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Ramòn y Cajal, considered by many to be the father of neuroscience, was the first to document in any great detail the complex structure and function of the human nervous system. In recognition of his achievements he was awarded the Nobel Prize in 1906, together with his contemporary, Camillo Golgi. Successive generations of neuroscientists added to his work, broadening our understanding of this field, but it was not until the Human Genome Project that it became possible to assimilate vast quantities of information from an entire genome or proteome. As a consequence, the number of biomolecules relevant to the study of neuronal biology and pathology has escalated. It therefore comes as no surprise to find that the literature on biomarkers is vast and encompasses a wide spectrum of disciplines from genetics to medical physics. This chapter focuses on the use of molecular biomarkers in neurodegeneration and the progress made so far. [ABSTRACT FROM AUTHOR]

Conventional magnetic resonance imaging (MRI) is widely used for the diagnosis and monitoring of multiple sclerosis (MS), because it is more sensitive than clinical assessment in detecting disease dissemination over space and time [1] and for revealing the occurrence of disease activity and the accumulation of disease burden over time. Nevertheless, the discrepancies between clinical and conventional MRI findings in patients with established MS [2] highlight the fact that conventional MRI is unable to reliably assess the more disabling pathological features of the disease, including axonal and neuronal loss. [ABSTRACT FROM AUTHOR]

During the past decade, several new medications have become available for the treatment of multiple sclerosis (MS). The main effect of these therapies, whether they are immunomodulatory or immunosuppressive types of treatment, has been their strong impact on the inflammatory component of the MS disease process. These anti-inflammatory therapies have, with various degrees of success, suppressed signs of inflammation as detected by magnetic resonance imaging (MRI) and have reduced the incidence of the clinical correlate to inflammation, i.e., the acute relapses [1-7], although they have had little effect on disease progression caused by permanent demyelination and axonal loss. Hence, it has been hypothesized that there are two different disease mechanisms at work in patients with MS: inflammation and neurodegeneration. The neurodegenerative disease process has been associated with the progressive phases of MS, either primary progressive (PP) MS or secondary progressive (SP) MS, during which the disease activity is thought to be driven by degenerative rather than inflammatory processes. However, recent studies have emphasized the presence of axonal damage early in the course of the disease [8], a fact that was already known by Charcot, as shown in his seminal studies of MS [9]. According to one theory, both inflammatory and degenerative disease processes are present from the onset of the disease and proceed independently; with inflammation being most prominent in the early phases of the disease, whereas neurodegeneration dominates during the later stages [10]. On the other hand, there are arguments for inflammation being the culprit for both acute relapses and disease progression [11-13]. Recent studies have indeed shown that inflammation is also prominent in patients with PPMS and SPMS, although this inflammation is thought to be compartmentalized within the CNS and is independent of the activation of T-cells in the peripheral bloodstream [14]. This low-burning, widespread inflammation is thought to be mediated by activated microglia that interact with T-and B-cells from infiltrates in the meninges and in the perivascular spaces, causing demyelination and axonal injury in plaques as well as diffusely in the white and gray matter of the brain [15, 16]. [ABSTRACT FROM AUTHOR]

Epidemiological studies indicate that about 90% of multiple sclerosis (MS) patients experience a progression of the disease at some time during their life [1, 2]. In about 15% of patients, the disease starts with an insidious onset followed by a progressive phase, with or without phases of stability; the so-called primary progressive (PP) MS. In all other patients, the early phase of MS is marked by acute attacks characterized by unifocal (2/3 of patients) or multifocal white matter disease [3]. Attacks are usually followed by complete or almost complete recovery; however, pathological studies demonstrate the presence of an axonal transection inside the lesion [4-6]. Axonal loss is predominant in lesions appearing in the early phases of the disease [7] and decreases over time. A large amount of damage occurs in areas with a considerable infiltration of T lymphocytes (especially CD8+ T cells) and macrophages [7], indicating a correlation between inflammation and axonal damage - a relationship which has also been shown by magnetic resonance imaging (MRI) studies. The acute axonal damage also occurs because of the products of inflammation, such as nitric oxide and tumor necrosis factor [8]. Recent studies indicate that a high level of electrical activity may increase the axonal degeneration of partially or completely demyelinated lesions at the nodes of Ranvier, as a consequence of the activation of glutamate receptors increasing the entry of calcium into the axon [9]. Recent studies suggest that axonal damage may also be independent of demyelination [10] and may be caused by antibodies against axonal antigens [11]. [ABSTRACT FROM AUTHOR]

The neuropathology of multiple sclerosis (MS) has been thoroughly and carefully described since the pioneer studies on the disease [1]. It was already clear in the last years of the 1800s that MS is an inflammatory disease of the central nervous system (CNS) with scattered areas of demyelination and relative sparing of axons. The astroglial and microglial reactions, the possible loss of neurons, the axonal injury, and the capacity of the CNS to partly remyelinate the damaged areas were all widely known and described. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases of the central nervous system (CNS) represent a large group of sporadic or inherited conditions which share the fundamental physiopathological feature of a progressive dysfunction and death of neurons belonging to different systems, which ultimately leads to regional and global brain atrophy. Although considerable advances in understanding the etiopathogenesis of these diseases have been made, to date no treatment capable of halting the progression of neurodegeneration in any of these diseases is available. [ABSTRACT FROM AUTHOR]

The disease mechanism of multiple sclerosis (MS) causes progressive subcellular and cellular changes that may ultimately be detected by magnetic resonance imaging (MRI): for instance, in normal-appearing white matter (NAWM) the effects of the disease gradually alter the macromolecular and cellular compartmentalization of water, causing subtle changes in magnetization transfer ratio (MTR) and diffusion-weighted imaging (DWI). Similarly, MS lesions are characterized by serial image changes in several MR image modalities. [ABSTRACT FROM AUTHOR]

Clinical trials of Alzheimer's disease (AD) traditionally use rating scales, such as neuropsychological tests, and disability scales as outcome measures. However, their intrinsic measurement variability, the slow disease progression, and the low efficacy of the drugs developed so far have led to trial designs with hundreds of subjects per treatment arm. The development of imaging markers with proven sensitivity to disease progression has recently paved the way for their use as outcome measures in clinical trials. The use of imaging measures has the double advantage of decreasing the number of subjects per treatment arm whilst also providing a direct measure of the degree of disease modification induced by the "active" molecules. A number of magnetic resonance (MR)-based markers have been developed for clinical trials of AD, all of which have their own strengths and weaknesses. Here, the most often used techniques, which could easily be exported to the study of neurodegeneration in clinical trials of multiple sclerosis, are reviewed. [ABSTRACT FROM AUTHOR]

A physician in a clinic would typically like an answer to the question: Who will benefit from this treatment? In particular, will this patient benefit from this treatment? In an effort to answer the question, astute clinicians observe patients serially; in other words, they will try a treatment on the patient and then adjust the therapy if his or her condition does not respond. Although the sample size in this experiment is n = 1, the observations collected over time for this patient and others provide a knowledge base and have led clinicians toward a major understanding of certain treatments. Often, and historically, these understandings, taken collectively, have informed practice standards. However, this approach runs the risk of underestimating the extent of unsuccessful treatments, due to a failure to examine those patients who do not return. [ABSTRACT FROM AUTHOR]

Traditionally, the clinical endpoints used to monitor clinical trials in multiple sclerosis (MS) are the occurrence of relapses (usually expressed as a rate over time), and the degree of disability, most commonly evaluated using the Expanded Disability Status Scale (EDSS) [1]. [ABSTRACT FROM AUTHOR]

Over the past decade, modern structural magnetic resonance imaging (MRI) techniques have been extensively used for the study of patients with multiple sclerosis (MS) [1] with the ultimate goal of increasing our understanding of the mechanisms responsible for the accumulation of irreversible disability. The application of these techniques has provided important insights into the pathobiology of MS. First, it has been demonstrated that MS-related damage is not restricted to T2-visible lesions, but also involves, diffusely, the normal-appearing white matter (NAWM) and gray matter (GM) [1]. Secondly, it has been shown that the neurodegenerative component of the disease is not a late phenomenon and that it is not completely driven by inflammatory demyelination [2]. Finally, the contribution of axon damage to the clinical manifestations of the disease and to its clinical worsening over time has been confirmed [3, 4]. Despite these improvements, the correlation between the results of MRI and clinical findings remains suboptimal. This might be explained, at least partially, by the variable effectiveness of reparative and recovery mechanisms following MS-related tissue damage. [ABSTRACT FROM AUTHOR]

In the last few years, there has been an increased appreciation of the apparently primary role of neuronal and axonal injury in the pathogenesis of multiple sclerosis (MS) [1, 2]. This has been driven to a significant degree by the results of proton magnetic resonance (MR) spectroscopy (1H-MRS) studies, which have emphasized that substantial neuroaxonal damage occurs inside the demyelinating lesions as well as in the normal-appearing white matter (NAWM) and gray matter (GM) of the brain of patients with MS [2, 3]. All this has been confirmed pathologically [1, 4, 5] and has led to a reconsideration of the role of axonal damage in MS [6]. [ABSTRACT FROM AUTHOR]

There has been an increasing interest in studying microvascular and brain perfusion abnormalities in multiple sclerosis (MS) due to the accumulating evidence regarding the primary vascular pathogenesis in MS [1-4]. Early microscopic investigations demonstrated perivascular inflammatory infiltrates, including macrophages, often found in close contact with the disintegrating myelin sheath [5], which were later described as a T-cell-mediated immune reaction causing the activation of macrophages that contained intracytoplasmic, myelin-reactive degradation products [6]. The intravascular fibrin deposition [7, 8] and venous occlusive changes with hemodynamic impairment have also been demonstrated in active MS lesions [9]. Therefore, not surprisingly, these essential vascular pathologies have effects on the cerebral blood perfusion, which may cause mitochondrial dysfunction and axonal degeneration. However, only recently, due to the major achievements of in vivo perfusion imaging, have we started to understand the mechanisms of hemodynamic changes and neurodegeneration occurring in MS. This chapter focuses on some of the recent developments in the field of vascular pathology and on some ongoing research using perfusion MRI, particularly dynamic susceptibility contrast-enhanced MRI (DSC-MRI), to investigate vascular neuropathology in MS. [ABSTRACT FROM AUTHOR]

Although conventional MRI cannot establish the mechanisms of neurodegeneration, increasingly sophisticated imaging techniques are making it possible to study these processes in vivo. Among the quantitative MRI techniques, magnetization transfer imaging (MTI) has been the most extensively applied to the assessment of multiple sclerosis (MS), due to its sensitivity to the most destructive pathological substrates of the disease. This chapter outlines the major contributions of MTI in detecting and monitoring neurodegeneration in MS and other CNS diseases. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) has become important in the early diagnosis and monitoring of various neurologic disorders including multiple sclerosis (MS). MRI has emerged as a key supportive therapeutic outcome measure in MS-related clinical trials. The limitations of conventional MRI surrogates have driven researchers to develop better biomarkers, including those capturing destructive aspects of the disease. In this chapter, we discuss the most recent data highlighting the role of hypointense lesions on T1-weighted images (black holes; BH) and gray matter (GM) damage in the MRI assessment of MS. We focus on the most relevant pathologic, MRI, and clinical correlation studies addressing BH and GM injury. [ABSTRACT FROM AUTHOR]

Neurophysiological methods, particularly evoked potentials (EPs; also known as evoked responses), are widely applied in the functional assessment of multiple sclerosis (MS), since they provide a quite reliable, even though indirect, measure of the extent of demyelination or axonal loss in a given nerve pathway. For this reason, they are used to indicate the involvement of sensory and motor pathways in the presence of vague disturbances and to detect clinically silent lesions, even though the latter application has been greatly reduced since the development of magnetic resonance imaging (MRI), which is more sensitive in detecting subclinical lesions. Nevertheless, the information provided by EPs is more strictly related to function than is the information obtained from structural MRI techniques. As O'Connor et al. [1] point out, it is impossible to "confidentially predict, from examining an MS patient's cranial MRI, what the clinical findings or EDSS score will be." In fact, the severity of the disease, assessed clinically, correlates well with the degree of neurophysiological abnormality found [2-4]. We briefly review the application of EPs in the assessment of the pathophysiology, diagnosis, and monitoring of MS. [ABSTRACT FROM AUTHOR]

In this chapter we provide a brief overview of atrophy measurements in people with multiple sclerosis (MS). In particular we highlight the main findings from previous MRI studies, the main methodologies used to measure atrophy including their pros and cons, and the clinical relevance of such measures. [ABSTRACT FROM AUTHOR]