Study On Cerebral White Matter Pathology And Functional Imaging In Patients With Alzheimer's Disease

Alzheimer's disease (AD) is the leading cause of dementia in the world. Clinical manifestation is memory decline in the early stage, and then show the decreased abilities of language, reasoning, judgment, calculation and orientation , mostly accompanied by behavioral disorders, personality change and daily living disturbances. AD is characterized pathologically by senile plaques (SPs), neurofibrillary tangles (NFTs), neuronal loss, and degeneration and atrophy of cerebral cortex. Mild cognitive impairment (MCI) has been described as a transitional period from healthy aging to clinically probable AD, when patients experience problems with memory, language, or other mental functions that are severe enough to be noticed by other people, but not serious enough to interfere with daily life. Patients who have amnestic MCI, suffering from symptoms that relate primarily to memory loss, are at the greatest risk of ultimately developing AD, and as a group convert to clinically probable AD over time at a rate of 10%～15% per year. Millions of Chinese now have AD, and the prevalence of the disease is accelerating rapidly as the population aging. Beyond the significant individual and societal burden of the disease, the economic impact of AD is staggering. There is no effective therapies for AD at present, and many researches focus on early diagnosis and intervention. Early AD and MCI is the primary target of several pharmacologic and vaccine treatments that are aimed at slowing or possibly halting the progression of AD pathology. Unfortunately, the diagnosis of AD can be made with high accuracy only in its late stage, at a time when there is little hope for therapeutic intervention.Structural neuroimaging has been playing a role in the early diagnosis of AD. Most previous studies went in for morphologic changes on MR imaging examinations of AD. For example, selective medial temporal lobe ,hippocampus, entorhinal cortex atrophy has been found in early AD. There is moderately strong evidence that visual hippocampal atrophy can accurately distinguish between patients who have AD and cognitively normal elders.However, when morphologic changes of hippocampus and entorhinal cortex are observed in patients with AD, the patients has become late stage. Recent study suggested that before changes of cortex, brain functions have been damaged, which may relate with interruption of information connection of cortex to cortex resulted from white matter lesions.White matter changes and lacunar infarcts are found frequently in brain of patients with vascular dementia(VD), especially of subcortical subtypes including Binswanger's disease. These pathological changes are generally considered to be a consequence of chronic ischemia associated with microangiopathy. However, abnormalities of white matter are not associated exclusively with VD and are common in most of patients with AD and some MCI patients. Although neuroimaging and pathoanatomic studies have confirmed both macroscopic and microscopic white matter changes in patients with AD and MCI, controversy exists regarding the clinical significance of these changes and the mechanisms underlying them. Although some studies have reported that individuals with AD have elevated WMLs compared with nondemented aging individuals, this pattern has not been uniformly observed. In addition, the relationship between WMLs and cognition in AD remains unclear. Some studies suggest that subjects with AD and WMLs perform worse than nondemented aging individuals on cognitive tasks, and others find no relationship between WMLs and cognition. Therefore, the clinical significance of WMLs in AD remains unclear, particularly in the earliest clinical stage of the disease. A quantitative study showed that WMLs was associated with reduced memory, processing speed, and executive functions. WMLs are consistently associated with age, hypertension, and other cardiovascular risk factors and are commonly considered part of the spectrum of vascular-related injury, despite nonspecific underlying pathologic changes.There is a increasing pathological evidence of marked damage and dysfunction in the white matter of patients with AD. Pathological evidence suggests that WMLs may play a role in the clinical symptoms of AD. Individuals with more WMLs have a higher risk of developing AD. Other studies indicate that changes in white matter in AD consist not only of neuronal loss, which would be typical of a primary gray matter process, but also loss of axons, oligodendrocytes, and lipid components, together with reactive astrocytosis, microscopic features that are more characteristic of primary white matter diseases.Before the development of quantitative measures, WMLs were assessed using visual rating scales. The development of fluid-attenuated inversion recovery (FLAIR) sequences has enabled semiautomated methods to be developed. Recently, WMLs volumes were measured in patients with AD using FLAIR images and a semiautomated segmentation method based on intensity thresholding to quantify WMLs.Conventional MRI imaging can show overall brain atrophy or atrophy of key brain structures in patients with AD, but has a limited capability to quantify changes in the subcortical white matter, particularly subtle changes not visualized on conventional MRI. Diffusion tensor imaging (DTI) is a non-invasive water diffusion technique and can be used for quantitatively in vivo measuring the degree and directionality of the displacement distribution of water molecules to provide information about the size, orientation, and geometry of brain structures, as well as to demonstrate the white matter abnormalities, including subtle changes not visualized on conventional MRI.Restricted by many factors including cell membranes, axonal membranes, cytoskeletal structure, such as neurofilaments and microtubules, the diffusion of water molecules in biological tissues may not be same in all direction. The preference of diffusion in fiber direction is called anisotropy. Fractional anisotropy (FA), one of the most robust measures of anisotropy, is useful for mapping the functional integrity and specific organization of white matter fibers. Mean diffusivity (MD) is a measure for randomized mean water diffusion. It can be used as a measure of alterations of brain white matter. Loss of oligodendrocytes and axons, together with reactive astrocytosis, in the white matter could explain some of the DTI abnormalities reported.Proton magnetic resonance spectroscopy (1H- MRS) is a valuable tool for the assessment of several biochemical compounds in the brain in vivo, such as N-acetylaspartate (NAA), myoinositol (mI), Choline (Cho) and Creatine (Cr). Most studies have found that a decreased NAA levels and increased mI levels are characteristics of 1H- MRS in AD. This finding reflects neuronal loss or damage as well as an increase in glial content or membrane abnormalities.In this study we applied neuropathological methods, conventional MRI scanning, DTI and 1H-MRS techniques to estimate WMLs and characteristics of imaging in patients with AD. In addition, the relationship between regional WMLs and cognitive function impairment was also investigated. The aim of present study is to further understand the effect of WMLs on cognitive, neurological, and neuropsychiatric symptoms.Part 1: A contrast study on white matter pathology and MRI in patients with Alzheimer's diseaseObjective:To explore the correlation of vascular pathologicl changes and MRI through a study on pathology and imaging of Alzheimer's disease (AD).Methods:(1) Neuropathological study: At autopsy, the brains of 4 cases with AD were fixed in formaldehyde, and were kept in it for 30 days and were later cut into 1cm thick whole-brain coronal slices. Histological sections were taken routinely from the frontal lobe, parietal lobe, occipital lobe, insula, Ammon's horn and hippocampal gyrus, basal ganglia and thalamus, as well as periventricular and deep white matter. Specimens were embedded in paraffin and stained with hematoxylin-eosin, Congo red, silver stainings, Gallyas silver dyeing, and immunohistochemistry for Tau, Ubiquitin,βA4 were also performed. The loss of neurons in all lobes of cerebral cortex, cingulate gyrus, amygdaloid nucleus, hippocampal gyrus, parahippocampal gyrus, meynert basal nuleus, substantia nigra, dorsal nucleus, dorsal nucleus of vagus nerve, senile plaques (SPs) and the changes of neurofibrillary tangles (NFTs) were observed in detail. Additionally, all cases were carefully analysed for additional white matter pathology, including neuronal degeneration, myelin attenuation, oligodendrocytic reduction, astrocytosis and small blood vessel changes. (2) Imaging study: Characteristics of brain atrophy and the severity of periventricular and subcortical deep white matter lesions (WMLs) were observed by magnetic resonance imaging (MRI) in all cases, and were compared to main pathological features.Results:(1) The degeneration of temporal lobe and parietal lobe, as well as frontal lobe, insula, was marked in all 4 cases, and the degeneration of medial temporal lobe was the most obvious; mild to severe damages of WMLs and small blood vessel degeneration were observed in all brains, especially in frontal lobe. The degeneration of white matter included marked myelin attenuation, oligodendrocytic reduction, astrocytosis, and amyloid deposition and fibrohyalinosis in small blood vessels. (2) Severe AD neuropathological findings, including loss of neurons, senile plaques(SPs) and NFTs were found in medial temporal lobe, hippocampal gyrus and frontal lobe, which in coincidence with imaging results. The pathological findings of white matter were also basically conformity with the changes of MRI.Conclusion:Not only gray matters, but white matters are affected in brain of AD patients. Neuropathological features are basically in conformity with the changes of MRI in gray matter and white matter lesions.Part 2: Study on correlation between white matter lesions and cognitive function in patients with mild and moderate Alzheimer's diseaseObjective: To investigate the nature of white matter lesions and its correlation to the cognitive function in patients with mild and moderate Alzheimer's disease (AD) by using 3 Tesla magnetic resonance imaging (MRI)Methods: We enrolled 56 patients with mild and moderate Alzheimer's disease, and 40 age and sex matched normal elderly controls. Age, sex, educational level and history were recorded. T2 fluid attenuated inversion recovery (FLAIR) sequence were used for analysis of load and extent of hyperintense lesions. A semi-quantitative rating scale described by Fazkas et al. and a semi-automated MRI quantitative method were used to measure the scores of periventricular white matter lesions (PVWMLs) and deep white matter lesions (DWMLs), and the volume of total WMLs (VWMLs). The relationship between white matter lesions and cognitive impairment [mini-mental status examination (MMSE); drawing clock test (DCT); ADAS-Cog] was analyzed.Results: (1) Volume of WMLs in AD patients was 27.4±13.9. Scores of PVWMLs and DWMLs in AD patients were 1.31±0.60 and 0.93±0.68 respectively, and in controls were 15.6±13.2,0.75±0.54 and 0.38±0.49, respectively. A significant difference between two groups were observed in VWMLs, scores of PVWMLs and DWMLs (P﹤0.05). When controlling for age the same results were found. (2) Correlation analysis revealed that there was no correlation between age and VWMLs in patients with AD (P﹥0.05). A significantly increased volume of VWMLs were found in AD patients with hypertension than without hypertension (t=2.26, P﹤0.05), and no significant differences between two groups were found in scores of PVWMLs and DWMLs. (3) After controlling for age, significant correlations between volume of WMLs and MMSE (r=-0.569, P﹤0.05), ADAS-Cog (r=0.515, P﹤0.01) and drawing clock test (r=-0.399, P﹤0.05).Conclusion: Our results reveal that patients with AD have more severe WMLs (including PVWMLs and DWMLs) than controls. Hypertension is the risk factor for WMLs, which supports the hypothesis that WMLs in AD patients are superimposed phenomena of vascular origin. Global cognitive functions, including executive function , may be disturbed by WMLs in AD patients.Part 3: Evaluation of microstructural white matter lesions in patients with mild and moderate Alzheimer's disease using diffusion tensor imagingObjective:To investigate the microstructural white matter lesions and its correlation with the cognitive function in patients with mild cognitive impairment (MCI) and mild and moderate Alzheimer's disease (AD) by using diffusion tensor imaging (DTI) technique.Methods:12 patients with MCI, 12 patients with mild and moderate AD, and 12 sex and age matched normal control (NC) were recruited. DTI images were acquired, and fractional anisotropy (FA),mean diffusivity (MD) of normal- appearing white matter (NAWM) in splenium of the corpus callosum, frontal, parietal, temporal, occipital lobes, and anterior and posterior limbs of the internal capsule were determined. These diffusion measurements were compared across the 3 groups, and significant differences were further performed for correlation with tests of cognitive function.Results:(1) Compared with NC group, MCI patients demonstrated decreased FA value only in the parietal lobe (P<0.05),FA values were 0.558±0.079 and 0.489±0.079, respectively. No significant difference in MD values was found between MCI patients and NC group in all brain regions (P﹥0.05). (2) FA values in NC group were 0.499±0.081, 0.558±0.079 and 0.440±0.061, and in AD patients were 0.405±0.072, 0.454±0.069 and 0.363±0.056 respectively in the frontal, parietal and temporal NAWM. FA values decreased significantly in AD patients (P<0.05). MD values in AD patients were 0.978±0.082, 0.920±0.054 and 0.817±0.045 in the splenium of the corpus callosum, frontal and parietal NAWM, respectively. MD values increased significantly in AD patients (P<0.05). No significant differences were found in the anterior and posterior limbs of the internal capsule and the occipital NAWM between AD patients and NC group (P﹥0.05). (3) Across all subjects, FA values in parietal and temporal lobes correlated with the scores of MMSE, word recall and word recognition (P<0.05), and FA values in the splenium of the corpus callosum NAWM correlated with word recognition (P<0.05). MD values in the splenium of the corpus callosum NAWM and parietal lobe correlated with MMSE, word recall and word recognition (P<0.05).Conclusions:The microstructural white matter in patients with MCI and mild and moderate AD may be selectively impaired, which is probably caused by combination of AD pathologies and vascular factors. These lesions are presented in the brain regions serving higher cortical functions, but not in the regions serving primary functions.Part 4: Evaluation of white matter lesions of the paraventricular white matter regions in patients with mild and moderate Alzheimer's disease using proton magnetic resonance spectroscopyObjective:To investigate the pattern of the cerebral white matter lesions of the bilateral paraventricular white matter regions in patients with mild and moderate Alzheimer's disease(AD) and healthy controls using proton magnetic resonance spectroscopy(~1H-MRS) and diffusion tensor imaging (DTI).Methods: 20 AD patients and 20 healthy controls were recruited. All subjects underwent clinical examination, neuropsychological assessment. The quantitative analysis of N-acetylaspartate (NAA), myoinositol (mI), Chotine(Cho) and Creatine(Cr) resonance signals in region of interests (ROIs) located in the paraventricular white matter region were bilaterally measured. Ratios of NAA/ Cr, mI/ Cr and Cho/ Cr were calculated in two groups. In addition, conventional MRI and DTI scanning were received, fractional anisotropy(FA) and mean diffusivity(MD) values of white matter in the same regions were measured respectively.Results:No significant difference between two groups was observed in NAA/ Cr ratio(P﹥0.05). A significantly increased mI/ Cr and Cho/ Cr were found in AD patients than in controls (P﹤0.05). FA and MD values in AD patients were 0.470±0.082 and 0.771±0.099, and in controls were 0.539±0.068 and 0.691±0.064, respectively. FA value decreased significantly in AD patients (P﹤0.05), MD value increased significantly in AD patients (P﹤0.05). After controlling for age-related, partial correlation analysis revealed a negtive correlation between mI/ Cr and FA value in the patients with AD (P﹤0.05). No correlation between mI/ Cr and MD was found(P﹥0.05).Conclusion:It is suggested that not only the gray matter is injured, but also the white matter is abnormal in AD patients. Combining 1H-MRS with DTI alterations could provide the valuable informations about white matter lesions in AD patients.