reijmer, J.P. Kistler Stroke Research Center, 175 Cambridge Street, Suite 300, Boston, Massachusetts 02114, USA. E-mail: [email protected] Greenberg receives research support from National Institutes of Health (R01 AG26484 and R01 NS070834). Reijmer receives research support from the American Heart Association (14POST20010031). Received 7 January 2015; revised 24 March 2015; accepted 26 March 2015

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Figure 1. Common ischemic lesions in patients with cerebral amyloid angiopathy (CAA). (A) White-matter hyperintensities on FLAIR; often following a predominantly posterior distribution in line with the posterior distribution of vascular amyloid pathology. (B) A small focal hyperintense lesion on diffusion weighted imaging (DWI), indicative of an acute microinfarct. (C) A chronic cortical microinfarct reflected by a hyperintense signal on 7-Tesla fluid attenuated inversion recovery. (D) A fractional anisotropy (FA) map reflecting the degree of anisotropic diffusion of water molecules. FA values are used to study alterations in white-matter microstructure not visible to the naked eye.

vessel wall, microaneurysm formation, perivascular microhemorrhages, and perivascular leakage of blood products.16,26–28 Cerebral amyloid angiopathy is often quantified based on the level of severity: mild, moderate, and severe CAA,12,16,29 though definitions vary substantially across different investigators. Moderate CAA is often defined as circumferential staining of Aβ in leptomeningeal and cortical blood vessels, while severe CAA is usually characterized by additional vascular pathologies such as concentric splitting of the vessel wall (double barreling) or appearance of Aβ in the perivascular neuropil (dyshoric changes).12,16,29 Moderate-to-severe CAA seems to be most strongly associated with clinical symptoms.12 Cerebral amyloid angiopathy is not equally distributed throughout the brain, but predominantly affects vessels in posterior cortical brain regions,8,30 whereas vessels in the brain stem and basal ganglia are relatively spared.8,11,26 Although in some very severe cases, CAA can also be found in the deep gray-matter regions.31 RADIOLOGIC MANIFESTATION OF CEREBRAL AMYLOID ANGIOPATHY: HEMORRHAGIC AND ISCHEMIC BRAIN INJURY A definite diagnosis of CAA can only be made through biopsy or autopsy, however, clinical diagnostic criteria called the Boston Journal of Cerebral Blood Flow & Metabolism (2015), 1 – 10

criteria, allow researchers to diagnose CAA during life with high specificity (88% to 92%).32,33 According to these criteria probable CAA is defined by the presence of multiple strictly lobar hemorrhages on T2* gradient-recalled echo or susceptibility weighted MRI. These may involve both macro-hemorrhages and micro-hemorrhages,34 herein referred to as ‘ICH’ and ‘microbleeds’, respectively. Radiologic–histopathologic studies have confirmed that microbleeds often reflect hemosiderin deposits from old microhemorrhages, and sometimes acute extravasations of red blood cells, although not invariably.35,36 More information on hemorrhagic lesions in CAA can be found in, e.g., Greenberg et al,37 Cordonnier et al,38 and Charidimou et al.39 Besides markers of hemorrhagic brain injury, CAA is associated with a wide range of imaging abnormalities that are assumed to be of ischemic origin, including WMH, microinfarcts, and alterations in diffusion tensor imaging (DTI) measures (Figure 1). Below we will discuss these less well-studied ischemic imaging markers of CAA and their relationship with CAA-related pathology. White-Matter Hyperintensities White-matter hyperintensities of presumed vascular origin can be detected on brain imaging as hyperintense lesions on T2© 2015 ISCBFM

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weighted MRI.40 They have shown to be more severe in individuals diagnosed with CAA than in clinically healthy older adults or in patients with Alzheimer’s disease.5,7 In cases with advanced CAA, WMH volume has shown to increase rapidly over time (18% increase in 1 to 2 years).41 The pathogenesis of WMH is heterogeneous and can involve ischemia, demyelination, and axonal loss.42–44 Pathologic examination of WMH in the brains of cases with CAA suggests an ischemic origin.9,45,46 One serial imaging study in patients with SVD showed that small silent acute infarcts approach the signal characteristics of WMH within a period of 16 weeks, indicating that WMH may partly be formed by tiny infarcts.47 Increased WMH volume in patients with CAA has been related to lower cerebral perfusion.7 Importantly, moderateto-severe WMH is also a frequent finding in adults with hereditary CAA (40 to 60 years) without a history of cardiovascular disease.48 At autopsy, the severity of the white-matter changes has shown to correlate with the severity of the vascular Aβ load.45 This finding was consistent with a recent imaging study using PiB (Pittsburg compound B) positron emission tomography (PET). Pittsburg compound B is a radiologic marker of amyloid plaques used to quantify cerebral amyloid load in vivo.49–51 Results showed a positive correlation between WMH volume and cortical PiB uptake in patients with CAA, but not in patients with Alzheimer’s disease or healthy elderly controls,5 suggesting a direct relationship between subcortical WMH and cortical CAA pathology. Furthermore, two studies found that the distribution of WMH in patients with CAA is predominantly posterior, in line with the predominant posterior distribution of CAA-related vascular amyloid.52,53 The robust association between CAA and WMH raises the intriguing question how Aβ deposits in cortical vessels can affect vascular territories in the deep white matter; or possibly, whether ischemic subcortical disease can trigger cortical Aβ deposition (See ‘Pathophysiologic mechanisms of ischemia’). Microinfarcts Microinfarcts are defined as microscopic regions (up to a few mm in dimension) of cellular death or tissue necrosis, sometimes with cavitation.10,54 At pathologic examinations, microinfarcts have consistently been found to be more common in CAA compared with nonCAA cases.6,8,9,55,56 Although microinfarcts are more frequent in CAA, the relationship with CAA severity is not entirely clear. Some neuropathologic studies found a correlation between CAA severity and microinfarct burden,13,56,57 but others were not been able to show such a relationship.6,8,9,58 One explanation for this might be the large number of factors that can cause microinfarcts in addition to CAA, such as arteriolosclerosis, microembolisms, hypertension, and hypotensive episodes as well as the limited amount of brain tissue that is generally sampled for neuropathologic evaluation, which makes it difficult to estimate the total infarct burden. Because of their small size, the majority of microinfarcts are not visible on conventional MRI scans.54 However, the cytotoxic edema that occurs in the acute phase of the infarct (first 1 to 2 weeks), can be visible on MRI as hyperintense foci of restricted diffusion on diffusion-weighted imaging (DWI). Focal DWI lesions have shown to be more common in patients with CAA-related ICH (15% to 23%) than in patients with Alzheimer’s disease and controls59,60 and continue to occur in high frequency beyond the post-ICH period.61 Importantly, DWI lesions have been found to be associated with other imaging markers of CAA (i.e., WMH volume and lobar microbleeds), but not with traditional vascular risk factors such as hypertension.59,60 Furthermore, DWI lesions in the white matter have found to cause chronic local microstructural injury.62 The fact that these DWI lesions are a frequent finding in CAA despite the short time window in which they remain visible has led to the belief that they are the most prevalent of all infarct types10,61,63 and therefore may have a substantial impact on © 2015 ISCBFM

cognitive functioning.12,64–66 The hypothesis that microinfarcts occur in large numbers in patients with CAA is supported by a recently developed mathematical model used to estimate the total microinfarct burden based on the number of microinfarcts found on routine postmortem examination.63 The model predicted that one or two microinfarcts on routine postmortem examination of an autopsied brain indicate hundreds to thousands of microinfarcts throughout the whole brain. The cumulative effect of these microinfarcts on the brain forms therefore a potential mechanism through which CAA can contribute to vascular cognitive impairment. The introduction of high field strength MRI makes it possible to detect some of the chronic microinfarcts in vivo. Recent radiologic– pathologic studies have shown that microinfarcts of approximately 1 to 2 mm can be detected on 3- and 7- Tesla in vivo MRI scans (Figure 1C).67,68 However, microinfarcts can be as small as 100 microns,54,63 thus a large proportion of these lesions remain invisible on brain imaging.10 The rapid development of imaging techniques and optimization of T1- and T2*-weighted MRI sequences, both on 7 Tesla and on lower field strength MRI, makes it likely that we will be able to quantify smaller lesions in vivo in the near future.69–71 Diffusion Tensor Imaging Microvascular tissue damage may also be detected with DTI. Diffusion tensor imaging is an MRI technique that can quantify alterations in the white-matter tissue at a microscopic scale by characterizing the diffusion of water molecules within the brain.72 Damage to tissue structure caused by, for example, demyelination or axonal loss will lead to alterations in the diffusion of water molecules reflected by a change in mean diffusivity (MD) and fractional anisotropy (FA). A limitation of DTI is its low specificity to pathology. Tissue properties unrelated to pathology such as the organization of axonal fibers can also cause changes in DTI parameters.72 Nevertheless, strong evidence exists that DTI is able to quantify vascular-related pathology. Changes in FA and MD within the white matter have robustly been shown in patients with SVD, both within WMH and in the so-called normal appearing white matter.73–75 In population-based cohorts, alterations in DTI parameters have been associated with an unfavorable vascular risk factor profile.76,77 Diffusion tensor imaging parameters have also found to be altered in patients with probable CAA (Figure 2).78–80 A recent study showed that diffusion abnormalities in CAA resemble the distribution of CAA pathology: betweengroup differences in FA were observed in white-matter tracts projecting onto the posterior cortex (i.e., the occipital, posterior temporal, and parietal lobes), whereas tracts projecting onto subcortical regions were relatively spared (Figure 2A).80 Furthermore, impairments in whole-brain white matter connectivity in CAA patients correlated with SVD burden on MRI (i.e., WMH, microbleeds, and total brain volume) and with cortical amyloid load as quantified with PiB positron emission tomography imaging.80 These findings suggest that CAA-related vasculopathy can indeed be captured with DTI. The CAA patients included in the aforementioned DTI studies were symptomatic with relatively high vascular lesion burden.78,80 A relevant question is whether DTI can also detect CAA-related abnormalities before the disease becomes symptomatic. In the Rotterdam study, a population-based study of older adults, strictly lobar microbleeds, suggestive of clinically silent CAA, was associated with altered FA and MD values.81 The association with FA/MD increased with higher lobar microbleed counts and was not explained by cardiovascular risk factors and other imaging markers of SVD. Furthermore, the association between lobar microbleeds and DTI parameters was confined to Apolipoprotein E4 carriers,81 an established genetic risk factor for CAA.82 Journal of Cerebral Blood Flow & Metabolism (2015), 1 – 10

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Figure 2. Two examples of white-matter injury in cerebral amyloid angiopathy (CAA) detected with diffusion tensor imaging (DTI). (A) DTIbased brain network analysis80 shows local differences in connectivity strength between patients with CAA (n = 38) compared with agematched controls (n = 29). Whole brain fiber tractography results were registered to a gray-matter atlas. Regional connectivity strength was defined as the mean fractional anisotropy (FA) of white-matter connections projecting to that node. Results show that tracts projecting to occipital, parietal, and temporal regions are most affected, whereas tracts projecting to subcortical regions are relatively spared. (B) Longitudinal region of interest (ROI)-based DTI analysis62 found that hyperintense lesions on diffusion-weighted imaging (DWI), indicative of acute microinfarcts, were associated with increases in normalized mean diffusivity (MD) at the location of the lesion (P o0.05; n = 9).

Overall, these findings support the possibility that DTI can capture CAA-related microvascular pathology, also in earlier stages of the disease. However, which structural properties drive the previously reported DTI findings remains an open question. Radiological–pathologic studies are needed to determine whether, e.g., microinfarct burden, axonal degeneration, or demyelination explains the alterations in DTI parameters in patients with SVD. PATHOPHYSIOLOGIC MECHANISMS OF ISCHEMIA IN CEREBRAL AMYLOID ANGIOPATHY The co-occurrence of hemorrhagic and ischemic brain lesions in CAA, in the absence of cardiovascular risk factors, has led to the belief that advanced CAA can cause both hemorrhagic and ischemic brain injury. One intuitive explanation is that CAA heightens the susceptibility to cerebral infarction via its deleterious effects on vessel architecture and vessel function.39,83 Advanced amyloid deposition in the vessel wall may cause impaired autoregulation, endothelial dysfunction, blood–brain barrier disruption, thickening of the vessel wall, or even vessel occlusion, thereby inducing hypoperfusion and ischemia around the amyloidladen vessels.15,57,83,84 Support for this notion comes from experimental studies in mouse models of CAA, demonstrating decreased vascular reactivity in response to physiologic or pharmacologic stimuli compared with wild-type mice.83,85–87 Furthermore, mice with CAA showed increased susceptibility to induced ischemia, reflected by lower cerebral blood flow and increased infarct volume after middle cerebral artery occlusion.83 It is not clear how well these animal models translate to the human disease, but the finding of impaired vascular reactivity in CAA is consistent with patient studies using functional transcranial Doppler88 and functional MRI (fMRI).89,90 Both methods estimate the increase in local blood flow in response to a stimulus. Patients with advanced CAA showed a reduced change in mean blood flow velocity88 and reduced amplitude and delayed time to peak of the BOLD (blood oxygen level-dependent) response89,90 compared with controls. Furthermore, the lower flow velocity response and longer BOLD time to peak in patients were related to greater WMH volume, independent of age, sex, and hypertension,88,89,90 providing a possible mechanism for subcortical ischemic injury. The authors hypothesize that impaired vasoreactivity in CAA might cause a mismatch between perfusion and metabolic demand, thereby inducing ischemic damage. Journal of Cerebral Blood Flow & Metabolism (2015), 1 – 10

Another line of experimental research has provided evidence that vascular dysfunction triggers accelerated amyloid deposition by interference with amyloid clearance pathways. Thromboses, atherosclerosis, or arterial stiffening may abolish the motive force necessary for drainage of Aβ through interstitial fluid pathways, which in turn enhances the accumulation of amyloid in the vessel wall.23,24,57,91 The hypothesis that common age-related vascular diseases, such as atherosclerosis and arterial stiffening, trigger vascular amyloid deposition could also explain the rapid increase in the prevalence of CAA with aging.3 An imaging marker of impaired clearance of interstitial fluid is dilated perivascular spaces.92 Dilated perivascular spaces in the white matter are a common finding in CAA93 and are associated with other imaging markers of SVD, including WMH.94,95 As such, dilated perivascular spaces may reflect a possible mechanistic link between CAA and subcortical white-matter disease. Third, ischemia may result from acute decreases in blood pressure after a hemorrhagic event.96 Secondary ischemic injury related to clearance of hemorrhagic products have also been observed.36,97 The large difference in distribution of hemorrhagic and ischemic lesions within patients with CAA, however, makes it unlikely that the majority of ischemic lesions have a hemorrhagic origin. Together, these findings suggest a complex and potentially self-reinforcing cycle, where amyloid deposition and vascular dysfunction exacerbate each other (Figure 3). CEREBRAL AMYLOID ANGIOPATHY-RELATED COGNITIVE IMPAIRMENT: CONTRIBUTION OF HEMORRHAGIC VS. ISCHEMIC BRAIN INJURY There is increasing evidence that CAA is an important contributor to cognitive impairment and dementia in the absence of ICH. The most direct evidence for an important role of CAA in dementia comes from clinical–pathological studies showing that the prevalence of CAA is consistently higher in demented compared with nondemented cases, even after controlling for age and Alzheimer type pathology (i.e., senile amyloid plaques and neurofibrillary tangles).4,11 In the Honululu Asia Aging Study, CAA was present in 55% of demented cases compared with 38% in nondemented cases.11 In the Medical Research Council study, the relationship between CAA and dementia was even stronger (odds ratio 9.3; confidence interval 2.7 to 41.0), after controlling for age, brain weight, neuritic and diffuse plaques, neocortical and © 2015 ISCBFM

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Figure 3. Possible pathways through which cerebral amyloid angiopathy (CAA) can cause ischemia. Amyloid β (Aβ) is suggested to accumulate and deposit in the vessel wall because of impairment in Aβ clearance. Advanced vascular amyloid deposition can result in vessel rupture and vessel narrowing. Possible processes that mediate either or both pathways include endothelial dysfunction, vessel stiffening, and impaired vasoreactivity. Arterial stiffening and impaired vasoreactivity may in turn abolish the motive force necessary for drainage of Aβ through interstitial pathways and further enhance the accumulation of amyloid.23,24,57,91 Hemorrhage may also contribute to secondary ischemia via acute decreases in blood pressure or inflammatory responses. Together, these findings suggest a complex and potentially self-reinforcing cycle, where amyloid deposition and vascular dysfunction exacerbate each other.

hippocampal neurofibrillary tangles, Lewy bodies, and cerebrovascular disease.4 In the Religious Orders Study,12 moderate-tosevere CAA (but not mild-to-moderate) was independently related to lower premortem performance on speed and episodic memory. The contribution of CAA to the development of dementia independent of Alzheimer pathology is further supported by the observation that patients with hereditary CAA develop cognitive impairment in the absence of Alzheimer's pathology.98 Since CAA often coexists with degenerative and other agerelated pathologies (e.g., atherosclerosis or Alzheimer’s pathology), it remains difficult to determine its independent impact on cognition. Another complicating factor in determining the cognitive profile of CAA is the presence of ICH, which may mask the more subtle effect of CAA-related SVD on cognition. Nevertheless, the above-mentioned findings in individuals without ICH strongly support an important role of CAA in the development of cognitive impairment and dementia. An open question is through which mechanistic pathway CAA causes cognitive impairment. One possibility is that CAA-related cortical lesions (e.g., microbleeds and microinfarcts) cause neuronal degeneration and malfunction in the surrounding tissue.99 In addition, CAA may impact cognition by its effect on the white matter. Disruption of white-matter tracts can have profound impact on the transfer and integration of information between brain regions.100 Loss of white-matter connectivity is primarily associated with slowing of information processing and attentional deficits, which resembles the cognitive profile of patients with CAA.12,80 To gain more insight into these possible pathways, we summarize below results from imaging and autopsy studies that have investigated the relationship between CAA-related hemorrhagic and ischemic SVD and cognition. Lobar Microbleeds and Cognition Multiple lobar microbleeds on MRI are the radiologic hallmark of CAA33 and have therefore long been regarded as a potential cause of CAA-related cognitive deficits. Although lobar microbleeds have found to be more common in patients with dementia than © 2015 ISCBFM

controls,101–104 their causal relationship with cognition seems relatively weak. Several population-based and memory clinic studies found no association between the presence or number of lobar microbleeds and cognitive performance78,102,104–107 or global cognitive decline.108,109 Positive associations between microbleeds and worse cognition are mainly found in individuals with a high MB count (45 or 47)110,111 or individuals diagnosed with symptomatic SVD.112–114 Affected cognitive domains included processing speed, executive functioning, and visuospatial memory.111,113,114 The relationship between microbleeds and cognition in those studies was partly independent of other imaging markers of SVD such as WMHs and lacunar infarcts, but effect sizes are relatively small (standardized Beta: 0.1 to 0.3 SD).110–112,114 The modest effect sizes, even in patients with high microbleed count, suggest that microbleeds do not substantially affect cognition by disrupting the surrounding tissue. This is in line with recent evidence from animal studies, showing very limited neuronal damage and even tissue recovery after inducing a microbleed.97 Possibly, the link between microbleeds and cognition is driven by more widespread underlying vascular pathology extending into the white matter. The fact that lobar microbleeds are associated with the same cognitive profile as subcortical white-matter disease, i.e., deficits in processing speed and executive functioning, supports this hypothesis.111,113,114 Ischemic White-Matter Disease and Cognition There is an abundant amount of literature linking WMH to cognition,115–117 but only one study that specifically addressed this relationship in patients with CAA.118 In that study, preICH cognitive impairment was associated with advanced WMH on CT or MRI. However, cognitive impairment was assessed with a standardized questionnaire, without quantitative assessment of cognition. Microinfarcts at autopsy have consistently been associated with an ante-mortem diagnosis of dementia in prospective cohort studies.64,119,120 Likewise, the presence of microinfarcts at autopsy has been associated with lower cognitive performance during life.65,119,121 These results are consistent with two recent in vivo imaging studies demonstrating a negative correlation between cortical microinfarcts and cognitive functioning in memory clinic patients.122,123 Whether the relationship between microinfarcts and cognition is similar in cases with CAA remains under investigation. Diffusion tensor imaging has been shown to be very sensitive to microstructural alterations in the white matter relevant to cognition.80,124,125 As discussed above, DTI abnormalities in patients with SVD may reflect ischemic-related pathology. In patients with SVD, DTI parameters such as FA and MD have been shown to explain more variance in cognition than WMH or lacunar infarcts.80,125,126 Two studies specifically addressed the relationship between DTI parameters and cognition in patients with probable CAA.80,127 Both studies included patients with ICH at the time of study enrollment. In one study, the authors estimated the presence of cognitive impairment before the ICH with a standardized questionnaire. The global mean diffusion coefficient of the white matter in the ICH-free hemisphere was associated with a 2.5-fold increased risk of pre-ICH cognitive impairment, independent of WMH, microbleeds, and cerebral atrophy.127 The other study80 combined DTI with fiber tractography to examine alterations in whole-brain connectivity using graph theory, also referred to as DTI-based network analysis.128 The DTI-based network analysis is a promising technique to study the structural basis of cognitive functions that rely on the interaction between widely distributed brain regions, such as executive functioning and information processing speed—cognitive functions that are preferentially affected in patients with SVD. Indeed, lower global network efficiency in CAA was positively correlated with reduced processing speed and executive functioning, independent of Journal of Cerebral Blood Flow & Metabolism (2015), 1 – 10

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6 Table 1.

Open questions to be addressed in future studies of CAA and SVD

Pathology of imaging markers - What are the pathologic substrates of imaging markers of SVD? What is the sensitivity and specificity of these imaging markers to underlying pathology? - Is the pathophysiology of ischemic and hemorrhagic imaging markers similar across different with vascular cognitive impairment? populations? Mechanistic questions - Are there direct links between ischemic and hemorrhagic brain lesions, or do they represent distinct outcomes of CAA pathology? - Are there particular CAA-related vasculopathic changes (e.g., vascular amyloid deposition, vessel-within-vessel formation, fibrinoid necrosis, luminal narrowing, and BBB disruption) associated with ischemic brain injury? - Is the degree of cortical abnormalities in CAA related to the degree of subcortical white-matter abnormalities on pathology and on imaging? Are these cortical and subcortical abnormalities spatially connected? Predictors of cognitive decline - Does the cognitive profile of CAA differ across different phenotypes? E.g., between patients with cooccurring Alzheimer's pathology, ICH, extensive WMH, microbleeds, or microinfarcts - Are different markers of SVD including large-scale markers of cortical and subcortical abnormalities (cortical thickness, DTI, T2*/T1 relaxation times) predictive of cognitive functioning and cognitive decline in patients with CAA? Abbreviations: BBB, blood–brain barrier; CAA, cerebral amyloid angiopathy; DTI, diffusion tensor imaging; ICH, intracerebral hemorrhage; SVD, small vessel disease; WMH, white-matter hyperintensity.

other MRI markers of SVD.80 Network efficiency was also related to gait velocity, another well-known clinical feature of SVD.129 Results were similar when only the network of the ICH-free hemisphere was considered. Partial correlation coefficients ranged between 0.3 and 0.5, comparable to associations found in other SVD populations.126,130 Thus, in addition to cortical injury, CAA-related white-matter lesions affect cognitive function at least partly through disruption of white-matter connectivity. TREATMENT Thus far, no specific disease modifying treatment has been identified for CAA. There is evidence that treatments approved for cognitive symptoms in patients with Alzheimer’s disease may also show symptomatic benefit in patients with vascular cognitive impairment. Although not specifically shown in patients with CAA, trials in patients with vascular dementia indicate that donepezil and galantamine have a modest effect on global cognition reflected by an improvement of 1 to 2 points on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) (donepezil131–134 and galantamine135,136) and improvement on a test for executive functioning.135 The benefits of memantine and rivastigmine in vascular cognitive impairment are less well established.137–140 A treatment-responsive form of nonhemorrhagic CAA is spontaneous CAA-related vascular inflammation. The CAA-related inflammation occurs in a distinct subgroup of patients with CAA in response to the vascular Aβ deposits and is characterized by diffuse WMH on brain MRI attributed to vasogenic edema, seizures, and cognitive decline.141–143 The CAA-related inflammation is associated with appearance of anti-Aβ autoantibodies in cerebrospinal fluid143 and appears to respond well to immunosuppressive therapy such as corticosteroids, reflected by a marked reduction of WMH volume and improvement of clinical symptoms within 1 to 2 weeks.141,142,144 FUTURE DIRECTIONS IN SMALL VESSEL DISEASE IMAGING Interaction Between Different Lesion Types The majority of markers for ischemic and hemorrhagic brain injury outlined above are not specific to CAA. Microbleeds, WMH, microinfarcts, and DTI abnormalities also occur in relation to other SVDs such as in patients with symptomatic stroke,145 type 2 diabetes,146 hypertensive arteriolosclerosis,147 or CADASIL.148 The observation that imaging markers of SVD often cooccur in the same patient suggests an intriguing interplay between different lesion types and lesion territories, i.e., between ischemic and Journal of Cerebral Blood Flow & Metabolism (2015), 1 – 10

hemorrhagic brain lesions but also between primarily cortical and subcortical injury. Cerebral amyloid angiopathy, a primary cortical pathology, may cause extensive abnormalities in the white-matter tissue. Conversely, in patients with CADASIL, vascular-related white-matter injury is suggested to cause cortical thinning in remotely connected cortical regions.149 A similar two-way interaction is suggested for hemorrhagic and ischemic lesions.150,151 Studies have found that the incidence of ischemic infarcts is relatively high in the period immediately after an ICH59,60,61,96 and associated with worse clinical outcome.152 Alterations in local hemodynamics, blood–brain barrier permeability, and release of inflammatory cytokines after an ICH might contribute to the pathogenesis of ischemic insults.152–154 Likewise, incident microbleeds have been detected at a relatively high rate after ischemic stroke.155 Even in asymptomatic patients with mild SVD, hemorrhagic and ischemic brain injury has been shown to progress at a similar rate.156 Although the causal pathways remain to be established, these findings strongly suggest that SVD etiologies with initially distinct effects on the cerebral microvasculature can trigger a cascade of events that can induce a broad range of small vascular lesions. Future longitudinal patient studies should map the ordering and location of these ischemic and hemorrhagic events to gain more insight into possible parallel or interacting pathways through which SVDs induce different lesion types (Table 1). Predictors of Cognitive Functioning There is a growing notion that the cumulative lesion burden, rather than the individual lesions themselves, determines cognitive outcome.157 The effect of CAA-related lesions, such as microinfarcts, on cognition may only be accurately determined if we take into account the burden of coexisting pathology. To capture the total lesion load in the brain, imaging markers are needed that are sensitive to a wide range of pathologic abnormalities such as edema, demyelination, axonal loss, neuronal loss, iron deposition, enlarged perivascular spaces, and reduced vascular density. Diffusion tensor imaging may in this regard be a promising method to quantify macrostructural as well as microstructural abnormalities within the white matter and its effect on brain connectivity.80,130 Diffusion imaging can also be used to assess cortical brain injury.158 Other promising sensitive measures of cortical integrity include cortical T171 and T2* mapping.69,70 Both T1 and T2* relaxation times have found to be sensitive to forms of tissue degradation that are not captured with standard cortical thickness measurements.70,71 © 2015 ISCBFM

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7 In addition, cumulative lesion burden is also expected to result in alterations of functional brain connectivity during rest as assessed with resting-state fMRI.159 Since fMRI relies on a vascular response, the challenge for future fMRI studies will be to disentangle the vascular effects of SVD from its neuronal effects in altering the BOLD response. Several methods have been proposed to deal with this issue (for review, Veldsman et al160). Because of their sensitivity to a wide range of pathologic abnormalities, the above structural and functional imaging markers have high potential to predict clinical outcome in patients with SVD. The underlying histopathology of these imaging markers is to a large extent still unclear, however. It is therefore important that radiologic–pathologic studies continue to define the histopathologic correlates of SVD imaging markers within different populations with vascular cognitive impairment, as well as to specify the sensitivity and specificity of those imaging markers to different lesion types (Table 1). CONCLUSIONS Ischemic lesions are a frequent finding in CAA and seem to have an important role in the development of CAA-related cognitive decline. These findings highlight the clinical importance of quantifying ischemic SVD in CAA on a macrostructutral and microstructural scale using advanced imaging methods to predict cognitive outcome. At the same time, we need a better understanding of the causal pathways underlying ischemic tissue injury in CAA. An important step in this regard is to bridge the gap between radiologic and pathologic findings by identifying the pathologic correlates of imaging markers of SVD. Furthermore, the progression of ischemic lesions and its effect on cognitive decline should not be studied in isolation, but in the context of coexisting pathology. Together, these insights will help us to develop and optimize treatment strategies for cognitive impairment in patients with CAA and other forms of SVD. AUTHOR CONTRIBUTIONS YDR drafted the article. SJV and SMG revised the article for important critical content. All authors substantially contributed to the conception and design of the manuscript and approved the final version for publication.

DISCLOSURE/CONFLICT OF INTEREST The authors state no conflict of interest.

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