Brain imaging of mild cognitive impairment and Alzheimer’s disease

The rapidly increasing prevalence of cognitive impairment and Alzheimer’s disease has the potential to create a major worldwide healthcare crisis. Structural MRI studies in patients with Alzheimer’s disease and mild cognitive impairment are currently attracting considerable interest. It is extremely important to study early structural and metabolic changes, such as those in the hippocampus, entorhinal cortex, and gray matter structures in the medial temporal lobe, to allow the early detection of mild cognitive impairment and Alzheimer’s disease. The microstructural integrity of white matter can be studied with diffusion tensor imaging. Increased mean diffusivity and decreased fractional anisotropy are found in subjects with white matter damage. Functional imaging studies with positron emission tomography tracer compounds enable detection of amyloid plaques in the living brain in patients with Alzheimer’s disease. In this review, we will focus on key findings from brain imaging studies in mild cognitive impairment and Alzheimer’s disease, including structural brain changes studied with MRI and white matter changes seen with diffusion tensor imaging, and other specific imaging methodologies will also be discussed.     

Correlations between hippocampal functional connectivity,structural changes,and clinical data in patients with relapsing-remitting multiple sclerosis: a case-control study using multimodal magnetic resonance imaging

Multiple sclerosis is associated with structural and functional brain alterations leading to cognitive impairments across multiple domains including attention,memory,and the speed of information processing.The hippocampus,which is a brain important structure involved in memory,undergoes microstructural changes in the early stage of multiple sclerosis.In this study,we analyzed hippocampal function and structure in patients with relapsing-remitting multiple sclerosis and explored correlations between the functional connectivity of the hippocampus to the whole brain,changes in local brain function and microstructure,and cognitive function at rest.We retrospectively analyzed data from 20 relapsing-remitting multiple sclerosis patients admitted to the Department of Neurology at the China-Japan Union Hospital of Jilin University,China,from April 2015 to November 2019.Sixteen healthy volunteers were recruited as the healthy control group.All participants were evaluated using a scale of extended disability status and the Montreal cognitive assessment within 1 week before and after head diffusion tensor imaging and functional magnetic resonance imaging.Compared with the healthy control group,the patients with relapsing-remitting multiple sclerosis had lower Montreal cognitive assessment scores and regions of simultaneously enhanced and attenuated whole-brain functional connectivity and local functional connectivity in the bilateral hippocampus.Hippocampal diffusion tensor imaging data showed that,compared with the healthy control group,patients with relapsing-remitting multiple sclerosis had lower hippocampal fractional anisotropy values and higher mean diffusivity values,suggesting abnormal hippocampal structure.The left hippocampus whole-brain functional connectivity was negatively correlated with the Montreal cognitive assessment score(r=-0.698,P=0.025),and whole-brain functional connectivity of the right hippocampus was negatively correlated with extended disability status scale score(r=-0.649,P=0.042).The mean diffusivity value of the left hippocampus was negatively correlated with the Montreal cognitive assessment score(r=-0.729,P=0.017)and positively correlated with the extended disability status scale score(r=0.653,P=0.041).The right hippocampal mean diffusivity value was positively correlated with the extended disability status scale score(r=0.684,P=0.029).These data suggest that the functional connectivity and presence of structural abnormalities in the hippocampus in patients with relapse-remission multiple sclerosis are correlated with the degree of cognitive function and extent of disability.This study was approved by the Ethics Committee of China-Japan Union Hospital of Jilin University,China(approval No.201702202)on February 22,2017.     

弥散张量纤维素成像三维重建皮质脊髓束定位脑初级运动功能区

Functional MRI (fMRI) is widely used as a non-invasive method for the evaluation of pre-operation motor function.However,patients with cortical function impairment,such as those with hemiparesis,can rarely achieve hand clenching,a typical fMRI task for central sulcus identification,and the method is also of limited use in uncooperative children.Thus,it is important to develop a new method for identifying primary motor areas (PMA) in such individuals.This study used corticospinal tractography to identify the PMA in 20 patients with deep-seated brain tumor.Two regions of interest were set within the brainstem for corticospinal tract (CST) fiber tracking:one at the level of the pons and the other at the level of the cerebral peduncle.The CST fiber tracking results and fMRI activation signals were merged with three-dimensional anatomic MRI findings.The consistency of identifying the PMA by CST and fMRI was analyzed.fMRI activation signals were distributed mainly in the contralateral central sulcus around the omega-shaped hand knob.The CST consistently propagated from the pons and cerebral peduncle to the suspected PMA location.There was a good correlation between CST fiber tracking results and fMRI activation signals in terms of their abilities to identify the PMA.The differences between fMRI and CST fiber tracking findings may result from our functional task,which consisted only of hand movements.Our results indicate that diffusion tensor imaging is a useful brain mapping technique for identifying the PMA in paralyzed patients and uncooperative children.     

Diffusion-weighted imaging and fluid-attenuated inversion recovery sequence in sporadic Creutzfeldt-Jakob disease One-case report

The diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) is extremely difficult.Diffusion-weighted imaging has been shown to be the most sensitive technique for the detection of signal alterations in sCJD patients.The present study analyzed the diagnostic value of diffusion-weighted imaging and fluid-attenuated inversion recovery sequence in the early stage of sCJD in one female patient and correlated the clinical symptoms during disease course and magnetic resonance manifestations.Thalamic and basal ganglia hyperintensities were observed on magnetic resonance images in a very early stage,i.e.,when the clinical typical manifestations of the disease were not present.With the progression of the disease,cortical and basal ganglia hyperintensities were observed on magnetic resonance images,showing an obvious cerebral atrophy.These findings suggest that diffusion-weighted imaging and fluid-attenuated inversion recovery sequence are helpful in diagnosing sCJD.     

Dental pulp stem cells for treating neurodegenerative diseases

<正>The hippocampal formation,important for spatial learning and memory function,exhibits high level of plasticity in response to behavioral changes as well as injury.Dysfunction of the hippocampus is one of the hallmark features of neurodegenerative diseases like temporal lobe epilepsy(TLE)and Alzheimer’s disease(AD)(Dhanush-     

The Glutamatergic Postrhinal Cortex–Ventrolateral Orbitofrontal Cortex Pathway Regulates Spatial Memory Retrieval

A deficit in spatial memory has been taken as an early predictor of Alzheimer's disease(AD) or mild cognitive impairment(MCI). The uncinate fasciculus(UF) is a long-range white-matter tract that connects the anterior temporal lobe with the orbitofrontal cortex(OFC)in primates. Previous studies have shown that the UF impairment associated with spatial memory deficits may be an important pathological change in aging and AD, but its exact role in spatial memory is not well understood. The pathway arising from the postrhinal cortex(POR) and projecting to the ventrolateral orbitofrontal cortex(vlOFC)performs most of the functions of the UF in rodents.Although the literature suggests an association between spatial memory and the regions connected by the POR–vlOFC pathway, the function of the pathway in spatialmemory is relatively unknown. To further illuminate the function of the UF in spatial memory, we dissected the POR–vlOFC pathway in mice. We determined that the POR–vlOFC pathway is a glutamatergic structure, and that glutamatergic neurons in the POR regulate spatial memory retrieval. We also demonstrated that the POR–vlOFC pathway specifically transmits spatial information to participate in memory retrieval. These findings provide a deeper understanding of UF function and dysfunction related to disorders of memory, as in MCI and AD.     

Intraoperative diffusion tensor imaging predicts the recovery of motor dysfunction after insular lesions

Insular lesions remain surgically challenging because of the need to balance aggressive resection and functional protection. Motor function deficits due to corticospinal tract injury are a common complication of surgery for lesions adjacent to the internal capsule and it is therefore essential to evaluate the corticospinal tract adjacent to the lesion. We used diffusion tensor imaging to evaluate the corticospinal tract in 89 patients with insular lobe lesions who underwent surgery in Chinese PLA General Hospital from February 2009 to May 2011. Postoperative motor function evaluation revealed that 57 patients had no changes in motor function, and 32 patients suffered motor dysfunction or aggravated motor dysfunction. Of the affected patients, 20 recovered motor function during the 6-12-month follow-up, and an additional 12 patients did not recover over more than 12 months of follow-up. Following reconstruction of the corticospinal tract, fractional anisotropy comparison demonstrated that preoperative, intraoperative and follow-up normalized fractional anisotropy in the stable group was higher than in the transient deficits group or the long-term deficits group. Compared with the transient deficits group, intraoperative normalized fractional anisotropy significantly decreased in the long-term deficits group. We conclude that intraoperative fractional anisotropy values of the corticospinal tracts can be used as a prognostic indicator of motor function outcome.     

MicroRNAs as diagnostic and therapeutic tools for Alzheimer's disease: advances and limitations

Alzheimer's disease(AD) is the most common age-related, progressive neurodegenerative disease. It is characterized by memory loss and cognitive decline and responsible for most cases of dementia in the elderly. Late-onset or sporadic AD accounts for 95% of cases, with age at onset 65 years. Currently there are no drugs or other therapeutic agents available to prevent or delay the progression of AD. The cellular and molecular changes occurring in the brains of individuals with AD include accumulation of β-amyloid peptide and hyperphosphorylated tau protein, decrease of acetylcholine neurotransmitter, inflammation, and oxidative stress. Aggregation of β-amyloid peptide in extracellular plaques and the hyperphosphorylated tau protein in intracellular neurofibrillary tangles are characteristic of AD. A major challenge is identifying molecular biomarkers of the early-stage AD in patients as most studies have been performed with blood or brain tissue samples(postmortem) at late-stage AD. Subjects with mild cognitive impairment almost always have the neuropathologic features of AD with about 50% of mild cognitive impairment patients progressing to AD. They could provide important information about AD pathomechanism and potentially also highlight minimally or noninvasive, easy-to-access biomarkers. MicroRNAs are dysregulated in AD, and may facilitate the early detection of the disease and potentially the continual monitoring of disease progression and allow therapeutic interventions to be evaluated. Four recent reviews have been published of microRNAs in AD, each of which identified areas of weakness or limitations in the reported studies. Importantly, studies in the last three years have shown considerable progress in overcoming some of these limitations and identifying specific microRNAs as biomarkers for AD and mild cognitive impairment. Further large-scale human studies are warranted with less disparity in the study populations, and using an appropriate method to validate the findings.     

Disrupted structural and functional brain connectomes in mild cognitive impairment and Alzheimer＇s disease

Alzheimer＇s disease （AD） is the most common type of dementia, comprising an estimated 60-80% of all dementia cases. It is clinically characterized by impairments of memory and other cognitive functions. Previous studies have demonstrated that these impairments are associated with abnormal structural and functional connections among brain regions, leading to a disconnection concept of AD. With the advent of a combination of non-invasive neuroimaging （structural magnetic resonance imaging （MRI）, diffusion MRI, and functional MRI） and neurophysiological techniques （electroencephalography and magnetoencephaJography） with graph theoretical analysis, recent studies have shown that patients with AD and mild cognitive impairment （MCI）, the prodromal stage of AD, exhibit disrupted topological organization in large-scale brain networks （i.e., connectomics） and that this disruption is significantly correlated with the decline of cognitive functions. In this review, we summarize the recent progress of brain connectomics in AD and MCI, focusing on the changes in the topological organization of large-scale structural and functional brain networks using graph theoretical approaches. Based on the two different perspectives of information segregation and integration, the literature reviewed here suggests that AD and MCI are associated with disrupted segregation and integration in brain networks. Thus, these connectomics studies open up a new window for understanding the pathophysiological mechanisms of AD and demonstrate the potential to uncover imaging biomarkers for clinical diagnosis and treatment evaluation for this disease.     

Magnetic resonance imaging markers for early diagnosis of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by selective and progressive degeneration, as well as loss of dopaminergic neurons in the substantia nigra. In PD, approximately 60-70% of nigrostriatal neurons are degenerated and 80% of content of the striatal dopamine is reduced before the diagnosis can be established according to widely accepted clinical diagnostic criteria. This condition describes a stage of disease called "prodromal", where non-motor symptoms, such as olfactory dysfunction, constipation, rapid eye movement behaviour disorder, depression, precede motor sign of PD. Detection of prodromal phase of PD is becoming an important goal for determining the prognosis and choosing a suitable treatment strategy. In this review, we present some non-invasive instrumental approaches that could be useful to identify patients in the prodromal phase of PD or in an early clinical phase, when the first motor symptoms begin to be apparent. Conventional magnetic resonance imaging (MRI) and advanced MRI techniques, such as magnetic resonance spectroscopy imaging, diffusion-weighted and diffusion tensor imaging and functional MRI, are useful to differentiate early PD with initial motor symptoms from atypical parkinsonian disorders, thus, making easier early diagnosis. Functional MRI and diffusion tensor imaging techniques can show abnormalities in the olfactory system in prodromal PD.     

Neuroimaging diagnosis for cerebral infarction An 8-year bibliometric analysis

OBJECTIVE: To identify global research trends in neuroimaging diagnosis for cerebral infarction using a bibliometric analysis of the Web of Science. DATA RETRIEVAL: We performed a bibliometric analysis of data retrieval for neuroimaging diagnosis for cerebral infarction containing the key words "CT, magnetic resonance imaging, MRI, transcranial Doppler, transvaginal color Doppler, digital subtraction angiography, and cerebral infarction" using the Web of Science. SELECTION CRITERIA: Inclusion criteria were: (a) peer-reviewed articles on neuroimaging diagnosis for cerebral infarction which were published and indexed in the Web of Science; (b) original research articles and reviews; and (c) publication between 2004-2011. Exclusion criteria were: (a) articles that required manual searching or telephone access; and (b) corrected papers or book chapters. MAIN OUTCOME MEASURES: (1) Annual publication output; (2) distribution according to country; (3) distribution according to institution; (4) top cited publications; (5) distribution according to journals; and (6) comparison of study results on neuroimaging diagnosis for cerebral infarction. RESULTS: Imaging has become the predominant method used in diagnosing cerebral infarction. The most frequently used clinical imaging methods were digital subtraction angiography, CT, MRI, and transcranial color Doppler examination. Digital subtraction angiography is used as the gold standard. However, it is a costly and time-consuming invasive diagnosis that requires some radiation exposure, and is poorly accepted by patients. As such, it is mostly adopted in interventional therapy in the clinic. CT is now accepted as a rapid, simple, and reliable non-invasive method for use in diagnosis of cerebrovascular disease and preoperative appraisal. Ultrasonic Doppler can be used to reflect the hardness of the vascular wall and the nature of the plaque more clearly than CT and MRI. CONCLUSION: At present, there is no unified standard of classification of cerebral infarction imaging. Detection of clinical super-acute cerebral infarction remains controversial due to its changes on imaging, lack of specificity, and its similarity to a space-occupying lesion. Neuroimaging diagno- sis for cerebral infarction remains a highly active area of research and development.     

Impairment of the nerve growth factor pathway driving amyloid accumulation in cholinergic neurons the incipit of the Alzheimer's disease story?

The current idea behind brain pathology is that disease is initiated by mild disturbances of common physiological processes. Overtime, the disruption of the neuronal homeostasis will determine irreversible degeneration and neuronal apoptosis. hTis could be also true in the case of nerve growth factor (NGF) al-terations in sporadic Alzheimer’s disease (AD), an age-related pathology characterized by cholinergic loss, amyloid plaques and neurofibrillary tangles. In fact, the pathway activated by NGF, a key neurotrophin for the metabolism of basal forebrain cholinergic neurons (BFCN), is one of the ifrst homeostatic systems affected in prodromal AD. NGF signaling dysfunctions have been thought for decades to occur in AD late stages, as a mere consequence of amyloid-driven disruption of the retrograde axonal transport of neuro-trophins to BFCN. Nowadays, a wealth of knowledge is potentially opening a new scenario: NGF signaling impairment occurs at the onset of AD and correlates better than amyloid load with cognitive decline. hTe recent acceleration in the characterization of anatomical, functional and molecular proifles of early AD is aimed at maximizing the efficacy of existing treatments and setting novel therapies. Accordingly, the elucidation of the molecular events underlying APP metabolism regulation by the NGF pathway in the sep-to-hippocampal system is crucial for the identiifcation of new target molecules to slow and eventually halt mild cognitive impairment (MCI) and its progression toward AD.     

Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease

The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.     

吸烟与健康人脑和脑室容积的改变

Previous studies have reported decreased cerebral volume as a result of smoking.However,little is known about accompanying changes in ventricular volume for healthy subjects who smoke,although ventricular volume is increased in patients with multiple sclerosis who smoke.The present study analyzed whether cerebral volume decreased with smoking through the use of magnetic resonance imaging.In addition,accompanying changes in ventricular volume that resulted from decreased cerebral volume and smoking were analyzed in healthy subjects.When multivariate analysis of covariance was performed by integrating the 2 age groups,aged 20-28 years and 40-49 years,with statistical significance,results showed that cerebral volume of smokers was smaller and ventricular volume was greater compared with the non-smokers.These findings suggest that ventricular volume changes could be utilized to characterize the effects of smoking.     

Advances in longitudinal studies of amnestic mild cognitive impairment and Alzheimer＇s disease based on multi-modal MRI techniques

Amnestic mild cognitive impairment （aMCI） is a prodromal stage of Alzheimer＇s disease （AD）, and 75%-80% of aMCI patients finally develop AD. So, early identification of patients with aMCI or AD is of great significance for prevention and intervention. According to cross-sectional studies, it is known that the hippocampus, posterior cingulate cortex, and corpus callosum are key areas in studies based on structural MRI （sMRI）, functional MRI （fMRI）, and diffusion tensor imaging （DTI） respectively. Recently, longitudinal studies using each MRI modality have demonstrated that the neuroimaging abnormalities generally involve the posterior brain regions at the very beginning and then gradually affect the anterior areas during the progression of aMCI to AD. However, it is not known whether follow-up studies based on multi-modal neuroimaging techniques （e.g., sMRI, fMRI, and DTI） can help build effective MRI models that can be directly applied to the screening and diagnosis of aMCI and AD. Thus, in the future, large-scale multi-center follow-up studies are urgently needed, not only to build an MRI diagnostic model that can be used on a single person, but also to evaluate the variability and stability of the model in the general population. In this review, we present longitudinal studies using each MRI modality separately, and then discuss the future directions in this field.     

Altered functional connectivity networks of hippocampal subregions in remitted late-onset depression:a longitudinal resting-state study

The regional specifi city of hippocampal abnormalities in late-life depression(LLD) has been demonstrated in previous studies. In this study,we sought to examine the functional connectivity(FC) patterns of hippocampal subregions in remitted late-onset depression(r LOD),a special subtype of LLD. Fourteen r LOD patients and 18 healthy controls underwent clinical and cognitive evaluations as well as resting-state functional magnetic resonance imaging scans at baseline and at ~21 months of follow-up. Each hippocampus was divided into three parts,the cornu ammonis(CA),the dentate gyrus,and the subicular complex,and then six seed-based hippocampal subregional networks were established.Longitudinal changes of the six networks over time were directly compared between the rL OD and control groups. From baseline to follow-up,the r LOD group showed a greater decline in connectivity of the left CA to the bilateral posterior cingulate cortex/precuneus(PCC/PCUN),but showed increased connectivity of the right hippocampal subregional networks with the frontal cortex(bilateral medial prefrontal cortex/anterior cingulate cortex and supplementary motor area). Further correlative analyses revealed thatthe longitudinal changes in FC between the left CA and PCC/PCUN were positively correlated with longitudinal changes in the Symbol Digit Modalities Test(r = 0.624,P = 0.017) and the Digit Span Test(r = 0.545,P = 0.044) scores in the r LOD group. These results may provide insights into the neurobiological mechanism underlying the cognitive dysfunction in r LOD patients.     

Leukocyte telomere length and plasma interleukin-1β and interleukin-18 levels in mild cognitive impairment and Alzheimer's disease: new biomarkers for diagnosis and disease progression?

正Alzheimer's disease and mild cognitive impairment biomarkers: Alzheimer's disease(AD) is a progressive neurodegenerative disease of advancing age.It affects around 47 million people in the world and the number is estimated to increase to 152 million by 2050.Someone develops dementia every three seconds and the current annual cost of dementia is estimated at US $1 trillion, a figure set to double by 2030(Alzheimer's Disease International, 2019).     

Validation of hyperintense middle cerebral artery sign in acute ischemic stroke Comparison between magnetic resonance imaging and angiography

We performed a retrospective analysis of non-contrast computed tomography (CT) scans, immediately subsequent magnetic resonance imaging (MRI), and cerebral angiography data from 30 consecutive patients with acute ischemic stroke within 6 hours after symptom onset. Results showed that eleven patients developed subsequent hemorrhagic transformation at follow-up. A hyperintense middle cerebral artery sign on MRI was found in six hemorrhagic patients, all of who had acute thrombosis formation on magnetic resonance angiography and digital subtraction angiography. No patients in the non-hemorrhagic group had hyperintense middle cerebral artery sign on MRI. The sensitivity, specificity, and positive predictive values of the hyperintense middle cerebral artery sign on MRI T1-weighted image for subsequent hemorrhagic transformation were 54.5%, 100%, and 100% respectively. Hyperdense middle cerebral artery sign on non-contrast CT was observed in nine patients, five of who developed hemorrhagic transformation. These data suggest that hyperintense middle cerebral artery sign on MRI T1-weighted image is a highly specific and moderately sensitive indicator of subsequent hemorrhagic transformation in patients after acute ischemic stroke, and its specificity is superior to CT.