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Journal of Alzheimer’s Disease 40 (2014) 123–134 DOI 10.3233/JAD-131709 IOS Press

Early Frontal Structural and Functional Changes in Mild White Matter Lesions Relevant to Cognitive Decline Xuan Suna,b,c,1 , Ying Liangb,c,1 , Jun Wangb,c , Kewei Chend , Yaojing Chenb,c , Xiaoqing Zhoub,c , Jianjun Jiaa,∗ and Zhanjun Zhangb,c,∗ a Department

of Geriatric Neurology, Chinese PLA General Hospital, Beijing, P.R. China Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, P.R. China c BABRI Centre, Beijing Normal University, Beijing, P.R. China d Banner Alzheimer’s Institute, Phoenix, AZ, USA b State

Accepted 5 November 2013

Abstract. White matter lesions (WMLs) are of considerable research interest because of their high prevalence and serious consequences, such as stroke and dementia. Most existing studies of WMLs have focused on severe WMLs, but mild WMLs, which are clinically and fundamentally significant, have been largely neglected. The present study is a comprehensive investigation on the injury pattern and on the anatomical, functional, and cognitive changes related to mild WMLs. These results may provide better understanding mild WMLs. Fifty-one human subjects with mild WMLs and 49 control participants completed serial neuropsychological tests and underwent a 3-T magnetic resonance imaging (MRI) scan that included diffusion tensor imaging, a resting-state functional MRI, and a structural MRI. We found declines in cognitive functions such as global function, executive function, and episodic memory in mild WMLs subjects. The white matter injuries in the mild WMLs subjects were mainly in the fibers that projected to frontal areas, while gray matter structures were relatively intact. The overall resting state function of the frontal area was significantly increased. The integrity of the neural fibers in the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus was significantly correlated with the cognitive scores in executive function and episodic memory in both the control and the mild WMLs group. These findings demonstrate that mild WMLs subjects exhibit abnormalities in both white matter structure and functional intrinsic brain activity and that such changes are related to several types of cognitive dysfunction. Keywords: Cognition, diffusion tensor imaging, mild white matter lesions, resting-state functional magnetic resonance imaging

INTRODUCTION White matter lesions (WMLs) in the brain, manifested as increased signal intensities on T2-weighted magnetic resonance imaging (MRI) [1], are extremely common in aging individuals. The prevalence of such

1 These

authors contributed equally to this work. to: Zhanjun Zhang, MD, State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China. Tel./Fax: +86 1058802005; E-mail: zhang [email protected]; Jianjun Jia, MD, Department of Geriatric Neurology, Chinese PLA General Hospital, Beijing 100853, P.R. China. Tel./Fax: +86 88840469; E-mail: [email protected]. ∗ Correspondence

changes in older people is close to 100% [2–5]. The current dominant view is that WMLs are a small-vessel ischemic disease [4, 6, 7] and that the incidence of WMLs is positively related to age [8, 9] and vascular risk factors [10–12]. WMLs are a progressive change and can be classified as mild WMLs and severe WMLs according to the progress of the pathology and clinical symptoms. Most previous studies have focused on severe WMLs because the patients showed apparent deficits in physical functions and significant defects in cognitive functions such as perceptual speed, semantics, and episodic memory [13–15]. Severe WMLs are also strongly associated with stroke [16–18], dementia

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[19, 20], Alzheimer’s disease [21, 22] and even death [23, 24]. However, mild WMLs and its health consequences should not be understated. Mild WMLs have high morbidities in older people: 8.7% for 65 to 75-yearolds in nine European countries [5] and 33% for the same age group in China [13]. A number of studies have additionally confirmed that the progression of WMLs can be prevented or even reversed [25, 26] if they are identified and clinically intervened early. This underscores the importance of investigating the injury characteristics of mild WMLs for clinical practice. Furthermore, the brain and behavioral injuries shown in mild WMLs patients are relatively “pure injuries of WMLs” compared with those of severe WMLs, which are often complicated with stroke [16–18] or Alzheimer’s disease. These complications make it difficult to determine which injuries are related to the WMLs themselves and which are secondarily related to the complications. Research on the injury characteristics and mechanisms of mild WMLs therefore has additional significant theoretical value. In clinical practice, mild WMLs are still often neglected. Physicians tend to give little attention to mild WMLs because they have a very insidious onset and patients show only mild and easily overlooked cognitive impairment [27, 28]. Also, there are only a few research studies of mild WMLs. The most extensive cognitive clinic-based study of WMLs reported a difference of 0.36 points in Mini-Mental State Examination (MMSE) scores between mild WMLs patients and healthy elderly people [29]. Another study also indicated that mild WMLs have a marginal effect on various cognitive domains [30]. However, the deeper mechanism of mild WMLs, i.e., the structural and functional aberrant pattern over the whole brain and its association with cognitive changes, is largely unknown at present. In the present study, we investigated cognitive function, structures of the brain white/gray matter, and resting brain functional activity in mild WMLs subjects, analyzing multimodal neuroimaging data in one cohort of individuals. Our findings might provide information on the characteristics and mechanisms of mild WMLs-related cognitive declines.

Group (BABRI), which is a longitudinal study investigating aging and cognitive impairment in urban elderly individuals in Beijing, China. There were 100 participants (51 with mild WMLs and 49 sociodemographically matched healthy controls). All of the participants were right-handed and were native Chinese speakers. All of the participants were between 50 and 85 years of age; had at least 6 years of education; had no structural abnormalities, such as tumors, subdural hematomas, or contusions due to previous head trauma; had no history of addiction, neurologic or psychiatric diseases; had no conditions known to influence cerebral function, including alcoholism, current depression, Parkinson’s disease, or epilepsy; and had no large vessel disease such as cortical or subcortical infarcts and watershed infarcts. All mild WMLs subjects were diagnosed according to ARWMC [31]. The controls showed no evidence of WMLs on structural MRIs. Demographic information for each group and between-group comparisons are presented in Table 1. The study was approved by the Institutional Review Board of the Beijing Normal University Imaging Center for Brain Research. Written informed consent was obtained from each participant. Cognitive assessment

METHODS

All participants underwent a comprehensive neuropsychological assessment that included a battery of neuropsychological tests. General mental status was assessed with the MMSE. Processing speed was assessed with the Digit Symb-Coding subtest of the Chinese revision of the Wechsler Adult Intelligence Scale (WAIS-RC) [32]. Verbal and nonverbal episodic memory tests included the Auditory Verbal Learning Test (AVLT) and the Recall component of the Rey-Osterrieth Complex Figure Test (ROCF) [33]. Executive function was assessed with the Stroop Test [34], the Trail Making Test (TMT) [35] and the clock drawing test. Verbal working memory was assessed with the Digit Span scores on the WAIS-RC. Verbal reasoning and abstract thinking were assessed with the Similarities subtest of the WAIS-RC. Lastly, language ability was assessed with the Boston Naming Test [36] and the Fluency. Neuropsychological characterizations for each group are presented in Table 1.

Participants

Image acquisition

Subjects with mild WMLs were recruited from the Beijing Aging Brain Rejuvenation Initiative Study

All subjects were scanned using a Siemens Trio 3.0 Tesla scanner in the Imaging Center for Brain Research

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Table 1 Demographics of all participants and neuropsychological test results

Age (years) Education (years) Gender (M/F) Hypertension, % Diabetes, % Hyperlipidemia, % Smoking, % Body mass index General mental status MMSE Episodic memory AVLT ROCF Recall Working memory Digit Span Processing speed Digit Symb-Coding Executive function TMT-BA time Stroop C-B Clock drawing Reasoning Similarities Language ability Boston naming test Fluency

Controls (n = 49)

mWMLs (n = 51)

T-value (χ2 )

p value

62.9 ± 6.6 10.4 ± 3.2 16/33 28.0 19.6 31.4 13.7 24.4 ± 2.4

65.3 ± 7.2 10.3 ± 3.4 22/28 16.3 10.2 36.7 8.2 24.9 ± 3.3

−1.64 0.187 2.10 2.0 1.73 0.32 0.79 −0.68

0.10 0.85 0.21 0.23 0.26 0.67 0.53 0.49

27.2 ± 1.7

26.2 ± 2.6

2.11

0.037*

4.9 ± 2.5 16.4 ± 10.6

3.4 ± 2.6 8.3 ± 6.5

3.03 4.65

0.003***

Early frontal structural and functional changes in mild white matter lesions relevant to cognitive decline.

White matter lesions (WMLs) are of considerable research interest because of their high prevalence and serious consequences, such as stroke and dement...
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