INTRODUCTION

Relatively few randomized controlled trials (RCTs) have been conducted in criminology and criminal justice; rarer still are multisite RCTs. Yet, as the field moves toward a more evidence-based perspective, we anticipate increases in the numbers of RCTs. The results of these trials will begin to identify efficacious interventions, and more sophisticated analyses will be required to identify interventions that accomplish the desired impact. Multisite RCTs provide a mechanism for increasing our understanding of what works for whom, and why, and in what environments.

Multisite studies are independent randomized experiments undertaken in two or more sites where researchers involved in the study plan and collaborate across these sites (Boruch 1997; Kraemer, 2000; Weisburd and Taxman, 2000). Some of the reasons for conducting multisite studies involve the need to replicate findings from initial single-site studies, to gain a sample size large enough to obtain sufficient power, and to discern moderate to small effect sizes. In addition to outlining further the definitional criteria of a multisite RCT, both of these justifications for conducting a multisite study are discussed in detail.

Key points

• MRS of the breast is more technically demanding than that in the brain.

• Cho levels have been reported to be higher in malignant breast cancer than in benign lesions and normal breast tissue.

• Early decreases in Cho signal intensity may be seen in lesions that respond to treatment.

• MRS is limited by sensitivity to lesions at least 1 cm3.

• Inadequate sensitivity may lead to false negatives, and both false positives and negatives may arise due to insufficient water and lipid suppression, or other artifacts.

Introduction: MRS of breast tissues

Although the vast majority of magnetic resonance spectroscopy (MRS) studies in humans have been performed to date in the central nervous system, there is growing interest in the application of MRS to other organ systems in the body. This is particularly true for areas such as breast cancer, where conventional diagnostic techniques have relatively limited sensitivity and/or specificity. MRS of the breast presents a number of technical challenges (described in detail later in this chapter) which are gradually being overcome, allowing clinical research studies to be performed. Early MRS studies of human breast cancer focused on the phosphorus (31P) nucleus, since localized, water-suppressed proton spectroscopy was not available at that time. However, with the development of improved gradient hardware, spatial localization, and water suppression techniques, 31P spectroscopy has largely been replaced by proton (1H) MRS. The much higher sensitivity of the proton nucleus allows spectra with higher signal-to-noise ratios (SNR) to be recorded from smaller volumes of tissue compared to 31P.

Key points

• TBI is a major cause of morbidity in young adults and children.

• Low levels of NAA and, if seen, increased lactate, in the early stage of injury are prognostic of poor outcome.

• Other common metabolic abnormalities in TBI (most of which also correlate with poor outcome) include increased levels of choline, myo-inositol, and glutamate plus glutamine.

• Metabolic abnormalities are observed with MRS in regions of the brain with normal appearance in conventional MRI.

• MRI and MRS are difficult to perform in acutely ill TBI patients: MRS may be more feasible in mild TBI patients for the purpose of predicting long-term cognitive deficits.

• The role of MRS in guiding TBI therapy is unknown.

• The comparative value of MRS compared to other advanced imaging modalities remains to be determined.

Introduction

Traumatic brain injury (TBI) is a leading cause of death and lifelong disability among children and young adults across the developed world. TBI is estimated to result in greater than $60 billion in direct and indirect annual costs due to health care and work loss disability. The Centers for Disease Control and Prevention (CDC) estimate that each year approximately 1.4 million Americans survive a TBI, among whom approximately 235,000 are hospitalized. Approximately 80,500 new TBI survivors are left each year with residual deficits consequent to their injury, which lead to long-term disabilities that may or may not be improved through rehabilitation. In 2001, 157,708 people died from acute traumatic injury, which accounted for about 6.5% of all deaths in the United States.

Key points

• Prostate cancer has a high incidence, and is one of the leading causes of death in men.

• The sensitivity and specificity of diagnosing prostate cancer with conventional imaging methods (ultra sound, MRI) is relatively low.

• The normal prostate contains high levels of citrate (Cit) which can be detected in the proton spectrum at 2.6 ppm. Other compounds detectable in vivo include creatine, choline, spermine, and lipids.

• Citrate is a strongly coupled mutiple at 1.5 and 3.0 T. For optimum detection, careful attention to pulse sequence parameters (TR, TE) is required. TE 120 ms is commonly used at 1.5 T, and TE 75–100 ms at 3 T.

• Multiple studies have reported that prostate cancer is associated with decreased levels of citrate and increased levels of Cho, compared to both normal prostate and also benign prostatic hyperplasia (BPH).

• MRS and MRSI of the prostate is technically challenging: water- and lipid-suppressed 3D-MRSI is the method of choice for most prostate spectroscopy studies.

• Some studies report that adding MRSI to conventional MRI increases sensitivity and specificity of prostate cancer diagnosis.

• MRSI is traditionally performed with an endorectal surface coil, but acceptable quality data may be obtained at 3 T with external phased-array coils which are more comfortable for patients.

Key points

• Despite the relatively common occurrence of neurodegenerative diseases, MRS is lightly used in these conditions, most likely because of lack of sensitivity and overlap of spectral findings in different disorders.

• MRS usually shows decreased levels of NAA in dementia.

• Dementias associated with gliosis (e.g. Alzheimer's) also have increased myo-inositol (mI).

• mI/NAA ratios correlate with clinical severity and histopathological involvement in Alzheimer's disease.

• mI/NAA ratios, and regional variations in metabolite levels, may be helpful in the differential diagnosis of different dementias (Alzheimer, vascular, frontotemporal, Lewy body).

• Parkinson's disease does not seem to be associated with any metabolic disorders, although other Parkinsonian disorders (e.g. multiple system atrophy) may show reduced NAA in the basal ganglia.

• Metabolic changes in Huntington's disease are unclear; some studies have reported elevated lactate levels in the basal ganglia, but others have not.

• Prion diseases are characterized by decreased NAA levels.

• In amyotrophic lateral sclerosis (ALS), upper motor neuron NAA decreases may be helpful in establishing a diagnosis.

Introduction

Neurodegenerative diseases include a very wide group of disorders affecting the central nervous system (CNS). Many of these disorders arise from the combined effects of genetic predisposition and environmental factors. This results in reduced cognition (e.g. Alzheimer's disease, dementia with Lewy bodies, and vascular dementia), motor system performance (e.g. amyotrophic lateral sclerosis), or both (e.g. Parkinson's disease and prion diseases).

Key points

• MRS is principally used as an adjunct diagnostic technique for evaluating patients with medically intractable epilepsy (in order to identify the seizure focus).

• Most commonly, NAA is reduced in epileptogenic tissue; metabolic abnormalities are often subtle.

• Metabolic abnormalities may be more widespread than seen on MRI, and present in the contralateral hemisphere.

• MRS may occasionally be helpful when other techniques (e.g. MRI) are either normal or non-specific.

• MRS measures of the inhibitory neurotransmitter GABA using spectral editing may help determine optimal drug regimen.

• MRS may also be a useful research tool for determining epileptogenic networks in the brain.

Introduction

Epilepsy, the condition of recurrent seizures, is a relatively common neurological disorder, estimated to affect between 1 and 2 million people in the US alone. A multitude of etiologies cause epilepsy, including tumors, developmental abnormalities, febrile illness, trauma, or infection. However, not infrequently, the cause is unknown. Many patients with epilepsy can be successfully treated pharmacologically, but when medical management fails to adequately control seizure activity, surgical resection of the epileptogenic tissue may be considered. For surgery to be successful, seizures must be of focal onset from a well-defined location. It has been estimated that up to 10% of patients with epilepsy are medically intractable, of whom approximately 20% may be candidates for surgical treatment. Traditionally, scalp electroencephalography (EEG) and often invasive (subdural grid or depth electrode) EEG are used to identify the epileptogenic regions of the brain, but increasingly magnetic resonance imaging (MRI), positron emission tomography (PET), ictal single photon emission computed tomography (SPECT), and, more recently, magnetoencephalography (MEG) are also used.

Key points

• Substantial regional variations in proton brain spectra exist; differences between gray and white matter, anterior–posterior gradients, and differences between the supra- and infra-tentorial brain are common.

• Spectra change rapidly over the first few years of life; at birth, NAA is low, and choline and myo-inositol are high. By about 4 years of age, spectra from most regions have a more “adult-like” appearance.

• In normal development, only subtle age-related changes are found between the ages of 4 and 20 years.

• In normal aging, only subtle age-related changes are found. A recent meta-analysis indicated the most common findings are mildly increased choline and creatine in frontal brain regions of elderly subjects (> 68 years), and stable or slightly decreasing (parietal regions only) NAA.

Introduction

Interpretation of spectra from patients with neuropathology requires a knowledge of the normal regional and age-related spectral variations seen in the healthy brain. This is a difficult issue, since spectra are quite dependent on the technique used to record them (particularly choice of echo time, and field strength), and also show quite large regional and age-related (at least in young children) dependencies. However, while there still remain some gaps in the literature (e.g. detailed, regional studies in very young children), for the most part regional and age-related changes in brain spectra are now well-characterized. This chapter reviews what is known about regional metabolite variations, as well as metabolic changes associated with brain development, and aging.

Key points

• MRS can provide useful clinical, metabolic information in infection, inflammation, and demyelination.

• Pyogenic abscess have a unique metabolic pattern with decreased levels of all normally observed brain metabolites, and elevation of succinate, alanine, acetate, and amino acids, as well as lipids and lactate. This pattern is quite distinct from that seen in brain tumors.

• Tuberculomas are characterized by elevated lipid and an absence of all other resonances.

• MRS is extensively used in research studies of HIV infection; early changes include elevated choline and myo-inositol perhaps associated with microglial proliferation, while later changes (associated with cognitive impairment, and dementia) include reduced NAA (neuronal loss).

• MRS may also be useful in assisting differential diagnosis in HIV-associated lesions.

• MRS shows decreased NAA (suggesting axonal dysfunction and loss) in early multiple sclerosis, as well as increased Cho and myo-inositol and lipids (suggesting demyelination). NAA correlates with clinical disability. White matter that appears normal on T2 MRI may be abnormal metabolically in MS. Lactate may be elevated in acute, inflammatory demyelination.

• Acute disseminated encephalomyelitis (ADEM) may show similar spectral patterns to MS; however, ADEM with good clinical outcome usually only shows mild NAA losses in lesions.

Introduction

Intracranial infection, inflammation, and demyelination include a wide range of disorders of the central nervous system (CNS). Magnetic resonance imaging (MRI) plays a crucial role in the diagnosis and therapeutic decision making in these diseases.

Key points

• Correct post-processing and quantitation are key aspects of in vivo MRS.

• Filtering, phase-correction and baseline correction improve MRS data.

• Peak area estimation can be done using parametric or non-parametric routines in either the time domain or frequency domains.

• “LCModel” software is becoming widely used and accepted, particularly for single-voxel MRS data.

• MRSI processing requires additional steps; k-space filtering and other manipulations can improve MRSI data quality.

• A variety of strategies are available for quantitation, based on either internal or external reference standards, or phantom replacement methodology.

• Quantitation routines should take into account voxel composition, particularly the amount of CSF partial volume present.

• MRS is sensitive to field inhomogeneity and other artifacts.

Introduction

Methods for spectral analysis and the quantitative analysis of spectral data are arguably as important as the techniques used to collect the data; the use of incorrect analysis methods can lead to systematic errors or misinterpretation of spectra. In general, the ultimate goal of spectral analysis is to determine the concentrations of the compounds present in the spectra. In MRS, the area under the spectral peak is proportional to the metabolite concentration; however, determining the proportionality constant can be challenging. In addition, peak area measurements in in-vivo spectroscopy are complicated by resonance overlap, baseline distortions, and lineshapes that often only poorly approximate conventional models such as Gaussian or Lorentzian functions. Therefore, quantitative analysis of in vivo MRS data is challenging. This chapter reviews basic spectral processing techniques, methods for determining peak areas, and strategies for calculating metabolite concentrations.

Key points

• 31P-MRS allows the detection of phosphate-containing metabolites that are central to energy metabolism, and therefore is particularly suitable for studying muscle physiology and its disorders in vivo.

• Time-resolved signals from inorganic phosphates, phosphocreatine, phosphodiesters/monoesters, and intermediates of ATP reflect physiologic changes in muscles during rest, exercise, and recovery.

• Quantitative analysis of metabolites allows estimates of cytosolic ADP based on a number of assumptions, and the recovery of ADP has been used as a measure of in vivo mitochondrial function.

• In pathologic states including metabolic (mitochondrial or glycolytic pathway) dysfunction, hereditary and acquired myopathies, 31P-MRS shows biochemical alterations (reduced PCr, increased Pi, slow ADP recovery) that tend to overlap between pathologies.

• Glycogenolytic disorders (such as McArdle's disease) may show paradoxical alkalosis during exercise.

• Muscle 31P-MRS is valuable in monitoring therapeutic response in a number of neuromuscular disorders.

• 1H-MRS currently has a limited role in the clinical evaluation of musculoskeletal disease, but has been used as a research tool to assess intramyocellular lipid, which has been implicated in skeletal muscle insulin resistance and type 2 diabetes mellitus.

Introduction

Magnetic resonance spectroscopy (MRS) of skeletal muscle has been studied over several decades. In particular, muscle MRS has been utilized to study carbohydrate metabolism (by 13-carbon (13C) MRS), lipid metabolism (by proton (1H) MRS) and, more widely, energy metabolism (by 31-phosphorus (31P) MRS).

Key points

• MR spectroscopy is a valuable tool to direct biochemistry work-up of patients with inborn errors of metabolism.

• Multivoxel MR spectroscopic imaging is the best method to study the heterogeneous anatomic distribution of metabolic diseases.

• The interpretation of MR spectra and MR images together increases diagnostic accuracy.

• Abnormal MR spectral peaks are diagnostic of a few hereditary metabolic disorders.

• Lactate is elevated in about half of patients with mitochondrial disorders, in most patients with leukoencephalopathies with demyelination or rarefaction of white matter, and in few with organic acidopathies targeting the subcortical gray matter nuclei.

• In patients with leukoencephalopathy, H-MRSI is a valuable tool for identifying one of the following three underlying tissue pathophysiologies: hypomyelination, demyelination, and rarefaction of white matter.

• MRS may be useful to monitor response to therapy when available.

Introduction

The advent of magnetic resonance (MR) imaging has changed the clinical approach to the evaluation of metabolic disorders. MR imaging is highly sensitive and plays a prominent role in the diagnostic evaluation of patients with metabolic disorders of the central nervous system (CNS). However, the structural and signal abnormalities detected on conventional MR imaging are often not specific enough to suggest a definite diagnosis in many of these complex disorders.

With advances in MR technology, proton MR spectroscopy (1H-MRS) has become more widely available, and now it can be performed with conventional MR imaging in the same study session. Nowadays, a complete imaging exam lasts no longer than 30 min at 1.5 Tesla or higher magnetic fields.