Special Issue Article

Leukoaraiosis with mild cognitive impairment Mi Te1, Ethan Zhao2, Zheng Xingyue1, Sun Qinjian1, Qu Chuanqiang1 1

Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China, 2 Wayne State University School of Medicine, Detroit, MI, USA As the ageing population continues to increase, the prevalence of age-related cognitive impairment has been on the rise. Mild cognitive impairment (MCI) is now widely recognised as the early stage of dementia. Mild cognitive impairment is closely associated with cerebral white matter lesions (WMLs), specifically in the case of leukoaraiosis (LA). A previous diffusion tensor imaging (DTI) has demonstrated that white matter changes might damage cognitive function in LA patients, and the cognitive function might decrease with the deterioration of LA. Through consulting and analysing documents, we found that both of them share similarities in risk factors, pathogenesis, pathological changes, and imaging manifestations. The main characteristics of LA patients with MCI (LACI) are the early and apparent manifestations of delayed memory, attention, impaired executive function, and close association with dementia. This analysis of LACI may contribute to an early diagnosis of LACI and provide possible treatment for LACI.

Keywords: Mild cognitive impairment, White matter lesions, Leukoaraiosis, Dementia

Mild cognitive impairment (MCI) refers to a clinical state between normal ageing and dementia that does not meet the diagnostic criteria for dementia. Leukoaraiosis (LA), one of the common cerebral white matter lesions (WMLs), is characterised by punctate or patchy hyperintensities in the periventricular or subcortical white matter observed on magnetic resonance imaging (MRI). Leukoaraiosis is a part of the ageing process and is indicative of brain damage in the elderly. As an early sign of dementia, LA is often accompanied by cognitive dysfunction. However, the pathogenesis of MCI in LA patients is poorly understood. In this paper, the risk factors, pathogenesis, pathological changes, imaging manifestations, and characteristics of LA patients with MCI (LACI), and its relationship to dementia will be summarised.

Risk Factors for the LACI Leukoaraiosis is described as an age-related WML, and approximately a quarter of individuals among the elderly over the age of 65 years suffer from different degrees of cerebral white matter changes.1 Similarly, Ganguli et al.2 have shown that ageing is a related risk factor for MCI. Numerous studies have shown that the number of cases of LACI increases with age. However, age may not necessarily be a decisive pathogenic factor for the MCI observed in LA patients because of the aetiological heterogeneity of Correspondence to: Qu Chuanqiang, Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China. Email: [email protected]

ß W. S. Maney and Son Ltd 2015 DOI 10.1179/1743132815Y.0000000028

MCI and the heritability of LA. Thus, the relationship between age and LACI requires further study. Vascular tone has been shown to be a significant risk factor for LA and MCI.3 A previous study demonstrated that the circadian disruption of blood pressure could damage small intracranial blood vessels and was closely associated with cognitive impairment.4 Furthermore, there was a correlation between cerebral WMLs and cognitive function decline in senile hypertension patients. In clinical practice, one or more risk factors for cardiovascular diseases are often seen in patients with LA, and diabetes is one of the common risk factors. Furthermore, studies have shown that the rate of cognitive decline was closely related to the duration of diabetes.5,6 Numerous studies have confirmed that hypertension, myocardial infarction, stroke, lacunar cerebral infarction, and white matter low perfusion of white matter were associated with LA. Together, these findings suggest that the incidence and development of the LACI may be closely related to cardiovascular risk factors, such as hypertension, diabetes, and cerebral infarction. Interestingly, the level of education can affect the relationship between the severe cerebral WMLs and the risk for MCI or dementia. A recent study7 has demonstrated a significant association between severe WMLs and increased MCI/dementia risk in lower education groups, but not in the higher education groups. Moreover, severe WMLs significantly increased the risk of developing MCI/dementia over a 7-year period in low educated

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participants. Thus it is possible that the level of education may be related to the incidence of LACI; however, the exact relationship remains unclear.

The Pathogenesis and Pathological Changes of the LACI The pathogenesis of LACI is poorly understood. Leukoaraiosis patients with MCI have been associated with age-related neurodegenerative changes in the cerebral white matter, vascular inflammatory injury, and the disruption of the bloodbrain barrier.

Degenerative ageing of cerebral white matter The neurodegenerative changes associated with ageing often lead to a decline in cognitive function.8 The reduction in volume and microstructural changes of cerebral white matter seen with ageing results in different degrees of cognitive impairment. A recent study showed that frontal and occipital WMLs were independently correlated with executive function and visuospatial and recall function, respectively, parietal WML volume was associated with orientation function and language impairment.9 And increasing age can also lead to the cerebral atrophy, which may accelerate the decline in cognitive function.10

Vascular inflammatory injury Many argue that LA is closely related to ischaemic injuries, and small vessel disease is one of the main mechanisms for MCI. The periventricular deep white matter is mainly supplied by the perforating artery, and ischaemic changes can easily appear in this area when cerebral ischaemia or hypoperfusion exists. However, it is worth noting that vessels are not static structures. They are dynamic and a compromised flow in one region of the brain, long term is ultimately compensated by ipsilateral angiogenesis, contralateral or collateral circulation providing the necessary blood via neo-angiogenesis. Various haemodynamic disorders, such as vessel wall thickening and vascular stenosis, may appear in the terminal deep perforating artery, which can lead to a reduction of cerebral blood flow and cerebral hypoperfusion.11 Reduced blood supply to the dominant hemisphere could potentially result in more serious clinical symptoms.12 Therefore, it is the chronic process with resultant damage to a particular area arising from compromised parent artery and collateral circulation, which results in MCI and its progression. Recent studies have shown that the inflammatory response is one of the important mechanisms of secondary damage after cerebral ischaemia. Neutrophil adhesion to the endothelium indicates a major component of ischaemia/reperfusion pathophysiology.13 According to Nagai et al.’s14 study of the 137 older women cases with memory impairment, the level of

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serum interleukin 6 (IL-6) was significantly correlated to periventricular hyperintensity and deep white matter hyperintensity scores. Besides IL-6, inflammatory mediators, such as tumour necrosis factor-alpha (TNF-alpha), IL-1 were also associated with post-ischaemic pathology.15 These findings suggest that the hypoxic ischaemic inflammatory reaction of small brain blood vessels may contribute to the incidence of LACI and accelerate its progression.

The bloodbrain barrier impairment Many studies have shown significantly increased levels of tau protein, inflammatory mediators, and C-reactive protein in the cerebrospinal fluid of patients with MCI, which were positively correlated with the severity of cognitive impairment. Through dynamic contrast-enhanced MRI and albumin index, a study of subjects with white matter damages of subcortical ischaemic vascular disease16 suggested that extensive WMLs were related to the destruction of bloodbrain barrier. The disruption of the bloodbrain barrier allows macromolecules, such as protein and cytokines, to permeate into the blood vessels, the perivascular space, and nervous tissues, resulting in white matter damage. The destruction of white matter tracts eventually leads to a decline in cognitive function. Therefore, impairment of the bloodbrain barrier may be a contributing factor for the incidence of LACI.

Magnetic Resonance Imaging Studies of the LACI Magnetic resonance diffusion tensor imaging (DTI) allows for the measurement of restricted diffusion of water in tissue. Diffusion tensor imaging is more sensitive than conventional MRI in assessing the relationship between LA and cognitive impairment.17 The DTI examination of 60 LA patients and 30 healthy elderly people to detect and fraction anisotropy (FA) of LA lesions suggested that FA of LA displayed characteristic changes. Thus, DTI could detect the macrostructaral changes of white matter with normal MRI, and these changes were related to cognitive function.18 Diffusion tensor imaging has also been used to assess the integrity of the parahippocampal white matter in MCI, as a first step in developing a noninvasive tool for early diagnosis. The use of DTI for in vivo assessment of the parahippocampal white matter might has been proved to be useful for identifying individuals with MCI at highest risk for conversion to Alzheimers’ disease (AD) and be valuable for assessing disease progression.19 In addition, another study suggested that it was feasible to use DTI technology to analyse the correlationship between vascular risk factors and cognitive

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dysfunction.20 Diffusion tensor imaging can be used not only to evaluate the relationship between cardiovascular factors and the incidence of LACI, but also to assess the severity and risk for LACI. Thus, DTI may be used for clinical diagnosis and management of LACI. Magnetic resonance spectroscopy (MRS) is a noninvasive technique that can be used to observe metabolic and biochemical changes in vivo. Using MRS to detect changes in the concentrations of the metabolites, the pathological changes of patients with LA can be evaluated.21 According to a populationbased study,22 the measurement of MRI and MRS markers can predict progression to MCI and cognitive decline in cognitively normal older adults.23 Thus MRS is a powerful tool for investigating the pathogenesis and pathological changes of LACI.

LACI progression and thus, reasonably, delay the clinical deterioration in dementia. The increase in lesion volume of LA can cause and aggravate cognitive impairment. The results of a quantitative analysis of the relationship between LA volume and cognitive function have shown that a greater volume of white matter hyperintensities was associated with poorer cognition.29 A previous study suggested that when cerebral WML volume increased to 25% in patients with LA, clinical signs would manifest, suggesting it might be the smallest volume to induce the cognitive impairment.30 The increase of LA damage volume has also been shown to aggravate existing the cognitive impairment. Moreover, severe age-related changes in white matter can independently and strongly predict rapid global functional decline.31

Characteristics of Cognitive Impairment in LACI

The LACI and Dementia

The LA patients are closely correlated with cognitive impairments of attention, memory, executive function, and information processing speed.24 The characteristics of cognitive impairment in LACI appear to be highly variable depending on the location, degree, and size of the lesion in LA. A study of the effects of age on long white matter tracts using diffusion tensor tractography has shown that FA in anterior tracts was primarily associated with executive tasks, whereas FA in posterior tracts was mainly associated with visual memory tasks. Moreover, tracts connecting frontal regions were highly correlated with performance on executive function tasks, whereas tracts connecting more posterior regions were highly correlated with performance on visual memory tests.25 Another study of WMLs in patients with MCI has demonstrated that periventricular WMLs were negatively associated with psychomotor speed, whereas subcortical WMLs were negatively correlated with visual memory.26 The severity of cognitive impairment has also been shown to increase as the number of WMLs in LA increase. A recent study27 demonstrated that above a certain threshold of damage, a pattern of WML clustering in the temporal region identified individuals at increased risk of MCI or dementia, and that it may facilitate the detection of patients at risk of MCI/dementia as this WML pattern is observed before the onset of clinical symptoms. Another study28 has shown that severe WMLs were associated with gait and stance abnormalities, upper motor signs, and fingertap slowing, and the presence and the occurrence of those neurological signs were independent of other vascular brain lesions, confirming that these lesions have clinical relevance. So potential interventions are able to halt or prevent

There has been an upward trend in the prevalence of dementia all over the world.32 And LA left the elderly individual at greater risk for developing dementia.33 A study of dementia showed that AD and vascular dementia (VaD) were the top two common causes of dementia in Asia.34 Alzheimers’ disease is a chronic neurodegenerative disease that usually starts slowly and gets worse over time. The most common early symptom is difficulty in remembering recent events (short-term memory loss). As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self-care, apraxia, and behavioural issues. The conversion rates from MCI to AD are not the same in different studies because of using different statistical standards, but the average annual conversion rate is within 1015%, far higher than that (12%) of the ordinary elderly, and the conversion rate from MCI to AD in 5 years is more than 50%.35 Forty studies were identified involving 1351 patients and 1097 healthy control subjects reporting either atrophy or decreases in glucose utilisation and perfusion, and the result may suggest that atrophy in the (trans-)entorhinal area/hippocampus and hypometabolism/hypoperfusion in the inferior parietal lobules predict most reliably the progression from amnestic MCI to AD.36 So with the aggravation of cognitive impairment (particularly memory impairment), the LACI may possibly develop into AD. Vascular dementia is a severe cognitive dysfunction syndrome caused by ischaemic or hemorrhagic stroke, and cerebrovascular diseases attributed to the hypoperfusion of brain areas that dominate memory, cognition, and behaviour. In the clinical setting, VaD is often accompanied with LA, and many patients with LA finally developed into VaD.

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Shim et al.’s37 research has shown that the FA value decreased in all the brain structures except the occipital lobe area, and FA value in the hippocampus was the lowest, and that the changes of white matter parietal lobe and centrum semiovale on DTI in patients with small vascular cognitive impairment were more closely associated with vascular lesions. Cerebral white matter changes on imaging examination in VCI patients are closely correlated with their clinical manifestations of cognitive impairment, and it is suggested that the LACI (especially accompanied with cerebrovascular diseases) are most likely to develop into VaD. Despite the current body of knowledge provided in this review, the damage threshold level of LA that causes cognitive dysfunction, the relationship between the damage locations and degrees of LA and that of cognitive impairment and whether premonitory WMLs in the LACI are indicative of progression to dementia. Leukoaraiosis is irreversible and progressive, and the therapeutic effect of commonly used drugs is limited. Once LA is complicated with MCI, the deterioration of LA may accelerate the cognitive impairment. Using advanced imaging techniques in clinical practice to detect the white matter microstructure changes associated with WMLs provides a powerful means of making an early diagnosis in patients with LACI, allowing for early-targeted interventions to delay the progress of cognitive impairment and reducing the risk of developing dementia.

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Disclaimer Statements Contributors Mi Te and Ethan Zhao are the main authors recognizing this review, and Zheng Xingyue, Sun Qinjian, and Qu Chuanqiang are the correctors. Funding The National Natural Science Foundation of China(30970991)and the Provincial Natural Science Foundation of Shandong (Y2007C043). Conflicts of interest

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Leukoaraiosis with mild cognitive impairment.

As the ageing population continues to increase, the prevalence of age-related cognitive impairment has been on the rise. Mild cognitive impairment (MC...
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