Magnetic resonance imaging and spectroscopy of the brain in HIV disease.
Neurocognitive impairment is a common complication of HIV infection, presenting as a wide spectrum of disorders ranging from mild forms of HIV-associated minor cognitive--motor disorders to severe forms of cognitive impairment, termed HIV-associated dementia . Since the introduction of combination antiretroviral therapy (cART), changes in the features of HIV-related neurocognitive impairment have been observed with a reduction in the incidence of HIV-associated dementia, although reports have described an increasing incidence of minor cognitive--motor disorders [2,3]. These changes may be attributable to the longer survival of an ageing HIV-infected population on antiretroviral therapy , or could reflect antiretroviral therapy-associated complications .
In clinical practice, brain imaging in the form of a computed tomography (CT) scan, and in some countries magnetic resonance imaging (MRI), has become routine to exclude other diagnoses, such as opportunistic infections, that may cause cerebral impairment. Other imaging modalities exist such as functional MRI (fMRI) and magnetic resonance spectroscopy (MRS). These applications, although they have been largely confined to research programmes to date, have increased our understanding of the pathophysiology of HIV infection in the brain.
Recent reviews have described the key findings from neuroimaging of HIV-related opportunistic infections and tumours of the central nervous system (CNS) . In this review, we will concentrate on published magnetic resonance studies to date, focusing on the direct effects of HIV on the CNS, and consider their implications in the post-cART era and the future applications of these techniques.
In each of the following sections a short overview describing the imaging technique is followed by relevant clinical studies.
Magnetic resonance imaging
One can approach MRI analysis of the neurodegenerative effects of HIV-1 on the living brain in two ways: structural or functional. Structural analysis uses mainly T1-weighted images, as this sequence is good for delineating brain anatomy. The structural assessment of brain atrophy can be either qualitative or quantitative. Quantitative studies rely on measuring the volume of a particular area of the brain on [T.sub.1] images by manually segmenting the anatomical area of interest (i.e. drawing a line round it) and counting the number of voxels within it (where for example 1 voxel = 1[mm.sup.3]).
In the pre-ART era, cerebral atrophy and white matter abnormalities were a commonly reported finding among HIV-infected individuals [7,8]. Atrophy is evident in both cortical and subcortical regions of the brain . Interestingly, the degree of atrophic change is associated with HIV concentration in discrete areas of the brain  and atrophy is reported to be predominant in the caudate nucleus .
White matter abnormalities associated with HIV infection are also well described and a common finding on neuroimaging. Reported abnormalities include focal high signal areas and reduced white matter volume . Differential diagnoses of such non-specific white matter changes are diverse and include other opportunistic diseases such as progressive multifocal leukoencephalopathy.
Although correlations have been described between cerebral atrophy, especially of the caudate nucleus, and cognitive function, such associations have not been demonstrated between white matter changes and CNS function . In the post-cART era basic MRI scanning continues to play a crucial role in the diagnosis of cerebral atrophy in HIV disease and in the exclusion of other pathological processes.
Magnetic resonance spectroscopy
Protonmagnetic resonance spectroscopy allows measurement of CNS metabolites in different areas in the brain. Hydrogen MRS ([sup.1]H-MRS) is based on the principle that protons in different chemical environments (in different molecules) have slightly different resonance properties. The brain can be divided up into tiny blocks (known as voxels) and the distribution of the resonances in the various protons in these voxels can be displayed as a spectrum. The area under the peak for each resonance provides a quantitative measure of the relative abundance of that compound. With [sup.1]H-MRS the largest peak will be the water ([H.sub.2]O) peak. Other main peaks include choline (Cho, a marker of cell membrane turnover), creatinine (Cr, a marker of metabolism), N-acetylaspartate (NAA, a component of the myelin sheath of nerve cells), myoinositol (mI, a glial cell marker) and lactate (elevated in some tumours) . It is therefore possible to characterise the chemical make-up and biochemical processes (the 'brain chemistry') in different parts of the brain based on the MRS spectra in different regions. Selection of a voxel and magnetic resonance spectra are shown in Figure 1.
Further to [sup.1]H-MRS, other spectra coils can be utilised such as phosphate spectroscopy ([sup.31]P-MRS) where phosphate metabolites can be characterised. This includes inorganic and organic phosphate metabolites and provides information on the status of energy phosphates and on phospholipid metabolism .
MRS data in HIV-infected subjects
In HIV-infected individuals, abnormalities in cerebral metabolite ratios were well described in the pre-cART era. Findings included an increase in frontal white matter mI [16,17] and decreased NAA in the white matter and basal ganglia . These abnormal metabolite ratios when compared with non-HIV-infected subjects suggest an inflammatory process in the CNS (mI being a glial cell inflammatory marker) and a reduction in neuronal mass (decreased NAA).
Changes in brain chemical composition may not be a surprising finding in subjects with advanced HIV infection. Can these data or other data be extrapolated to patients receiving modern cART? Schweinsburg et al.  compared frontal lobe white and grey matter NAA measurements of 18 HIV-infected subjects receiving didanosine- or stavudine-containing regimens (nucleoside reverse transcriptase inhibitors likely to cause mitochondrial toxicity), 14 HIV-infected subjects receiving zidovudine and lamivudine, 16 HIV-infected individuals not taking antiretroviral therapy, and 17 HIV-negative individuals who acted as controls. Those receiving didanosine or stavudine had a significant (11.4%) decrease in concentrations of frontal white matter NAA compared with the HIV-negative controls, whereas NAA levels in the other HIV-infected groups were intermediate. Furthermore, reductions in frontal lobe white matter NAA were associated with longer periods of didanosine or stavudine exposure. In clinical practice, different nucleoside analogues are associated with different degrees of mitochondrial dysfunction and this is the first report to directly observe drug-specific toxicities in the brain with the agents most associated with peripheral mitochondrial dysfunction.
[FIGURE 1 OMITTED]
Young persons with HIV infection may be prone to neurological disease , and there are limited data that describe changes on MRS in children with HIV-1 infection . A recent report has described MRS changes in children on stable antiretroviral therapy compared to a control group . Ratios of mI/Cr were elevated in the left frontal brain of children on cART compared to a control group, suggesting an ongoing inflammatory process.
Functional MRI measures the haemodynamic response of the brain to changes in neural activity. Active neurones extract oxygen from the blood at a greater rate than adjacent inactive neurones, resulting in localised increased levels of deoxyhaemoglobin compared with oxyhaemoglobin. The differences in magnetic susceptibility between oxyhaemoglobin and deoxyhaemoglobin lead to magnetic signal variation that can be detected by the MRI scanner. A thought or action can be repeated many times and statistical methods can be used to determine the areas of the brain that reliably have more of this signal difference as a result, and therefore which areas of the brain are more active during that thought or action. This method is called 'blood oxygen level-dependent' (BOLD) MRI [22,23]. Haemoglobin is diamagnetic when oxygenated but paramagnetic when deoxygenated, resulting in BOLD contrast, given the use of an appropriate magnetic resonance pulse sequence (T2- or [T2.sup.*]-weighted images usually). Increased concentrations of oxygenated haemoglobin, and increased magnetic susceptibility, result in higher BOLD signal intensity.
[FIGURE 2 OMITTED]
Increases in cerebral blood flow that outstrip changes in oxygen consumption will lead to increases in oxyhaemoglobin; conversely, decreases in cerebral blood flow that outstrip changes in oxygen consumption will cause decreased BOLD signal intensity. Figure 2 illustrates the increase in BOLD signal seen in the visual cortex of a subject upon visual stimulation.
The BOLD signal consists of cerebral blood flow contributions from larger arteries and veins, as well as smaller vessels and capillaries. Functional MRI has now largely superseded nuclear medicine techniques. It avoids radiation, is well tolerated and easily accessible.
Functional MRI data in HIV-infected subjects
Functional MRI reports have described impaired functioning in HIV-infected subjects in several areas of the CNS, including the pre-frontal cortex [23,24], medial temporal areas  and basal ganglia . Interestingly, many of these studies have been undertaken in subjects receiving antiretroviral therapy with suppressed plasma HIV-RNA. In a recent study, fMRI and neurocognitive testing were undertaken in three groups of subjects: healthy controls, HIV-infected subjects not yet requiring antiretroviral therapy and HIV-infected subjects on stable therapy including nucleoside analogues and who had an undetectable plasma viral load . HIV-infected subjects in both groups showed greater load-dependent increases in brain activation in the right frontal regions compared to the control group. This observation was most marked in the group receiving antiretroviral therapy. The authors concluded that they may be observing a toxicity effect associated with chronic use of antiretroviral therapy such as long-term brain mitochondrial toxicities, which have also been suggested in the MRS studies mentioned above .
These findings suggest that HIV-positive subjects, whether or not on current antiretroviral therapy, have a significant reduction in attention networking such that the frontal lobes use more oxygen to perform certain tasks compared to control groups. Furthermore, these observations were most marked in subjects on stable antiretroviral therapy . Although such changes may not be of clinical importance to everyday life tasks, the long-term effects of such changes require close monitoring.
In the post-cART era, although the incidence of frank AIDS-related dementia has declined, reports have highlighted ongoing subtle neurocognitive defects observed in HIV-infected subjects on stable antiretroviral therapies. The long-term implications of these deficits remain unknown, and tools to monitor cerebral function will be paramount in the future description and evaluation of these processes. Techniques such as MRS and fMRI, where significant abnormalities have been detected in HIV-infected subjects on stable antiretroviral therapies, may play a crucial role in the characterisation of CNS function and our future understanding of these processes.
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Correspondence to: Alan Winston, St Mary's Hospital, Praed Street, Imperial College London, London W2 1NY, UK Email: firstname.lastname@example.org
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|Title Annotation:||LEADING ARTICLE|
|Author:||Descamps, M.J.L.; Hyare, H.; Stebbing, J.; Winston, A.|
|Publication:||Journal of HIV Therapy|
|Date:||Sep 1, 2008|
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