**1. Introduction**

234 Advances in Brain Imaging

Tervaniemi, M.; Rytkonen, M.; Schröger, E.; Ilmoniemi, R. & Näätänen, R. (2001). Superior

Towle, V.L.; Bolanos, J.; Suarez, D.; Tan, K.; Grzesczuk, R.; Levin, D.N.; Cakmur, R.; Frank,

*Mem.,* Vol. 8, pp. 295-300

pp. 861-866.

formation of cortical memory traces for melodic patterns in musicians. *Learn. &* 

S.A. & Spire, J.P. (1993). The spatial location of EEG electrodes: locating the bestfitting sphere relative to cortical anatomy. *Electroenceph. Clin. Neurophysiol.,* Vol. 86,

> The term 'leukoaraiosis', derived from the Greek 'leuko' meaning white and 'araios' meaning rarefied, was introduced in 1987, as a "neutral term, exact enough to define whitematter changes in the elderly or the demented, general enough that it serves as a description and a label, and demanding enough that it calls for a precise clinical and imaging description accompanied when possible by pathologic correlations" (Hachinski et al., 1987).

> When the term leukoaraiosis (LA) was introduced, only CT imaging was widely available. Similar appearance is conspicuous, and more florid on T2-weighted magnetic resonance imaging (MRI), particularly on fluid attenuated inversion recovery (FLAIR) images. Leukoaraiosis is currently defined as diffuse, confluent white matter abnormality (low density on CT, hyperintensity on T2-weighted or FLAIR MRI), often with irregular margins, commonly seen in the normal elderly and in association with vascular risk factors such as hypertension, or in context of cognitive impairment. The term was introduced to avoid confusing an imaging appearance with a specific pathology (O'Sullivan, 2008). Leukoaraiosis can be focal, patchy or diffuse area in the white matter and it is located periventricularly or deeper in the white matter.

> Leukoaraiosis severity has traditionally been graded by visual scales. Simples scales like that of van Swieten divide the appearances into only two grades of severity; more complex scales like the Fazekas scale discriminates "punctate", "early confluent" and "confluent" white matter lesions, while the Sheltens scale adopts a 0-6 scale in multiple anatomical regions (including periventricular and nonperiventricular white matter lesions - WML; periventricular hyperintensities are further separated into frontal, occipital, and lateral aspects) (O' Sullivan, 2008; Scheltens et al., 1993, as cited by Bohnen et al., 2009). Other rating scales of WML are the Brant-Zawadzki Scale and the Cardiovascular Health Study Scale both of which place relatively more emphasis on periventricular WML (Bohnen et al., 2009). However, even fully quantitative volumetric measurements of leukoaraiosis correlate weakly with cognitive and physical function, suggesting that T2-weighted MRI provides only a rough impression of the severity of the underlying pathology (O' Sullivan, 2008).

> T2-weighted imaging is sensitive to liquid, gliosis and the effects of demyelination. FLAIR images are heavily T2-weigtened with cerebrospinal fluid suppression. This makes it

White Matter Changes in Cerebrovascular Disease: Leukoaraiosis 237

Newer MRI sequences can provide useful additional information. Diffusion-weighted imaging, for example, allows the distinction of new lacunar infarcts from background leukoaraiosis. In patients who presents with intracerebral haemorrhage, especially lobar haemorrhage, gradient acho (T2\*-weighted) images should be performed to look for evidence of previous haemorrhages or microbleeds. In terms of quantifying white matter damage, several techniques (such as diffusion tensor MRI) are proving superior to T2 weighting imaging. Diffusion tensor MRI provides a much better index of white matter damage, and simple whole-brain measurements, such as diffusion histograms, can help track disease progression. Diffusion tensor MRI also demonstrates the variability in the extent of white matter disruption both within lesions and in normal-appearing white matter

Several studies have described the prevalence of leukoaraiosis in different population groups, but there is considerable variability in the published figures. This variability can be attributed to the heterogeneity of age and vascular risk factors of patients with different imaging modalities used and differences in the scales used to define the leukoaraiosis. Often, when first discovered, white matter hyperintensities occur in the context of relatively normal brain function. But these lesions are not normal as they indicate an increased risk for stroke, cognitive decline, dementia, and death, as reported by Debette and Markus (2010) at the end of their metanalysis of the existing literature through November 2009. They examined 46 prospective longitudinal studies and found that white matter hyperintensities predict an increased risk of stroke (hazard ratio 3.3), dementia (hazard ratio 1.9) and death

Roppele et al. (2010) performed magnetization transfer imaging in 328 neurologically asymptomatic Austrian Stroke Prevention Study participants (age range, 52–87 years). FLAIR was used to delineate white matter hyperintensities and to define normal-appearing brain tissue. The magnetization transfer ratio was measured globally in normal-appearing brain tissue by using a histogram analysis technique and focally in white matter hyperintensities. Associations of magnetization transfer ratio metrics with sex and a large battery of different cerebrovascular risk factors (age, arterial hypertension, diabetes mellitus, smoking, body mass index, cholesterol and triglyceride levels, glycated hemoglobin, and the presence of cardiac disease) were assessed with univariate and multiple regression analysis. Age was seen to affect all magnetization transfer ratio histogram metrics of normalappearing brain tissue, and a faster decrease of the magnetization transfer ratio peak height occurred in men. Independent associations with magnetization transfer ratio metrics were found for arterial hypertension and diabetes mellitus. Besides lesion grade, arterial hypertension was also significantly associated with a lower magnetization transfer ratio in

The pathogenesis of leukoaraiosis remains controversial. It is unclear whether the mechanisms are the same for large and small punctate foci and for extensive diffuse

(O' Sullivan, 2008).

2.0 (hazard ratio 2.0).

white matter hyperintensities.

**3. Pathophysiology of leukoaraiosis** 

**2. Epidemiology of leukoaraiosis**

possible to detect also leukoaraiotic lesions situated close to the cerebrospinal fluid and to differentiate Virchow-Robin spaces from leukoaraiosis. The decline in cerebral blood flow in areas with leukoaraiosis can be detected with imaging techniques such as average apparent diffusion coefficient (ADCav) where tissues with faster diffusion appear bright and tissues with slower diffusion dark. Normally axons produce significant hindrance to water diffusion but leukoaraiosis causes axonal loss and furthermore leads to an increase in water content of the tissue which can be detected with these imaging techniques. DWI (diffusion weighted MRI) makes it possible to differentiate acute and chronic ischemic stroke lesions from leukoaraiosis. In DW images, tissues with faster diffusion appear dark and tissues with slower diffusion bright (Helenius et al., 2002, as cited by Kurkinen, 2009).

Fig. 1. Cerebral MRI scan showing leukoaraiosis (arrows); left: axial T2 weighted; right: coronal FLAIR sequence.

Fig. 2. MR images from a 76-year old patient; left: T2- weighted sequence showing leukoaraiosis (white arrow) and perivascular dilated spaces (black arrow); right: Proton density sequence showing leukoaraiosis (white arrow).

Newer MRI sequences can provide useful additional information. Diffusion-weighted imaging, for example, allows the distinction of new lacunar infarcts from background leukoaraiosis. In patients who presents with intracerebral haemorrhage, especially lobar haemorrhage, gradient acho (T2\*-weighted) images should be performed to look for evidence of previous haemorrhages or microbleeds. In terms of quantifying white matter damage, several techniques (such as diffusion tensor MRI) are proving superior to T2 weighting imaging. Diffusion tensor MRI provides a much better index of white matter damage, and simple whole-brain measurements, such as diffusion histograms, can help track disease progression. Diffusion tensor MRI also demonstrates the variability in the extent of white matter disruption both within lesions and in normal-appearing white matter (O' Sullivan, 2008).

## **2. Epidemiology of leukoaraiosis**

236 Advances in Brain Imaging

possible to detect also leukoaraiotic lesions situated close to the cerebrospinal fluid and to differentiate Virchow-Robin spaces from leukoaraiosis. The decline in cerebral blood flow in areas with leukoaraiosis can be detected with imaging techniques such as average apparent diffusion coefficient (ADCav) where tissues with faster diffusion appear bright and tissues with slower diffusion dark. Normally axons produce significant hindrance to water diffusion but leukoaraiosis causes axonal loss and furthermore leads to an increase in water content of the tissue which can be detected with these imaging techniques. DWI (diffusion weighted MRI) makes it possible to differentiate acute and chronic ischemic stroke lesions from leukoaraiosis. In DW images, tissues with faster diffusion appear dark and tissues with

 Fig. 1. Cerebral MRI scan showing leukoaraiosis (arrows); left: axial T2 weighted; right:

Fig. 2. MR images from a 76-year old patient; left: T2- weighted sequence showing leukoaraiosis (white arrow) and perivascular dilated spaces (black arrow); right: Proton

density sequence showing leukoaraiosis (white arrow).

slower diffusion bright (Helenius et al., 2002, as cited by Kurkinen, 2009).

coronal FLAIR sequence.

Several studies have described the prevalence of leukoaraiosis in different population groups, but there is considerable variability in the published figures. This variability can be attributed to the heterogeneity of age and vascular risk factors of patients with different imaging modalities used and differences in the scales used to define the leukoaraiosis. Often, when first discovered, white matter hyperintensities occur in the context of relatively normal brain function. But these lesions are not normal as they indicate an increased risk for stroke, cognitive decline, dementia, and death, as reported by Debette and Markus (2010) at the end of their metanalysis of the existing literature through November 2009. They examined 46 prospective longitudinal studies and found that white matter hyperintensities predict an increased risk of stroke (hazard ratio 3.3), dementia (hazard ratio 1.9) and death 2.0 (hazard ratio 2.0).

Roppele et al. (2010) performed magnetization transfer imaging in 328 neurologically asymptomatic Austrian Stroke Prevention Study participants (age range, 52–87 years). FLAIR was used to delineate white matter hyperintensities and to define normal-appearing brain tissue. The magnetization transfer ratio was measured globally in normal-appearing brain tissue by using a histogram analysis technique and focally in white matter hyperintensities. Associations of magnetization transfer ratio metrics with sex and a large battery of different cerebrovascular risk factors (age, arterial hypertension, diabetes mellitus, smoking, body mass index, cholesterol and triglyceride levels, glycated hemoglobin, and the presence of cardiac disease) were assessed with univariate and multiple regression analysis.

Age was seen to affect all magnetization transfer ratio histogram metrics of normalappearing brain tissue, and a faster decrease of the magnetization transfer ratio peak height occurred in men. Independent associations with magnetization transfer ratio metrics were found for arterial hypertension and diabetes mellitus. Besides lesion grade, arterial hypertension was also significantly associated with a lower magnetization transfer ratio in white matter hyperintensities.

#### **3. Pathophysiology of leukoaraiosis**

The pathogenesis of leukoaraiosis remains controversial. It is unclear whether the mechanisms are the same for large and small punctate foci and for extensive diffuse

White Matter Changes in Cerebrovascular Disease: Leukoaraiosis 239

Supporting the role of ischemia in the pathogenesis of leukoaraiosis, the results of a study showed a statistically significant correlation between the presence and severity of leukoaraiosis and degree of carotid stenosis. A trend toward increased risk of development of leukoaraiosis in carotids with fatty plaques also was observed. The data confirmed that the development of leukoaraiosis is strongly correlated with age (Saba et al., 2009). A further study showed a statistically significant correlation between increased carotid artery wall

Histopathological evidence of endothelial cells activation and retraction with increased vascular permeability, increased circulating levels of leukocyte adhesion molecules such as ICAM1 (intercellular adhesion molecule-1) and E selectin (shed from the surface of activated endothelial cells) and a rise in the markers of coagulation activation (including thrombinantithrombin complex and prothrombin fragments 1+2) have been reported in patients with small vessels desease compared with controls (Lin et al., 2000, Hassan et al., 2003, Fassbender et al., 1999, Tomimoto et al., 1999, as cited by Birns & Kalra, 2008). In addition, serum concentration of thrombomodulin and von Willebrand factor, which are both molecular markers of endothelial cell damage, have been shown to correlate with MRI evidence of small

vessels disease (Ishii et al., 1991, Kohriyama et al., 1996 as cited by Birns & Kalra, 2008).

A number of studies have shown that chronic hypertension predisposed to impaired bloodbrain barrier function, with endothelial cell retraction, increased vascular permeability and greater susceptibility to white matter injury for relatively small insults (Tomimoto et al., 1996, Lin et al., 2000, Pantoni, 2002, Wardlaw et al., 2003, Birns et al., 2005, as cited by Birns

In patients with subcortical white matter disease, plasma proteins have been found in the tissue around perforating arteries and increased concentrations of a number of proteins in the cerebro-spinal fluid have been found compared with controls, supporting the idea that the proteins reached the cerebro-spinal fluid via leakage from small perforating arteries

One study has demonstrated intravenously injected contrast agent to leak into the brain, particularly in the territory of the perforating arteries, more in those with leukoaraiosis than

Murata et al (1981) hypothesized that disturbances in cerebro-spinal fluid circulation may play a role in the pathogenesis of leukoaraiosis. Roman suggested that increased accumulation of cerebro-spinal fluid in the ventricules raises the interstitial pressure in the periventricular parenchyma, thus causing ischaemia to the white matter (Roman, 1991,

Schneider et al (1997) showed plasma viscosity to be elevated in patients with leukoaraiosis and lacunar infarction and considered that it may alter cerebro-spinal fluid properties and

(Akiguchi et al., 1998., Pantoni et al., 1993, as cited by Birns & Kalra, 2008).

in controls (Starr et al., 2003, as cited by Birns & Kalra, 2008).

**3.3 Disturbances in cerebro-spinal fluid circulation** 

Kimura et al., 1992, as cited by Birns & Kalra, 2008 ).

favour chronic ischaemic white matter damage.

thickness and LA (and its severity) (Saba et al., 2011).

& Kalra, 2008).

**3.4 Plasma viscosity** 

**3.2 Endothelial dysfunction/blood-brain barrier abnormalities** 

leukoaraiosis. Moreover, pathological changes could be consequences of reaching the white matter rather than causes of it.

It has been assumed that the ischemic insult, responsible for LA, results from the vulnerable nature of the long penetrating end-arteries that feed the deep white matter. The deep brain structures (white matter and deep gray nuclei) are supplied by perforating arteries that are end-arteries with no collateral supply. These penetrating arteries do not arborise but give off perpendicularly oriented short branches that irrigate the white matter, each of which provides the blood supply to a cylindrically shaped metabolic unit. In the region between the cortical and ventricular surfaces, centripetal and centrifugal penetrating arteries from an internal watershed area lacking anastomoses is particularly susceptible to being injured as a result of systemic or focal decreases in cerebral blood flow (Rowbotham et al., 1965, De Reuck, 1971, as cited by Birns & Kalra, 2008).

At the vascular level, the continuum extends from the findings of hyaline thickening of the walls of small arteries to the lipohyalinosis (a major disruption in wall with infiltration of macrophages and luminal narrowing). At the level of the parenchyma, there is a loss of myelin and axons with a glial reaction and even areas of infarction (Fazekas et al., 1993, Lotz et al., 1986).

The main pathogenic hypotheses involve:

#### **3.1 Ischemia, cerebral vasoreactivity and autoregulation**

The pathological studies suggest that leukoaraiosis is one manifestation of cerebral small vessel disease. This is supported by strong pathological and clinical associations with the other major manifestation of small vessel disease—lacunar stroke. The pathogenesis of cerebral small vessels disease is still a matter of investigation but both clinical and pathological studies support the most popular hypothesis that acute disruption of blood supply in one arterial territory results in lacunar infarction while a more chronic and widespread reduction in perfusion causes leukoaraiosis. This is consistent with the spatial pattern and distribution of leukoaraiosis, which arises first in those areas furthest from the origin of the arterioles in the periventricular and deep white matter regions (Hassan et al., 2003, Pantoni, 2002, as cited by Birns & Kalra, 2008).

Reductions in white matter perfusion in leukoaraiosis have been demonstrated using xenon-CT, MRI, PET and SPECT and in some studies, the degree of hypoperfusion has been found to correlate with the severity of leukoaraiosis (Oishi et al., 1999, Miyazawa et al., 1997, as cited by Birns & Kalra, 2008 ). Furthermore, quantitative perfusion and diffusion tensor MRI studies have revealed reduced cerebral blood flow in normal appearing white matter in periventricular regions in patients with leukoaraiosis, suggesting that areas are "at risk." (O' Sullivan, 2001, 2002). Two studies on the relationship between cerebrovascular reactivity and cerebral small vessels disease (which excluded patients with carotid artery stenoses or those undertoken soon after an acute ischaemic event, knowing the effect of these comorbidities on cerebrovascular reactivity) demonstrated impaired reactivity in patients with multiple lacunar infarctions but no association between cerebrovascular reactivity and the severity of leukoaraiosis on brain MRI (Molina et al., 1999, Cupini et al., 2001 as cited by Birns & Kalra, 2008).

leukoaraiosis. Moreover, pathological changes could be consequences of reaching the white

It has been assumed that the ischemic insult, responsible for LA, results from the vulnerable nature of the long penetrating end-arteries that feed the deep white matter. The deep brain structures (white matter and deep gray nuclei) are supplied by perforating arteries that are end-arteries with no collateral supply. These penetrating arteries do not arborise but give off perpendicularly oriented short branches that irrigate the white matter, each of which provides the blood supply to a cylindrically shaped metabolic unit. In the region between the cortical and ventricular surfaces, centripetal and centrifugal penetrating arteries from an internal watershed area lacking anastomoses is particularly susceptible to being injured as a result of systemic or focal decreases in cerebral blood flow (Rowbotham et al., 1965, De

At the vascular level, the continuum extends from the findings of hyaline thickening of the walls of small arteries to the lipohyalinosis (a major disruption in wall with infiltration of macrophages and luminal narrowing). At the level of the parenchyma, there is a loss of myelin and axons with a glial reaction and even areas of infarction (Fazekas et al., 1993, Lotz

The pathological studies suggest that leukoaraiosis is one manifestation of cerebral small vessel disease. This is supported by strong pathological and clinical associations with the other major manifestation of small vessel disease—lacunar stroke. The pathogenesis of cerebral small vessels disease is still a matter of investigation but both clinical and pathological studies support the most popular hypothesis that acute disruption of blood supply in one arterial territory results in lacunar infarction while a more chronic and widespread reduction in perfusion causes leukoaraiosis. This is consistent with the spatial pattern and distribution of leukoaraiosis, which arises first in those areas furthest from the origin of the arterioles in the periventricular and deep white matter regions (Hassan et al.,

Reductions in white matter perfusion in leukoaraiosis have been demonstrated using xenon-CT, MRI, PET and SPECT and in some studies, the degree of hypoperfusion has been found to correlate with the severity of leukoaraiosis (Oishi et al., 1999, Miyazawa et al., 1997, as cited by Birns & Kalra, 2008 ). Furthermore, quantitative perfusion and diffusion tensor MRI studies have revealed reduced cerebral blood flow in normal appearing white matter in periventricular regions in patients with leukoaraiosis, suggesting that areas are "at risk." (O' Sullivan, 2001, 2002). Two studies on the relationship between cerebrovascular reactivity and cerebral small vessels disease (which excluded patients with carotid artery stenoses or those undertoken soon after an acute ischaemic event, knowing the effect of these comorbidities on cerebrovascular reactivity) demonstrated impaired reactivity in patients with multiple lacunar infarctions but no association between cerebrovascular reactivity and the severity of leukoaraiosis on brain MRI (Molina et al., 1999, Cupini et al., 2001 as cited by

matter rather than causes of it.

et al., 1986).

Birns & Kalra, 2008).

Reuck, 1971, as cited by Birns & Kalra, 2008).

The main pathogenic hypotheses involve:

**3.1 Ischemia, cerebral vasoreactivity and autoregulation** 

2003, Pantoni, 2002, as cited by Birns & Kalra, 2008).

Supporting the role of ischemia in the pathogenesis of leukoaraiosis, the results of a study showed a statistically significant correlation between the presence and severity of leukoaraiosis and degree of carotid stenosis. A trend toward increased risk of development of leukoaraiosis in carotids with fatty plaques also was observed. The data confirmed that the development of leukoaraiosis is strongly correlated with age (Saba et al., 2009). A further study showed a statistically significant correlation between increased carotid artery wall thickness and LA (and its severity) (Saba et al., 2011).

#### **3.2 Endothelial dysfunction/blood-brain barrier abnormalities**

Histopathological evidence of endothelial cells activation and retraction with increased vascular permeability, increased circulating levels of leukocyte adhesion molecules such as ICAM1 (intercellular adhesion molecule-1) and E selectin (shed from the surface of activated endothelial cells) and a rise in the markers of coagulation activation (including thrombinantithrombin complex and prothrombin fragments 1+2) have been reported in patients with small vessels desease compared with controls (Lin et al., 2000, Hassan et al., 2003, Fassbender et al., 1999, Tomimoto et al., 1999, as cited by Birns & Kalra, 2008). In addition, serum concentration of thrombomodulin and von Willebrand factor, which are both molecular markers of endothelial cell damage, have been shown to correlate with MRI evidence of small vessels disease (Ishii et al., 1991, Kohriyama et al., 1996 as cited by Birns & Kalra, 2008).

A number of studies have shown that chronic hypertension predisposed to impaired bloodbrain barrier function, with endothelial cell retraction, increased vascular permeability and greater susceptibility to white matter injury for relatively small insults (Tomimoto et al., 1996, Lin et al., 2000, Pantoni, 2002, Wardlaw et al., 2003, Birns et al., 2005, as cited by Birns & Kalra, 2008).

In patients with subcortical white matter disease, plasma proteins have been found in the tissue around perforating arteries and increased concentrations of a number of proteins in the cerebro-spinal fluid have been found compared with controls, supporting the idea that the proteins reached the cerebro-spinal fluid via leakage from small perforating arteries (Akiguchi et al., 1998., Pantoni et al., 1993, as cited by Birns & Kalra, 2008).

One study has demonstrated intravenously injected contrast agent to leak into the brain, particularly in the territory of the perforating arteries, more in those with leukoaraiosis than in controls (Starr et al., 2003, as cited by Birns & Kalra, 2008).

#### **3.3 Disturbances in cerebro-spinal fluid circulation**

Murata et al (1981) hypothesized that disturbances in cerebro-spinal fluid circulation may play a role in the pathogenesis of leukoaraiosis. Roman suggested that increased accumulation of cerebro-spinal fluid in the ventricules raises the interstitial pressure in the periventricular parenchyma, thus causing ischaemia to the white matter (Roman, 1991, Kimura et al., 1992, as cited by Birns & Kalra, 2008 ).

#### **3.4 Plasma viscosity**

Schneider et al (1997) showed plasma viscosity to be elevated in patients with leukoaraiosis and lacunar infarction and considered that it may alter cerebro-spinal fluid properties and favour chronic ischaemic white matter damage.

White Matter Changes in Cerebrovascular Disease: Leukoaraiosis 241

changes, decreased cerebral blood flow, endothelial dysfunction, and vasogenic edema in

It has been also demonstrated homocysteine (which is toxic to the endothelium) to be a strong risk factor for small-vessel disease on 90 patients with leukoaraiosis and lacunar infarction compared to 52 patients with isolated lacunar infarction after controlling for both conventional risk factors and age (Hassan at al., 2004, Khan et al., 2007, as cited by Birns &

Matrix metalloproteinases are neutral proteases that disrupt the blood-brain barrier and degrade myelin basic protein under conditions of neuroinflammation. Candelario-Jalil et al., studied 60 patients with suspected vascular cognitive impairment due to small vessel disease (twenty-five of which were classified as subcortical ischemic vascular disease, whereas other groups included mixed Alzheimer disease and vascular cognitive impairment, multiple strokes, and leukoaraiosis when white matter lesions were present and the diagnosis of vascular cognitive impairment was uncertain) by measuring metalloproteinase-2, metalloproteinase-3 and metalloproteinase-9 activity as well as the albumin level in the cerebrospinal fluid. They found that increased levels of metalloproteinases are associated with increased cerebrospinal fluid albumin and suggest that they may contribute to the pathophysiology of subcortical ischemic vascular disease.

Since necrosis is not obvious in LA lesions, Brown et al. investigated the occurrence of apoptosis. They obtained 1.5-cm-thick coronal brain slices at autopsy from two patients with LA. MRI was performed on the brain slices. Sections were stained by several methods including the terminal deoxynucleotidyl transferase dUTP (uridine 5'-triphosphate) nick end labeling (TUNEL) method for DNA fragmentation. The presence of numerous scattered cells in the LA lesions showing DNA fragmentation suggests that those cells are damaged and dying, at least some by apoptosis. The apoptosis in the white matter adjacent to the LA lesions suggests progressive cell loss and expansion of the LA lesions (Brown et al., 2002).

RNA expression was assessed in the blood of individuals with and without extensive white matter hyperintensities (WMH) to search for evidence of oxidative stress, inflammation, and other abnormalities described in WMH lesions in brain. Cluster and principal components analyses showed that the expression profiles for almost 300 genes distinguished WMH+ from WMH− subjects. Function analyses suggested that WMHspecific genes were associated with oxidative stress, inflammation, detoxification, and hormone signaling, and included genes associated with oligodendrocyte proliferation, axon

Fernandez-Cadenas et al. analyzed 212 single nucleotide polymorphisms (SNPs) in 142 patients with ischaemic stroke, generating a total of 30104 genotypes. Seventy-nine subjects (55.6%) presented leukoaraiosis measured by the Fazekas scale and 69 (48.6%) by agerelated white matter changes (ARWMC) scale. This study revealed that the genes associated with leukoaraiosis were involved in blood-brain barrier (BBB) homeostasis (Fernandez-

repair, long-term potentiation, and neurotransmission (Xu et al., 2010).

cerebral white matters.

**3.7 Others hypothesis** 

Kalra, 2008).

**3.8 Genetic factors** 

Cadenas et al., 2010).

## **3.5 Platelet hyperaggregability and other coagulation abnormalities**

Fujita et al (2011) demonstrated a significantly increased incidence of platelet hyperaggregability in 73 patients with leukoaraiosis compared with 102 controls. Twentyone patients with leukoaraiosis and uncorrected platelet hyper-aggregability were compared with 21 controls matched for age, grade of leukoaraiosis and observation period whose platelet hyper-aggregability was corrected. The results of their study showed that the progress of leukoaraiosis is significantly inhibited by long-term correction of platelet hyperaggregability, suggesting platelet hyper-aggregability as a risk factor for leukoaraiosis

Martí-Fàbregas et al. (2002) investigated whether there is a direct correlation between plasma fibrinogen levels and the amount of leukoaraiosis in 28 patients with symptomatic small-vessel disease. They found a significant correlation between plasma fibrinogen levels and the amount of leukoaraiosis in patients with symptomatic cerebral small-vessel disease. This result suggests that fibrinogen may be involved in the pathophysiology of leukoaraiosis in these patients.

Hassan et al showed that while tissue factor and the ratio of tissue factor to TFPI (tissue factor pathway inhibitor) did not differ significantly between patients with small vessel disease and controls, the tissue factor/TFPI ratio was higher in small vessel disease patients with leukoaraiosis compared with isolated lacunar infarction (Hassan et al., 2003, as cited by Birns & Kalra, 2008).

#### **3.6 Cerebral venous circulation impairment**

Some authors found an age-related gradual increase in the thickness of the walls of veins and venules near the lateral ventricles and a striking degree of vessels wall thickening, resulting in narrowed lumina and even occlusion, in patients with leukoaraiosis. The thickened vascular walls stained strongly for collagens I and III. In the studied cases, the degree of venous collagenosis statistically correlated with the severity of leukoaraiosis. The authors questioned whether increased resistance to venous blood flow resulting from the venous stenosis, might induce chronic ischaemia and/or oedema in the deep white matter, perhaps somehow leading to leukoaraiosis, or indeed whether the collagenosis itself occurs as a result of ischaemia (Moody et al., 1995, Brown et al., 2002, as cited by Birns & Kalra, 2008).

More recently, Chung & Hu (2010) hypothesed that chronic cerebral hypoperfusion associated with vasogenic edema, microbleeding or/and endothelial dysfunction found in leukoaraiosis favors venous ischemia, in stead of arterial ischemia, as its pathogenesis. Given that the involved regions in leukoaraiosis (periventricular and subcortical regions) are the drainage territory of deep cerebral venous system and the watershed region between the superficial and deep cerebral venous system respectively, and adding the facts that periventricular venule collagenosis, and retinal and intraparenchymal venules dilatation are related to the severity of leukoaraiosis, the authors suggested that cerebral venous hypertension caused by downstream venous outflow impairment might play a major role in the pathogenesis of leukoaraiosis. Jugular venous reflux is therefore suggested to play a key role in the pathogenesis of leukoaraiosis through a sustained or long-term repetitive retrograde-transmitted cerebral venous pressure and venous outflow insufficiency, which might lead to chronic cerebral venous hypertensions, abnormal cerebral venules structural changes, decreased cerebral blood flow, endothelial dysfunction, and vasogenic edema in cerebral white matters.

#### **3.7 Others hypothesis**

240 Advances in Brain Imaging

Fujita et al (2011) demonstrated a significantly increased incidence of platelet hyperaggregability in 73 patients with leukoaraiosis compared with 102 controls. Twentyone patients with leukoaraiosis and uncorrected platelet hyper-aggregability were compared with 21 controls matched for age, grade of leukoaraiosis and observation period whose platelet hyper-aggregability was corrected. The results of their study showed that the progress of leukoaraiosis is significantly inhibited by long-term correction of platelet hyperaggregability, suggesting platelet hyper-aggregability as a risk factor for leukoaraiosis

Martí-Fàbregas et al. (2002) investigated whether there is a direct correlation between plasma fibrinogen levels and the amount of leukoaraiosis in 28 patients with symptomatic small-vessel disease. They found a significant correlation between plasma fibrinogen levels and the amount of leukoaraiosis in patients with symptomatic cerebral small-vessel disease. This result suggests that fibrinogen may be involved in the pathophysiology of

Hassan et al showed that while tissue factor and the ratio of tissue factor to TFPI (tissue factor pathway inhibitor) did not differ significantly between patients with small vessel disease and controls, the tissue factor/TFPI ratio was higher in small vessel disease patients with leukoaraiosis compared with isolated lacunar infarction (Hassan et al., 2003, as cited by

Some authors found an age-related gradual increase in the thickness of the walls of veins and venules near the lateral ventricles and a striking degree of vessels wall thickening, resulting in narrowed lumina and even occlusion, in patients with leukoaraiosis. The thickened vascular walls stained strongly for collagens I and III. In the studied cases, the degree of venous collagenosis statistically correlated with the severity of leukoaraiosis. The authors questioned whether increased resistance to venous blood flow resulting from the venous stenosis, might induce chronic ischaemia and/or oedema in the deep white matter, perhaps somehow leading to leukoaraiosis, or indeed whether the collagenosis itself occurs as a result of ischaemia (Moody et al., 1995, Brown et al., 2002, as cited by Birns & Kalra,

More recently, Chung & Hu (2010) hypothesed that chronic cerebral hypoperfusion associated with vasogenic edema, microbleeding or/and endothelial dysfunction found in leukoaraiosis favors venous ischemia, in stead of arterial ischemia, as its pathogenesis. Given that the involved regions in leukoaraiosis (periventricular and subcortical regions) are the drainage territory of deep cerebral venous system and the watershed region between the superficial and deep cerebral venous system respectively, and adding the facts that periventricular venule collagenosis, and retinal and intraparenchymal venules dilatation are related to the severity of leukoaraiosis, the authors suggested that cerebral venous hypertension caused by downstream venous outflow impairment might play a major role in the pathogenesis of leukoaraiosis. Jugular venous reflux is therefore suggested to play a key role in the pathogenesis of leukoaraiosis through a sustained or long-term repetitive retrograde-transmitted cerebral venous pressure and venous outflow insufficiency, which might lead to chronic cerebral venous hypertensions, abnormal cerebral venules structural

**3.5 Platelet hyperaggregability and other coagulation abnormalities** 

leukoaraiosis in these patients.

**3.6 Cerebral venous circulation impairment** 

Birns & Kalra, 2008).

2008).

It has been also demonstrated homocysteine (which is toxic to the endothelium) to be a strong risk factor for small-vessel disease on 90 patients with leukoaraiosis and lacunar infarction compared to 52 patients with isolated lacunar infarction after controlling for both conventional risk factors and age (Hassan at al., 2004, Khan et al., 2007, as cited by Birns & Kalra, 2008).

Matrix metalloproteinases are neutral proteases that disrupt the blood-brain barrier and degrade myelin basic protein under conditions of neuroinflammation. Candelario-Jalil et al., studied 60 patients with suspected vascular cognitive impairment due to small vessel disease (twenty-five of which were classified as subcortical ischemic vascular disease, whereas other groups included mixed Alzheimer disease and vascular cognitive impairment, multiple strokes, and leukoaraiosis when white matter lesions were present and the diagnosis of vascular cognitive impairment was uncertain) by measuring metalloproteinase-2, metalloproteinase-3 and metalloproteinase-9 activity as well as the albumin level in the cerebrospinal fluid. They found that increased levels of metalloproteinases are associated with increased cerebrospinal fluid albumin and suggest that they may contribute to the pathophysiology of subcortical ischemic vascular disease.

Since necrosis is not obvious in LA lesions, Brown et al. investigated the occurrence of apoptosis. They obtained 1.5-cm-thick coronal brain slices at autopsy from two patients with LA. MRI was performed on the brain slices. Sections were stained by several methods including the terminal deoxynucleotidyl transferase dUTP (uridine 5'-triphosphate) nick end labeling (TUNEL) method for DNA fragmentation. The presence of numerous scattered cells in the LA lesions showing DNA fragmentation suggests that those cells are damaged and dying, at least some by apoptosis. The apoptosis in the white matter adjacent to the LA lesions suggests progressive cell loss and expansion of the LA lesions (Brown et al., 2002).

#### **3.8 Genetic factors**

RNA expression was assessed in the blood of individuals with and without extensive white matter hyperintensities (WMH) to search for evidence of oxidative stress, inflammation, and other abnormalities described in WMH lesions in brain. Cluster and principal components analyses showed that the expression profiles for almost 300 genes distinguished WMH+ from WMH− subjects. Function analyses suggested that WMHspecific genes were associated with oxidative stress, inflammation, detoxification, and hormone signaling, and included genes associated with oligodendrocyte proliferation, axon repair, long-term potentiation, and neurotransmission (Xu et al., 2010).

Fernandez-Cadenas et al. analyzed 212 single nucleotide polymorphisms (SNPs) in 142 patients with ischaemic stroke, generating a total of 30104 genotypes. Seventy-nine subjects (55.6%) presented leukoaraiosis measured by the Fazekas scale and 69 (48.6%) by agerelated white matter changes (ARWMC) scale. This study revealed that the genes associated with leukoaraiosis were involved in blood-brain barrier (BBB) homeostasis (Fernandez-Cadenas et al., 2010).

White Matter Changes in Cerebrovascular Disease: Leukoaraiosis 243

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.,

 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

Stage II leukoaraiosis (Brant-Zawadzki scale) was present frequently in patients with

Stage III leukoaraiosis (Brant-Zawadzki scale) predominated in patients with chronic

Stage IV (Brant-Zawadzki scale) in our studied group was found in those with

Severity of neurologic symptoms was in direct proportion with severity of

Presence of leukoaraiosis was associated with increased risk of stroke recurrence

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

Leukoaraiosis associated cognitive decline and brain atrophy in 66% of cases.

1995, Yamauchi et al., 2002, as cited by Inzitari, 2003).

leukoaraiosis. The study revealed that:

Severity of leukoaraiosis increased with age.

(almost half of the cases) (Hâncu et al., 2009).

acute stroke.

vascular lesions.

leukoaraiosis.

**4.2 Large arteries stroke** 

disease and cardioembolism.

Binswanger disease.
