Brain Magnetic Resonance in the Diagnostic Evaluation of Mitochondrial Encephalopathies

Brain MR imaging techniques are important ancillary tests in the diagnosis of a suspected mitochondrial encephalopathy since they provide details on brain structural and metabolic abnormalities. This is particularly true in children where non-specific neurologic symptoms are common, biochemical findings can be marginal and genetic defects may be not discovered. MR imaging modalities include conventional, or structural, imaging (MRI) and functional, or ultrastructural, imaging (spectroscopy, MRS; diffusion, DWI-ADC; perfusion, DSCI––ASL). Among them MRI and MRS are the main tools for diagnosis and work up of MD, and this review will focus mainly on them. The MRI findings of MD are very heterogeneous, as they depend on the metabolic brain defects, age of the patient, stage and severity of the disease. No correlation has been found between genetic defects and neuroimaging picture; however, some relationships between MR findings and clinical phenotypes may be identified. Different combinations of MRI signal abnormalities are often encountered but the most common findings may be summarized into three main MR patterns: (i) non-specific; (ii) specific; (iii) leukodystrophic-like. Regarding the functional MR techniques, only proton MRS plays an important role in demonstrating an oxidative metabolism impairment in the brain since it can show the accumulation of lactate, present as a doublet peak at 1.33 ppm. Assessment of lactate should be always performed on brain tissue and on the ventricular cerebral spinal fluid. As for MRI, metabolic MRS abnormalities can be of different types, and two distinct patterns can be recognized: non-specific and specific. The specific metabolic profiles, although not frequent to find, are highly pathognomonic of MD. The un-specific metabolic profiles add value to structural images in allowing to define the lesion load and to monitor the response to therapy trials.     

Magnetic resonance imaging: opportunities for rheumatoid arthritis disease assessment and monitoring long-term treatment outcomes

Early diagnosis of rheumatoid arthritis (RA) combined with early initiation of an appropriate treatment regimen is acknowledged as an important factor in improving clinical outcomes in patients with RA. Early diagnosis allows treatment intervention to occur sooner in order to inhibit the progression of structural joint damage as well as providing improved patient quality of life. Unfortunately, early diagnosis has been challenging due to the non-specific signs and symptoms associated with many polyarthropathies and the lack of accurate definitive diagnostic tests that can accurately classify RA at presentation. The emphasis on early diagnosis has fueled the need for powerful, sensitive, non-invasive imaging techniques that not only accurately define RA and give an indication of prognosis, but can also serve as a tool to monitor long-term treatment outcomes. This article reviews the potential uses of magnetic resonance imaging as a tool for the classification, documentation, and clinical monitoring of RA.     

Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics

Alzheimer's disease is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are beta-amyloid (Abeta) plaques, neurofibrillary tangles, synaptic loss and reactive gliosis. The current therapeutic effort is directed towards developing drugs that reduce Abeta burden or toxicity by inhibiting secretase cleavage, Abeta aggregation, Abeta toxicity, Abeta metal interactions or by promoting Abeta clearance. A number of clinical trials are currently in progress based on these different therapeutic strategies and they should indicate which, if any, of these approaches will be efficacious. Current diagnosis of Alzheimer's disease is made by clinical, neuropsychologic and neuroimaging assessments. Routine structural neuroimaging evaluation with computed tomography and magnetic resonance imaging is based on non-specific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of Alzheimer's disease. Functional neuroimaging techniques such as functional magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and single photon emission computed tomography, possibly in conjunction with other related Abeta biomarkers in plasma and CSF, could prove to be valuable in the differential diagnosis of Alzheimer's disease, as well as in assessing prognosis. With the advent of new therapeutic strategies there is increasing interest in the development of magnetic resonance imaging contrast agents and positron emission tomography and single photon emission computed tomography radioligands that will permit the assessment of Abeta burden in vivo.     

Magnetic resonance spectroscopy and measurement of tau epitopes of autopsy proven sporadic Creutzfeldt-Jakob disease in a patient with non-specific initial EEG, MRI and negative 14-3-3 immunoblot

Limited potential of electroencephalogram (EEG), magnetic resonance images (MRI) and cerebrospinal fluid (CSF) test for 14-3-3 protein in the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) resulted in developments in diagnostic premortem tehniques. Recent studies provided evidence that magnetic resonance spectroscopy (MRS) and measurement of total-tau (T-tau) and phospho-tau (P-tau) may be useful to identify patients with CJD. We combined detected metabolic changes in the brain by MRS and measured T-tau and tau-pT181 by ELISA, and tau-pT231 by Westernblot in a patient with autopsy proven sCJD. Our results show that in contrast to negative CSF 14-3-3 protein, nonspecific EEG and MRI, MRS revealed metabolic alterations in regions of the brain that has appeared normal on MRI, and tau tests has shown measurable levels of phosphorylated and non-phosphorylated isoforms in CSF. We conclude that rapidly progressive dementia with negative 14-3-3 test and non-specific initial EEG and MRI must still be considered in the differential diagnosis of the sCJD. Combination of serial functional MRI along with MRS study and measurement of tau ratio could improve the early diagnosis of sCJD. The current case is the first attempt to study results of the use of MRS and tau tests in a case of sCJD with diagnostic dilemma.     

Mouse models in neurological disorders: Applications of non-invasive imaging

Neuroimaging techniques represent powerful tools to assess disease-specific cellular, biochemical and molecular processes non-invasively in vivo. Besides providing precise anatomical localisation and quantification, the most exciting advantage of non-invasive imaging techniques is the opportunity to investigate the spatial and temporal dynamics of disease-specific functional and molecular events longitudinally in intact living organisms, so called molecular imaging (MI). Combining neuroimaging technologies with in vivo models of neurological disorders provides unique opportunities to understand the aetiology and pathophysiology of human neurological disorders. In this way, neuroimaging in mouse models of neurological disorders not only can be used for phenotyping specific diseases and monitoring disease progression but also plays an essential role in the development and evaluation of disease-specific treatment approaches. In this way MI is a key technology in translational research, helping to design improved disease models as well as experimental treatment protocols that may afterwards be implemented into clinical routine. The most widely used imaging modalities in animal models to assess in vivo anatomical, functional and molecular events are positron emission tomography (PET), magnetic resonance imaging (MRI) and optical imaging (OI). Here, we review the application of neuroimaging in mouse models of neurodegeneration (Parkinson's disease, PD, and Alzheimer's disease, AD) and brain cancer (glioma).     

磁共振成像对乳腺肿瘤的诊断价值

乳腺癌是危及女性健康的常见恶性肿瘤之一,病死率较高,且发病年龄呈年轻化趋势。目前临床对乳腺疾病的检查方法很多,既往检查主要包括钼靶、超声等,因价格便宜、操作方便,已成为常规的乳腺疾病检查方法,但两者的敏感性和特异性较低并有自身的局限性。CT软组织分辨率较高,但检查过程中的X线剂量较大,并且动态增强时间较长,故作为乳腺钼靶的补充检查手段。这些检查方法对乳腺疾病均有不同的诊断意义,在当前众多诊断乳腺疾病方法中,具有无辐射,较高软组织分辨力及可多方位多层面成像的乳腺磁共振(MRI)成像有其独到的优势,某些方面能弥补超声和钼靶检查的局限性,乳腺磁共振可提供病灶形态学和增强血流动力学表现,可用于常规检查方法不能确诊病灶的鉴别诊断。乳腺肿瘤MRI成像对临床诊断、鉴别诊断及手术方案的选择有着极其重要的作用。本文就乳腺MRI影像技术、MRI影像学表现及其临床应用予以综述,探讨MRI在乳腺肿瘤中的应用。     

Pathogenesis and brain functional imaging in nocturnal enuresis: A review

Nocturnal enuresis is a common and distressing developmental disease, which may cause various degrees of psychosocial stress and impairment to self-esteem in affected children as well as agitation to their parents or caregivers. Nevertheless, the etiology and pathogenesis of nocturnal enuresis are not understood. Currently, nocturnal enuresis is generally considered a multifactorial disease associated with a complex interaction of somatic, psychosocial, and environmental factors. A variety of postulations have been proposed to explain the occurrence and progression of nocturnal enuresis, including hereditary aberration, abnormal circadian rhythm of antidiuretic hormone secretion during sleep, bladder dysfunction, abnormal sleep, difficulties in arousal, neuropsychological disorders, and maturational delays of the brain. In recent decades, the introduction of functional neuroimaging technologies has provided new approaches for uncovering the mechanisms underlying nocturnal enuresis. The main neuroimaging modalities have included brain morphometry based on structural magnetic resonance imaging (MRI), task-based and event-related functional MRI (fMRI), and resting-state fMRI. The relevant studies have indicated that nocturnal enuresis is associated with functional and structural alterations of the brain. In this review, we briefly summarized the popular hypotheses regarding the pathogenesis of nocturnal enuresis and the current progress of functional neuroimaging studies in examining the underlying mechanisms thereof.     

多功能磁共振造影剂研究进展

磁共振成像技术因对人体无创、任意方向断层扫描三维图像且分辨率较高、提供形态与功能两方面诊断评价等突出优点,成为了临床上用于疾病诊断的重要手段之一。临床上使用磁共振造影剂可以提高成像的分辨率和灵敏度,提高图像质量,增强对比度和可读性。但是,各种成像技术由于实现原理不同,具有各自的优势和缺陷,靠传统单一的诊断模式无法提供疾病的全面信息,因而在对各种复杂疾病进行诊断时会受到一定的限制。因此,将磁共振成像与其他成像技术如CT成像、超声成像等联合起来使用,则可以达到优势互补的效果,能为疾病的临床诊断提供更快捷精确的信息,同时可将磁共振成像与各种治疗方式结合在一起,即开发基于磁共振成像的诊断治疗一体化试剂,以实现对疾病的即时治疗和实时监控。本文主要介绍了磁共振成像造影剂的原理和种类,并且综述了目前国内外在基于磁共振成像的多功能造影剂/诊疗制剂这一领域的研究进展,最后就未来可能的研究方向进行了展望。     

Plaque imaging and characterization using magnetic resonance imaging: towards molecular assessment

Identification of high-risk atherosclerotic lesions prone to rupture and thrombosis may greatly decrease the morbidity and mortality associated with atherosclerosis. High-resolution magnetic resonance imaging (MRI) has recently emerged as one of the most promising techniques for the non-invasive study of atherothrombotic disease, as it can characterize plaque composition and monitor its progression. The development of MRI contrast agents that specifically target components of the atherosclerotic plaque may enable non-invasive detection of high-risk lesions. This review discusses the use of high-resolution MRI for plaque detection and characterization and the potentials of "Molecular Imaging" using a variety of molecules present in atherosclerotic plaques that may serve as targets for specific contrast agents to allow the identification of high-risk atherosclerotic lesions in-vivo. Ultimately, such agents may enable treatment of "high-risk" patients prior to lesion progression and occurrence of complications.     

Biomarkers in Parkinson’s disease (recent update)

Parkinson’s disease (PD) is the second most common neurodegenerative disorder mostly affecting the aging population over sixty. Cardinal symptoms including, tremors, muscle rigidity, drooping posture, drooling, walking difficulty, and autonomic symptoms appear when a significant number of nigrostriatal dopaminergic neurons are already destroyed. Hence we need early, sensitive, specific, and economical peripheral and/or central biomarker(s) for the differential diagnosis, prognosis, and treatment of PD. These can be classified as clinical, biochemical, genetic, proteomic, and neuroimaging biomarkers. Novel discoveries of genetic as well as nongenetic biomarkers may be utilized for the personalized treatment of PD during preclinical (premotor) and clinical (motor) stages. Premotor biomarkers including hyper-echogenicity of substantia nigra, olfactory and autonomic dysfunction, depression, hyposmia, deafness, REM sleep disorder, and impulsive behavior may be noticed during preclinical stage. Neuroimaging biomarkers (PET, SPECT, MRI), and neuropsychological deficits can facilitate differential diagnosis. Single-cell profiling of dopaminergic neurons has identified pyridoxal kinase and lysosomal ATPase as biomarker genes for PD prognosis. Promising biomarkers include: fluid biomarkers, neuromelanin antibodies, pathological forms of α-Syn, DJ-1, amyloid β and tau in the CSF, patterns of gene expression, metabolomics, urate, as well as protein profiling in the blood and CSF samples. Reduced brain regional N-acetyl-aspartate is a biomarker for the in vivo assessment of neuronal loss using magnetic resonance spectroscopy and T₂ relaxation time with MRI. To confirm PD diagnosis, the PET biomarkers include [¹⁸F]-DOPA for estimating dopaminergic neurotransmission, [¹⁸F]dG for mitochondrial bioenergetics, [¹⁸F]BMS for mitochondrial complex-1, [¹¹C](R)-PK11195 for microglial activation, SPECT imaging with ¹²³Iflupane and βCIT for dopamine transporter, and urinary salsolinol and 8-hydroxy, 2-deoxyguanosine for neuronal loss. This brief review describes the merits and limitations of recently discovered biomarkers and proposes coenzyme Q₁₀, mitochondrial ubiquinone-NADH oxidoreductase, melatonin, α-synculein index, Charnoly body, and metallothioneins as novel biomarkers to confirm PD diagnosis for early and effective treatment of PD.     

Multimodal magnetic resonance imaging of the central nervous system

The physiological and biochemical properties of the diseased brain that can be explored with magnetic resonance imaging (MRI) are increasing. Progress in MR-based technology affords a large panel of MRI sequences that explore different phenomena and, thus, provide complementary informations. The diagnostic accuracy of MRI is improved by the combination of all MR modalities. However, this abundance of data requires an efficient multiparametric analysis to fully achieve the goal of the multimodal strategy. We will discuss the potential impact of this advanced MRI analysis in the clinical management and the therapeutical strategies of the most common brain pathologies (intracranial tumors, multiple sclerosis, stroke, epilepsy and dementia). This non-invasive approach is of utmost importance since it already improves the diagnosis and the therapeutic choice in the management of several central nervous system diseases.     

Complex neuroradiological diagnosis in case of atherosclerotic lesion of the carotid arteries

The diagnostic arsenal for extracranial stenosis includes both ultrasound techniques, such as transcranial Doppler and duplex sonography, which are not only screening methods, but also are used at surgery, and high-tech neuroradiological techniques, such as spiral computed tomographic and magnetic resonance angiography, which can visualize structural changes in the vessel walls and qualitatively and functionally evaluate blood flow in the vascular bed. The purpose of this investigation was to determine the efficacy of non-invasive diagnostic methods, such as magnetic resonance angiography, including phase-contrast magnetic resonance angiography and spiral computed tomographic angiography, in the detection and comprehensive evaluation of stenoses and to compare the feasibilities of noninvasive procedures with the gold standard--selective angiography.     

Zonal variation of MRI-measurable parameters classifies cartilage degradation

Osteoarthritis (OA) is a degenerative joint disease resulting in the deterioration of articular cartilage, a tissue with minimal ability to self-repair. Early diagnosis of OA with non-invasive imaging techniques such as magnetic resonance imaging (MRI) could provide an opportunity to intervene and slow or reverse this degeneration process. This study examines the classification of degradation states using MRI measurements.Enzymatic degradation was used to specifically target proteoglycans alone, collagen alone and both cartilage components sequentially. The resulting degradation was evaluated using MRI imaging techniques (T₁, T₂, diffusion tensor imaging, and gadolinium enhanced T₁) and derived measures of water, glycosaminoglycan and collagen content. We compared the classification ability of full thickness averages of these parameters with zonal averages (superficial, medial, and deep). Finally, we determined minimum variables sets to identify the smallest number of variables that allowed for complete separation of all degradation groups and ranked them by impact on the separation.Zonal analysis was much more sensitive than full thickness averages and allowed perfect separation of all four groups. Superficial zone cartilage was more sensitive to enzymatic degradation than the medial or deep zone, or the full thickness average. Variable ranking consistently identified collagen content and organization as the most impactful variables in the classification algorithm.The aim of this study is to classify cartilage degradation using only non-invasive MRI parameters that could be applied to OA diagnosis. Our results highlight the importance of zonal variation in the diagnosis of cartilage degeneration. Our novel, non-invasive collagen content measurement was crucial for complete separation of degraded groups from control cartilage. These findings have significant implications for clinical cartilage MRI for disease diagnosis.     

14-3-3 and enolase abundances in the CSF of Prion diseased rats

ABSTRACT

Creutzfeldt-Jakob disease (CJD) is characterized by an extended asymptomatic preclinical phase followed by rapid neurodegeneration. There are no effective treatments. CJD diagnosis is initially suspected based upon the clinical presentation of the disease and the exclusion of other etiologies. Neurologic symptoms are assessed in combination with results from cerebrospinal fluid (CSF) biomarker abundances, electroencephalography (EEG), magnetic resonance imaging (MRI), and in some countries, real-time quaking-induced conversion (RT-QuIC). Inconsistencies in sensitivities and specificities of prion disease biomarker abundance in CSF have been described, which can affect diagnostic certainty, but the utility of biomarkers for prognosis has not been fully explored. The clinical presentation of CJD is variable, and factors such as prion protein polymorphic variants, prion strain, and other genetic or environmental contributions may affect the disease progression, confounding the appearance or abundance of biomarkers in the CSF. These same factors may also affect the appearance or abundance of biomarkers, further confounding diagnosis. In this study, we controlled for many of these variables through the analysis of serial samples of CSF from prion-infected and control rats. Prion disease in laboratory rodents follows a defined disease course as the infection route and time, prion strain, genotype, and environmental conditions are all controlled. We measured the relative abundance of 14-3-3 and neuron-specific enolase (NSE) in CSF during the course of prion infection in rats. Even when disease-related, environmental and genetic variables were controlled, CSF 14-3-3 and NSE abundances were variable. Our study emphasizes the considerable diagnostic and prognostic limitations of these prion biomarkers.     

Metabolomics and mitochondrial dysfunction in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by cognitive impairment, progressive neurodegeneration, and Aβ accumulation. Aβ oligomers can lead to synaptic damage via alterations in glutamate receptors and excitotoxicity, as well as mitochondrial dysfunction. AD is associated with various biological indicators, including (1) predisposing factors such as genetic risk factors, (2) laboratory markers such as Aβ and tau protein, and (3) diagnostic markers such as MRI and PET findings. However, these markers are not confirmed, invasive, or expensive. In the present study, we employed nuclear magnetic resonance (NMR) methods that are inexpensive, time-efficient, and can be performed using samples obtained from various easily accessible sources such as cerebrospinal fluid, plasma, and peripheral tissue, thus highlighting the clinical utility of this approach. NMR analyses of blood metabolites showed that glutamine, glutamate, leucine, oxaloacetate, aspartate, isoleucine, and 3-hydroxyisovalerate are increased in patients with AD compared with control individuals. These metabolites seem to be related to mitochondrial dysfunction. Our data indicated that 3-hydroxyisovalerate, which is linked to known pathologic processes associated with mitochondrial dysfunction and accelerated neurodegeneration, was increased in the blood samples of patients with AD.     

Automated,High Accuracy Classification of Parkinsonian Disorders: A Pattern Recognition Approach

Progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and idiopathic Parkinson’s disease (IPD) can be clinically indistinguishable, especially in the early stages, despite distinct patterns of molecular pathology. Structural neuroimaging holds promise for providing objective biomarkers for discriminating these diseases at the single subject level but all studies to date have reported incomplete separation of disease groups. In this study, we employed multi-class pattern recognition to assess the value of anatomical patterns derived from a widely available structural neuroimaging sequence for automated classification of these disorders. To achieve this, 17 patients with PSP, 14 with IPD and 19 with MSA were scanned using structural MRI along with 19 healthy controls (HCs). An advanced probabilistic pattern recognition approach was employed to evaluate the diagnostic value of several pre-defined anatomical patterns for discriminating the disorders, including: (i) a subcortical motor network; (ii) each of its component regions and (iii) the whole brain. All disease groups could be discriminated simultaneously with high accuracy using the subcortical motor network. The region providing the most accurate predictions overall was the midbrain/brainstem, which discriminated all disease groups from one another and from HCs. The subcortical network also produced more accurate predictions than the whole brain and all of its constituent regions. PSP was accurately predicted from the midbrain/brainstem, cerebellum and all basal ganglia compartments; MSA from the midbrain/brainstem and cerebellum and IPD from the midbrain/brainstem only. This study demonstrates that automated analysis of structural MRI can accurately predict diagnosis in individual patients with Parkinsonian disorders, and identifies distinct patterns of regional atrophy particularly useful for this process.     

Use of magnetic resonance imaging for the evaluation of vascular malformations of the lower extremity

Vascular malformations are anatomically subdivided according to the predominant channel anomaly into either capillary, arterial, venous, lymphatic, or combinations. They can be further subdivided into high- or low-flow malformations. Any lesion that has an arterial component is considered a high-flow malformation. Once the diagnosis of a vascular malformation is made, it is of paramount importance to define not only the flow characteristics but also the full range of extension, because the prognosis and appropriate treatment vary substantially for each type of anomaly. The two most useful noninvasive imaging techniques for assessing vascular malformations are magnetic resonance imaging (MRI) and ultrasonography. The aim of this review is to give surgeons involved in treating patients with vascular malformations an opportunity to gain some background on MRI scans when assessing vascular malformations. Although MRI is a powerful modality for assessing vascular malformations, we will also discuss some of the limitations of MRI. We further suggest a diagnostic flow chart developed on the basis of MRI features designed to help determine the composition of a vascular birthmark when intervention is anticipated.     

Modern methods of neuro-visualization of brain pathology in central form of Recklinghausen's disease

The paper reviews the data available in the literature on the diagnosis of brain lesions in the central form of Recklinghausen's disease (neurofibromatosis) by magnetic resonance imaging. The results of a clinical observation of 10 children suffering trom neurofibromatosis and the data of electroencephalography, computed tomography and MRI are given and analyzed. Conclusions are made on the magnitude of and the most common site of MRI changes. It is suggested that MRI shows a higher sensitivity in detecting brain lesions in Recklinghausen's disease than other diagnostic techniques.     

Le diagnostic et le suivi thérapeutique des tumeurs cérébrales intra-parenchymateuses par l’imagerie par résonance magnétique multimodale

The multimodal magnetic resonance imaging (MMRI) has an important role in cancer care. This non-invasive and non-ionizing technique provides vital information for the diagnosis and answers to various questions of clinicians before, during and after treatment. The MMRI can specify the localization expanding process; it allows establishing the differential diagnosis of a brain tumor and a circumscribed lesion of another type, to approach the diagnosis of the tumor lesion nature as well as establishing the histological grade of glial tumor in view of lesion monitoring after treatment. The multimodal magnetic resonance imaging has a major contribution to the management progress of the brain tumors. Thus, this paper reviews the value of these MRI modalities in the diagnosis, management and therapy of brain tumors.     

Mitochondrial diseases mimicking neurotransmitter defects

OBJECTIVES: Mitochondrial disorders are clinically heterogeneous. We aimed to describe 5 patients who presented with a clinical picture suggestive of primary neurotransmitter defects but who finally fulfilled diagnostic criteria for mitochondrial disease. METHODS: We report detailed clinical features, brain magnetic resonance findings and biochemical studies, including cerebrospinal fluid (CSF) biogenic amine and pterin measurements, respiratory chain enzyme activity, and molecular studies. RESULTS: The 5 patients had a very early onset age (from 1 day to 3 months) and a severe clinical course. They all showed a clinical picture suggestive of infantile hypokinetic-rigid syndrome (hypokinesia, hypomimia, slowness of reactions, tremor), other abnormal movements (myoclonus, dystonia), axial hypotonia, limb hypertonia, feeding difficulties, and psychomotor delay. Abnormal CSF findings among the 4 patients without treatment included low levels of homovanillic acid (HVA) in 3 patients, with associated low 5-hydroxyindoleacetic acid (5-HIAA) concentrations in two of them. Absent or mild and transitory improvement was observed after treatment with L-dopa. A diagnosis of mitochondrial disorder was finally made due to the appearance of hyperlactacidemia, diverse respiratory chain defects, and multisystemic involvement. CONCLUSIONS: Secondary neurotransmitter disturbances may occur in mitochondrial diseases. Differential diagnosis of hypokinetic-rigid syndrome presenting in infancy could also include paediatric mitochondrial disorders.