**4.1 Stroke**

Although patients with cerebrovascular disease may have white matter abnormalities related to large-vessel, embolic or ischemic-hypoxic etiologies, by far small-vessel disease is believed to be the most common substrate in case of diffuse, bilateral, preferential white matter involvement (Gomes & Caplan, 2008).

Leukoaraiosis (LA) is a common finding in stroke (particularly ischemic) and shares similar risk factors and pathophysiologic mechanisms with both ischemic and hemorrhagic stroke. LA may also be an independent predictor of stroke outcomes.

After an acute ischemic stroke LA is associated with an increased risk of death or dependency, recurrent stroke, intracerebral hemorrhage under anticoagulation, myocardial infarction, and poststroke dementia. There is increasing evidence from neuroimaging studies to support the concept that some cases of LA are caused by white matter infarcts, which may be particularly frequent in patients with widespread small vessel disease. Th e relatively similar distribution of LA regardless of the distribution of vascular pathology suggests a conserved vulnerability to white matter injury across various vascular diseases, possibly related to the resting patterns of blood fl ow (Mijajlovic et al., 2011).

LA is frequently observed in patients with acute stroke, ischemic as well as hemorrhagic. Previous studies indicated that LA was strongly associated with lacunar strokes rather than non-lacunar, territorial strokes. Stroke and LA are likely two related diseases. In many aspects, LA is an ischemic disease, as is ischemic stroke. Also, intracerebral hemorrhage (ICH) and LA share a common cause, that of arterial hypertension. If LA shares with stroke (ischemic and hemorrhagic) common mechanisms, and the appearance of LA on imaging predicts stroke, then, according to the current terminology, LA can be regarded as an intermediate surrogate of stroke. (Jimenez-Conde et al., 2010, Pu et al., 2009, Lee et al., 2008, Inzitari, 2003, as cited by Mijajlovic et al., 2011)

Putaala et al. hypothesized that risk factors, neuroimaging characteristics, and associations with the overt clinical stroke may be diff erent in young patients with ischemic stroke with or without silent brain infarcts (SBIs) and LA. Of the 669 patients included, 86 (13%) had SBIs, 50 (7%) had LA, 17 (3%) had both, and 550 served as controls. Most SBIs were located in basal ganglia (39%) or subcortical regions (21%), but cerebellar SBIs also were rather frequent (15%). LA was mainly mild to moderate. Silent cardioembolism may in part explain the frequency of cerebellar SBIs in younger patients. As observed, younger stroke patients tend to have more frequently overt posterior territory ischemia and cerebellar infarcts. Th is observation, jointly with the frequency of cerebellar SBIs, might reflect the same, yet unclear, pathophysiologic mechanisms. Independent risk factors for SBIs in younger adults were type 1 diabetes, obesity, smoking, and increasing age. Risk factors for LA were type 1 diabetes, obesity, female sex, and increasing age. Small-vessel disease was the predominant cause of stroke in both those with SBIs (31%) and LA (44%) (Putaala et al., 2009, as cited by Mijajlovic et al., 2011).

Prospective observations further corroborated the relationship between LA and stroke and the distinct role of lacunar infarcts. The presence of LA on CT scan predicted subsequent stroke in patients with first-ever lacunar stroke, in those with lacunar or cortical infarction,

Although patients with cerebrovascular disease may have white matter abnormalities related to large-vessel, embolic or ischemic-hypoxic etiologies, by far small-vessel disease is believed to be the most common substrate in case of diffuse, bilateral, preferential white

Leukoaraiosis (LA) is a common finding in stroke (particularly ischemic) and shares similar risk factors and pathophysiologic mechanisms with both ischemic and hemorrhagic stroke.

After an acute ischemic stroke LA is associated with an increased risk of death or dependency, recurrent stroke, intracerebral hemorrhage under anticoagulation, myocardial infarction, and poststroke dementia. There is increasing evidence from neuroimaging studies to support the concept that some cases of LA are caused by white matter infarcts, which may be particularly frequent in patients with widespread small vessel disease. Th e relatively similar distribution of LA regardless of the distribution of vascular pathology suggests a conserved vulnerability to white matter injury across various vascular diseases,

LA is frequently observed in patients with acute stroke, ischemic as well as hemorrhagic. Previous studies indicated that LA was strongly associated with lacunar strokes rather than non-lacunar, territorial strokes. Stroke and LA are likely two related diseases. In many aspects, LA is an ischemic disease, as is ischemic stroke. Also, intracerebral hemorrhage (ICH) and LA share a common cause, that of arterial hypertension. If LA shares with stroke (ischemic and hemorrhagic) common mechanisms, and the appearance of LA on imaging predicts stroke, then, according to the current terminology, LA can be regarded as an intermediate surrogate of stroke. (Jimenez-Conde et al., 2010, Pu et al., 2009, Lee et al., 2008,

Putaala et al. hypothesized that risk factors, neuroimaging characteristics, and associations with the overt clinical stroke may be diff erent in young patients with ischemic stroke with or without silent brain infarcts (SBIs) and LA. Of the 669 patients included, 86 (13%) had SBIs, 50 (7%) had LA, 17 (3%) had both, and 550 served as controls. Most SBIs were located in basal ganglia (39%) or subcortical regions (21%), but cerebellar SBIs also were rather frequent (15%). LA was mainly mild to moderate. Silent cardioembolism may in part explain the frequency of cerebellar SBIs in younger patients. As observed, younger stroke patients tend to have more frequently overt posterior territory ischemia and cerebellar infarcts. Th is observation, jointly with the frequency of cerebellar SBIs, might reflect the same, yet unclear, pathophysiologic mechanisms. Independent risk factors for SBIs in younger adults were type 1 diabetes, obesity, smoking, and increasing age. Risk factors for LA were type 1 diabetes, obesity, female sex, and increasing age. Small-vessel disease was the predominant cause of stroke in both those with SBIs (31%) and LA (44%) (Putaala et al.,

Prospective observations further corroborated the relationship between LA and stroke and the distinct role of lacunar infarcts. The presence of LA on CT scan predicted subsequent stroke in patients with first-ever lacunar stroke, in those with lacunar or cortical infarction,

possibly related to the resting patterns of blood fl ow (Mijajlovic et al., 2011).

**4. Specific features of LA in the main types of cerebrovascular diseases** 

**4.1 Stroke** 

matter involvement (Gomes & Caplan, 2008).

Inzitari, 2003, as cited by Mijajlovic et al., 2011)

2009, as cited by Mijajlovic et al., 2011).

LA may also be an independent predictor of stroke outcomes.

in elderly patients with gait problems and LA on CT scan, and in patients with lacunar stroke or trivial neurological symptoms. Recurrent stroke was predominantly of the lacunar type. When studies took into account the severity of LA the risk of recurrence proved to be proportional to the extent of LA (Miyao et al., 1992, van Zagten et al., 1996, Inzitari et al., 1995, Yamauchi et al., 2002, as cited by Inzitari, 2003).

Fig. 3. Cerebral MRI (axial T2 weighted sequences) of a 70 years old male, known with arterial hypertension, diabetes mellitus, and a left posterior cerebral arterial ischemic stroke 3 years ago, admitted for right hemiparesis and mixed aphasia; an old stroke in the left posterior cerebral artery territory (black arrow) and leukoaraiosis (white arrow) can be seen.

In 2008 we attempted to assess the correlation between leukoaraiosis and associated vascular pathologies in a group of 50 hospitalized patients whose cerebral MRI revealed leukoaraiosis. The study revealed that:


#### **4.2 Large arteries stroke**

In most of the studies, cortical territorial infarct was largely less probable than lacunar or hemorrhagic stroke as recurrent stroke. The main causes of cortical infarcts are large-artery disease and cardioembolism.

White Matter Changes in Cerebrovascular Disease: Leukoaraiosis 245

Although leukoaraiosis and lacunar infarcts are often found together, in individual patients one type of imaging appearance may predominate, leading to the notion of subtypes of diffuse small vessel disease; either what has been labelled as ischaemic leukoaraiosis (defined by the combination of leukoaraiosis with a history of a clinical lacunar syndrome), or isolated lacunar infarction (in which a similar clinical presentation is accompanied by multiple lacunar lesions but no leukoaraiosis on imaging). These two imaging types have

Fig. 5. Cerebral MRI (above: axial T2 weighted sequences, left-below: coronal FLAIR sequence, right-below: diffusion-weighted sequence) showing an old right temporal lobe ischemic stroke (black arrow), acute left temporo-frontal ischemic stroke (white horizontal arrow), leukoaraiosis (white vertical arrow) and diffusion – hypersignal spots in left

temporal lobe (curved white arrows).

**4.3 Lacunar stroke** 

Fig. 4. Cerebral CT scan showing leukoaraiosis (white arrow) in a pacient with an old ischemic stroke in the left middle cerebral artery territory (white curved arrow).

In regard to the first mechanism, while cross-sectional data from the patients randomized in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) showed an inverse relationship between the degree of carotid stenosis and presence of LA, a few population studies have consistently reported an association between intima-media thickness or the presence of carotid plaques and white matter hyperintensities on MRI, even after adjustment for other vascular risk factors. Atrial fibrillation, a major cause of cardioembolic stroke, was found to be negatively associated with LA in 1 study and positively associated in 2 other studies. These conflicting results are likely justified by the variable impact of age and other age-related vascular risk factors as confounders for these associations (Brun & Englund, 1986, Pico et al., 2002, Bots et al., 1993, Manolio et al., 1999, Henon et al, 1996, Raiha et al., 1993, as cited by Inzitari 2003).

In a Korean study, a significant association between leukoaraiosis and the stroke subtypeswas found. The large-artery-disease group had a higher prevalence of leukoaraiosis than did the other groups (55.4% in the large-artery-disease group, 30.3% in the lacunar group and 14.3% in the cardioembolic group, P = 0.016 by chi-square test). On the multivariate linear regression analysis, age, the presence of hypertension, previous stroke and stroke subtype were independently associated with the presence of leukoaraiosis. In the sub analysis of the large-artery-disease group, the leukoaraiosis had a tendency to be more prevalent in the mixed and intracranial stenosis group than did the extracranial stenosis group (45.5% in the mixed group, 40.3% in the intracranial group and 26.9% in the extracranial group, P = 0.08 by chi-square test). The association of leukoaraiosis with largeartery disease in this study might be due to the relatively high prevalence of intracranial occlusive lesions in Korean stroke patients compared to other ethnic groups (Lee et al., 2008).

Fig. 4. Cerebral CT scan showing leukoaraiosis (white arrow) in a pacient with an old ischemic stroke in the left middle cerebral artery territory (white curved arrow).

Henon et al, 1996, Raiha et al., 1993, as cited by Inzitari 2003).

2008).

In regard to the first mechanism, while cross-sectional data from the patients randomized in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) showed an inverse relationship between the degree of carotid stenosis and presence of LA, a few population studies have consistently reported an association between intima-media thickness or the presence of carotid plaques and white matter hyperintensities on MRI, even after adjustment for other vascular risk factors. Atrial fibrillation, a major cause of cardioembolic stroke, was found to be negatively associated with LA in 1 study and positively associated in 2 other studies. These conflicting results are likely justified by the variable impact of age and other age-related vascular risk factors as confounders for these associations (Brun & Englund, 1986, Pico et al., 2002, Bots et al., 1993, Manolio et al., 1999,

In a Korean study, a significant association between leukoaraiosis and the stroke subtypeswas found. The large-artery-disease group had a higher prevalence of leukoaraiosis than did the other groups (55.4% in the large-artery-disease group, 30.3% in the lacunar group and 14.3% in the cardioembolic group, P = 0.016 by chi-square test). On the multivariate linear regression analysis, age, the presence of hypertension, previous stroke and stroke subtype were independently associated with the presence of leukoaraiosis. In the sub analysis of the large-artery-disease group, the leukoaraiosis had a tendency to be more prevalent in the mixed and intracranial stenosis group than did the extracranial stenosis group (45.5% in the mixed group, 40.3% in the intracranial group and 26.9% in the extracranial group, P = 0.08 by chi-square test). The association of leukoaraiosis with largeartery disease in this study might be due to the relatively high prevalence of intracranial occlusive lesions in Korean stroke patients compared to other ethnic groups (Lee et al.,

Fig. 5. Cerebral MRI (above: axial T2 weighted sequences, left-below: coronal FLAIR sequence, right-below: diffusion-weighted sequence) showing an old right temporal lobe ischemic stroke (black arrow), acute left temporo-frontal ischemic stroke (white horizontal arrow), leukoaraiosis (white vertical arrow) and diffusion – hypersignal spots in left temporal lobe (curved white arrows).

#### **4.3 Lacunar stroke**

Although leukoaraiosis and lacunar infarcts are often found together, in individual patients one type of imaging appearance may predominate, leading to the notion of subtypes of diffuse small vessel disease; either what has been labelled as ischaemic leukoaraiosis (defined by the combination of leukoaraiosis with a history of a clinical lacunar syndrome), or isolated lacunar infarction (in which a similar clinical presentation is accompanied by multiple lacunar lesions but no leukoaraiosis on imaging). These two imaging types have

White Matter Changes in Cerebrovascular Disease: Leukoaraiosis 247

prevalent among 116 patients with ICH than among 155 control patients without ICH. In an analysis with a multivariate adjustment for other vascular risk factors, the association was almost fully explained by the higher prevalence of arterial hypertension and lacunar infarcts

The Stroke Prevention in Reversible Ischemia Trial (SPIRIT), a prospective trial of secondary prevention with anticoagulation and target international normalized ratio (INR) values of 3.0 to 4.5 in patients with cerebral ischemia of presumed arterial origin, revealed the independent role of LA as a risk factor for major bleeding during anticoagulation after cerebral ischemia (Gorter, 1999). This was confirmed by a recent study which investigated radiographic and clinical characteristics of patients with warfarin-related ICH following ischemic stroke. The 26 eligible ICH cases and 56 controls were compared for vascular risk factors, stroke characteristics, and extent of leukoaraiosis (graded in anterior and posterior brain regions on a validated scale of 0 to 4). Leukoaraiosis was found to be an independent risk factor for warfarin-related ICH in survivors of ischemic stroke, including those in the

 Fig. 7. Cerebral MRI scan (left: axial T2 weighted sequence; right: coronal FLAIR image) showing right temporo-parietal primary intracerebral hematoma (vertical arrow), mixed cerebral atrophy, leukoaraiosis (horizontal arrow), in a 65 years old male, known with untreated arterial hypertension, smoker, admitted for left hemiplegia suddenly occurred.

The distribution of white matter lesions in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoaraiosis (CADASIL) has been reported to be distinct from those in patients with ischemic leukoaraiosis and Binswanger's disease. In earlier European studies, diagnostic significance of white matter lesions in the temporopolar region (Tp), medial frontopolar region (Fp) and external capsule (EC) was stressed in diagnosing

on CT scan (Selekler & Erzen, 1989, Inzitari et al., 1990, as cited by Inzitari, 2002).

commonly employed range of anticoagulation (Smith et al., 2010).

**4.5 CADASIL** 

CADASIL (Tomimoto et al., 2005).

recently been shown to differ in their risk factor profile; age and hypertension are most strongly associated with ischaemic leukoaraiosis while hypercholesterolaemia, diabetes mellitus and myocardial infarction are more associated with isolated lacunar infarction. These findings suggest some differences in pathogenesis, with leukoaraiosis, perhaps reflecting a non-atheromatous pathology of smaller calibre vessels than those implicated in lacunar infarcts. A better appreciation of distinct subtypes may explain conflicting results about the association of certain novel risk factors with stroke; for example, although homocysteine is a risk factor for both types of manifestation, it has a much stronger association with ischaemic leukoaraiosis than with isolated lacunar infarction (Khan et al., 2007, Hassan at al., 2004, as cited by O' Sullivan, 2008).

White matter hyperintensities on magnetic resonance imaging can be used as surrogate markers of small vessel disease (Wallin & Fladby, 2010).

Rost et al. measured WMH volume (WMHV) in cohorts of prospectively ascertained patients with acute ischemic stroke (AIS) (n = 891) and ICH (n = 122). Patients with larger WMHV were more likely to have lacunar stroke compared with cardioembolic, large artery, or other stroke subtypes (*p* < 0.03). In a separate analysis, greater WMHV was seen in ICH compared with lacunar stroke and in ICH compared with all ischemic stroke subtypes combined (*p* < 0.007). These data support the model that increasing WMHV is a marker of more severe cerebral small-vessel disease (Rost et al., 2010).

Fig. 6. Cerebral MR scan of a 60 years old female (left: T2 weighted sequence; right: diffusion weighted sequence) showing an old microbleeding (horizontal arrow), lacunar ischemic strokes (vertical arrow) and leukoaraiosis (curved arrow).

#### **4.4 Hemorrhagic stroke**

2 cross-sectional studies of hospitalized stroke patients reported in 1989 and 1990, for the first time, the association between LA and ICH. The latter of the 2 studies also examined the possible confounders for this association. In this study extensive LA was over twice more

recently been shown to differ in their risk factor profile; age and hypertension are most strongly associated with ischaemic leukoaraiosis while hypercholesterolaemia, diabetes mellitus and myocardial infarction are more associated with isolated lacunar infarction. These findings suggest some differences in pathogenesis, with leukoaraiosis, perhaps reflecting a non-atheromatous pathology of smaller calibre vessels than those implicated in lacunar infarcts. A better appreciation of distinct subtypes may explain conflicting results about the association of certain novel risk factors with stroke; for example, although homocysteine is a risk factor for both types of manifestation, it has a much stronger association with ischaemic leukoaraiosis than with isolated lacunar infarction (Khan et al.,

White matter hyperintensities on magnetic resonance imaging can be used as surrogate

Rost et al. measured WMH volume (WMHV) in cohorts of prospectively ascertained patients with acute ischemic stroke (AIS) (n = 891) and ICH (n = 122). Patients with larger WMHV were more likely to have lacunar stroke compared with cardioembolic, large artery, or other stroke subtypes (*p* < 0.03). In a separate analysis, greater WMHV was seen in ICH compared with lacunar stroke and in ICH compared with all ischemic stroke subtypes combined (*p* < 0.007). These data support the model that increasing WMHV is a marker of

Fig. 6. Cerebral MR scan of a 60 years old female (left: T2 weighted sequence; right: diffusion weighted sequence) showing an old microbleeding (horizontal arrow), lacunar ischemic

2 cross-sectional studies of hospitalized stroke patients reported in 1989 and 1990, for the first time, the association between LA and ICH. The latter of the 2 studies also examined the possible confounders for this association. In this study extensive LA was over twice more

2007, Hassan at al., 2004, as cited by O' Sullivan, 2008).

markers of small vessel disease (Wallin & Fladby, 2010).

more severe cerebral small-vessel disease (Rost et al., 2010).

strokes (vertical arrow) and leukoaraiosis (curved arrow).

**4.4 Hemorrhagic stroke** 

prevalent among 116 patients with ICH than among 155 control patients without ICH. In an analysis with a multivariate adjustment for other vascular risk factors, the association was almost fully explained by the higher prevalence of arterial hypertension and lacunar infarcts on CT scan (Selekler & Erzen, 1989, Inzitari et al., 1990, as cited by Inzitari, 2002).

The Stroke Prevention in Reversible Ischemia Trial (SPIRIT), a prospective trial of secondary prevention with anticoagulation and target international normalized ratio (INR) values of 3.0 to 4.5 in patients with cerebral ischemia of presumed arterial origin, revealed the independent role of LA as a risk factor for major bleeding during anticoagulation after cerebral ischemia (Gorter, 1999). This was confirmed by a recent study which investigated radiographic and clinical characteristics of patients with warfarin-related ICH following ischemic stroke. The 26 eligible ICH cases and 56 controls were compared for vascular risk factors, stroke characteristics, and extent of leukoaraiosis (graded in anterior and posterior brain regions on a validated scale of 0 to 4). Leukoaraiosis was found to be an independent risk factor for warfarin-related ICH in survivors of ischemic stroke, including those in the commonly employed range of anticoagulation (Smith et al., 2010).

Fig. 7. Cerebral MRI scan (left: axial T2 weighted sequence; right: coronal FLAIR image) showing right temporo-parietal primary intracerebral hematoma (vertical arrow), mixed cerebral atrophy, leukoaraiosis (horizontal arrow), in a 65 years old male, known with untreated arterial hypertension, smoker, admitted for left hemiplegia suddenly occurred.

#### **4.5 CADASIL**

The distribution of white matter lesions in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoaraiosis (CADASIL) has been reported to be distinct from those in patients with ischemic leukoaraiosis and Binswanger's disease. In earlier European studies, diagnostic significance of white matter lesions in the temporopolar region (Tp), medial frontopolar region (Fp) and external capsule (EC) was stressed in diagnosing CADASIL (Tomimoto et al., 2005).

White Matter Changes in Cerebrovascular Disease: Leukoaraiosis 249

involvement of the external capsule and anterior temporal white matter; and in cerebral amyloid angiopathy, there is relatively more posterior than anterior leukoaraiosis. Even so, in CADASIL and cerebral amyloid angiopathy patients, as well as others, the greatest burden of lesions is in the periventricular white matter around the frontal and occipital horns, with varying amounts of involvement of areas of subcortical white matter. The probability of subcortical white matter involvement varies inversely with the distance from

Fig. 8b. Same case: FLAIR hypersignal in the anterior pole of the temporal lobe,

of the perforating arteries at the base of the brain and brain stem (Smith 2010).

Cerebral amyloid angiopathy affects the arteries of the leptomeninges and cortex, with little involvement of the penetrating arteries in the white matter and essentially no involvement

In Alzheimer's disease, and in patients with mild cognitive impairment, some of whom will have prodromal Alzheimer's, white matter changes correlate with serum levels of the Ab 1-40 peptide, which is the predominant peptide found in vessel deposits in cerebral amyloid angiopathy. But intriguingly, plasma Ab also correlates with the severity of white matter lesions in the population-based Rotterdam study. Given that cerebral amyloid angiopathy is a rare cause of leukoaraiosis at the population level, this suggests that Ab has an impact on white matter damage even in patients with arteriosclerotic small vessel disease and no pathological evidence of cerebral amyloid angiopathy. The underlying mechanisms of this association are not yet clear. Conversely, pathological studies in Alzheimer's disease suggest that arteriosclerotic small vessel disease can drive more extensive amyloid deposition and neurofibrillary tangle formation, which is consistent with epidemiological evidence that vascular risk factors are important, and suggests that the interaction may work in both directions (Gurol et al., 2006, van Dijk et al., 2004, Thal et al., 2003, as cited by O' Sullivan,

the ventricular margin (Smith, 2010).

characteristic for CADASIL.

**4.6 Amyloid angiopathy** 

2008).

More recently, however, high sensitivity and specificity of Tp lesions have been demonstrated. Tomimoto et al examined the frequencies of CADASIL-associated lesions in 17 non-demented patients with ischemic leukoaraiosis and 20 patients with Binswanger's disease. The results indicated that Tp lesions were useful diagnostic marker in diagnosing CADASIL, whereas Fp and EC lesions were non-specifically observed (Tomimoto et al., 2005).

Fig. 8a. MR images from a 24-year old man with CADASIL; left: FLAIR diffuse hypersignal of the periventricular and deep white matter (leukoaraiosis) and small cerebrospinal fluid intensity area (lacunar subcortical infarction); right: T1 hyposignal (leukoaraiosis) and fluid intensity area (lacunar subcortical infarction) in the corresponding regions.

An intersting feature of leukoaraiosis, with possible relevance to the pathogenesis of the lesions, is the relatively conserved anatomic distribution across individuals and different vascular diseases. Exceptions are that in CADASIL, there is relative preferential involvement of the external capsule and anterior temporal white matter; and in cerebral amyloid angiopathy, there is relatively more posterior than anterior leukoaraiosis. Even so, in CADASIL and cerebral amyloid angiopathy patients, as well as others, the greatest burden of lesions is in the periventricular white matter around the frontal and occipital horns, with varying amounts of involvement of areas of subcortical white matter. The probability of subcortical white matter involvement varies inversely with the distance from the ventricular margin (Smith, 2010).

Fig. 8b. Same case: FLAIR hypersignal in the anterior pole of the temporal lobe, characteristic for CADASIL.

#### **4.6 Amyloid angiopathy**

248 Advances in Brain Imaging

More recently, however, high sensitivity and specificity of Tp lesions have been demonstrated. Tomimoto et al examined the frequencies of CADASIL-associated lesions in 17 non-demented patients with ischemic leukoaraiosis and 20 patients with Binswanger's disease. The results indicated that Tp lesions were useful diagnostic marker in diagnosing CADASIL, whereas Fp and EC lesions were non-specifically observed (Tomimoto et al.,

Fig. 8a. MR images from a 24-year old man with CADASIL; left: FLAIR diffuse hypersignal of the periventricular and deep white matter (leukoaraiosis) and small cerebrospinal fluid intensity area (lacunar subcortical infarction); right: T1 hyposignal (leukoaraiosis) and fluid

An intersting feature of leukoaraiosis, with possible relevance to the pathogenesis of the lesions, is the relatively conserved anatomic distribution across individuals and different vascular diseases. Exceptions are that in CADASIL, there is relative preferential

intensity area (lacunar subcortical infarction) in the corresponding regions.

2005).

Cerebral amyloid angiopathy affects the arteries of the leptomeninges and cortex, with little involvement of the penetrating arteries in the white matter and essentially no involvement of the perforating arteries at the base of the brain and brain stem (Smith 2010).

In Alzheimer's disease, and in patients with mild cognitive impairment, some of whom will have prodromal Alzheimer's, white matter changes correlate with serum levels of the Ab 1-40 peptide, which is the predominant peptide found in vessel deposits in cerebral amyloid angiopathy. But intriguingly, plasma Ab also correlates with the severity of white matter lesions in the population-based Rotterdam study. Given that cerebral amyloid angiopathy is a rare cause of leukoaraiosis at the population level, this suggests that Ab has an impact on white matter damage even in patients with arteriosclerotic small vessel disease and no pathological evidence of cerebral amyloid angiopathy. The underlying mechanisms of this association are not yet clear. Conversely, pathological studies in Alzheimer's disease suggest that arteriosclerotic small vessel disease can drive more extensive amyloid deposition and neurofibrillary tangle formation, which is consistent with epidemiological evidence that vascular risk factors are important, and suggests that the interaction may work in both directions (Gurol et al., 2006, van Dijk et al., 2004, Thal et al., 2003, as cited by O' Sullivan, 2008).

White Matter Changes in Cerebrovascular Disease: Leukoaraiosis 251

Neurologic manifestations are among the features of many multisystem autoimmune connective tissue disorders with various clinical presentations. Areas of patchy cortical or subcortical abnormality (hyperdensity on CT scan, T2 hyperintensity on MRI) may

 Fig. 10. MR images from a 51-year-old female with rheumathoid arthritis; T2 hypersignal (left) and FLAIR hypersignal (right) spots at the level of deep white matter can be seen.

Leukoaraiosis is a radiological finding whose pathogenesis or clinical significance is not completely acknowledged. LA predispose to stroke, independent of other stroke risk factors. Typically, leukoaraiosis predict a lacunar ischemic stroke but in patients with LA the risk of cortical infarct is also increased, as is that of vascular death. The presence of extensive LA predisposes to ICH, especially in patients treated with anticoagulants for secondary prevention after an ischemic stroke. Consequently, it is important for practicians to correctly

We are grateful to Dr. Virgil Ionescu and Dr. Mariana Bardaş for the images of this chapter.

Birns J. & Kalra L. (2008).Pathogenesis of Cerebral Small Vessel Disease, In: *Brain Hypoxia-*

*Ischemia Research Progress*, O.M. Roux, (Ed.), 113-130, Nova Science Publisher Inc.,

assess LA in all patients presenting with cerebro-vascular pathology.

ISBN: 978-1-60456-139-5, New York, USA

correspond to small vessel vasculitis or cerebritis (Ramachandran, 2011).

**4.7 Collagen arteritis** 

**5. Conclusions** 

**6. Acknowledgements** 

**7. References** 

Leukoaraiosis is also increasingly recognised as a feature of sporadic cerebral amyloid angiopathy, without Alzheimer's disease.Amyloid deposits are found in more proximal portions of the small penetrating arteries than arteriosclerotic changes and it is not known whether these deposits alone, without downstream arteriosclerosis, are sufficient to cause leukoaraiosis. Notably, leukoaraiosis is found in some of the genetic amyloid angiopathies (for example, familial British dementia) suggesting that amyloid angiopathy alone is sufficient to cause this imaging appearance (Greenberg et al., 2004, as cited by O' Sullivan, 2008).

Fig. 9a. MR images from a 71-year-old man with probable cerebral amyloid angiopathy and leukoaraiosis; left: T2 hypersignal at the level of periventricular and deep white matter; right: FLAIR hypersignal at the level of the periventricular white matter.

Fig. 9b. Same case: MR diffusion weighted image (DWI) and apparent diffusion coefficient (ADC) mapping; no apparent diffusion coefficient (ADC) restriction can be observed in the affected areas (leukoaraiosis).

## **4.7 Collagen arteritis**

250 Advances in Brain Imaging

Leukoaraiosis is also increasingly recognised as a feature of sporadic cerebral amyloid angiopathy, without Alzheimer's disease.Amyloid deposits are found in more proximal portions of the small penetrating arteries than arteriosclerotic changes and it is not known whether these deposits alone, without downstream arteriosclerosis, are sufficient to cause leukoaraiosis. Notably, leukoaraiosis is found in some of the genetic amyloid angiopathies (for example, familial British dementia) suggesting that amyloid angiopathy alone is sufficient to

cause this imaging appearance (Greenberg et al., 2004, as cited by O' Sullivan, 2008).

 Fig. 9a. MR images from a 71-year-old man with probable cerebral amyloid angiopathy and leukoaraiosis; left: T2 hypersignal at the level of periventricular and deep white matter;

Fig. 9b. Same case: MR diffusion weighted image (DWI) and apparent diffusion coefficient (ADC) mapping; no apparent diffusion coefficient (ADC) restriction can be observed in the

affected areas (leukoaraiosis).

right: FLAIR hypersignal at the level of the periventricular white matter.

Neurologic manifestations are among the features of many multisystem autoimmune connective tissue disorders with various clinical presentations. Areas of patchy cortical or subcortical abnormality (hyperdensity on CT scan, T2 hyperintensity on MRI) may correspond to small vessel vasculitis or cerebritis (Ramachandran, 2011).

Fig. 10. MR images from a 51-year-old female with rheumathoid arthritis; T2 hypersignal (left) and FLAIR hypersignal (right) spots at the level of deep white matter can be seen.
