阿尔茨海默病脑磁共振研究

目的 了解Ａｌｚｈｅｉｍｅｒ病（ＡＤ）脑结构性变化的特点及与健康老人增龄性改变的差异。方法 对２２例ＡＤ和２９例健康老人分别按年龄为６０～６５岁、６６～７０岁和７０岁以上三组,ＡＤ为ａｄ１、ａｄ２和ａｄ３组,健康老人为ｎｏｒ１、ｎｏｒ２和ｎｏｒ３组。全部对象作ＭＲＩ检查。结果 ｎｏｒ３的灰质体积、总脑脊液体积及右侧海马体积与ｎｏｒ１和ｎｏｒ２相比有显著差异;与健康老人相比,ＡＤ的灰质体积,双侧海马体积显著降低,而总脑脊液、脑室外脑脊液、侧脑室、三脑室和四脑室体积显著升高。结论 与健康老人增龄性变化相比,ＡＤ脑结构性改变的涉及范围广,变化幅度大。     

Longitudinal Functional Alterations in Asymptomatic Women at Risk for Alzheimer''s Disease

PURPOSE: The authors sought to determine whether known alterations of brain function in normal individuals who are at high risk for Alzheimer's disease (AD) worsen or stay the same after a significant interval of time. METHODS: The authors used functional magnetic resonance imaging (fMRI) to observe cortical activation during confrontation naming in 14 women with high AD risk and 10 with low risk, based on family history and apolipoprotein-E4 allele status. They repeated the identical scan protocol in the same patients after 4 years. RESULTS: fMRI activation in high-AD-risk participants was found to be further diverged from that of their low-AD-risk counterparts over this period. CONCLUSION: fMRI may report on the presence and progression of neuropathology in the ventral temporal cortex or in functionally connected regions in presymptomatic AD.     

Amygdalar volume and psychiatric symptoms in Alzheimer's disease: an MRI analysis

OBJECTIVES: We measured the volumes of the amygdala to test the hypothesis that the reduction of amygdalar volume may be associated with psychiatric symptoms in Alzheimer's disease. MATERIALS AND METHODS: Twenty-seven patients underwent neuropsychological investigation including the assessment of general clinical severity by the Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory (NPI). All patients underwent magnetic resonance imaging (MRI) of the head, from which the volumes of the amygdalae were measured. The obtained values were compared with those of controls (n = 15). RESULTS: Patients with Alzheimer's dementia showed significant reduction in MRI volumetric measurements compared with controls. We found a significant correlation of MMSE score and absolute amygdala volume (r = 0.62, P < 0.01). Neither the absolute nor relative volume of the amygdala showed any correlation with NPI scores. CONCLUSIONS: The atrophy of the amygdala does not have a direct association with the existence of neuropsychiatric symptoms. MRI volumetry of the amygdala may be relevant as a marker of dementia severity in Alzheimer's disease.     

Functional MRI in the early detection of dementias

Functional MRI is a non-invasive imaging technology that can illuminate regional brain activity during the performance of a task, such as a memory paradigm, or at rest. fMRI data can be acquired during a session in which MRI data is also acquired to measure grey and white matter regional brain structure, and these measures can be analyzed together to investigate the relationships between altered regional brain function, structure, and cognitive task performance in neurologic illness. Data will be reviewed on the application of fMRI to the early detection of physiologic abnormalities associated with neurodegenerative diseases that cause dementia, and to differential diagnosis of dementias. Recent fMRI work will also be reviewed on the identification of abnormalities in regional brain function prior to dementia, the use of these measures to predict cognitive decline, and their application in investigations of alterations in regional brain networks that subserve cognitive function. Finally, the use of fMRI as a biomarker in clinical trials of putative neurotherapeutics for dementias will be discussed.     

Choline production from choline-containing phospholipids: A hypothetical role in Alzheimer''s disease and aging

1. Deficits in certain long-axon cholinergic brain neurons have been demonstrated both in senile dementia of the Alzheimer type (SDAT) and, to a lesser degree, in association with the cognitive and memory impairments sometimes seen with normal aging. Our studies support a hypothesis concerning the selective vulnerability of these neurons.

2. In our superfused brain slice system, acetylcholine (ACh) release was dependent on the concentration of exogenous choline, at rest and during electrical stimulation.

3. Decreases in intracellular levels of ACh and choline accounted for only a small fraction of the quantities of these compounds released into the superfusates, suggesting that some tissue pool of bound choline, such as the phospholipids (PL), might have liberated choline.

4. In choline-free medium, the release and tissue content of ACh were sustained: thus, choline released from the putative endogenous pool can be utilized for ACh synthesis.

5. We hypothesize that the use, by cholinergic neurons, of choline originating from the breakdown of membrane PL, may result in an impoverishment in certain PL. Since only cholinergic neurons use their membrane PL as a reservoir for their neurotransmitter's precursor, this relationship might explain the major deficits in long-axon cholinergic nerve terminals seen in SDAT and other age-related memory disorders.     

Self-consciousness and Alzheimer''s disease

OBJECTIVES: To propose a neuropsychological study of the various aspects of self-consciousness (SC) in Alzheimer's disease. METHODS: Forty-five patients with probable mild or moderate AD were included in the study. Severity of their dementia was assessed by the Mini Mental State (MMS). Fourteen questions were prepared to evaluate SC. RESULTS: No significant correlations were found between SC score and educational level, age, and duration of disease. A significant correlation was found between SC score and the severity of dementia, whereas frontal disturbances were just short of the significance threshold. The various aspects of SC were not impaired to the same degree. The most disturbed ones were awareness of cognitive deficiencies, moral judgements and prospective memory. The least disturbed aspects were awareness of identity and of mental representation of the body. Items relating to anosognosia and moral judgements were significantly correlated with the MMS score, whereas affective state, body representation disorders, prospective memory, and capacities for introspection were not related to the severity of the dementia. Consciousness of identity was sound, regardless of MMS score. CONCLUSIONS: AD clearly induces an heterogeneous impairment of SC. SC requires a convergence of many neural networks. In AD, neuronal alterations involve many cortical areas and information sent to the associative frontal cortex from memory, language and visuospatial areas is lacking or disturbed. Thus, the sequential order of successive stimuli cannot be maintained by the heteromodal associative cortex (dorsal convexity of the prefrontal cortex), and the supramodal associative cortex (located rostrally in the frontal lobes) is unable to provide reliable monitoring and assessment of simultaneous neural cognitive networks carrying insufficient and inadequate input. The core deficiency in AD patients might be impaired SC equated with the disability to maintain sequential and simultaneous "attention to life". The Self-Consciousness Questionnaire, a clinical scale providing multidimensional measurement, indicates that different aspects of consciousness are not correlated with overall cognitive deficiency as determined by the MMSE.     

Magnetic resonance imaging, Down's syndrome and Alzheimer's disease: research and clinical implications

Background The diagnosis of Alzheimer's disease (AD) remains at times difficult to make using available neuropsychological measures. Neuro‐imaging is a relatively new form of detecting the changes associated with dementia. The present study investigated the role of magnetic resonance imaging (MRI) in diagnosing AD in adults with Down's syndrome (DS). Methods Subjects with DS and Alzheimer‐type dementia were matched to non‐demented controls with DS. Magnetic resonance imaging findings (i.e. volumetric and two‐dimensional scans) were compared between the two groups in order to show a relationship between the changes of AD and structural MRI abnormalities. Results Specific structural abnormalities which are seen in non‐intellectually disabled subjects with dementia are also found in individuals with both DS and AD. However, such findings cannot be used to diagnose clinical AD with good accuracy in adults with DS. A number of practical issues of patient compliance and over‐sedation are demonstrated by the findings. Conclusions Magnetic resonance imaging has an important but limited role to play in the management of AD in the population with DS. If intravenous sedation is used, medical support is essential to prevent a serious mishap.     

Neuropsychological differentiation between normal aging, Alzheimer''s disease and vascular dementia

A random sample of 182 elderly community residents and 211 demented patients were studied using the D-Test Battery based on the Luria's neuropsychological investigation method. A steady but selective cognitive impairment was observed with increasing age in normal healthy subjects. The most sensitive areas of cognition to the effects of normal aging were mnestic and conceptual functions, as well as arithmetical skills. The age-related changes could be clearly differentiated from the changes found in patients with mild degree of dementia. The test also differentiated patients with mild, moderate and severe dementia from each other on the basis of their social competence. It failed to demonstrate specific patterns of impairment and to clearly differentiate between patients with Alzheimer's disease and vascular dementia who had the same degree of cognitive decline. Further qualitative analyses are needed to improve the sensitivity and specificity of the test.     

Magnetic resonance imaging and computed tomography in Alzheimer's disease

Structural neuroimaging with CT and MRI plays an important role in the routine clinical investigation of dementia patients. One major purpouse of the technique is to exclude secondary, treatable dementia disorders. In this respect these techniques are of utmost importance. Another major purpose of these techniques is to differentiate AD from healthy controls and other dementias.
Although some research groups have reported a high sensitivity and specificity for diagnosing AD by measuring the volumes (with MRI) of structures in the temporal lobes, there are no unequivocal "radiological" markers (such as the size of the lateral ventricles or sulci) that can differentiate AD from controls or vascular dementia. There have been a large number of CT and MRI studies showing that the volumes of the temporal lobes or part of the temporal lobes, such as the hippocampal formation are reduced in AD, as compared to healthy subjects.
The role of white matter changes (WMH, leukoaraiosis) in the development of AD or as a diagnostic marker for AD is unclear. The degree of WMH has been shown to be strongly age dependent and there are contradictory data concerning its relation to cognitive decline. There is stronger agreement concerning the relationship between LA assessed with CT and cognitive functions than there is between WMH on MRI and cognitive functions.
Correlative studies with MRI, CT and SPECT or PET are few. Usually the sensitivity and specificity of diagnosing AD can be increased by combining two or more modalities. One other goal with this approach is to use one structural modality, such as MRI or CT as a template for functional images in order to obtain a higher accuracy in measurement of blood perfusion or glucose metabolism.     

皮质下缺血性脑血管病MRI与血管性痴呆的相关性研究

目的:探索皮质下缺血性脑血管病MRI表现与血管性痴呆之间的关系。方法:对比分析了皮质下多发梗死28例痴呆患者和33例非痴呆患者的MRI表现,采用Logistic回归分析皮质下缺血性血管性痴呆的影像学相关高危因素。结果:痴呆组中顶叶皮质下、内囊膝部和丘脑的梗死发生率,顶叶皮质下、侧脑室体旁前部、内囊膝部和丘脑平均梗死数目,4级LA的出现率以及所有脑萎缩指标均明显大于对照组(P<0.05)。但Logistic回归后,只有平均脑沟宽度、侧脑室指数和丘脑梗死的数目进入了方程。结论:皮质下缺血性血管性痴呆可能与脑萎缩的程度和丘脑梗死的数目密切相关。     

T1‐Weighted MRI shows stage‐dependent substantia nigra signal loss in Parkinson's disease

Depigmentation of the substantia nigra is a conspicuous pathological feature of Parkinson's disease and related to a loss of neuromelanin. Similar to melanin, neuromelanin has paramagnetic properties resulting in signal increase on specific T1‐weighted magnetic resonance imaging. The aim of this study was to assess signal changes in the substantia nigra in patients with Parkinson's disease using an optimized neuromelanin‐sensitive T1 scan. Ten patients with Parkinson's disease and 12 matched controls underwent high‐resolution T1‐weighted magnetic resonance imaging with magnetization transfer effect at 3T. The size and signal intensity of the substantia nigra pars compacta were determined as the number of pixels with signal intensity higher than background signal intensity + 3 standard deviations and regional contrast ratio. Patients were subclassified as early stage (n = 6) and late stage (n = 4) using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr Parkinson's disease staging scale. The T1 hyperintense area in the substantia nigra was substantially smaller in patients compared with controls (?60%, P < .01), and contrast was reduced (?3%, P < .05). Size reduction was even more pronounced in more advanced disease (?78%) than in early‐stage disease (?47%). We present preliminary findings using a modified T1‐weighted magnetic resonance imaging technique showing stage‐dependent substantia nigra signal reduction in Parkinson's disease as a putative marker of neuromelanin loss. Our data suggest that reduction in the size of neuromelanin‐rich substantia nigra correlates well with postmortem observations of dopaminergic neuron loss. Further validation of our results could potentially lead to development of a new biomarker of disease progression in Parkinson's disease. © 2011 Movement Disorder Society     

Serum auto-antibodies in Alzheimer''s disease

The prevalence and clinical significance of non-CNS auto-antibodies in the serum of patients with probable and possible Alzheimer's disease (AD) was determined. Serum was obtained from 88 patients and 55 normal controls. Serum from each subject was tested for the presence of seven different auto-antibodies. Auto-antibodies were detected in 44% of the subjects with probable AD, 70% with possible AD with cerebrovascular disease (CVD), 45% with possible AD and other disease and 42% of normal controls. Although a subpopulation of AD patients with CVD showed a trend to an increased predisposition to develop autoimmune disease, these results do not support the relationship of AD and serum auto-antibodies or autoimmune disease.     

Potential role of high‐field MRI for studies in Parkinson's disease

Recent advancements in high field magnetic resonance imaging (MRI) technology (3 T and higher), providing increased signal sensitivity and images with more prominent contrasts intrinsic to the brain, offer new opportunities for assessing brain alterations in Parkinson's disease (PD). In this article, the principle benefits of high field MRI for PD research are described and new findings at high magnetic fields are reviewed. Several high field MRI methodologies, including structural MRI, imaging of brain iron, diffusion tensor imaging, arterial spin labeling perfusion imaging, rotating frame imaging, and magnetic resonance spectroscopy, are critically reviewed for their potential roles in studies of PD. © 2009 Movement Disorder Society     

A quantitative analysis of CT and cognitive measures in normal aging and Alzheimer's disease

Patients with presumptive Alzheimer's disease (AD) and healthy community volunteers received computed tomographic (CT) brain scans and cognitive tests. The CT scans were quantitatively analyzed with a semiautomated thresholding technique to derive volumetric measures of cerebrospinal fluid (CSF)-to-tissue ratios in six regions of interest (ROIs): lateral ventricles, vertex sulci, frontal sulci, Sylvian fissures, parieto-occipital sulci, and third ventricle. Regression analysis was performed on CT data from 85 older volunteers (ages 51–82) to generate age norms for each ROI. Within this group, tissue loss, as measured by the % CSF in each ROI, was highly correlated with age, although each ROI showed different rates of change over age. For all ROIs, the AD group had significantly more tissue loss than expected in normal aging. In addition, AD patients with a presenescent onset (before age 65) tended to have greater vertex sulcal and frontal sulcal tissue reduction than AD patients with a senescent onset (age 65 or after). When regional tissue reduction, corrected for age, was correlated with cognitive test scores, two sets of double dissociations emerged within the AD group: large CT z scores (i.e., decreased tissue and increased CSF) of frontal sulci, but not of the third ventricle, correlated with low Comprehension and Boston Naming Test scores, whereas large CT z scores of the third ventricle, but not of the frontal sulci, correlated with low scores on Digit Symbol and Picture Arrangement. These results suggest that heterogeneity of structural and functional integrity exists among patients with AD.     

Mamillary bodies in Alzheimer''s disease

The number of senile (neuritic) plaques (SP) and neurofibrillary tangles (NFT) in mamillary bodies (MB) and in the dorsomedial nucleus of the thalamus (DMNT) were assessed in 25 cases of definite Alzheimer's disease. In 20 cases with AD without other CNS disease the MB and DMNT showed SP and/or NFT in 19 (95%). No correlation was found between the number of SP and NFT and the duration or age of onset of the disease. In patients with AD plus another CNS disease, there were fewer SP and NFT regardless of duration and age at onset of the disease. AD is a diffuse disorder with cortical and subcortical changes. The involvement of MB and DMNT suggests that subcortical structures are also implicated in the memory disorder of AD. The association of AD with other diseases that can themselves cause dementia requires further studies, especially regarding the pattern of topographic distribution of the degenerative changes.     

轻度阿尔茨海默病患者磁共振成像及磁共振氢质子波谱研究

目的　探讨磁共振成像 (magneticresonanceimaging,MR)及磁共振氢质子波谱 (1H magneticresonancespectroscopy ,1H MRS)对轻度阿尔茨海默病 (Alzheimerdisease ,AD)患者的早期诊断。方法　对 18例临床确诊轻度AD患者和 2 0名正常对照者的MR及1H MRS进行分析 :MR上观察两组的海马回钩间距 (AB)及同层颅腔左右径 (CD)并计算两者间 (AB/CD)的比值 ;对两组额、颞叶区行1H MRS检测 ,得到N 乙酰天门冬氨酸 (N acetylaspartate ,NAA)峰、肌酸 (creatine ,Cr)峰、胆碱 (choline ,Cho)峰的积分值及计算NAA/Cr、NAA/ (Cr Cho)。对 2组检测值 ( x±s)行t检验。结果　AD组的AB =(2 7 5 3± 2 1)mm ,AB/CD =(0 2 2± 0 0 5 )mm及额、颞叶的NAA分别是 32 74± 4 72和35 38± 3 5 2 ,颞叶的NAA/Cr=2 4 6± 0 4 3,与正常对照组比较均有统计学差异 (P <0 0 5 )。用ROC法找出诊断阈值并联合应用诊断早期AD ,敏感性为 87% ,特异性为 94 %。结论　海马回钩间距及其与同层颅腔左右径比值的增大 ;额、颞叶NAA的减少 ,尤其是颞叶NAA的减少有助于对轻度AD患者的早期诊断。     

阿尔茨海默病和血管性痴呆的颅脑核磁共振定量研究

目的测量阿尔茨海默病（AD）、血管性痴呆（VD）患者颅脑MRI片上的海马结构（HF）、胼胝体（CC）、侧脑室（LV）、外侧裂（SL）、白质疏松（LA）体积，建立判别函数，进行判别分析，提高区分AD组、VD组与老年健康对照组（NC）间的准确性。方法应用GE Signa 1．5T超导磁共振成像系统，对AD组、VD组、NC组各20例进行颅脑扫描，根据体视学的卡瓦列里原理，构建测试网格，对HF、CC、LV、SL、LA体积进行测量，建立判别函数，进行判别分析。结果AD组、VD组HF、CC体积均显著小于NC组，LV、SL、LA体积显著大于NC组；AD组的HF、LA体积均显著小于VD组。Fisher判别函数示判别总符合率为83.3％，AD组为95％，VD组为75％，NC组为80％。结论测量颅脑MRI的HF、CC、LV、SL、LA体积，建立判别函数，对AD、VD患者的临床诊断及鉴别诊断可能有一定的指导意义。     

Hippocampal membrane alteration in Alzheimer''s disease

The biophysical properties of hippocampal membrane preparations from patients with Alzheimer's disease were examined by fluorescence spectroscopy using the membrane lipid probe 1,6-diphenyl-1,3,5-hexatriene (DPH) and its cationic derivative 1-[4-(trimethylamino)-phenyl]-6-phenyl-1,3,5-hexatriene (TMA-DPH). Results of these experiments suggest that Alzheimer's disease is associated with a biophysical alteration in superficial regions of brain cell membranes, as reflected by the mobility of TMA-DPH. In contrast, no change in the mobility of DPH, which preferentially localizes to the hydrocarbon core, was observed. Although a trend was observed for TMA-DPH mobility to parallel histopathologic severity in hippocampal specimens, the biophysical changes did not appear to reflect a loss of neuronal membranes relative to glial membranes or the presence of senile plaques or neurofibrillary tangles.     

Evidence for decreased transport of tryptophan hydroxylase in Alzheimer''s disease

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin and a specific marker for serotonergic neurons. These neurons are affected in Alzheimer's disease (AD) in several ways: serotonin is decreased in axon terminals, serotonin neurons accumulate neurofibrillary protein, and these neurons are lost in AD brains. One subcellular mechanism which may underlie degeneration of neurons in AD is decreased axonal transport with accumulation of enzymes and their potentially toxic metabolites in the cell body. To determine whether there is a defect in axonal transport in serotonin neurons in AD we measured TPH activity, serotonin and its oxidative metabolite 5-hydroxyindoleacetic acid (5-HIAA) in dorsal raphe cell bodies from Alzheimer and control cases. TPH activity is increased 4.7-fold in raphe neuron cell bodies in Alzheimer brains. Serotonin and 5-HIAA are increased by 4.0- and 2.0-fold, respectively in Alzheimer compared to control raphe cell bodies. In contrast, in synaptic terminals of the amygdala 5-HT and 5-HIAA were decreased by 41% and 50%, respectively in the same AD cases. We propose that the accumulation of TPH and its products in the raphe perikarya in AD results from a diminished transport of TPH to axon terminals. The accumulation of oxidative metabolites of serotonin may contribute to the degeneration of serotonergic neurons in AD.     

Clinical correlates of high signal lesions on magnetic resonance imaging in Alzheimer's disease

Summary The pathophysiology and clinical significance of high signal lesions, visualized on magnetic resonance imaging (MRI) in patients with Alzheimer's disease (AD), remain controversial. Since they are known to correlate with vascular disease and vascular risk factors, we reviewed the clinical correlates of periventricular high signal (PVH) and subcortical white matter lesions (WML) in a sample of 106 patients with probable AD, excluding persons with treated vascular risk factors or symptomatic cerebrovascular and cardiovascular disease. Grade 2 PVH were seen in 26 (25%) and scattered WML were identified in 29 (18%). PHV were associated with advancing age and gait disturbance. WML were associated with gait disturbance and incontinence. Neither radiologic finding was related to dementia severity. The findings suggest that these lesions are common in patients with AD even when those with evidence of cerebrovascular disease are excluded; their presence, therefore, should not preclude a diagnosis of AD. Additionally, the data suggest that HSL on MRI may be one of many risk factors associated with functional disability in persons with probable AD.