Special Section: Modeling HIV and Alcohol’s Effects
Focus on the Brain: HIV Infection and Alcoholism
Comorbidity Effects on Brain Structure and Function
Margaret J. Rosenbloom, M.A., Edith V. Sullivan, Ph.D., and Adolf Pfefferbaum, M.D.
MARGARET J. ROSENBLOOM, M.A., is a research scientist with appointments in the Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, and the Neuroscience Program, SRI International, Menlo Park, California.
EDITH V. SULLIVAN, PH.D., is a professor in the Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California.
ADOLF PFEFFERBAUM, M.D., is a professor emeritus in the Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California, and director of the Neuroscience Program, SRI International, Menlo Park, California.
Both HIV infection and alcohol abuse have negative effects on the brain, with some unique to each condition and others shared by both conditions. Investigators have used magnetic resonance imaging to study the size and integrity of various brain structures in participants with alcoholism, HIV infection, or both conditions and in healthy control subjects. In these studies, alcoholics exhibited enlarged, cerebrospinal fluid-filled spaces (i.e., ventricles) as well as tissue shrinkage in various brain regions (e.g., the corpus callosum and frontal cortex), whereas study participants with asymptomatic HIV infection showed few abnormalities. Those with both HIV infection and alcoholism also had these volume abnormalities, particularly if they had experienced an AIDS-defining event. Diffusion tensor imaging, which measures the integrity of white matter fibers, has identified abnormalities of constituents of these fibers in both diseases. Again, people with HIV infection plus alcoholism show the greatest abnormalities, particularly those with a history of an AIDS-defining event. Magnetic resonance spectroscopy, which assesses the levels of brain metabolites and selective neurotransmitters, has revealed different patterns of deficits in biochemical markers of brain integrity in individuals singly affected and a compounding of effects in individuals with both HIV infection and alcoholism. Finally, neuropsychological studies have revealed impairment in selective functions involving working memory, visuospatial abilities, and movement speed that are especially likely to occur in people with comorbid HIV infection and alcoholism. Thus, alcoholism is a major risk factor for development of neuropathology and its functional sequelae in HIV-infected people. Key words: Alcohol abuse; alcoholism; risk factors; human immunodeficiency virus; acquired immune deficiency syndrome; brain; brain function; brain structure; neuropathology; magnetic resonance imaging; diffusion tensor imaging
The incidence of alcohol abuse and dependence among individuals infected with human immunodeficiency virus (HIV) is high. Those with concurrent HIV infection and alcohol abuse are at risk of poorer clinical outcome for a variety of reasons that are described in detail elsewhere in this issue of Alcohol Research & Health. HIV infection and excessive alcohol use each have specific negative effects on central nervous system (CNS) structure, chemistry, and function, some of which are unique to each disease and some of which are shared. Thus, the brains of people with a history of excessive alcohol consumption are particularly vulnerable to further insult when newly exposed to the HIV virus. Continued excessive drinking can exacerbate the new liability from HIV infection, especially in those who develop an AIDS-defining event, such as severely low numbers of immune cells (i.e., CD4+ T-cell count under 200/mm3) targeted by HIV infection. The many factors affecting this dynamic interaction of effects of alcohol abuse and HIV infection on the brain are challenging to identify and disentangle but are likely to include the following: general health; cognitive status; age at HIV infection; length and severity of alcohol history before HIV infection; quantity, frequency and pattern of alcohol use after HIV infection; the lag between the HIV diagnosis and start of antiretroviral treatment; diligence in medication compliance; and whether other drugs of abuse are used.
One method for identifying how the effects of excessive alcohol use and HIV infection interact in the brain is to follow people with both active alcoholism and HIV infection and to compare changes in their cognition and brain status over time with changes in individuals with only one condition and control subjects with neither condition; this is known as a four-group comparison. Given the human condition, such studies (especially longitudinal ones entailing repeated examination of the same individuals over an extended time) are necessarily naturalistic and not ethically or practically amenable to formal experimental control over relevant variables, such as alcohol or illicit drug use, nutrition, medication, or risky behavior. Nonetheless, cross-sectional comparisons (i.e., examination at a single time of many different individuals) between the four groups can provide provisional answers to the question of how and in what way HIV infection exacerbates the damage caused by pre-existing alcoholism or, conversely, how excessive alcohol use exacerbates the damage caused by pre-existing HIV infection. This analysis is best performed with a study sample in which the comorbid group is comparable in severity of their HIV disease to HIV-only participants and in severity of alcohol disease to alcohol-only participants (see Rosenbloom et al. 2007b). If alcohol exacerbates the effects of HIV infection, the comorbid group would be predicted to demonstrate greater deficits than either single-diagnosis group, especially for those measures that are affected by both diseases. Such compounded effects could be additive in some cases and synergistic in others.
This brief review summarizes evidence of regional CNS damage from neuroimaging studies using noninvasive magnetic resonance (MR) technologies for in vivo examination of brain structure (conventional magnetic resonance imaging [MRI]), white matter fiber integrity (MR diffusion tensor imaging [DTI]), and brain chemistry (MR spectroscopy [MRS]) in people comorbid for alcoholism and HIV infection compared with single-diagnosis groups and unaffected control subjects. (For more information on these technologies, see the textbox.) Overviews of these methods also are detailed elsewhere (Adalsteinsson et al. 2002; Meyerhoff 2001). Also summarized is evidence from neuropsychological studies examining cognitive and motor functions in the four study groups.
MRI AND BRAIN MACROSTRUCTURE
Conventional structural MRI studies collect high-resolution images of the whole brain and permit measurement of the size and shape of brain structures and some aspects of brain tissue integrity.
Findings From Subjects With Alcoholism
Structural MRI studies of uncomplicated alcoholism typically report increased size of the cerebrospinal fluid-filled spaces in the brain (e.g., ventricular enlargement) as well as gray matter and white matter volume shrinkage (Fein et al. 2002; Gazdzinski et al. 2005; Pfefferbaum et al. 1992, 2001), most prominent in frontal cortical regions (Cardenas et al. 2007; Pfefferbaum et al. 1997) and subcortical and cerebellar structures (Makris et al. 2008; Sullivan and Pfefferbaum 2009). These volume abnormalities may be dose related (Cardenas et al. 2005; Pfefferbaum et al. 1998), at least partially reversed with extended sobriety (Carlen et al. 1978; O’Neill et al. 2001; Pfefferbaum et al. 1995; Rosenbloom et al. 2007a), and return with relapse to drinking (O’Neill et al. 2001; Pfefferbaum et al. 1995). Damage to the frontal cortex may contribute to impairment in problem solving and inhibiting undesirable and risky behaviors, whereas damage to the cerebellum likely contributes to the difficulties in balance and gait that frequently are observed in alcoholics.
Findings From Subjects With HIV Infection
Structural MRI studies of HIV infection report little to no brain volume abnormalities in asymptomatic HIV-infected individuals, but there is substantial neuropathology in symptomatic cases (i.e., those with clinically detectable motor, cognitive, or behavioral symptoms) (Aylward et al. 1995; Jernigan et al. 1993). Brain abnormalities include ventricular enlargement, widespread tissue shrinkage, frontal white matter and caudate volume loss (Aylward et al. 1995; Di Sclafani et al. 1997; Stout et al. 1998), and thinning of the cortex (Thompson et al. 2005) and corpus callosum (Pfefferbaum et al. 2006c). The extent of tissue volume shrinkage or ventricular expansion increases with advancing clinical stage, as determined using Centers for Disease Control and Prevention criteria (Di Sclafani et al. 1997; Thompson et al. 2006), and is related to presence or worsening of cognitive deficits (Heaton et al. 1995; Heindel et al. 1994; Stout et al. 1998).
Findings From Subjects With HIV Infection Plus Alcoholism
In a structural MRI study using the four-group method, there was a graded pattern of ventricular enlargement. The total ventricular system of the uncomplicated HIV group was larger than that of controls, the HIV group comorbid with alcoholism was yet larger, and the alcoholism group was the largest of the three patient groups. The pattern of callosal thinning showed a similar graded effect. In the HIV group comorbid for alcoholism, larger volumes of the third ventricle correlated with lower CD4+ cell counts. When the HIV group was divided according to whether participants had ever met criteria for AIDS (i.e., an AIDS-defining event or low CD4+ T-cell counts ≤200/mm3), alcohol abuse was shown to have a dramatically compounding effect in those with HIV+AIDS but not in those with HIV infection who had not suffered an AIDS-defining event (figures 1 and 2). The effect was especially notable in the genu of the corpus callosum and the frontal and body regions of the lateral ventricles (Pfefferbaum et al. 2006c).
DTI AND BRAIN WHITE MATTER MICROSTRUCTURE
DTI yields measures of the microstructural integrity of white matter (Le Bihan 2003) and provides a method to ascertain how various pathologies affect the microstructure of the brain. Studies typically examine DTI metrics in a defined region of white matter, such as the corpus callosum or centrum semiovale, or can examine tissue integrity along a statistically extracted fiber bundle, a procedure known as quantitative fiber tracking (Gerig et al. 2005). Although fiber tracking does not actually identify anatomically specific fibers or fiber bundles, tractography can provide a statistical and graphical representation along the length of fiber bundles (Mori and van Zijl 2002; Rosenbloom and Pfefferbaum 2008). DTI’s sensitivity to detection of disruption of microstructural integrity of white matter may provide an early indication of the potential for HIV-associated dementia (Berger and Avison 2001) and signs of insult from co-existing alcoholism (Pfefferbaum et al. 2007a).
Findings From Subjects With Alcoholism
Among alcoholics, DTI has revealed evidence for disruption of microstructural constituents of white matter even in regions appearing normal on conventional structural imaging (Pfefferbaum et al. 2006a; Pfefferbaum and Sullivan 2002). Chronic alcohol abuse also disrupts microstructure in localized regions of white matter, such as the corpus callosum, and widely distributed regions throughout the centrum semiovale (Pfefferbaum et al. 2006a, b) or in right hemisphere white matter tracts linking prefrontal and limbic systems (Harris et al. 2008). A fiber tracking study examining the integrity of a broad range of white matter tracts across the brain found that frontal and superior sites (frontal forceps, internal and external capsules, fornix, and superior cingulate bundle and longitudinal fasciculi) showed greatest abnormalities in alcoholics relative to controls, while more posterior and inferior bundles were relatively spared (Pfefferbaum et al. 2009b). Poor performance on tests of working memory, visuospatial ability, and gait and balance have been linked to compromised white matter microstructure and amount of alcohol drunk in a lifetime in alcoholics (Pfefferbaum et al. 2006a). Disruption of the myelin sheaths may contribute to slowed motor performance by alcoholics (Pfefferbaum et al. 2009b).
Findings From Subjects With HIV-Infection
Examination of HIV-infected individuals with DTI has revealed microstructural abnormalities of the genu and splenium of the corpus callosum and frontal and parietal subcortical white matter related to disease severity (Filippi et al. 2001). Signs of compromised integrity also can be found in regions of white matter appearing normal on conventional MRI (Stebbins et al. 2007). DTI studies have found signs of compromised white matter integrity in normal-appearing periventricular white matter and the corpus callosum that correlated with low CD4+ counts and high viral loads in HIV-infected subjects (Filippi et al. 2001).
Fiber tracking analysis revealed that posterior but not anterior corpus callosum fibers are affected in nondemented HIV-infected patients (Pfefferbaum et al. 2009a). Altered DTI metrics, primarily reflecting axonal compromise, have been found in the following fibers bundles:
By contrast, pontocerebellar projection fibers were particularly resistant to HIV effects, as were commissural fibers coursing through premotor and sensorimotor callosal sectors (Pfefferbaum et al. 2009a). Cognitive impairment has been related to white matter degradation and is more severe in patients whose HIV infection has progressed to AIDS (Gongvatana et al. 2009). Similarly, slower speed on tests of finger movement and eye-hand coordination is related to degradation of posterior callosal fibers (Pfefferbaum et al. 2007b).
Findings From Subjects With HIV-Infection Plus Alcoholism
A DTI fiber tracking study examined the effects of HIV-alcoholism comorbidity in the four-group model (Pfefferbaum et al. 2007a). The microstructural integrity of fiber bundles coursing through the genu and splenium of the corpus callosum showed evidence of severe compromise in those with alcoholism whose HIV infection history included an AIDS-defining event (figure 3). Measures of DTI provided indirect support for greater disruption of the myelin sheath covering the axon (i.e., fatty cell body that insulates the axon and promotes speed of communication between cells) in alcoholism (Pfefferbaum et al. 2009b) than of the axon itself as observed in HIV infection (Pfefferbaum et al. 2009a). The functional significance of these callosal fiber tracking measures in the AIDS+alcoholism group was demonstrated by analyses showing that greater degradation of fiber integrity was associated with slower and less dexterous manual motor performance and greater postural instability while standing (Pfefferbaum et al. 2009b).
MRS AND BRAIN CHEMISTRY
MRI and DTI are imaging modalities based primarily on the detection of water protons, their immediate environment, and their mobility. Other constituents, including selective metabolites and neurotransmitters, also are present on the proton spectrum but in smaller quantities than water, yet visible using other MR technologies, such as MR spectroscopy (MRS) and MR spectroscopic imaging (MRSI) (Adalsteinsson et al. 2002; Meyerhoff 2001). A substantial body of research using proton MRS and MRSI (also known as chemical shift imaging [CSI]) has revealed declines in N-acetyl aspartate (NAA), a marker of living neurons, in short-term abstinent alcoholics, with change toward normalization of NAA in longer-term abstinent alcoholics (Durazzo et al. 2006). Use of proton MRS in HIV infection has provided evidence for metabolite abnormalities notable in the basal ganglia, even early in the course of HIV infection (Chang et al. 2008). A proton MRSI study of combined disease effects on the parietal-occipital cortex indicated that only the comorbid (HIV+alcoholism) group was affected, exhibiting a significant deficit in NAA (figure 4). Although neither HIV infection nor alcoholism alone resulted in such a deficit, each disease carried a liability that put dually affected individuals at a heightened risk of neuronal compromise (Pfefferbaum et al. 2005).
In addition to proton (1H) spectroscopy, other resonances (e.g., carbon [13C] and phosphorous [31P]) that provide unique brain metabolic information can be studied, albeit with difficulty because of their low spectral signal (i.e., low signal-to-noise ratio). A 31P MRS study (see Meyerhoff 2001) noted a cumulative but not interactive or synergistic effect of HIV infection and alcoholism. The symptomatic HIV group and the alcoholic group both had low concentrations of the brain energy metabolites associated with cell membrane breakdown (phosphodiester) and building (phosphocreatine) in superior white matter, and individuals with both conditions had augmented metabolite deficits (Meyerhoff et al. 1995).
NEUROPSYCHOLOGICAL FUNCTIONING IN HIV–ALCOHOLISM COMORBIDITY
An extensive literature is available that describes patterns of neuropsychological impairment associated with alcoholism (for reviews, see Oscar-Berman and Marinkovic 2007; Sullivan 2000) and HIV infection (see Special Section, “HIV/NeuroAIDS” in Neuropsychology Review, June 2009). Significantly fewer studies have considered the effects of HIV+alcoholism comorbidity on cognitive and motor functioning, but an emerging literature indicates that such comorbidity exerts selective rather than simply global adverse effects on component processes of functions. To date, functions examined and found to be disproportionately affected by the combined diseases include speeded performance involving finger movements and eye-hand coordination (i.e., visuomotor speed) (Fama et al. 2007; Rothlind et al. 2005), sustained attention (Sassoon et al. 2007), conflict resolution and attentional allocation (Schulte et al. 2008), associative learning (Sassoon et al. 2007), immediate episodic memory (Fama et al. 2009), and speeded finger movements (Fama et al. 2007).
Brain regions likely contributing to performance on these tasks and known to be disrupted by alcoholism or HIV infection independently or by their combination include the following:
A useful neuropsychological model to explain some of the results is based on the observation that alcoholism has a frontocerebellar substrate of dysfunction, whereas HIV infection has a frontostriatal substrate of dysfunction. Tasks invoking both of these circuits and the tracts linking these regions (figure 5) may be at particular at risk of disruption from both conditions (Pfefferbaum et al. 2002).
The combined effects of alcoholism and HIV infection on brain structure, chemistry, and function are most devastating in individuals who have experienced an AIDS-defining event. This negative synergism suggests that alcohol is particularly toxic to the HIV-infected brain after a certain stage of the disease; similarly, the alcoholic brain is particularly susceptible to the effects of AIDS. These effects place dually affected individuals at compounded risk for brain functional and structural insult even prior to developing clinically defined dementia, thereby highlighting the relevance of examining groups affected by both conditions (see Fein et al. 1995; Meyerhoff 2001; Pfefferbaum et al. 2007a; Pfefferbaum et al. 2002; Rothlind et al. 2005). The substantial effect of the alcoholism–AIDS interaction on ventricular volumes and callosal size and microstructure, in the context of the modest changes observed in non-AIDS, non-alcohol–abusing HIV-infected individuals, highlights the need to consider alcohol use disorders as a major risk factor for developing neuropathology among HIV-infected persons (Pfefferbaum et al. 2007a). Further, the high prevalence of alcoholism in HIV-infected individuals and the interfering effect of alcohol abuse on HIV pharmacological response and therapy compliance underscore the need to recognize the independent and synergistic contributions of each condition to brain structure and function (Pfefferbaum et al. 2006c). The extent to which the deficits in patients with comorbid HIV infection and alcoholism are reversible with abstinence from alcohol and careful adherence to antiretroviral treatments requires investigation using longitudinal study.
This work was support by National Institute on Alcohol Abuse and Alcoholism grants AA–012999, AA–017347, AA–005965, AA–012388, and AA–017168.
The authors declare that they have no competing financial interests.
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