Human immunodeficiency virus (HIV) affects more than 1 million individuals in the
United States and over 40 million people worldwide.[1] Advances in combination antiretroviral treatment (cART) have transformed HIV from
a rapidly fatal disease to a manageable chronic condition.[2]
[3]
[4] The proportion of older HIV-infected (HIV+) individuals is rapidly growing. More
than half of all HIV+ individuals in the United States are expected to be greater
than 50 years old by 2015.[5] HIV infected (HIV+) individuals receiving cART can now expect to live almost as
long as HIV-uninfected (HIV-) individuals.[6]
Despite these advances, eradication of HIV from the brain has not occurred. The prevalence
of HIV-associated neurocognitive disorders (HAND) has remained constant (∼ 40%) despite
more available and effective antiretrovirals.[7]
[8] Soon after seroconversion, HIV rapidly spreads throughout the brain. Some HIV+ individuals
who have effective plasma HIV-1 RNA suppression with cART still develop HAND.[9] The continued presence of HAND in the cART era may result from nonmutually-exclusive
factors including irreversible injury prior to initiating cART, persistent HIV-1 RNA
in the central nervous system (CNS) compartment,[10] antiretroviral toxicities,[11]
[12]
[13] and/or persistent low-level inflammation in the CNS.[14] A major effort has begun to optimize therapy for HAND by addressing persistent HIV
reservoirs and immunologic activation in the brain.
HAND is often difficult to characterize in the typical outpatient visit (15–30 min).
Multiple connections throughout the brain are often affected leading to the complex
series of clinical signs and symptoms.[15] Recent criteria have subdivided HAND into three categories: asymptomatic neurocognitive
impairment (ANI), mild neurocognitive disorder (MND), and HIV associated dementia
(HAD).[8] These definitions are based upon an individual's performance on neuropsychological
performance (NP) testing and self-reported activities of daily living. However, limitations
exist with the current HAND criteria.[16] Often NP testing (∼ 3 h) is performed in a research setting at certain sites.[8] A continuum of HAND may occur instead of set distinctions.[17] Unlike other neurodegenerative disorders (i.e., Alzheimer's disease),[18] additional biomarkers (cerebrospinal fluid [CSF] or neuroimaging) have not been
included in the HAND diagnosis. Biomarkers of HAND that are both easy to perform and
clinically relevant remain an unmet need.
Neuroimaging techniques may therefore have increased utility in the diagnosis and
management of HAND. A variety of novel noninvasive neuroimaging techniques have been
developed and hold great promise as they often can be added to conventional sequences.
Of note, three magnetic resonance imaging (MRI) techniques have been used in the neuroHIV
research setting: metabolic (magnetic resonance spectroscopy [MRS]), structural (MRI
volumetrics and diffusion tensor imaging (DTI)), and functional (functional MRI [fMRI]).
This review is not meant to be a comprehensive review of all MRI techniques and does
not focus on other neuroimaging modalities (e.g., positron emission tomography [PET][19]).
Cerebral Metabolite Imaging using Magnetic Resonance Spectroscopy
MRS has been one of the most consistently used neuroimaging methods during the pre-
and post-cART eras.[20]
[21]
[22]
[23] A current PubMed search reveals more than 75 articles that describe studies that
have used this technique to detect HIV-associated changes in cerebral metabolites
(key search terms: “MRS,” “brain,” and “HIV”). Please see [Table 1] for a select list of MRS studies performed in HIV+ patients. MRS detects the signal
produced by protons of specific molecules within a volume of brain. Signal amplitude
of a particular molecule X (AX) of interest is proportional to the number of moles of X (NX) with the brain volume (VB) interrogated. Typical molecules measured include (1) N-acetyl aspartate (NAA)- a
neuronal marker, (2) choline (Cho)- a marker of cellular proliferation and inflammatory
response, (3) creatine (Cr)- a measure of brain energy metabolism and reference marker,
(4) myo-inositol (MI)- a marker of gliosis, and (5) glutamine (Gln)/glutamate (Glu)-
measures of neurotoxicity due to excess n-methyl-d-aspartate (NMDA) receptor activation.
Table 1
Select citations of magnetic resonance spectroscopy (MRS) in HIV+ patients
|
Reference
|
Subjects
|
% HIV+ on cART
|
HAND classification
|
Field strength
|
Regions of interest
|
Major findings
|
|
Cysique et al, 2013[20]
|
92 HIV+ (56 y), 30 HIV- (55 y) 100% male
|
100%
|
NA
|
3 T
|
FWM, caudate, parietal cortex
|
HIV+ had lower NAA and increased MI in FWM, lower NAA in caudate, and higher Cho/NAA
and MI in parietal cortex. HIV and aging interaction in NAA FWM
|
|
Valcour et al, 2013[67]
|
61 acute HIV+ (35 y), no HIV-
|
0%
|
14 ANI
8 MND
6 HAD
|
1.5 T
|
FGM, FWM, BG, occipital gray matter
|
Blood CD14+ associated with lower NAA and higher MI in FGM, FWM and BG
|
|
Sailasuta et al, 2012[26]
|
31 acute HIV+ (30 y)
26 chronic HIV+ (34 y)
10 HIV- (36 y)
|
0% Primary HIV+ not on cART, 100% chronic HIV+
|
NA
|
1.5 T
|
FWM, FGM, BG,occipital gray matter
|
Acute HIV+ had elevated Cho/Cr in BG and occipital gray matter compared with chronic
HIV+ and HIV-. cART in acute HIV+ led to normalization of Cho/Cr in BG
|
|
Valcour et al, 2012[25]
|
20 acute HIV+ (31 y, 90% male, no HIV-
|
0%
|
NA
|
1.5 T
|
FGM, FWM, occipital gray matter, BG
|
Acute HIV+ had elevated Cho/Cr in occipital gray matter. Higher CSF neopterin was
associated with elevated Cho/Cr in occipital gray matter and elevated MI/Cr in FWM.
|
|
Harezlak et al, 2011[22]
|
240 HIV+ (47 y)
28 HIV - (53 yo)
|
100%
|
124 ADC 0
66 ADC 0.5
60 ADC >1
|
Not stated
|
BG, FWM, FGM
|
Increased MI/Cr and Cho/Cr in BG, FGM, FWM in all HIV+ groups compared with HIV-
Decreased Glu/Cr in FWM of ADC 0. Decreased NAA/Cr in ADC >1 compared with other HIV+
groups.
|
|
Lentz et al, 2011[21]
|
9 primary HIV+ (39 y)
9 HIV- (31 y)
100% male
|
Baseline: 22.2%
2-mon: 44.4%
6-mon: 55.6%
|
All asymptomatic
|
1.5T
|
FGM, FWM, and BG
|
Cho/Cr increased in FWM and FGM at 2- and 6-mon in primary HIV+. Higher levels of
peripheral CD16+ monocytes were associated with lower NAA and higher Cho.
|
|
Letendre et al, 2011[1]
|
129 HIV+ (42 y, 89% male), no HIV-
|
91%
|
30 ADC 0
83 ADC 1
14 ADC 2
2 ADC 3
|
1.5 T
|
Parietal cortex, WM (including FWM), BG
|
Higher CSF IP-10 correlated with lower NAA/Cr in FWM and higher MI/Cr in the parietal
cortex, FWM, and BG. Higher CSF MCP-1 correlated with lower NAA/Cr in FWM and parietal
cortex.
|
|
Ernst et al, 2010[32]
|
45 HIV+ (46 y, 93% male)
46 HIV- (43 y, 80% male)
|
100%
|
27 cognitively normal 6 ANI
10 MND
2 HAD
|
3 T
|
BG, FGM, FWM, parietal cortex
|
Lower Glu in parietal GM in HIV+ with cognitive deficits. Lower Glu in BG in HIV+
with no cognitive deficits.
|
|
Mohamed et al, 2010[29]
|
86 HIV+ (47 y, 69% male), no HIV-
|
100%
|
21 ADC 0
31 ADC 0.5
24 ADC > 1
|
3 T
|
FWM and BG
|
Patients with ADC >1 had decreased Glu, Glu/Cr and increased MI, MI/Cr in FWM and
decreased NAA in the BG.
|
|
Paul et al, 2008[30]
|
22 HIV+ (38 y, 86% male)
20 HIV- (35 y, 47% male)
|
> 50%
|
6 ADC 0
16 ADC 1
|
1.5 T
|
BG
|
Cho/Cr higher and NAA/Cr lower in HIV+ vs. HIV-. MRS measures correlated with NP testing
|
|
Schweinsburg et al, 2005[37]
|
18 HIV+ (32 y), 17 HIV- (28 y)
|
67%
|
NA
|
1.5 T
|
FGM and FWM
|
HIV+ patients on NRTIs had lower NAA in the FWM compared with HIV-. HIV+ patients
not receiving NRTIs had intermediate NAA levels.
|
|
Chang et al, 2004[96]
|
100 HIV+ (40 y) 37 HIV- (34 y)
Cohort 77% male
|
100%
|
61 cognitively normal 39 cognitively impaired
|
1.5 T
|
FWM, BG, parietal cortex
|
MI/Cr increased in WM of cognitively normal HIV+
MI/Cr Increased in WM and BG of cognitively impaired HIV+
Cho/Cr Increased in WM and BG of cognitively impaired HIV+
NAA/Cr decreased in WM and BG of cognitively impaired HIV+
CSF viral load correlated with increase MI/Cr and Cho/Cr in WM and decreased NAA/Cr
in parietal cortex
Aging and HIV infection have additive effect on increased MI/Cr and Cho/Cr in BG and
WM
|
|
Yiannoutsos et al, 2008[31]
|
100 HIV+, no HIV-
|
NA
|
NA
|
1.5 T
|
FWM, FGM, BG, parietal cortex
|
Three metabolic patterns: (1) inflammatory (elevated MI/Cr in all regions and elevated
Cho/Cr in the FWM and parietal cortex); (2) basal ganglia (elevated NAA/Cr and Cho/Cr);
(3) neuronal (reduced NAA/Cr in FGM and parietal cortex).
|
Abbreviations: ADC, AIDS dementia complex; BG, basal ganglia; cART, combination antiretroviral
therapy; Cho, choline; Cr, creatine; FWM, frontal white matter; FGM, frontal gray
matter; Glu, glutamate; Gln, glutamine; HIV, human immunodeficiency virus; MI, myoinositol;
NAA, N-acetyl aspartate; NA, not available; WM, white matter.
In general, MRS can be performed on conventional MRI scanners, but technical assistance
is needed to ensure good-quality scans are obtained. MRS studies should be carefully
performed to ensure homogeneity of the magnetic field and suppression of the water
signal.[24] Depending on both the institution and time available for scanning, single- or multi-voxel
MRS has been acquired using a variety of acquisition techniques to yield qualitative
versus semiquantitative versus quantitative values. Due to quantification limitations,
calibration is often performed using a phantom or an internal signal (e.g. water (H2O) or Cr). This can result in metabolite ratios rather than absolute concentrations
(e.g., NAA/Cr).
Though often limited to certain brain regions (e.g., frontal gray, frontal or parietal
white matter, and basal ganglia), MRS provides key insights into the dynamic changes
in the brain metabolic profile from primary (≤ 1 year since seroconversion) to chronic
(> 1 year since seroconversion) infection. Soon after seroconversion, MRS metabolites
have been shown to be affected.[21]
[25]
[26]
[27] HIV+ patients scanned during the first year of infection have increased Cho/Cr in
the frontal and white matter[21] compared with HIV- controls. A subsequent study confirmed these findings with primary
HIV+ individuals having higher Cho/ Cr in the basal ganglia compared with HIV- controls.[25] Observed MRS changes are correlated with markers of CNS infection and inflammation
(detectable HIV-1 RNA and chemokines)[25] and neuronal injury (neurofilament light chain).[27] Within chronically infected patients, brain metabolite changes are also evident.
Many studies have often observed reductions in NAA and concomitant increases in Cho
and MI.[22]
[28]
[29]
[30]
[31] More recent MRS studies performed at higher magnetic fields using newer analysis
methods have demonstrated reductions in Glu[32] and Gln.[29] Observed MRS changes in chronically infected HIV+ patients are proportional to the
degree of cognitive impairment.[22]
[29] While increases in MRS markers of inflammation (Cho and MI) are seen in cognitively
normal HIV+ patients, greater changes in inflammation (Cho and MI) and neuronal loss
(NAA/Cr and Glu/ Cr) are observed in HAND patients.[22]
[29]
[32]
The introduction of cART has dramatically reduced the more severe forms of HAND and
can also lead to improvements, but not normalization, of brain metabolites.[31]
[33]
[34] Early treatment with cART may be neuroprotective and mitigate the early inflammatory
changes seen in primary HIV+ patients. Commencement of therapy soon after diagnosis
normalizes Cho/Cr in the basal ganglia within 6 months.[26] Several clinical trials have started to include MRS markers to evaluate the efficacy
of adjunctive therapy for HAND.[35] This technique may have great potential in future early prevention studies.
Increasing evidence has also suggested that certain antiretrovirals may cause mitochondrial
toxicity and lead to neuronal loss.[12]
[36] Chronically infected HIV+ patients on cART regimens that included nucleotide reverse
transcriptase inhibitors (NRTIs) had significant reductions in NAA in the frontal
white matter compared with HIV- controls. HIV+ individuals receiving alternative cART
regimens that did not include NRTIs exhibited intermediate decreases in NAA.[37] A more recent study has observed that HIV+ patients receiving NRTIs had reductions
in parietal and frontal gray matter Glu that were predictive of worse cognitive performance.[32]
With a larger proportion of HIV+ growing older with the disease, several studies have
started to investigate the interaction between HIV and aging using MRS. HIV+ patients
have been shown to have significant reductions in Glu to levels equivalent to those
in HIV- controls a decade older.[32] Another study confirmed these findings by demonstrating that HIV+ patients exhibited
age dependent declines in NAA and Gln, such that the metabolic profile of a 30-year-old
HIV+ patient was equivalent to a 56-year-old HIV- control.[22] In both instances, though HIV and aging effects were observed, no interaction was
present.
Overall, MRS offers a valuable method for monitoring HIV-associated neuropathologic
changes. Observed MRS changes may be more sensitive than conventional MRI alone and
could augment current neuroimaging protocols. MRS measures may detect subtle early
changes associated with HIV infection, and concentrations or ratios of cerebral metabolites
measured by MRS could be used as a quantitative indicator of cerebral involvement.
In addition, MRS could be used to evaluate the efficacy of therapeutics directed against
HIV infection within the CNS during early stages of infection. Some limitations exist
in the current MRS HIV research literature, including mostly cross-sectional studies,
as well as analyses restricted to specific regions of interest. However, MRS results
suggest that contributions of inflammation, aging, and drug toxicity could all contribute
to the continued prevalence of HAND. Additional studies that include more HIV- controls
are needed. Longitudinal studies, with a focus on repeated imaging of HIV+ patients
as they transition through different stages of infection, as well as prior to and
after stable cART, are needed. In addition, the impact of comorbidities (e.g., hepatitis,
substance abuse, etc.) on MRS measurements should be more fully characterized in HIV+
patients.
Structural Neuroimaging
Volumetrics Analysis of MRI
Volumetric MRI examines particular regions of interest and assesses if abnormal structural
changes are present in affected individuals compared with healthy controls.[38] This method provides a useful tool to rule out alternate etiologies and can support
a diagnosis of HAND. Specific structures or general brain regions (e.g., white and
gray matter) are analyzed.[39] A PubMed search using keyword search terms “MRI,” “volume,” “brain,” and “HIV” identifies
more than 60 articles. Please see [Table 2] for a select list of MRI volumetric studies performed in HIV+ patients. Typically,
higher field MRI (initially 1.5 T and now 3 T) has been used to acquire high resolution
T1-weighted images. In particular, a magnetization prepared rapid acquisition gradient
echo (MPRAGE) image provides the greatest contrast for segmenting gray matter, white
matter, and CSF. Although not typically acquired with conventional imaging sequences,
the MPRAGE sequence can be obtained on most MRI scanners.
Table 2
Select citations of magnetic resonance imaging (MRI) of volumetrics in HIV+ patients
|
Reference
|
Subjects
|
% HIV+ on cART
|
HAND classification
|
Field strength
|
Regions of interest
|
Major findings
|
|
Bonnet et al, 2013[104]
|
400 HIV+ (47 y, 79% male),
no HIV-
|
89%
|
21% ANI
31% MND
7% HAD
|
1.5 T
|
GM and WM
|
MND or HAD had lower WM and GM than ANI.
|
|
Fennema-Nostestine et al, 2013[105]
|
75 HIV+ (45 y,
83% male),
no HIV-
|
79%
|
NA
|
1.5 T
|
Total cerebral WM, abnormal WM, subcortical and cortical GM, and ventricular and sulcal
CSF
|
Greater plasma CD4 recovery associated with increased abnormal WM and subcortical
GM volumes. Virologic suppression was independently associated with increased GM volume.
|
|
Kallianpur et al, 2013[61]
|
135 HIV+ (54 y, 91% male),
12 HIV-(54 y, 100% male)
|
100%
|
NA
|
3 T
|
Caudate, amygdala, hippocampus, thalamus, nucleus accumbens, putamen, globus pallidus,
subcortical and cortical GM, cerebral WM, cerebellar GM, cerebellar WM, brainstem,
lateral ventricles
|
HIV+ subjects with detectable viral load in the periphery had decreases in cerebellar
and subcortical GM compared with HIV+ subjects with undetectable viral load. HIV+
subjects with detectable viral load had ventricular enlargement and reduction of caudate,
putamen, thalamus, hippocampus, nucleus accumbens, brainstem, total cortical GM, and
cerebral WM compared with HIV-
|
|
Ances et al, 2012[50]
|
52 HIV+ (36 y, 91% male),
26 HIV- (35 y, 77% male)
|
50%
|
NA
|
3 T
|
Amygdala, caudate, thalamus, hippocampus, putamen, corpus callosum, cerebral GM and
WM
|
HIV+ subjects had reduction in amygdala, caudate, and corpus callosum compared with
HIV-. Both HIV and aging were independently associated with volume reductions
|
|
Becker et al, 2012[65]
|
84 HIV+ (38 y)
76 HIV- (39 y)
100% male
|
NA
|
NA
|
3 T
|
GM and WM
|
HIV+ subjects had greater GM loss in posterior and inferior temporal lobe, parietal
cortex, and cerebellum compared with HIV-. Both aging and HIV affect WM and GM volumes.
Cardiovascular disease risk factors were not associated with brain volume loss.
|
|
Pfefferbaum et al, 2012[55]
|
127 HIV+, (45 y, 70% male),
218 HIV- (47 y, 69% male)
|
87%
|
NA
|
1.5 T
|
Lateral frontal, medial frontal, temporal, parietal, occipital, caudate, putamen,
globus pallidus, hippocampus, amygdala, thalamus
|
HIV+ subjects had reduced thalamic and frontal volumes compared with HIV-. Volume
loss correlated with CD4 nadir and history of AIDS.
|
|
Ragin et al, 2012[51]
|
43 HIV+ (33 y, 88% male)
21 HIV- (31 y, 76% male)
|
47%
|
NA
|
3 T
|
Total brain volume, cortical and subcortical GM, WM, ventricular volume
|
HIV+ subjects had reductions in total and cortical GM and increase in the ventricular
volume compared with HIV-.
|
|
Thames et al, 2012[57]
|
20 HIV+ (53 y, 60% male),
no HIV-
|
100%
|
50% had HAND
|
1.5 T
|
Putamen and caudate
|
Impaired word generation significantly predicted reduction in caudate volume
|
|
Towgood et al, 2012[66]
|
40 HIV+ (47 y),
42 HIV- (45 y)
100% male
|
100%
|
NA
|
3 T
|
Total GM and WM
|
HIV+ subjects had reduced GM volume in the medial and superior frontal gyri compared
with HIV-. HIV and aging were independently associated with reduced frontotemporal
GM and WM volumes.
|
|
Jernigan et al, 2011[42]
|
251 HIV+ (44 y, 82% male),
no HIV-
|
76%
|
37% neurocognitively impaired
|
1.5 T
|
Total WM, abnormal WM, subcortical and cortical GM
|
Lower CD4 nadir and higher current CD4 cell counts were associated with lower total
WM and subcortical GM volumes. Detectable HIV in the CSF correlated with total WM
volume loss. Longer cART exposure correlated with reduced WM volumes and increased
ventricular volumes.
|
|
Ragin et al, 2011[62]
|
8 HIV+ (51 y, 75% male),
no HIV-
|
100%
|
NA
|
3 T
|
Cerebral cortex, cerebral WM, caudate, putamen, pallidum, accumbens, amygdala, hippocampus,
thalamus, cerebellar cortex, cerebellar WM
|
MMP-7 significantly correlated with brain atrophy in multiple brain regions.
|
|
Cohen et al, 2010[52]
|
82 HIV+ (46 y, 52% male),
no HIV-
|
80%
|
16% ADC >1
|
1.5 T
|
Cortical and subcortical GM; WM; total ventricular volume; frontal, parietal, temporal,
and occipital lobes
|
HIV+ subjects with cognitive impairment had greater reductions in GM and parietal
cortical volumes and increased ventricular volumes. Nadir CD4 and duration of infection
correlated with volumetric reductions in WM, GM, parietal, temporal, and frontal lobes;
and hippocampal volume.
|
|
Cardenas et al, 2009[28]
|
39 HIV+ (45 y),
30 HIV- (42 y)
100% male
|
100%
|
NA
|
1.5T
|
Total, frontal, temporal, parietal, and occipital WM and GM
|
HIV+ subjects had greater WM volume loss than SN controls. Greater rates of WM and
GM volume loss were found in HIV+ subjects with detectable plasma HIV viral loads.
|
|
Castelo et al, 2007[56]
|
22 HIV+ (43 y)
22 HIV- (43 yo)
|
77%
|
NA
|
3 T
|
Hippocampus, caudate nucleus, putamen, globus pallidus
|
HIV+ subjects had putamen hypertrophy compared with HIV-. Enlarged putamen correlated
with increased CD4 cell counts.
|
|
Thompson et al, 2005[49]
|
26 HIV+ (47y, 96% male)
14 HIV- (38 yo, 57% male)
|
50%
|
NA
|
1.5 T
|
Cortical GM
|
HIV+ patients had volumetric loss within primary sensory, motor, and premotor cortices
compared with HIV-. Volumetric loss in frontopolar areas correlated with nadir CD4+
cell counts.
|
|
Patel et al, 2002[53]
|
20 HIV+, NAS (36 y, 77% male),
no HIV-
|
94%
|
8 ADC 0
5 ADC 0.5
2 ADC 1
|
1.5 T
|
Total GM volume
|
Greater cognitive impairment was associated with greater volume loss.
|
Abbreviations: ADC, AIDS dementia complex; AIDS, acquired immunodeficiency syndrome;
ANI, asymptomatic neurocognitive impairment; cART, combination antiretroviral therapy;
GM, gray matter; HAND, HAD, HIV-associated dementia; HIV-associated neurocognitive
disorders; HIV, human immunodeficiency virus; MND, mild neurocognitive disorder; NA,
not available; WM, white matter.
Early volumetric work concentrated on measuring ratios of subcortical (e.g., caudate)
to intraventricular volumes. This technique could not isolate the location of atrophy
and missed brain regions not within the field of view.[40] Semi- or fully automated methods have been developed for segmenting the brain based
on voxel signal intensity properties of tissues.[41]
[42]
[43] Currently, a variety of preprocessing programs are available, but some experience
is needed for analysis.
In the pre- and early antiretroviral era, significant volume loss was observed in
the basal ganglia, posterior cortex, and total white matter of HIV+ patients compared
with age-matched HIV- individuals.[44]
[45]
[46] Atrophy was greatest in more advanced stages of infection, but changes were seen
even in cognitively normal HIV+ individuals.[47] Subsequent studies in the cART era have demonstrated subcortical and cortical atrophy
in HIV+ patients[42]
[48]
[49]
[50] (see [Fig. 1]). HIV+ individuals, especially those with an acquired immunodeficiency syndrome-
(AIDS-) defining event, have thinner cortical thickness (primary sensory, and motor),[49] smaller cortical volumes,[28]
[42]
[49]
[51]
[52] and larger total ventricular size.[49]
[52] Ongoing brain volume loss occurs despite initiation of cART.[28]
[50] Changes in brain volume may commence early as cortical atrophy and expansion of
the third ventricle are observed in primary HIV infection.[51]
Fig. 1 Freesurfer segmentation of cortical (A) and subcortical (B) regions of the brain. (C) Comparison of volumes from the right caudate for human immunodeficiency virus-negative
(HIV-) controls and HIV+ patients. Overall, HIV+ patients had significantly smaller
volumes (p < 0.05).
Volumetric changes also correlate with NP testing and clinical measures. Several studies
have reported structure-function relations with poorer cognitive or motor performance
associated with smaller brain volumes.[30]
[49]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60] Both greater viral burden (plasma HIV-1 RNA, CSF HIV-1 RNA, peripheral monocyte
DNA) and immune response to the virus (nadir CD4+ T lymphocyte counts) are associated
with greater volume loss.[28]
[42]
[52]
[54]
[55]
[60]
[61]
[62]
Common comorbidities may also contribute to volume abnormalities in HIV+ patients.
Hepatitis C coinfection,[42] alcoholism,[55] cigarette smoking,[63] and small-vessel disease[64] may exacerbate brain atrophy in the setting of HIV infection. Furthermore, characteristic
volume loss associated with aging may independently affect certain brain structures
in older HIV+ individuals.[50]
[55]
[65]
[66] Older HIV+ individuals suffering from multiple comorbidities may experience greater
cumulative volume losses, increasing their risk for HIV-induced neurocognitive impairment.[67]
Overall, MRI volumetric analysis demonstrates that brain structure abnormalities begin
early and progress throughout the course of HIV infection. Brain structural integrity
in HIV likely reflects dynamic effects of current immune status and active viral replication,
superimposed on possible residual effects associated with severe prior immunosuppression
and other comorbidities. Though most MRI volumetric studies have been performed cross
sectionally, additional longitudinal studies could assess for risk factors for developing
HAND and response to therapy. Future studies should include more HIV- controls for
comparison.
Diffusion Tensor Imaging
More recently, diffusion tensor imaging (DTI) has become a popular method for studying
white matter structural integrity.[59]
[68]
[69]
[70] A PubMed search including the keywords “DTI,” “brain,” and “HIV” identified more
than 30 articles. Please see [Table 3] for a select list of DTI studies performed in HIV+ patients. DTI measures the diffusion
of water molecules in white matter. Movement of water can be anisotropic with diffusion
greater along the length of the fiber (longitudinal direction) than perpendicular
to it (radial or transverse direction), as myelin may restrict diffusion.[71] For each voxel, a tensor is calculated that describes the three-dimensional shape
of diffusion of water. The fiber direction is indicated by the tensor's main eigenvector.
Diffusion along the major axis is assumed to reflect diffusivity parallel to the white
matter tract. Mean diffusivity (MD) reflects the average diffusion in the major axis
and the two minor axes. Fractional anisotropy (FA) is a value between zero and one
and provides a measure of the general shape of the ellipsoid.[72]
Table 3
Select citations of diffusion tensor imaging (DTI) in HIV+ patients
|
Reference
|
Subjects
|
% on cART
|
HAND classification
|
Field strength
|
Findings
|
|
Zhu et al., 2013[87]
|
50 HIV+ (48 y, 65% male)
13 HIV - (51 y, 23% male)
|
100%
|
86% neurologically asymptomatic
14% mild cognitive impairment
|
1.5 T
|
Compared with controls, HIV+ neurologically asymptomatic individuals showed increased
MD in the posterior hemispheres. HIV+ individuals with mild cognitive impairment showed
additional increased MD in prefrontal areas and decreased FA compared with HIV- controls
and HIV+ neuroasymptomatic individuals. These findings correlated with duration of
infection and multiple cognitive domains.
|
|
Du et al., 2012[86]
|
10 HIV+ (53 y, 80% male),
24 HIV- (49 y, 67% male)
|
100%
|
NA
|
1.5 T
|
FA was affected most in HIV+ patients compared with HIV- controls
|
|
Hoare et al., 2012[84]
|
128 HIV+ (29 y, 33% male),
32 HIV- (25 y, 39% male)
|
0%
|
NA
|
3 T
|
Lower FA values correlated with poorer prospective memory performance in HIV+ individuals
|
|
Stubbe-Drger et al., 2012[85]
|
19 HIV+ (41 y, 100% male)
19 HIV- (41 y, 79% male)
|
68%
|
NA
|
3 T
|
FA was reduced in HIV+ subjects compared with HIV- controls
|
|
Gongvatana et al., 2011[73]
|
85 HIV+ (45 y, 67% male), no HIV-
|
81%
|
48% neurocognitively impaired
|
3 T
|
Higher current CD4 cell count correlated with higher FA in parietal lobes. Initiation
of cART correlated with higher FA in temporal lobes.
|
|
Muller-Oehring et al., 2010[106]
|
21 HIV+ (43 y, 76% male)
19 HIV- (42 y, 58% male)
|
71.00%
|
NA
|
1.5 T
|
HIV+ participants showed poor fiber integrity in posterior portion of the corpus callosum
compared with HIV- controls In HIV+ subjects compromised callosal fiber integrity
was correlated with poorer neuropsychological performance
|
|
Pfefferbaum et al., 2009[83]
|
42 HIV+ (43 y, 69% male)
88 HIV- (45 y, 48% male)
|
79%
|
NA
|
1.5 T
|
HIV+ participants exhibited higher MD than HIV- controls in the posterior corpus callosum,
internal and external capsules, and superior cingulate bundles.
|
|
Chen et al., 2009[89]
|
29 HIV+ (35 y, 75% male)
18 HIV- (40 y, 50% male)
|
62%
|
28% HAD
|
3 T
|
HIV+ participants with HAD exhibited significantly MD in the parietal white matter.
Widespread FA and MD abnormalities were present in HIV+ patients compared with HIV-
controls.
|
|
Stebbins et al., 2007[78]
|
30 HIV+ (45 y, 53% male),
30 HIV- (41 y, 43% male)
|
77%
|
NA
|
1.5 T
|
HIV+ patients had lower whole brain FA and higher whole brain MD compared with HIV-
controls. Whole-brain FA and MD did not significantly correlate with cognitive performance
measures in HIV+ patients.
|
|
Pfefferbaum et al., 2009[107]
|
94 HIV+ (43 y, 74% male)
130 HIV- (45 y, 54% male)
|
68%
|
NA
|
N A
|
HIV+ subjects with a history of an AIDS-defining event, CD4+ cell count < 200, or
alcoholism had greater abnormalities in MD and FA compared with HIV- controls.
|
|
Wu et al, 2006[74]
|
11 HIV+ (49 y, 82% male)
11 HIV- (42 y, 82% male)
|
91%
|
6 MSK 0.5
4 MSK 1
1 MSK 2
|
1.5 T
|
HIV+ patients exhibited significantly reduced splenium FA values compared with HIV-
controls. Changes in FA in HIV+ patients correlated with neuropsychological performance.
Increases in MD in the splenium in HIV+ patients correlated with neuropsychological
performance.
|
|
Thurnher et al., 2005[75]
|
60 HIV+ (42 y, 80% male)
30 HIV- (40 y, 73% male)
|
NA
|
NA
|
1.5 T
|
In HIV+ patients FA was significantly decreased in the genu of the corpus callosum
compared with HIV- controls.
|
|
Ragin et al., 2005[79]
|
11 HIV+ (49 y, 82% male),
11 HIV- (42 y, 82% male)
|
91%
|
NA
|
1.5 T
|
HIV+ subjects had increased MD in the putamen and centrum semiovale compared with
HIV- controls. MD values in putamen correlated with neuropsychological performance
in HIV+ patients.
|
|
Pomara et al., 2001[76]
|
6 HIV+ (40 y, 67% male),
9 HIV- (43 y, 78% male)
|
83%
|
NA
|
NA
|
In HIV+ subjects, FA was increased in the internal capsule and decreased in the FWM
compared with HIV- controls.
|
Abbreviations: ADC, AIDS dementia complex; AIDS, acquired immunodeficiency syndrome;
ANI, asymptomatic neurocognitive impairment; cART, combination antiretroviral therapy;
FA, fractional anisotropy; HAD, HIV-associated dementia; HAND, HIV-associated neurocognitive
disorders; HIV, human immunodeficiency virus; MD, mean diffusivity; MND, mild neurocognitive
disorder; MSK, Memorial Sloan Kettering scale; NA, not available.
In general, DTI can be performed on conventional MRI scanners, but technical assistance
is required. Depending on both the institution and time available for scanning, DTI
with either single or multiple diffusion sensitivity parameters (“b values”) can be
performed. A minimum of six directions is acquired. Conventional preprocessing packages
exist, but experience is required for analysis.
Variable results have been observed when DTI has been used to study the effects of
HIV on white matter integrity.[60]
[66]
[68]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83] In general, many studies have shown that HIV leads to an increase in MD and a decrease
in FA within white matter tracts (including the corpus callosum [CC] and centrum semiovale
[CSO]) (see [Fig. 2]). However, subtle differences exist in the location of these changes depending on
the study.[84]
[85]
[86]
[87] For example, Filippi and colleagues showed a decrease in FA and an increase in MD
in the genu and splenium of the CC of HIV+ patients.[80] Thurnher and colleagues observed a reduction in FA within the genu of the CC of
HIV+ patients.[75] Wu and colleagues reported a reduction in FA within the splenium of the CC in HIV+
individuals. This reduction in FA was associated with worsening motor speed performance.[74] However, Wright and colleagues observed a reduction in MD throughout the CC and
CSO of HIV+ patients compared with HIV- controls.[88] Instead of region of interest analyses, a voxelwise analysis can also be performed.
Gongvtana and colleagues showed significantly higher MD and lower FA throughout the
white matter of HIV+ individuals compared with HIV- controls.[73]
Fig. 2 Voxelwise comparisons for fractional anisotropy (FA) (A) and mean diffusivity (MD) (B) between HIV- controls and HIV+ patients using Tract-Based Spatial Statistics (TBSS).
Red: p = 0.05; Orange: p = 0.03; Yellow: p = 0.01.
Typically, comparisons have been performed between HIV+ and HIV- controls. HIV+ individuals
receiving cART (HIV+/cART+) and those naïve to cART (HIV+/cART-) have often been merged
into a single group. The few studies that have investigated the effects of cART on
DTI parameters in HIV+ individuals have shown conflicting results. Pffeferbaum and
colleagues demonstrated that HIV+/cART- individuals had significantly higher MD values
in the inferior cingulate bundle, occipital forceps, and superior longitudinal fasciculus
compared with HIV- controls or HIV+/cART+.[83] However, Chen and colleagues noted no significant differences in DTI parameters
between HIV+/cART- and HIV+/cART+ patients.[89] A decrease in FA was seen in the temporal lobes of HIV+/cART+ compared with HIV+/cART-
individuals,[73] suggesting possible neurotoxicity. More recently, Wright and colleagues demonstrated
that initiation of cART led to significant increases in MD, but not FA in the CC and
CSO of HIV+ patients.[88]
In summary, DTI may be a more sensitive method than conventional T2-weighted imaging
for detecting subtle changes despite the presence of normal appearing white matter
in HIV+ patients. Most DTI studies have been cross sectional, and studied changes
in chronic or advanced HIV infection. The effects of early HIV infection or of cART
initiation on the white matter have not been systematically assessed by DTI. Furthermore,
few DTI studies have included enough HIV- controls. Additional studies comparing DTI
parameters to CSF biomarkers and assessing the potential impact of comorbidities need
to be performed.
Functional Magnetic Resonance Imaging
A nascent literature has started to develop utilizing blood oxygen-level dependent
(BOLD) fMRI to investigate the effects of HIV on brain function.[90] A PubMed search using “fMRI,” “BOLD,” and “HIV” as keyword search terms yielded
nine articles. Although the BOLD sequence can be performed on conventional MRI scanners,
additional technical assistance is required for designing functional task paradigms.
Preprocessing programs are available, but significant experience is needed.
Fluctuations in the BOLD response within specific brain regions indirectly reveal
the coupling between changes in neuronal activity and cerebral blood flow for a particular
stimulus.[91] Increases or decreases in brain activation during a task, as compared with rest
or a neutral task, are assumed to be related to the cognitive function that is under
investigation.[92] HIV+ patients have greater parietal activation for a simple attention task and greater
frontal and parietal activation during more complex attention tasks.[93] These BOLD changes in HIV+ patients may reflect increased recruitment of additional
areas to meet cognitive demands[32]
[33]
[56]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101] A recent systematic meta-analysis of BOLD fMRI studies using various functional
tasks in HIV+ patients was performed using an activation likelihood estimation (ALE).
HIV+ patients had greater functional activation within the left inferior frontal gyrus
and caudate nucleus compared with HIV- controls.[102] Dysfunction in this frontostriatal network was qualitatively related to neurocognitive
impairment. When assessed at rest, functional connections between brain networks may
be compromised in HAND, in ways that are similar to aging.[103]
To date, most BOLD fMRI studies have been performed in a limited number of HIV+ patients
with most receiving cART. Only a few studies have started to assess the impact of
comorbidities such as methamphetamine use. A common task paradigm has not been developed
across studies or sites. Additional BOLD fMRI studies are needed to evaluate the efficacy
of novel therapies.
The Future of Advanced Neuroimaging
Considerable progress has been made in applying MRI methods to understand neuroHIV.
However, most studies have compared HIV+ individuals to HIV- controls with secondary
comparisons concentrating on HAND diagnosis or certain laboratory measures or comorbidities.
Further studies that investigate the pathophysiology of spread of the disease throughout
the brain are needed. These studies could help predict which HIV+ patients are at
increased risk for developing HAND.
For neuroimaging to take the next step, these techniques need to be included not only
within research criteria for HAND, but also in the evaluation of therapeutics. This
can be accomplished by using a common protocol at multiple research sites. This protocol
should include multiple MRI modalities. A first attempt has been made by the AIDS
Clinical Trial Group (ACTG) with multiple sites scanning HIV+ patients using the same
imaging paradigm. Results from this pilot study were encouraging and it is hoped that
a similar protocol can be rolled out to more sites. Cross-modality comparisons within
the same HIV+ individual will provide us a more complete understanding of the HIV
pathophysiology.
